able...T able of C onTenTs | S umário Volume 41, Issue 4 Oct/Nov/Dec - 2019 ISSN 0101-2800 Official Organ of the Brazilian Society of Nephrology Órgão Oficial da Sociedade Brasileira

Table of ConTenTs | Sumário

Volume 41, Issue 4Oct/Nov/Dec - 2019ISSN 0101-2800

Official Organ of the Brazilian Society of Nephrology

Órgão Oficial da Sociedade Brasileira de Nefrologia

Quarterly EditionPublicação Trimestral

EditorialS | EditoriaiS

Prevention of intradialytic hypotensive episodes: is setraline an effective pharmacological approach? 445Prevenção da hipotensão intradialítica: seria a sertralina uma abordagem farmacológica eficaz?Panagiotis I. Georgianos • Rajiv Agarwal

Not transplanting kidney donors with acute kidney injury: a missed opportunity? 448Não transplantar doadores de rim com lesão renal aguda: uma oportunidade perdida?Naoka Murakami • Leonardo V. Riella

original articlES | artigoS originaiS

Antioxidant effect of endothelin-1 receptor antagonist protects the rat kidney against chronic injury induced by hypertension and hyperglycemiaEfeito antioxidante de antagonista dos receptores de endotelina-1 protege ratos contra lesão renal crônica induzida por hipertensão e hiperglicemiaAgnaldo Caires • Marcia Bastos Convento • Bianca Castino • Ala Moana Leme • Edson de Andrade Pessoa • Alef Aragão • Nestor Schor • Fernanda Teixeira Borges

Braz. J. Nephrol. (J. Bras. Nefrol.),2019;41(4):i-iii i

aCuTe Kidney injury | lesão renal aguda

basiC researCh | Pesquisa básiCa

dialysis and exTraCorPoreal TreaTmenT | diálise e TraTamenTo exTraCorPóreo

Risk factors and mortality in patients with sepsis, septic and non septic acute kidney injury in ICUFatores de risco e mortalidade dos pacientes com sepse, lesão renal aguda séptica e não séptica na UTIKellen Hyde Elias Pinheiro • Franciana Aguiar Azêdo • Kelsy Catherina Nema Areco • Sandra Maria Rodrigues Laranja

Functional iron deficiency in patients on hemodialysis: prevalence, nutritional assessment, and biomarkers of oxidative stress and inflammationDeficiência funcional de ferro em pacientes em hemodiálise: prevalência, avaliação nutricional e de biomarcadores de estresse oxidativo e de inflamaçãoJuliana Carvalho Romagnolli Plastina • Vitor Y. Obara • Décio Sabbatini Barbosa • Helena Kaminami Morimoto • Edna Maria Vissoci Reiche • Andrea Graciano • Vinicius Daher Alvares Delfino

472

451

Metabolic and volume status evaluation of hemodialysis patients with and without residual renal function in the long interdialytic intervalAvaliação metabólica e volêmica no maior intervalo interdialítico de pacientes em hemodiálise com e sem função renal residualLenina Ludimila Sampaio de Almeida • Luís Henrique Bezerra Cavalanti Sette • Fernando Luiz Affonso Fonseca • Leila Silveira Vieira da Silva Bezerra • Francisco Hélio Oliveira Júnior • Ronaldo Roberto Bérgamo

Effects of sertraline in the prevention of low blood pressure in patients undergoing hemodialysisEfeitos da sertralina na prevenção de hipotensão arterial em pacientes submetidos à hemodiáliseChristine Zomer Zomer Dal Molin • Thiago Mamoru Sakae • Fabiana Schuelter-Trevisol • Daisson Jose Trevisol

Possible association between dysnatremias and mortality during hospitalization in patients undergoing acute hemodialysis: analysis from a Peruvian retrospective cohortPossível associação entre distúrbios do sódio e mortalidade hospitalar em pacientes submetidos a hemodiálise aguda: análise de uma coorte retrospectiva peruanaEdward Mezones-Holguin • Roberto Niño-Garcia • Percy Herrera-Añazco • Álvaro Taype-Rondan • Josmel Pacheco-Mendoza • Adrian V. Hernandez

462

481

492

CliniCal invesTigaTion | invesTigação ClíniCa

501

ii Braz. J. Nephrol. (J. Bras. Nefrol.),2019;41(4):i-iii

525

559

563

569

574

517

538

Hyponatremia in elderly patients with fragility fractures of the proximal femur: a cross-sectional studyHiponatremia em pacientes idosos com fratura proximal de fêmur por fragilidade: um estudo transversalAída Fernanda Batista Rocha • Marcus Villander Barros De Oliveira Sá • Ubirace Fernando Elihimas Junior

Incidence and risk factors for major infections in hospitalized children with nephrotic syndromeIncidência e fatores de risco para infecções graves em crianças hospitalizadas com síndrome nefróticaManish Kumar • Jaypalsing Ghunawat • Diganta Saikia • Vikas Manchanda

Hepatitis C in Hemodialysis Units: diagnosis and therapeutic approachHepatite C nas Unidades de Hemodiálise: diagnóstico e abordagem terapêuticaNatasha Silva Constancio • Maria Lucia Gomes Ferraz • Carmen Tzanno Branco Martins • Angiolina Campos Kraychete • Paulo Lisboa Bitencourt • Marcelo Mazza do Nascimento

review arTiCles | arTigos de revisão

Fluid and hemodynamic management in hemodialysis patients: challenges and opportunitiesManejo hídrico e hemodinâmico em pacientes em hemodiálise: desafios e oportunidades Bernard Canaud • Charles Chazot • Jeroen Koomans • Allan Collins

549

uPdaTe arTiCles | arTigos de aTualização

A call-to-action for sustainability in dialysis in BrazilUm apelo pela sustentabilidade na diálise no BrasilJosé A. Moura-Neto • Katherine Barraclough • John W. M. Agar

Takayasu arteritis: differential diagnosis in a teenager with severe acute kidney injury - a case reportArterite de Takayasu: diagnóstico diferencial em adolescente com lesão renal aguda grave - relato de casoNara Thaisa Tenório Martins Braga • Adriana Banhos Carneiro • Kathia Liliane da Cunha Ribeiro Zuntini • Flávio Bezerra de Araújo • Elizabeth De Francesco Daher

Case rePorTs | relaTos de Caso

Refractory ascites and graft dysfunction in early renal transplantation Ascite refratária e disfunção do enxerto no pós-transplante renal precoceCatarina Pereira Eusébio • Sofia Correia • Filipa Silva • Manuela Almeida • Sofia Pedroso • La Salete Martins • Leonídio Diais • José Queirós • Helena Pessegueiro • Ramon Vizcaíno • António Castro Henriques

Chikungunya in a kidney transplant recipient: a case reportChikungunya em um receptor de transplante renal: relato de casoRenato Demarchi Foresto • Daniel Wagner de Castro Lima Santos • Maria Amélia Aguiar Hazin • Alejandro Túlio Zapata Leyton • Nayara Cordeiro Tenório • Laila Almeida Viana • Marina Pontello Cristelli • Hélio Tedesco Silva Júnior • José Osmar Medina Pestana

509Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitusZinco-alfa2-glicoproteina (ZAG) como biomarcador precoce de nefropatia diabética em pacientes com diabetes mellitus tipo 2Mohamed Elsheikh • Khaled A Elhefnawy • George Emad • Mabrouk Ismail • Maher Borai

ePidemiology and CliniCal nePhrology | ePidemiologia e nefrologia ClíniCa

PediaTriC nePhrology | nefrologia PediáTriCa

renal TransPlanTaTion | TransPlanTe renal

Kidney transplantation with donors in severe acute kidney injury. Should we use these organs? Retrospective Case SeriesTransplante renal com doadores em lesão renal aguda severa. Devemos utilizar esses órgãos? Série de casos retrospectivaGuilherme Palhares Aversa Santos • Luis Gustavo Modelli de Andrade • Mariana Farina Valiatti • Mariana Moraes Contti • Hong Si Nga • Henrique Mochida Takase

533

PersPeCTives/oPinion | PersPeCTivas/oPinião

Endothelial lesion and complement activation in patients with Scleroderma Renal CrisisLesão endotelial e ativação do complemento em pacientes com crise renal esclerodérmicaNey Arencibia Pérez • María Luisa Agüera Morales • Rafael Sánchez Sánchez • Rosa María Ortega Salas • Rafael Ángel Fernández de la Puebla • Mario Espinosa Hernández

579

leTTer | CarTa

Nephrologists and patients: between vulnerability and equityNefrologistas e pacientes: entre a vulnerabilidade e a equidadeFábio Humberto Ribeiro Paes Ferraz • Cibele Isaac Saad Rodrigues • Giuseppe Cesare Gatto • Natan Monsores de Sá

584

iii Braz. J. Nephrol. (J. Bras. Nefrol.),2019;41(4):i-iii

Carmen Tzanno BranCo marTins (PresidenT)miguel Carlos riella (PresidenT)José osmar medina de aBreu PesTana (PresidenT)ana maria misael da silva (viCe-PresidenT)dirCeu reis da silva (viCe-PresidenT)elisa mieko suemiTsu Higa (viCe-PresidenT)

alexandre silvesTre CaBral (direCTor)João damásio soTTero simões (viCe-direCTor)alessandro Barilli alves

José mario FranCo de oliveira

marTa vaz dias de souza Boger

riCardo FurTado de CarvalHo

silvia Corradi de Faria

ana maria misael da silva (direCTor)Jose andrade moura neTo (viCe-direCTor)angiolina CamPos krayCHeTe

dirCeu reis da silva

kleyTon de andrade BasTos

maria Cláudia Cruz andreoli

ronaldo d’avila

Carmen Tzanno BranCo marTins (direCTor)marilda mazzali (viCe-direCTor)elizaBeTH de FranCesCo daHer

JoCemir ronaldo lugon

lúCio roBerTo requião moura

marCus gomes BasTos

maria almerinda riBeiro alves

Carlos Perez gomes (direCTor)krissia kamile singer WallBaCH (viCe-direCTor)elias marCos silva FlaTo

elisa mieko suemiTsu Higa

marCelo augusTo duarTe silveira

mariana FonTes Turano

CiBele isaaC saad rodrigues (direCTor)Carlos eduardo Poli Figueiredo (viCe-direCTor)Fernando anTonio de almeida

maria elieTe PinHeiro

rogério andrade mulinari

rogério BaumgraTz de Paula

seBasTião rodrigues Ferreira FilHo

gianna masTroianni kirszTaJn (direCTor)CrisTina gaTTo CoelHo da roCHa (viCe-direCTor)arTur quinTiliano Bezerra da silva

marCus viniCius de Pádua neTTo

PaTríCia Ferreira aBreu

PaTríCia maria Pereira alBuquerque

viviane CaliCe da silva

irene de lourdes noronHa (direCTor)José de resende Barros neTo (viCe-direCTor)Jenner Cruz

leda aPareCida daud loTaiF

maria izaBel neves de Holanda

mary Carla esTevez diz

naTHalia da FonseCa PesTana

José Hermogenes roCCo suassuna (direCTor)eduardo roCHa (viCe-direCTor)alan CasTro

emmanuel de almeida Burdmann

lilian Pires de FreiTas do Carmo

luis yu

mauriCio younes iBraHim

maria goreTTi moreira guimarães Penido (direCTor)lilian monTeiro Pereira Palma (viCe-direCTor)marCelo de sousa Tavares

olBeres viTor Braga de andrade

reJane de Paula meneses Bernardes

vera Hermina kalika koCH

President: Marcelo Mazza do Nascimentonational Vice President: Daniel Costa Chalabi Calazans

General secretary: Andrea Pio de AbreuFirst secretary: Ricardo Portiolli Franco

treasurer: David José de Barros MachadoscientiFic director: Vinicius Daher Alvares Delfino

director oF associatiVe Policies: Cinthia Kruger Sobral VieiraVice President north: Karla Cristina Silva PetrucelliVice President northeast: Wagner Moura BarbosaVice President Midwest: Ciro Bruno Silveira Costa

Vice President southeast: Osvaldo Merege Vieira NetoVice President south: Denise Rodrigues Simão

FellyPe de CarvalHo BarreTo (direCTor)aluizio BarBosa de CarvalHo (viCe-direCTor)leandro Junior luCCa

melani riBeiro CusTódio

rodrigo Bueno de oliveira

rosa maria aFFonso moysés

vanda JorgeTTi

Brazilian society oF nePhroloGy

executiVe Board 2019/2020

audit coMMittee

leGal dePartMent

dePartMent oF dialysis

dePartMent oF education and certiFication

dePartMent oF renal PhysioloGy and PathoPhysioloGy

dePartMent oF hyPertension

dePartMent oF ePideMioloGy and renal disease PreVention

dePartMent oF clinical nePhroloGy

dePartMent oF Pediatric nePhroloGy

dePartMent oF acute renal Failure

dePartMent oF Mineral Bone MetaBolisM disorders in chronic Kidney disease

Braz. J. Nephrol. (J. Bras. Nefrol.),2019;41(4):iviv

álvaro PaCHeCo e silva FilHo (direCTor)gusTavo Fernandes Ferreira (viCe-direCTor)Fernando das merCês luCas Junior

Hélady sanders PinHeiro

maria CrisTina riBeiro de CasTro

miguel moyses neTo

Tainá veras de sandes FreiTas

dePartMent oF Kidney transPlants

Rua Machado Bittencourt, 205 - 5º andar - conj. 53Vila Clementino, São Paulo - SP CEP 04044-000Telefone: 55 11 5579-1242E-mail: [email protected]. Site: https://bjnephrology.org/

Brazilian Journal of Nephrology (Jornal Brasileiro de Nefrologia) has as principle to publish scientific articles resulting of clinical and experimental investigation related to nephrologic themes.

The Brazilian Journal of Nephrology (Jornal Brasileiro de Nefrologia) is associated with ABEC and indexed on the following databases and information sources: Scopus, PubMED Central, MEDLINE/PubMed, SciELO, LILACS, DOAJ and Latindex.Edited by: Brazilian Society of Nephrology.

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our Mission

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oBserVations

Braz. J. Nephrol. (J. Bras. Nefrol.) 2019;41(4):v v

Prof. Dr. Miguel Carlos Riella Evangelic School of Medicine - Curitiba, PR, Brazil (Professor of Medicine)Pro-Renal Brazil Foundation - Curitiba, PR, Brazil (President)

Prof. Dr. José Augusto Barbosa de Aguiar (in memorian) - 1979-1981Prof. Dr. César Costa - 1982Prof. Dr. Emil Sabbaga (in memorian) -1983-1984Prof. Dr. José Francisco Figueiredo-1985-1989Prof. Dr. Horácio Ajzen (in memorian) -1990-1993

Prof. Dr. Décio Mion Jr.-1994-2001Prof. Dr. João Egídio Romão Junior-2002-2004Prof. Dr. Jocemir Ronaldo Lugon-2005-2006Prof. Dr. Marcus Gomes Bastos -2007-2012Prof. Dr. João Egídio Romão Junior – 2013-2014

Andrea Pio de Abreu - USP, São Paulo, SP, BrazilAnderson Ricardo Roman Gonçalves - UNIVILLE - Joinville, SC, BrazilArif Asif - Jersey Shore Univeristy Medical Center - Neptune City, NJ, USAFellype Carvalho Barreto - UFPR - Curitiba, PR, BrazilFernando das Mercês de Lucas Júnior - UFMG - Belo Horizonte, MG, Brazil

Marina Pontello Cristelli – Hrim, São Paulo, SP, BrasilPaulo Novis Rocha - UFBa - Salvador, BA, BrazilRoberto Ceratti Manfro - UFRGS - Porto Alegre, RS, BrazilRodrigo Bueno de Oliveira - UNICAMP - Campinas, SP, BrazilSérgio Gardano Elias Bucharles - UFPR - Curitiba, PR, BrazilThyago Proença de Moraes - PUCPR - Curitiba, PR, Brazil

Daniel Costa Calazans - FSFX - Ipatinga, MG, BrazilDaniela Ponce - UNESP - Botucatu, SP, BrazilEmmanuel Burdmann - USP - São Paulo, SP, BrazilJosé Hermogenes Rocco Suassuna - UERJ - Rio de Janeiro, RJ, BrazilLucia da Conceição Andrade - USP - São Paulo, SP, BrazilLuis Yu - USP - São Paulo, SP, BrazilMaurício Younes Ibrahim - UERJ - Rio de Janeiro, RJ, Brazil

Cibele Isaac Saad Rodrigues - PUC - Sorocaba, SP, BrazilGiovanio Silva - USP - São Paulo, SP, BrazilLuis Cuadrado Martin – UNESP – Botucatu, SP, BrazilRogério de Paula - UFJF - Juiz de Fora, MG, BrazilSebastião Rodrigues Ferreira Filho - UFU - Uberlândia, MG, Brazil

Antonio Carlos Seguro - USP - São Paulo, SP, BrazilNiels Olsen Saraiva Camara - USP - São Paulo, SP, BrazilRoberto Zatz - USP - São Paulo, SP, Brazil

José Hermogenes Rocco Suassuna - UERJ - Rio de Janeiro, RJ, BrazilMaria Eugênia F. Canziani - UNIFESP - São Paulo, SP, BrazilRafael Weissheimer - PUCPR - Curitiba, PR, Brazil

Elizabeth de Francesco Daher - UFC - Fortaleza, CE, Brazil

Elizabeth de Francesco Daher - UFC - Fortaleza, CE, BrazilJocemir Ronaldo Lugon - UFF - Niterói, RJ, BrazilJosé Hermogenes Rocco Suassuna - UERJ - Rio de Janeiro, RJ, Brazil

Aluizio Barbosa de Carvalho - UNIFESP - São Paulo, SP, BrazilMelani Ribeiro Custodio - USP - São Paulo, SP, BrazilRosa M. Affonso Moyses - USP - São Paulo, SP, Brazil

Editorial Board

Editor-in-Chief

Associated Editors

Editors Emeriti

Section Editors

Acute Renal Injury

Arterial Hypertension

Chronic Kidney Disease

Communicable Diseases

Disorders of Bone and Mineral Metabolism

Experimental Nephrology

General Nephrology

Cristian Vidal Riella - Harvard Medical School - Boston, MA, USALuiz Fernando Onuchic - USP - São Paulo, SP, Brazil

Genetics

Cristiane Bitencourt Dias - USP - São Paulo, SP, BrazilElizabeth de Francesco Daher - UFC - Fortaleza, CE, BrazilGianna Mastroiani Kirsztajn - UNIFESP - São Paulo, SP, BrazilMarcio Dantas - USP - Ribeirão Preto, SP, BrazilRui Toledo Barros - USP - São Paulo, SP, Brazil

Glomerulopathies and Tubulointerstitial Diseases

Jocemir Lugon - UFF - Niterói, RJ, BrazilJorge Paulo Strogoff De Mattos - UFF - Niterói, RJ, BrazilManuel Carlos Martins Castro - USP - São Paulo, SP, BrazilMarcelo Mazza do Nascimento - UFPR - Curitiba, PR, BrazilMaria Eugênia F. Canziani - UNIFESP - São Paulo, SP, BrazilRosilene Motta Elias - USP - São Paulo, SP, Brazil

Hemodialysis

Domingos Candiota Chula - Fundação Pró-Renal - Curitiba, PR, BrazilLilian Pires de Freitas do Carmo - UFMG - Belo Horizonte, MG, BrazilMarcus Gomes Bastos - UFJF - Juiz de Fora, MG, BrazilRicardo Portiolli Franco - Fundação Pró-Renal - Curitiba, PR, BrazilRodrigo Peixoto Campos - UFAL - Maceió, AL, Brazil

Interventional Nephrology

Andrea Carla Bauer - UFRS - Porto Alegre, RS, BrazilClaudia Felipe - UNIFESP - São Paulo, SP, BrazilElizete Keitel - UFCSPA - Porto Alegre, RS, BrazilFlávio Teles de Farias Filho - UNCISAL - Maceió, AL, BrazilGisele Meinerz - Santa Casa de Misericordia de Porto Alegre - Porto Alegre, RS, BrazilIrene L. Noronha - USP - São Paulo, SP, BrazilJuliana Mansur - UNIFESP - São Paulo, SP, BrazilLeonardo Vidal Riella - Harvard Medical School - Boston, MA, USA

Kidney Transplantation

Manuel Carlos Martins Castro - USP - São Paulo, SP, BrazilMarcelo Mazza do Nascimento - UFPR - Curitiba, PR, Brazil

Braz. J. Nephrol. (J. Bras. Nefrol.),2019;41(4):vi-viivi

Aldo Peixoto - University de Yale - New Haven, CT, USAAllan Collins - University of Minnesota - Lexington, MA, USAAluizio Barbosa De Carvalho - UNIFESP - São Paulo, SP, BrazilAmy Barton Pai - Albany Medical College - Albany, NY, USAAna Maria Cusumano - Instituto Universitário CEMIC - Buenos Aires, ArgentinaAnupam Agarwal - University of Alabama at Birmingham, AL, USABengt Lindholm - Karolinska Instituted - Estocolmo, SuéciaBrett Cullis - Greys e St Annes Hospital - Pietermaritzburg, Kwazulu - Natal, South AfricaCharles O’neil - Hospital Ar North Adams - Atlanta, GA, USACristianne Da Silva Alexandre - UFPB - João Pessoa, PB, BrazilDomingos D´Ávila - PUC - Porto Alegre, RS, BrazilEdison Souza - UERJ - Rio de Janeiro, RJ, BrazilEduardo Rocha - UFRJ - Rio de Janeiro, RJ, BrazilEleonora Moreira Lima - UFMG - Belo Horizonte, MG, BrazilElias David Neto - USP - São Paulo, SP, BrazilFernando C. Fervenza - Campus Rochester Nathodist - Rochester, MN, USAFernando Neves - British Hospital - Lisboa, PortugalFrancisco de Assis Rocha Neves - UnB - Brasília, DF, BrazilFrancisco Veronese - UFRGS - Porto Alegre, RG, BrazilGeorgi Abraham - University Sri Ramachandra - Chennai, TN, IndiaGuillermo Garcia Garcia - University of Guadalajara Health Sciences Center - Guadalajara, Jalisco, MexicoHelady Sanders Pinheiro - UFJF - Juiz de Fora, MG, BrazilJochen Raimann - Renal Research Institute - New York, NY, USAJoel Kopple - Roanld Reagan University of California - Los Angeles, CA, USAJorge Paulo Strogoff De Mattos - UFF - Niterói, Rj, BrazilJose Pacheco M. Ribeiro Neto - Instituto Materno Infantil Prof. Fernando Figueira - Recife, PE, BrazilJoseph Bonventre - Hospital Brighan - Boston, MA, USAJuan Fernandez Cean - Centromed - Montevideo, UruguayLucila Maria Valente - UFPE - Recife, PE, Brazil

Luis Alberto Batista Peres - UNIOESTE - Cascavel, PR, BrazilLuiz Antonio Miorin - Santa Casa - São Paulo, SP, BrazilLuiz Carlos Ferreira Andrade - UFJF - Juiz de Fora, MG, BrazilMarcello Tonelli - University de Alberta - University of Alberta - Alberta, CanadaMaria Fernanda Soares - Fundação Pró - Renal - Curitiba, PR, BrazilMario Abbud Filho - FAMERP - São José do Rio Preto, SP, BrazilMauricio Younes Ibrahim - UERJ - Rio De Janeiro, RJ, BrazilMaurilo Nazaré Leite Jr. - UFF - Rio de Janeiro, RJ, BrazilNatalia Fernandes - UFJF - Juiz de Fora, MG, BrazilNathan Levin - Good Health Medical - New York, NY, USAPaulo Benigno Pena Batista - EBMSP - Salvador, BA, BrazilPaulo C. Koch Nogueira - Unifesp - São Paulo, SP, BrazilPedro Gordan - UEL - Londrina, PR, BrazilPeter Blake - University of Western Ontario London - Edmonton, CanadaPeter Stenvinkel - Karolinska Instituted - Estocolmo, SwedenRashad S. Barsoum - Cairo University - Cairo, EgitoRichard Glassock - School of Medicina at UCLA - Los Angeles, USARichard Johnson - University of Colorado - Denver, CO, USARogério Baumgratz - UFJF - Juiz De Fora, MG, BrazilSaraladevi Naicker - University of the Witwatersrand - Johannesburg, ZA, South AfricaSergio Mezzano - Faculdade de Medicina Va - Valdivia, ChileSteve Ash - Nercy Medical Center - Des Moines - Lafayette, CA, USAVanda Jorgetti - USP - São Paulo, SP, BrazilVinicius Daher A. Delfino - UEL - Londrina, PR, BrazilVivekanand Jha - University de Oxford - Chandigarh, Punjabe, IndiaWilliam Couser - University of Washington in Seattle - Seattle, USAWolfgang Winkelmeyer - Baylor College of Medicina Houston - Houston, TX, USAYusuke Tsukamoto - Laboratory of computational Astrophysics - Riken - Tokio, JapanYvoty Alves Sens - Santa Casa - São Paulo, SP, BrazilZiad Massy - UniParis Ouset University (UVSQ) - Amiens, France

Editorial Board

Ita Pfefermann Heilberg - UNIFESP - São Paulo, SP, BrazilJosé Augusto Meneses da Silva - Núcleo de Nefrologia de B. Horizonte - Belo Horizonte, MG, BrazilMaurício de Carvalho - UFPR - Curitiba, PR, Brazil

Lithiasis

Gianna M. Kirsztajn - UNIFESP - São Paulo, SP, BrazilGuillermo Garcia Garcia - University of Guadalajara - Guadalajara, Jalisco, Mexico Ricardo Cintra Sesso - UNIFESP - São Paulo, SP, Brazil

Nephrology and Clinical Epidemiology

Andreia Watanabe - USP - São Paulo, SP, BrazilChristiane Ishikawa Ramos - UNIFESP - São Paulo, SP, BrazilCristina Martins - Fundação Pró-Renal - Curitiba, PR, BrazilFabiana Baggio Nerbass - Fundação Pró-Rim - Joinville, SC, BrazilLilian Cuppari - Fundação Oswaldo Ramos - São Paulo, SP, Brazil

Nutritional Sciences

Andreia Watanabe - USP - São Paulo, SP, BrazilClotilde Druck Garcia - Santa Casa - Porto Alegre, RS, Brazil Daltro Zunino - Hospital Universitário Evangelico de Curitiba - Curitiba, PR, Brazil

Pediatric Nephrology

Hugo Abensur - USP - São Paulo, SP, BrazilKleyton de Andrade Bastos - UFSE - Aracaju, SE, Brazil

Peritoneal Dialysis

Physical Therapy Specialty

Antonio Carlos Seguro - USP - São Paulo, SP, BrazilClaudia Maria de Barros Helou - USP - São Paulo, SP, Brazil

Physiology

Luciana Chiavegato - UNIFESP - São Paulo, SP, Brazil

Aakash Shingada - DNB medicine, DNB PGY3 Nephrology, Sir Ganga Ram Hospital, New Delhi, ÍndiaBianca Garcez Massignan – Curitiba, PR, BrazilDivya Bajpai - Seth G. S. M. C & K. E. M. H and K. E. M. Hospital, Mumbai, Maharashtra, IndiaEdgar V. Lerma - FACP, FASN, FAHA, FASH, FNLA, FNKF, FASDIN, FPSN (Hon)Geraldo Bezerra da Silva Junior – UNIFOR, Fortaleza, CE, BrazilJoel M Topf - Oakland University, William Beaumont School of Medicine, Rochester, MI, USAJosé Andrade Moura-Neto - Salvador, BA, BrazilPablo Rodrigues Costa Alves - UFPB - João Pessoa, PB, BrazilRodrigo Dias de Meira – UPF, Passo Fundo, RS, BrazilThiago de Azevedo Reis – Brasília, DF, Brazil

Social Media and Visual Abstract

Marilda Mazzali - UNICAMP - Campinas, SP, BrazilMario Abbud Filho - FAMERP - São José do Rio Preto, SP, BrazilTaina Sandes Freitas - UFC - Fortaleza, CE, BrazilValter Duro Garcia - Santa Casa - Porto Alegre, RS, Brazil

Lucimary de Castro Sylvestre - PUCPR - Curitiba, PR, BrazilMaria Goretti M. Penido - UFMG - Belo Horizonte, MG, BrazilVera Koch - USP - São Paulo, SP, Brazil

Braz. J. Nephrol. (J. Bras. Nefrol.),2019;41(4):vi-vii vii

445

Editorials | Editoriais

AuthorsPanagiotis I. Georgianos1

Rajiv Agarwal2

1 Aristotle University of Thessaloniki, AHEPA Hospital, 1st Department of Medicine, Section of Nephrology and Hypertension, Thessaloniki, Greece.2 Indiana University, School of Medicine, Department of Medicine, Division of Nephrology and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.

Submitted on: 08/30/2019.Approved on: 09/09/2019.

Correspondence to:Rajiv Agarwal.E-mail: [email protected]

Prevention of intradialytic hypotensive episodes: is setraline an effective pharmacological approach?

Prevenção da hipotensão intradialítica: seria a sertralina uma abordagem farmacológica eficaz?

DOI: 10.1590/2175-8239-JBN-2019-0175

Intradialytic hypotension (IDH) is an im-portant clinical complication of hemodi-alysis for patients, physicians, and dialysis technicians and nurses. Besides causing uncomfortable symptoms (i.e. cramps or postdialysis fatigue), IDH is associated with an increased risk for vascular access thrombosis,1 inadequate delivery of dialy-sis, and future cardiovascular morbidity and mortality.2 Whether these risks are causal remains unknown. The European Best Practice Guidelines (EBPG) define IDH as a drop in systolic blood pressure (SBP) ≥ 20 mmHg or decrease in mean arterial pressure by 10 mmHg, being ac-companied by symptoms of end-organ ischemia and necessitating nursing inter-ventions.3 This clinically relevant and rig-orous definition is difficult to apply since many of the elements of the definitions are missing from administrative databas-es. Perhaps more troubling is the fact that this definition has not been consistently adopted in clinical research. Due to sub-stantial heterogeneity in the way that IDH has been defined across studies, the exact burden of this complication remains un-known.4 In a recent meta-analysis with 5 studies that included 1694 patients, the prevalence of hemodialysis sessions com-plicated by IDH as defined by the EBPG criteria was 10.1% (range 5.0 to 30.8%); among 203,768 patients in 5 other stud-ies, the nadir SBP < 90 mmHg had a prev-alence of 11.6% (range 6.7% to 17.2%).5 However, the proportion of patients with frequent IDH varied from study to study because of varying definitions of frequent IDH.5 Definitions of frequent IDH ranged from at least one session in 3 months to 33% of the sessions over 3 months.

Although the complications of IDH are well-recognized, the close relationship between IDH and interdialytic hyperten-sion is underappreciated. This is because recurrent episodes of IDH and manage-ment strategies commonly applied (i.e., premature cessation of dialysis, hyper-tonic saline infusion, increase in dialysate sodium concentrations) act as barriers against dry-weight achievement and pre-dispose these patients to risks arising from volume overload leading to interdialytic hypertension.6 Thus, the scenario of a pa-tient presenting recurrent episodes of IDH to be concomitantly on a volume-expand-ed state with uncontrolled blood pressure (BP) outside of dialysis is not rare.

In this issue of the Brazilian Journal of Nephrology, Molin C. et al.7 report a “double-blind, placebo-controlled, cross-over” study testing the efficacy of the selective serotonin reuptake inhibitor ser-traline in preventing IDH. According to the inclusion/exclusion criteria, partici-pants had IDH complication (defined as a drop of ≥ 30 mmHg in SBP within dialysis or predialysis SBP ≤ 100 mmHg accom-panied by symptoms requiring nursing interventions) in at least 50% of dialysis sessions over a 3-month period prior to study enrollment. In addition, patients having SBP < 90 mmHg during dialysis or diastolic BP < 40 mmHg could qualify. Finally, any patient requiring intervention regardless of the BP criteria could be in-cluded in this study. Participants entered an initial 6-week placebo phase and then were switched to active-treatment with sertraline for another 6 weeks.7 Among 55 patients screened, 18 (32%) met the prespecified inclusion/exclusion criteria

https://orcid.org/0000-0001-7065-2096

https://orcid.org/0000-0001-8355-7100

Braz. J. Nephrol. (J. Bras. Nefrol.) 2019;41(4):445-447

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and 16 patients completed the trial. The occurrence of IDH episodes did not significantly differ between the sertraline and placebo phases. However, the risk of reporting adverse intradialytic symptoms was 42% higher with placebo [hazard ratio (HR): 1.42; 95% confidence interval (CI): 1.02-2.02].7 This effect was accompanied by 59% higher likelihood for nursing intradialytic interventions during the placebo phase (HR: 1.59; 95% CI: 1.03-2.48).7

Although interventional studies are important and the efforts of Molin et al. are worthy of appreciation, a number of lessons can be taken from this report. This study is not double-blind because the investiga-tors were aware of the drug assignment, therefore it has a single-blind, placebo run-in design. Second, a cross-over design conventionally means that patients on placebo switch to drug and those on drug switch to placebo; no cross-over took place in that study, which had simply a before-and-after study design. The sample size estimation assuming a 90% effect size (reduction in IDH from 50% to 5%) required 30 pa-tients according to the authors, yet 16 were included. Thus, the study is underpowered despite evaluating a large effect size. The 95% CIs reported for intradia-lytic BP measurements are not credible given the large standard deviations. Finally, the Kaplan-Meier curves displayed do not agree with the p value of the log-rank tests reported. Thus, on many counts, the study is squarely negative.

Sertraline has been tested as a pharmacological approach for orthostatic hypotension, neurocardio-genic syncope, or IDH. The main mechanism through which this agent exerts a favorable hemodynamic ac-tion is the amelioration of the paradoxical sympathet-ic withdrawal induced by a sudden surge of serotonin in the central nervous system. In accordance with the above results of the Molin study,7 earlier intervention-al studies enrolling hemodialysis patients with IDH failed to show improvement in the incidence of IDH or cardiac output, central blood volume, and periph-eral vascular resistance in response to therapy with sertraline.8 Other studies have associated sertraline administration with improvement in nadir intradia-lytic SBP or with fewer nursing interventions required for IDH.9 However, these studies suffer from certain methodological limitations and, mainly, they lack a proper adjudication of intradialytic hypotensive epi-sodes.9 In our interpretation, the currently available evidence cannot demonstrate a clear hemodynamic

benefit of sertraline in preventing IDH. This agent, however, appears to exert a favorable anti-depressant action that is accompanied by less frequent reporting of uncomfortable intradialytic symptoms. Whether this anti-depressant effect is translated into a long-term benefit on domains of health-related quality of life remains to be elucidated in larger studies with lon-ger follow-up periods.

The question that remains crucial is how can we prevent the occurrence of IDH and how can we im-prove patient outcomes. A summary of measures that may be beneficial is provided in Table 1. In our practice, the first-line management of IDH incorpo-rates a careful assessment of dry-weight.4,6 Although increasing dry-weight is commonly used as an ini-tial approach to reduce the necessity for aggressive ultrafiltration rates, this decision should be carefully balanced against its potential risks. Since routine BP recordings taken within the dialysis unit cannot ac-curately detect the presence of interdialytic hyperten-sion,10 we recommend home BP monitoring in order to assess BP control in the interdialytic period. In patients experiencing frequent episodes of IDH but their out-of-dialysis BP is inadequately controlled or manifest other signs of volume excess, increasing dry-weight is not a quick fix for this complex condi-tion. In this rather common scenario, dietary sodium restriction, avoidance of intradialytic sodium gain through individualized prescription of dialysate so-dium concentrations, and extending the duration of dialysis to at least 4 hours/session are more effective strategies to limit interdialytic weight gain, preserve the hemodynamic stability with ultrafiltration, and

Table 1 intErvEntions that may bE bEnEficial in prEvEnting intradialytic hypotEnsion

Intervention

1) Dry weight assessment

2) Dietary sodium restriction

3) Individualized dialysate sodium prescription

4) Ensure the adequate duration of dialysis (at least 4 hours 3 times per week)

5) Avoid eating during dialysis

6) Cool dialysate

7) Optimize antihypertensive regimen (i.e., discontinue short-acting BP-lowering medications prior to dialysis)

8) Ultrafiltration modeling

9) Consider to increase the dialysis frequency (i.e., short-daily dialysis)


Prevention of intradialytic hypotensive episodes

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improve the overall BP control.4,6 A recent analy-sis of 10,250 participants in phase 4 of the Dialysis Outcomes and Practice Patterns Study (DOPPS) sup-port that this therapeutic approach is associated with improvement in clinical outcomes11. A facility prac-tice of timely dry-weight assessment was associated with 28% reduced risk of cardiovascular mortality (HR: 0.72; 95% CI: 0.55-0.95).11 By contrast, rou-tine use of sodium profiling as a measure against IDH (an approach that results in positive net intradialytic sodium balance) was associated with 34% higher risk of cardiovascular mortality (HR: 1.34; 95% CI: 1.04-1.73).11 Nonetheless, we believe that that the dialysis prescription needs to be individualized.

In conclusion, IDH is a common complication that limits the adequacy of dialysis and worsens the patient outcomes. In our practice, we base the man-agement of IDH on the adequate assessment of dry weight and sodium restriction. Based on the available evidence, the use of sertraline or other agents (i.e. car-nitine, midodrine) appears to be of no value in pre-venting IDH.

acknowledgmenTs

R.A. is supported by NIH 5 R01 HL126903 and a grant from VA Merit Review 1-I01CX001753.

Disclosures: RA has the following disclosures:Member of data safety monitoring committees:

Astra Zeneca, Ironwood Pharmaceuticals;Member of steering committees of randomized

trials: Akebia, Bayer, Janssen, Glaxo Smith Cline, Relypsa, Sanofi and Genzyme US Companies;

Member of adjudication committees: Bayer, Boehringer Ingelheim, Janssen;

Member of scientific advisory board or consul-tant: Celgene, Daiichi Sankyo, Inc, Eli Lilly, Relypsa, Reata, Takeda Pharmaceuticals, USA, ZS Pharma;

PIG has nothing to disclose.

RefeRences

1. Chang TI, Paik J, Greene T, Desai M, Bech F, Cheung AK, et al.; Intradialytic hypotension and vascular access thrombosis. J Am Soc Nephrol 2011;22:1526-33.

2. Stefánsson BV, Brunelli SM, Cabrera C, Rosenbaum D, Anum E, Ramakrishnan K, et al. Intradialytic hypotension and risk of cardiovascular disease. Clin J Am Soc Nephrol 2014;9:2124-32.

3. Kooman J, Basci A, Pizzarelli F, Canaud B, Haage P, Fouque D, et al. EBPG guideline on haemodynamic instability. Nephrol Dial Transplant 2007;22:ii22-ii44.

4. Agarwal R. How can we prevent intradialytic hypotension? Curr Opin Nephrol Hypertens 2012;21:593-9.

5. Kuipers J, Verboom LM, Ipema KJR, Paans W, Krijnen WP, Gaillard CAJM, et al. The Prevalence of Intradialytic Hypoten-sion in Patients on Conventional Hemodialysis: A Systematic Review with Meta-Analysis. Am J Nephrol 2019;49:497-506.

6. Georgianos PI, Agarwal R. Epidemiology, diagnosis and man-agement of hypertension among patients on chronic dialysis. Nat Rev Nephrol 2016;12:636-47.

7. Dal Molin CZZ, Sakae TM, Schuelter-Trevisol F, Trevisol DJ. Effects of sertraline in the prevention of low blood pressure in patients undergoing hemodialysis. J Bras Nefrol 2019;pii: S0101-28002019005022101.

8. Brewster UC, Ciampi MA, Abu-Alfa AK, Perazella MA. Addi-tion of sertraline to other therapies to reduce dialysis-associated hypotension. Nephrology (Carlton) 2003;8:296-301.

9. Dheenan S, Venkatesan J, Grubb BP, Henrich WL. Effect of sertraline hydrochloride on dialysis hypotension. Am J Kidney Dis 1998;31:624-30.

10. Agarwal R, Peixoto AJ, Santos SF, Zoccali C. Pre- and postdial-ysis blood pressures are imprecise estimates of interdialytic am-bulatory blood pressure. Clin J Am Soc Nephrol 2006;1:389-98.

11. Dasgupta I, Thomas GN, Clarke J, Sitch A, Martin J, Bieber B, et al. Associations between Hemodialysis Facility Practices to Manage Fluid Volume and Intradialytic Hypotension and Patient Outcomes. Clin J Am Soc Nephrol 2019;14:385-93.

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Not transplanting kidney donors with acute kidney injury: a missed opportunity?

Não transplantar doadores de rim com lesão renal aguda: uma oportunidade perdida?

AuthorsNaoka Murakami1

Leonardo V. Riella1

1 Harvard Medical School, Brigham & Women’s Hospital, Transplantation Research Center, Boston, MA, United States of America.

DOI: 10.1590/2175-8239-JBN-2019-0194


Correspondence to:Leonardo V. Riella E-mail: [email protected]

Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD). In the US, studies have shown a clear survival benefit of transplantation even when the recipients are HLA-incompatible with positive cross-matches, compared with remaining on the waitlist1. However, organ shortage has been a universal challenge for the transplant field and the number of patients on the waitlist continues to rise. In order to expand the organ donor pool, several approaches have been taken, including kidney swap programs for sensitized patients or ABO-incompatible living donor-recipient pairs. For deceased donors, the use of expanded criteria donors, transplantation from HCV-positive donors to HCV-negative recipients, and use of HIV-positive organs have been implemented. Despite these efforts, the organ discard rate is still high at about 20% of all organ offers2, and the rate is higher in donors with acute kidney injury (AKI). The most common reason for turning down organ offers is the “inadequate” quality of the organs based on biopsy, followed by either AKI or expanded criteria donor with significant kidney risk factors. This tendency continues after incorporation of a new kidney allocation policy in the US in 2014. Therefore, it is of particular importance to determine long-term outcomes of recipients who received kidneys from AKI donors and to establish the risk factors for post-transplant kidney dysfunction.

In this issue of the BJN, Takase3 and colleagues retrospectively reviewed their single-center experience of kidney transplantation from deceased donors

with severe AKI. Among 732 consecutive deceased donor kidney transplant cases between 2010 and 2018, four cases with pre-procurement creatinine levels above 6.0 mg/dL were identified. In all four cases, donors were young (range 35-43), initial creatinine at presentation was normal, all had acute rhabdomyolysis as a cause of AKI, and pre-donation biopsy showed acute tubular necrosis (ATN) without glomerular, tubular, or vascular abnormalities. Cold ischemia time was long in all cases, ranging from 20 to 25 hours. Though all cases were complicated by delayed graft function (DGF), all organs were successfully transplanted and recipients’ allograft function was excellent [range 48-98 mL/min/1.73m2] at the latest follow-up (range 5 months to 2.7 years post-transplant).

The utility of kidneys from deceased donors with AKI has gained more attention recently, in accordance with the interest to expand the donor pool and to lower the organ discard rate. It has been reported that the discard rate increases stepwise with higher AKI stages, with Acute Kidney Injury Network (AKIN) stage 3 having an odds ratio for discard of 2.74. Recent study by Heilman et al. analyzed 1,313 transplanted kidneys, of which 934 (75.7%) had AKI and 447 (34%) had AKIN stage 3 AKI. They showed that stages of AKI did not affect long-term kidney survival (median follow-up 3-4.5 years post-transplant), though the incidence of DGF was significantly higher in recipients who received kidneys from AKIN stage 2 and 3 donors5. Similarly, Hall et al. conducted a multi-center retrospective

https://orcid.org/0000-0001-8168-5811

https://orcid.org/0000-0002-7636-3196


Acutely injured kidneys for transplantation

2

study of 2,430 kidneys (585 kidneys (24%) with AKI, 85 (3.5%) with AKIN stage 3 AKI) and suggested that there was no difference in composite 3-year graft survival associated with AKI stages6. On the other hand, a study using transplant registry in UK (n=11,646; 1,869 (6.0%) with AKI and 172 (1.5%) with AKIN stage 3 AKI) reported slightly lower graft survival 1-, 3-, and 5-year post-transplant in AKI group compared with non-AKI group7, which the authors discussed might not be clinically relevant (for example, 5-yr graft survival of 78% in non-AKI vs. 76% in AKI group) (Table 1). Nevertheless, these studies were observational and we should be cautious on extrapolating the results to all AKI donors, since the analyses only included the organs that physicians considered “viable” for transplantation despite AKI, and could potentially overestimate the outcomes.

How can we best determine whether the organs from AKI donors should be considered for transplantation or not? As Heilman et al. suggested, several studies explored the use of pre-procurement biopsy for guidance; two biopsy scoring systems have been proposed to evaluate the quality of kidney before procurement: Banff scoring system and Remuzzi score. Data suggest using the value of pre-procurement pathology findings to predict outcomes. However, decision-making based on histological findings comes with challenges such as significant inter-observer

variability in pathology readings, different pathology preparation (frozen section vs. paraffin section) and necessity of urgent reading, which might result in a below-optimal histological interpretation.

At the same time, we should keep in mind that local logistical factors and allocation policy play a great role in organ distribution. In Brazil, there is a documented higher incidence of AKI in ICU and limited resources in organ transportation compared to other countries. For example, once the patients are classified as brain-dead, renal perfusion support is not commonly provided, which could precipitate kidney injury. In addition, after procurement, the organ is often transported for long distances, across states8, using local transportation lines and not on perfusion pump, which prolongs cold ischemia time and inevitably increases the risk of further kidney injury. This is a relatively common situation in developing countries; strategies to best allocate and maximize organ offers in places with limited resources are needed.

In conclusion, it is noteworthy that AKI organs may have acceptable graft survival in the long term. It is crucial to individualize the risk evaluation when using these organs based on the cause of AKI, ischemic time, size/age mismatch, and immunological risks. Lastly, pre-transplant donor biopsy may also

Table 1 graft failurE and dgf incidEncE basEd on donor aKin stagEs

Analysis follow-up

length

AKIN 0/No AKI

AKIN 1

Cr increase >0.3 mg/dL or to 1.5-1.9 times

baseline

AKIN 2

2-2.9 times baseline

AKIN 3

3.0 times baseline. Cr

>4.0 mg/dL or initiation on RRT

Heilman et al.4

U.S. (Single-center)

Median 4 years

Graft Failure (HR)

1.0 (ref)0.97

(0.67-1.40)0.74

(0.45-1.24)0.70

(0.45-1.10)

DGF Incidence (%)

33.90% 33.5% 44% 75.4%

Hall et al.5

U.S (Multi-center)

3 years

Graft Failure (HR)

1.0 (ref)0.92

(0.73-1.14)0.73

(0.48-1.11)0.92

(0.58-1.47)

DGF Incidence (%)

39% 56%*

Boffa et al.6

U.K. (UK Transplant Registry)

1 year

Graft Failure (HR)

1.0 (ref) 1.20 (1.03-1.41)*

DGF Incidence (%)

28% (1.00)

35% (1.15-1.54)

43% (1.37-2.03)

55% (2.25-3.96)

*All AKI stages combined. HR: hazard ratio (95% Confidence Interval). AKI: acute kidney injury, Cr: creatinine, DGF: delayed graft function

AKIN stages based on serum creatinine are shown (refer to AKI Network website (www.AKINET.org) for full definition).


Acutely injured kidneys for transplantation

3

serve as a complementary tool for the final decision by excluding scarring and other irreversible injuries.

auThoRs conTRibuTions

Naoka Murakami and Leonardo V. Riella contributed substantially to the conception or design of the study; collection, analysis, or interpretation of data; writing or critical review of the manuscript; and final approval of the version to be published.

conflicT of inTeResT

The authors declare that they have no conflict of interest related to the publication of this manuscript.

RefeRences

1. Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 2016 Mar 10;374(10):940-50.

2. Husain SA, King KL, Pastan S, Pazter RE, Cohen DJ, Radhakrishnan J, et al. Association between declined offers of deceased donor kidney allograft and outcomes in kidney transplant candidates. JAMA Netw Open. 2019 Aug 2;2(8):e1910312.

3. Santos GPA, Andrade LGM, Valiatti MF, Contti MM, Nga HS, Takase HM. Kidney transplantation with donors in severe acute kidney injury. Should we use these organs? Retrospective Case Series. Braz J Nephrol [Internet]. 2019; [cited 2019 sep 27]; ahead of print. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-28002019005027102&lng=en DOI: http://dx.doi.org/10.1590/2175-8239-jbn-2018-0264

4. Hall IE, Schroppel B, Doshi MD, Ficek J, Weng FL, Hasz RD, et al. Associations of deceased donor kidney injury with kidney discard and function after transplantation. Am J Transplant. 2015 Jun;15(6):1623-1631.

5. Heilman RL, Smith ML, Smith BH, Kumar A, Srinivasan A, Huskey JL, et al. Long-term outcomes following kidney transplantation from donors with acute kidney injury. Transplantation. 2019;103(9):e263-e272.

6. Hall IE, Akalin E, Bromberg JS, Doshi MD, Greene T, Harhay MN, et al. Deceased-donor acute kidney injury is not associated with kidney allograft failure. Kidney Int. 2019 Jan;95(1):199-209.

7. Boffa C, Van de Leemkolk F, Curnow E, Van der Heide JH, Gilbert J, Sharples E, et al. Transplantation of kidneys from donors with acute kidney injury: friend or foe?. Am J Transplant. 2017 Feb;17(2):411-419.

8. Santos RP, Carvalho ARS, Peres LAB. Kidney transplantation epidemiology in Brazil. Nefrologia. 2019 Jul/Aug;39(4):402-410.

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original articlE | artigo original

AuthorsAgnaldo Caires1

Marcia Bastos Convento1

Bianca Castino2

Ala Moana Leme1

Edson de Andrade Pessoa1

Alef Aragão2

Nestor Schor1*

Fernanda Teixeira Borges1,2

1 Universidade Federal de São Paulo, Departamento de Medicina, Disciplina de Nefrologia, São Paulo, SP, Brasil.2 Universidade Cruzeiro do Sul, Programa Interdisciplinar em Ciências da Saúde, São Paulo, SP, Brasil.


Correspondence to:Fernanda Teixeira Borges.E-mail: [email protected]

* In memorian.

Antioxidant effect of endothelin-1 receptor antagonist protects the rat kidney against chronic injury induced by hypertension and hyperglycemiaEfeito antioxidante de antagonista dos receptores de endotelina-1 protege ratos contra lesão renal crônica induzida por hipertensão e hiperglicemia

Hipertensão e Diabetes Mellitus figuram como as duas principais causas de doença renal crônica que culmina em doença renal terminal. Uma vez que os dois fatores de risco são comuns e podem se sobrepor, no-vas abordagens preventivas e terapêuticas se fazem necessárias. O macitentan (MAC) é um novo antagonista não-seletivo dos re-ceptores da endotelina-1 (ET-1). O presente estudo teve como objetivo avaliar os efeitos do bloqueio crônico dos receptores da ET-1 com MAC sobre a alteração da função re-nal em animais hipertensos e hiperglicêmi-cos. Ratos geneticamente hipertensos foram divididos em grupos com animais hiperten-sos de controle (HT-CTL), hipertensos e hiperglicêmicos (HT+DIAB) e hipertensos e hiperglicêmicos tratados com 25 mg/kg de macitentan (HT-DIAB+MAC25) via gava-gem por 60 dias. Foram avaliados função renal e parâmetros associados ao estresse oxidativo e nitrosativo. Exames de imunois-toquímica foram realizados para lipocalina associada à gelatinase neutrofílica (NGAL), ET-1 e catalase no córtex renal. O grupo HT+DIAB exibiu diminuição da função re-nal e aumento na expressão de NGAL no córtex renal, bem como estresse oxidativo aumentado. O tratamento com MAC foi as-sociado a atenuação da produção de ET-1 e NGAL e maior ativação das defesas antio-xidantes (expressão de catalase) e elevação da produção de óxido nítrico. Além disso, o MAC evitou exacerbação da lesão oxidan-te (medida por hidroperóxidos urinários e peroxidação lipídica), melhorando assim a função renal. Nossos resultados sugerem que o efeito antioxidante do antagonista dos receptores da ET-1 MAC esteja imbri-cado no aprimoramento da função renal observada em ratos hipertensos e hipergli-cêmicos.

Resumo

Palavras-chave: Ratos; Insuficiência Renal Crônica; Endotelina-1; Antioxidantes.

Hypertension and Diabetes mellitus are the two main causes of chronic kidney disease that culminate in the final stage of kidney disease. Since these two risk factors are common and can overlap, new approaches to prevent or treat them are needed. Macitentan (MAC) is a new non-selective antagonist of the endothe-lin-1 (ET-1) receptor. This study aimed to evaluate the effect of chronic block-ade of ET-1 receptor with MAC on the alteration of renal function observed in hypertensive and hyperglycemic animals. Genetically hypertensive rats were divid-ed into control hypertensive (HT-CTL) group, hypertensive and hyperglycemic (HT+DIAB) group, and hypertensive and hyperglycemic group that received 25 mg/kg macitentan (HT-DIAB+MAC25) via gavage for 60 days. Kidney function and parameters associated with oxida-tive and nitrosative stress were evaluated. Immunohistochemistry for neutrophil gelatinase-associated lipocalin (NGAL), ET-1, and catalase in the renal cortex was performed. The HT+DIAB group showed a decrease in kidney function and an in-crease in NGAL expression in the renal cortex, as well as an increase in oxidative stress. MAC treatment was associated with attenuated ET-1 and NGAL produc-tion and increases in antioxidant defense (catalase expression) and nitric oxide pro-duction. In addition, MAC prevented an increase in oxidant injury (as measured by urinary hydroperoxide and lipid peroxi-dation), thus improving renal function. Our results suggest that the antioxidant effect of the ET-1 receptor antagonist MAC is involved in the improvement of kidney function observed in hypertensive and hyperglycemic rats.

absTRacT

Keywords: Rats; Renal Insufficiency, Chronic; Endothelin-1; Antioxidants.

DOI: 10.1590/2175-8239-JBN-2018-0162

https://orcid.org/0000-0001-9921-9106

https://orcid.org/0000-0002-6410-8817

https://orcid.org/0000-0002-9146-2627

https://orcid.org/0000-0002-9790-0915


Antioxidant effect of endothelin-1 against kidney chronic injury

452

inTRoducTion

Diabetes mellitus (DM) and hypertension are the main causes of chronic kidney disease (CKD) and its progression to end-stage renal disease1. The inciden-ce of CKD increases with age in both developed and developing countries2,3. Therefore, new strategies to prevent the development of CKD are necessary.

One common model of type 2 DM is the induc-tion in rats through with a single injection of low-do-se streptozotocin4. Spontaneously hypertensive rats (SHR) are an animal model frequently used to stu-dy essential (or primary) genetic hypertension5. The induction of diabetes in the SHR model6 accelerates the development of diabetic nephropathy and chronic kidney disease (CKD).

Diabetic nephropathy (DN) is a strong risk fac-tor for vascular disease, common among patients with type 2 DM, and characterized by podocyte in-jury, proteinuria, glomerular fibrosis, and a decrea-se in glomerular filtration7. Features of DN include hyperglycemia, inflammation, reactive oxygen species (ROS) production, and endothelin-1 (ET-1) and re-nin-angiotensin system (RAS) activation8.

Untreated, diabetic nephropathy is the leading cause of end-stage chronic kidney disease9. CKD is characterized by an increase in kidney injury markers (urine albumin > 30 mg/24 h or albumin/creatinine ratio higher than 30 mg/g), tubular damage and im-paired ionic excretion, abnormal histologic findings on kidney biopsy specimens, and decrease in the glo-merular filtration rate (< 60 mL/min/1.73 m2), among other findings10.

ROS are involved in the pathophysiology of CKD, and NADPH oxidases are the main sources of ROS in many tissues11-13.

ET-1 modulates renal blood flow by regulating the vascular tone14. It is produced by endothelial cells, but under pathophysiological conditions, it can be produ-ced by podocytes, and mesangial and parietal epithe-lial cells15. ET-1 exerts its function in target cells via two receptors, ETA and ETB15.

ETA receptor activation mediates vasoconstric-tion, vascular cell proliferation, and proteinuria16. Differently, ETB receptor activation releases vasodila-ting substances such as nitric oxide and prostacyclin, leading to vasodilation first and then vasoconstriction, stimulates sodium reabsorption in collecting ducts, and development of proteinuria17. Circulating ET-1 levels are increased in hypertensive patients18.

ET-1 and the RAS interact in renal tissues. Angiotensin II increases ET-1 production and upre-gulates ETA receptor expression in the kidney19,20. Together, both peptides can produce pre- and post--glomerular vasoconstriction, mesangial cell contrac-tion, glomerular filtration rate decrease, extracellular matrix production and increase in tubular sodium reabsorption21. It is reasonable to propose that ET-1 receptor blockade may be beneficial in diabetic nephropathy.

Indeed, clinical trials to study the effect of the ET-1 antagonist atrasentan in DN are documented22. Currently, however, the principal therapeutic use of ET-1 receptor antagonists is in the treatment of idio-pathic pulmonary fibrosis and pulmonary arterial hypertension23,24. For the first time, the present study evaluates the effect of macitentan, a new non-selective ET-1 receptor antagonist used in the treatment of pul-monary hypertension, on the progression of kidney injury observed in hypertensive and hyperglycemic rats.

meThods

animal trEatmEnt

The experimental protocol was approved by the Ethics Committee (CEP 798483) of the Universidade Federal de São Paulo (UNIFESP) and was performed in accordance with the Brazilian guidelines for scien-tific animal care and use25,26. Animals were obtained from the Centro de Desenvolvimento de Modelos Experimentais para Medicina e Biologia (CEDEME) of UNIFESP.

Thirty genetically hypertensive (SHR) male rats, aged 6 weeks and weighing 170-200 g, were main-tained in metabolic cages. The cages were kept in a temperature (21 ± 2°C) and humidity-controlled (60 ± 10%) room with a 12-h dark/light (artificial lights, 7 a.m.–7 p.m.) cycle and hourly air exhaust (15 min/h).

After an adaptation period of two weeks, the ani-mals were divided into three groups, and during the 60-day study, all animals were fed standard rat chow ad libitum with free access to water.

Ten genetically hypertensive (HT) rats that were maintained in the control (CTL) situation received one intravenous injection of distilled water (vehicle only) and the group was named HT-CTL.

Twenty rats received one intravenous injection of 60 mg/kg streptozotocin (Sigma-Aldrich, Saint Louis, USA) in citrate buffer 0.1 M, pH 4.4), and only rats



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with blood glucose higher than 400 mg/dL were se-lected. Half of these were maintained in the HT and hyperglycemic (DIAB) group, and the group was na-med HT-DIAB. The remaining 10 rats were treated with daily macitentan (MAC) with 25 mg/kg admi-nistration by gavage for 60 days and the group was named HT-DIAB+MAC25.

At 0 (basal), 30, and 60 days after the beginning of experimental protocols, all animals were weighed, blood samples were collected from the lateral tail vein, and rats were maintained in metabolic cages for 24 h for urine collection, and the urine volume was quantified. The animals were euthanized 60 days af-ter the beginning of the experimental protocol with a toxic ip dose of ketamine (90 mg/kg)/xylazine (10 mg/kg), (Agribands de Brasil Ltda, SP, Brazil). The right and left kidneys were then removed for immunohisto-chemical analysis. Biochemical parameters were mea-sured in plasma and urine samples.

mEasurEmEnt of body wEight

The rats were weighed monthly using a 2610 scale (Labortex, SP, BRAZIL) and the result was reported in grams.

mEasurEmEnt of systolic blood prEssurE (map)

Systolic blood pressure was indirectly measured by tail plethysmography. Rats were placed in a warm chamber for 10 min, and the cuff and wrist recei-ver were attached to the tail. Blood pressure was recorded using an electric sphygmomanometer cou-pled to a 2-channel Gould model 2200 S polygraph (Record 2200S, Gould Inc., Cleveland, Ohio, USA). Measurements were taken at 0, 24, and 48 h, and the results are reported as means ± SD.

biochEmical analysis

The levels of plasma creatinine and plasma urea were assayed spectrophotometrically according to standard procedures, using commercially available diagnostic kits (Labtest Diagnostic, Brazil). Creatinine was de-termined by a colorimetric method based on the Jaffé reaction27. Urea was determined using a colorimetric assay based on urease activity28. Plasma glucose con-centration was determined using tail blood samples (Accuchek, Boehringer Mannheim, Indianapolis, Ind., USA). Levels of creatinine, urea, and glucose are reported in mg/dL.

Urine sodium concentrations were determined with a Micronal B462 flame photometer (Micronal, São Paulo, Brazil). Sodium excretion is reported as percentage of mEq/24 h. Urinary protein was quanti-fied using a colorimetric method based on pyrogallol red-molybdate29. The results are reported as mg pro-tein/24 h urine.

oxidativE strEss studiEs

To assess lipid peroxidation, levels of the peroxida-tion product malondialdehyde were determined by measuring thiobarbituric acid-reactive substances (TBARS)30. For the quantification, 0.4 mL of the uri-ne sample diluted with 0.6 mL water was added to a reaction mixture consisting of 1.0 mL 17.5% trichlo-roacetic acid (TCA) and 1.0 mL 0.6% thiobarbituric acid to form a red compound. This mixture was hea-ted in a water bath at 95°C for 20 min; the solution was then removed from the water bath and cooled on ice, followed by the addition of 1.0 mL 70% TCA. The solution was homogenized and incubated for 20 min followed by spectrophotometric measurement at 534 nm (A = 1.56×105 M/cm). The data are reported as nM/mg urinary creatinine.

Urinary peroxides were determined by the fer-rous oxidation of xylenol orange version 2 (FOX-2) method31. Ferrous iron is oxidized to ferric iron by peroxides contained in the samples. Xylenol orange reagent shows high selectivity for the Fe3+ ion, pro-ducing a purplish-blue complex whose absorbance can be measured at 560 nm (A = 4.3×104 M/cm). The following reagent was prepared: 90 mL methanol; 10 mL double distilled water; 100 µM xylenol orange; 4 mM butylated hydroxytoluene (BHT); 25 mM sul-furic acid and 250 µM ferrous ammonium sulfate. The urine sample (100 µL) was mixed with 900 µL of FOX-2 reagent, vortexed and incubated for 30 minu-tes at room temperature. Solutions were then centri-fuged at 15,000 g for 10 min at 4ºC for the removal of protein residues. The absorbance at 560 nm was read against a blank. The data are reported as nmol/g urinary creatinine.

nitric oxidE dEtErmination

Nitric oxide (NO) was determined by the Griess me-thod32. A mixture of 1% sulfanilamide (in 5% H3PO4) and 0.1% naphthylethylenediamine solution (Sigma-Aldrich, Saint Louis, USA) was added to the urine samples, and the absorbance at 546 nm was measured



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using a GENESYS 2 spectrophotometer (Spectronic Instruments, Rochester, USA). Nitrite, one of the stable metabolites of NO, was then estimated from a standard curve constructed using NaNO2. The as-sessment of the urine creatinine was performed and used to normalize the NO concentrations. The data are reported as nM/mg urinary creatinine.

immunohistochEmistry

Kidneys were dissected along the non-hilar axis and fixed in 10% phosphate-buffered formalin (Erviegas, Brazil). Kidney sections were fixed with 4% buffered paraformaldehyde, embedded in para-ffin (Erviegas, Brazil) and 4-µm thick sections were prepared. Kidney sections were deparaffinized and rehydrated. Endogenous peroxidase activity was blocked with 5% H2O2 in absolute methanol for 10 min at room temperature. To expose the antigens, kidney sections were boiled in a target retrieval solu-tion [1 mmol/L tris(hydroxymethyl)aminomethane (Tris), pH 9.0, with 0.5 mM ethylene glycol tetraa-cetic acid (EGTA)] for 10 min. Nonspecific binding was prevented by incubating the sections in phos-phate buffered saline (PBS) containing 1% bovine serum albumin (BSA), 0.05% saponin, and 0.2% gelatin. Sections were then incubated overnight at 4°C with primary antibodies against ET-1 (1:200, rabbit anti-rat; ABCAM, MA, USA), neutrophil gelatinase-associated lipocalin (NGAL) (1:200, rab-bit anti-rat; ABCAM, MA, USA) or catalase (1:200, rabbit anti-rat; ABCAM, MA, USA), for 18 hours at 4°C. Sections were washed and incubated with appropriate streptavidin- peroxidase-conjugated se-condary antibodies (Dako, Glostrup, Denmark) for 1 h at room temperature. The sites of antibody-anti-gen reactions were visualized by staining with 0.5% 3,3’-diaminobenzidine tetrachloride (Dako). Digital photomicrographs were taken through a Leica DM 1000 upright microscope connected to a works-tation computer through the Leica DFC 310 FX, LAS 3.8 Microscope Camera (Leica, Switzerland). Ten photomicrographs along the renal cortex were taken, the light brown staining was quantified (LAS software, version 3.8) and averaged for each rat. The data are reported as percentage of stained area.

wEstErn blotting

The protein concentration was verified by the method of Lowry33. Cells and kidney tissues were lysed with

a 200-µL RIPA lysis buffer per plate (100 mm2). The lysates were centrifuged at 12,000 g for 5 min at 4°C, and the supernatants were stored at −80°C. Proteins (30 µg) were separated by 10% polyacrylamide gel electrophoresis and transferred to polyvinylidene flu-oride (PVDF) membranes using a Mini Trans-Blot Electrophoretic Transfer Cell (BioRad, CA, USA). Nonspecific binding sites were blocked with 5% al-bumin (v/v) in TBS buffer. The immunoblots were incubated overnight at 4°C with renin (1:500, Santa Cruz, TX, USA), angiotensin I (1:500, Santa Cruz, TX, USA), angiotensin II (1:500, Santa Cruz, TX, USA), or GAPDH (1:500, Abcam, MA, USA) primary antibodies. After washing three times with TBS-T, the membranes were incubated for 1 h at 4°C in HRP-conjugated secondary antibodies (1:100,000; Santa Cruz TX, USA). Immunoreactive protein bands were visualized using Pierce ECL Plus Chemiluminescent substrate (Thermo Fisher, USA). Images were obtained and analyzed with an Alliance 7 Chemiluminescence documentation system (UVITEC, Cambridge, UK). The immunoblot band intensities were quantified using Image J software and reported as the renin/GAPDH, Angiotensin I/GAPDH, and Angiotensin II/GAPDH ratio.

statistical analysis

Results are reported as a means ± SE. Data were analyzed by two-way analysis of variance (ANOVA) followed by the Tukey’s post-hoc test, and p < 0.05 was considered statistically significant.

ResulTs

Table 1 shows the mean body weight (g) of the groups during the experiment. The mean weight of the HT-DIAB and HT-DIAB+MAC25 groups was significantly lower than that of the CTL group after 30 days of study.

There was no difference in the MAP in HT-DIAB and HT-DIAB+MAC25 groups when compared to the HT-CTL group within their respective experimen-tal period. There was an increase in blood glucose in all experimental groups at 30 and 60 days when com-pared to their respective HT-CTL group.

All experimental groups exhibited an increase in urine production at 30 and 60 days when compared to their respective HT-CTL group.

The HT-DIAB group showed a significant increase in plasma creatinine and urea when compared to the



455

Weight (g) HT-CTL HT-DIAB HT-DIAB + MAC 25mg

BASAL 174,00 ± 10,19 167,38 ± 10,76 189,17 ± 13,38

30 DAYS 279,00 ± 18,46 184,75 ± 12,75 * 182,83 ± 17,74 *

60 DAYS 318,71 ± 19,49 191,25 ± 21,33 ** 172,50 ± 19,42 **

MAP (mmHg) HT-CTL HT-DIAB HT-DIAB+MAC 25 mg

BASAL 173,00 ± 5,67 178,00 ± 5,14 176,83 ± 4,28

30 DAYS 178,86 ± 4,61 187,88 ± 7,05 191,00 ± 7,30

60 DAYS 181,43 ± 2,76 190,50 ± 6,70 195,17 ± 5,33

Plama Glucose (mg/dl) HT-CTL HT-DIAB HT-DIAB + MAC 25 mg

BASAL 100,29 ± 8,29 100,29 ± 8,29 89,00 ± 0,82

30 DAYS 94,43 ± 2,17 418,50 ± 73,66 * 524,83 ± 7,21 *

60 DAYS 127,71 ± 14,11 541,38 ± 18,67 ** 516,33 ± 30,79 **

Urine Volume (ml) HT-CTL HT-DIAB HT-DIAB + MAC 25 mg

BASAL 11,11 ± 1,41 9,12 ± 0,84 12,83 ± 0,91

30 DAYS 13,05 ± 1,57 76,83 ± 8,98 * 78,33 ± 7,03 *

60 DAYS 13,91 ± 1,69 85,00 ± 5,80 ** 78,33 ± 9,80 **

Plasma Creatinine (mg/dl) HT-CTL HT-DIAB HT-DIAB + MAC

BASAL 0,69 ± 0,07 0,61 ± 0,04 0,63 ± 0,05

30 DAYS 0,70 ± 0,06 0,85 ± 0,09 0,69 ± 0,05 ¥

60 DAYS 0,65 ± 0,03 0,98 ± 0,09 ** 0,72 ± 0,01 ¥¥

Plasma Urea (mg/dl) HT-CTL HT-DIAB HT-DIAB+MAC 25 mg

BASAL 26,59 ± 2,57 26,43 ± 3,22 23,00 ± 1,08

30 DAYS 38,86 ± 7,84 67,84 ± 11,12 * 55,75 ± 9,41 ¥

60 DAYS 36,53 ± 6,09 72,73 ± 11,04 ** 47,25 ± 5,65

Urine Sodium (mEq/24h) HT-CTL HT-DIAB HT-DIAB+MAC 25 mg

BASAL 10,61 ± 3,05 8,38 ± 2,35 14,11 ± 1,81

30 DAYS 12,97 ± 2,68 55,24 ± 3,28 * 56,46 ± 5,34 *

60 DAYS 10,61 ± 1,27 72,33 ± 14,10 ** 44,42 ± 6,39 **

Urine Protein (mg/24h) HT-CTL HT-DIAB HT-DIAB+MAC 25 mg

BASAL 8,79 ± 2,20 6,29 ± 1,21 10,04 ± 1,12

30 DAYS 12,85 ± 1,28 36,71 ± 4,89 * 29,81 ± 4,00 *

60 DAYS 10,97 ± 2,17 30,02 ± 3,58 ** 21,40 ± 4,79 ** ¥¥

Table 1 physiological paramEtErs of gEnEtically hypErtEnsivE (shr) animals in thE control group (ht-ctl), hypErtEnsivE and hypErglycEmic animals (ht-diab), hypErtEnsivE and hypErglycEmic animals trEatEd with macitEntan (ht-diab+mac25) for basal, 30 and 60 days

HT-CTL group at 60 days. Notably, plasma creatinine and urea in the rats of the HT-DIAB+MAC25 group at 30 and 60 days were not statistically different when compared to their respective HT-CTL group.

The renal tubular function was evaluated by me-ans of sodium excretion. In all experimental groups, we observed an increase in sodium excretion at 30 and 60 days when compared to their respective HT-CTL

group. No statistical difference in sodium excretion was found between the diabetic rats treated or not with macitentan.

We observed a significant increase in urinary protein excretion in the HT-DIAB group in comparison to the HT-CTL group in all experimental periods. In the HT-DIAB+MAC25 group, we also observed an increase in protein excretion at 30 and 60 days when compared to

Data are reported as means ± SE. The significance level for a null hypothesis was set at 5% (p < 0.05). (*) compared to the HT-CTL 30 days group; (¥) compared to the HT-DIAB 30 days group, (**) compared to the HT-CTL 60 days group, and (¥¥) compared to the HT-DIAB 60 days group (ANOVA followed by the Tukey’s post-hoc test). N = 10 per group.



456

Figure 1. Light microscopy of immunostained kidney sections A, Neutrophil gelatinase-associated lipocalin (NGAL 200×), endothelin-1 (ET-1, 200×), and catalase (200×) in genetically hypertensive rats in the control group (HT-CTL), hypertensive and hyperglycemic animals (HT-DIAB), hypertensive and hyperglycemic animals treated with macitentan (HT-DIAB+MAC25) for 60 days (final day of the experiment). B, Quantitative analyses of kidney sections stained for NGAL, ET-1, and catalase. Data are reported as %. The significance level for a null hypothesis was set at 5%. **p < 0.05 compared to the HT-CTL 60 days group and ¥¥ p < 0.05 compared to the HT-DIAB 60 days group (ANOVA followed by the Tukey’s post-hoc test). N= 10 per group.

their respective HT-CTL group. Nevertheless, diabetic rats treated with macitentan exhibited significantly de-creased urinary protein excretion when compared to the HT-DIAB group at 60 days, suggesting improved renal barrier function.

Immunostaining for ET-1 and NGAL at 60 days is shown in Figure 1. We observed an increase in the labeling of ET-1 and NGAL in the HT-DIAB group compared to the HT-CTL group, and a decrease when comparing the HT-DIAB+MAC25 group with the HT-DIAB group. MAC attenuated the increase in ET-1 and NGAL (a renal injury marker), corrobora-ting the hypothesis of a beneficial effect on the kidney.

Figure 1 demonstrates the immunostaining for catalase at 60 days. We observed that the HT-DIAB group did not stimulate the expression of this an-tioxidant enzyme. However, the HT-DIAB+MAC25 group exhibited increase of catalase compared to the HT-CTL and HT-DIAB groups, suggesting an antio-xidant potential for macitentan.

Figure 2 analyzes the RAS through protein expres-sion and their respective graphical quantifications. In the HT-DIAB group, there was an increase in the

production of angiotensin II. The HT-DIAB+MAC25 group, which had decreased ET-1 production, de-monstrated an increase in the expression of the renin as well as angiotensin II.

Figure 3 A shows the urinary levels of lipid pe-roxidation (TBARS). There was an increase in lipid peroxidation in the HT-DIAB group at 30 days when compared to their HT-CTL group. Conversely, in the HT-DIAB+MAC25 group, lipid peroxidation was not statistically different when compared to the HT-CTL group in all experimental periods.

Urinary hydroperoxides (Figure 3B) evaluated by FOX-2 increased in the HT-DIAB group at 30 and 60 days, but in the HT-DIAB+MAC25 group, an increa-se was seen only at 30 days. Additionally, at 60 days, the HT-DIAB+MAC25 group had similar lower levels when compared to the control rats. This result suggests, again, a potential antioxidant effect of macitentan.

Figure 3C analyzes urinary NO levels. Although there is a trend indicative of an increase, urinary NO levels in the HT-DIAB group were not statistically different when compared to those in the HT-CTL group at 30 and 60 days. However, the group treated



457

Figure 2. Renin, angiotensin I (ANG I), and angiotensin II (ANG II) analysis. A, Western blot image of kidney cortex of genetically hypertensive rats (SHR) in the control group (HT-CTL), hypertensive and hyperglycemic animals (HT-DIAB), and hypertensive and hyperglycemic animals treated with macitentan (HT-DIAB+MAC25) for 60 days (final day of the experiment). B,C, and D, Quantitative analyses of immunoblot images were obtained by ImageJ software. Data are reported as means ± SE. The significance level for a null hypothesis was set at 5%. ** p < 0.05compared to the HT-CTL 60 days group and ¥¥ p < 0.05 compared to the HT-DIAB 60 days group (ANOVA followed by the Tukey’s post-hoc test). N = 10 per group.

Figure 3. Analysis of the formation of reactive oxygen species and reactive nitrogen species. A, Quantitative analyses of thiobarbituric reactive substances (TBARS). B, Urinary hydrogen peroxide was measured by a modified ferrous ion oxidation xylenol orange version-2 (FOX-2). C, Nitric oxide (NO) in genetically hypertensive rats in the control group (HT-CTL), hypertensive and hyperglycemic animals (HT-DIAB), and hypertensive animals treated with Macitentan (HT-DIAB+MAC25) for basal, 30, and 60 days. Data are reported as means ± SE. The significance level for a null hypothesis was set at 5%. *p < 0.05 compared to the HT-CTL 30 days group; ¥P<0.05 compared to the HT-DIAB 30 days group, **p < 0.05 compared to the HT-CTL 60 days group, and ¥¥ p < 0.05 compared to the HT-DIAB 60 days group (ANOVA followed by the Tukey’s post-hoc test). N = 10 per group.



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with macitentan showed a significant increase in uri-nary NO concentration when compared to the HT-CTL group at 30 and 60 days. Since the renal injury determined by NGAL (Figure 1) decreased with the treatment of macitentan 25 mg/kg, the NO produced by the kidney may contribute to the amelioration of renal failure.

discussion

Our experimental model utilized spontaneously hypertensive rats with concomitant hyperglycemia induced by streptozotocin. This model was chosen because the coexistence of DM and systemic arterial hypertension (SAH) increases the risk of developing chronic renal failure. This experimental model has characteristics very similar to diabetic renal injury found in humans.

We observed signs of diabetes including elevated glycemia, polyuria (due to hyperglycemic osmotic diuresis), and decreased body weight. In association with increased systolic blood pressure, these para-meters lead to progressive loss of renal function. We identified proteinuria, increased sodium excretion, and increased creatinine and urea in hypertensive and hyperglycemic rats.

NGAL is a reliable diagnostic and prognostic bio-marker for acute kidney injury (AKI) as its levels rise 2 h after the kidney injury. Moreover, studies have shown that NGAL levels in AKI and stable CKD groups are higher than those of control groups34-36, corroborating our results, since there was an increase in NGAL in the hypertensive and hyperglycemic rats at 60 days.

Recent studies have demonstrated the role of ET-1 in the initial phase of DN. Specifically, the expression of ET-1 receptors can be stimulated by hyperglycemia37. The kidney is an essential site of its production; ET-1 causes increased renal vascular resistance, reduced renal blood flow and glomerular filtration rate, and inhibition of salt and water reabsorption37.

At the same time, the RAS is also actively involved in the genesis and progression of DN, and there is already evidence of an interaction between ET-1 and other vasoactive substances, such as angiotensin II38.

Our results show that the kidneys of hypertensive and hyperglycemic rats exhibited stimulation of an-giotensin II as well as ET-1, confirming the participa-tion of these mediators of inflammation and endothe-lial dysfunction, respectively.

Oxidative and nitrosative stress play an important role in diabetes progression39,40. The hypertensive and hyperglycemic rats in our study showed an increase in the renal lipid peroxidation, urinary peroxides, and NO levels.

Since ET-1 plays an important role in the progres-sion of diabetes, this study aimed to test a possible contribution of the effect of macitentan, which is a non-selective antagonist of ETA and ETB receptors and has received approval from the U.S. Food and Drug Administration (FDA) in 2014. However, other ET-1 selective antagonists have been used in the pre-vention of diabetic nephropathy, including use in cli-nical trials22. The macitentan was studied in hyper-glycemia-induced kidney injury in mouse models of type 2 diabetes41, but inasmuch hypertension and dia-betes are major risk factors for chronic kidney disea-se, our study evaluated the effect of ET-1 antagonist on renal function of rats simultaneously hypertensive and diabetic.

The dose of macitentan used in this study is con-sistent with that found in other studies41,42. Initially, we observed that hypertensive and hyperglycemic rats treated with 25 mg/kg of the antagonist exhibited neither a significant increase in the plasma concen-tration of creatinine and urea, nor an increase in the excretion of proteins. These results, together with the decrease in the expression of NGAL, suggest impro-vement in renal function.

ET-1 promotes natriuresis by acting on the collec-ting duct cells via ETB receptors43. However, we did not observe a significant decrease in sodium excretion in hypertensive and hyperglycemic rats treated with the antagonist macitentan. One hypothesis concerns the approximate 50-fold selectivity of macitentan for ETA receptors42, which would cause the effects of ET-1 mediated by the ETB receptor, such as natriuresis, to be at least partially preserved.

To confirm the effect of macitentan on the kidney, we analyzed the labeling for ET-1 and confirmed that there was a decrease in labeling in the renal tissue of hypertensive and hyperglycemic rats treated with ma-citentan. This result demonstrated that ET-1 receptor blockade decrease the production of this vasocons-triction agent.

Since ET-1 reduces the rate of glomerular filtra-tion by promoting contraction of the afferent and efferent arterioles, ET-1 blockade may explain in part the improvement in renal function. However, in our



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experimental conditions, we observed that ET-1 re-ceptor blockade increased the production of angio-tensin II in renal tissue, which could counteract ET-1 receptor blockade by acting at its AT1 receptor, pro-moting arteriolar vasoconstriction.

Another hypothesis is that NO may act as a func-tional antagonist of angiotensin II, inhibiting vaso-constriction in glomerular arterioles44,45. The use of macitentan in hypertensive and hyperglycemic rats further increased urinary excretion of NO (165%). This increase in NO production may explain, at least in part, the improvement in kidney function indicated by the improvement in renal blood flow via the va-sodilator effect of NO. It has already been shown in rabbit kidney that ET-1 stimulates the production of NO through the activation of ETB receptors46. Since macitentan is more selective for the ETA receptor, this increase in urinary output and excretion may be due to the action of the ETB receptor42,43.

Interestingly, the use of macitentan stimulated the expression of catalase, an important antioxidant en-zyme. The increase in lipid peroxidation and urinary hydrogen peroxides was prevented by MAC treat-ment, suggesting that hydrogen peroxide was degra-ded by the catalase enzyme into water and oxygen47.

conclusion

We report that macitentan (25 mg/kg) inhibited the progression of renal injury induced by hyperglycemia and hypertension in rats, possibly by potentiating the antioxidant defense and preventing the increase of oxidative stress. A limitation of our work is the lack of nore specific markers of kidney function, but the markers used in the present study are those currently used in clinical practice. In conclusion, blocking the ET-1 receptor with macitentan may be an alternative in the prevention of DN in hyperglycemic and hyper-tensive rats. Intervention with macitentan should be confirmed in human clinical trials.

acknowledgmenTs

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico Tecnológico (CNPq), Financiadora de Estudos e Projetos (FINEP), Fundação Oswaldo Ramos (FOR), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2013/0945-5) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

auThoRs’ conTRibuTion

AC, EAP, AA conducted the experiments; AC and FTB designed the experimental protocol. AC, MBC, and FTB wrote the manuscript; NS critically evalua-ted the results and revised the manuscript. All authors read and approved the final manuscript.


We have no direct or indirect commercial financial incentive associated with publishing this article. Additionally, the authors have no conflicts of interest, and the source of extra-institutional funding is indica-ted in the manuscript.

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462


AuthorsKellen Hyde Elias Pinheiro1

Franciana Aguiar Azêdo1

Kelsy Catherina Nema Areco1

Sandra Maria Rodrigues Laranja¹,²

1 Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Nefrologia, São Paulo, SP, Brazil.2 Hospital do Servidor Público Estadual de São Paulo, Francisco Morato de Oliveira, São Paulo, SP, Brazil.

Submitted on: 11/19/2018Approved on: 06/25/2019.

aArticle based on the master's thesis entitled Risk factors and mortality in patients with Sepsis-induced Acute Kidney Injury presented in 2012 at the Federal University of São Paulo - Paulista Medical School/Department of Nephrology.

Correspondence to:Kellen Hyde Elias Pinheiro.E-mail: [email protected]

Risk factors and mortality in patients with sepsis, septic and non septic acute kidney injury in ICU

Fatores de risco e mortalidade dos pacientes com sepse, lesão renal aguda séptica e não séptica na UTI

A Lesão Renal Aguda (LRA), cuja etiologia mais frequente é sepse, tem incidência de 5-6% na Unidade de Terapia Intensiva (UTI). Objetivo: Avaliar pacientes que permaneceram mais de 48 horas na UTI e desenvolveram LRA ou Doença Renal Crônica agudizada (DRCag) e/ou sepse; identificar fatores associados e causas que possam afetar a evolução desses pacientes. Método: Estudo prospectivo, observacional, coorte e quantitativo dos pacientes em UTI entre maio a dezembro de 2013 com sepse e LRA. Excluídos pacientes < 48 horas e/ou dialíticos prévios. Resultados: Dos 1156 pacientes admitidos, 302 foram incluídos e divididos em grupos: sem sepse e sem LRA (SSSLRA), apenas sepse (S), LRA séptica (LRAs), LRA não séptica (LRAns), DRCag séptica (DRCags), DRCag não séptica (DRCagns). Foi verificado que 94% apresentaram algum grau de lesão renal; Kidney Disease Improving Global Outcomes (KDIGO) 3 foi predominante nos grupos sépticos (p = 0.018); o nefrologista foi chamado apenas em 23% dos pacientes não sépticos vs. 54% dos sépticos (p < 0.001); houve necessidade de diálise em 8% dos não sépticos vs. 37% dos sépticos (p < 0.001); necessidade de Ventilação Mecânica (VM) em 61% da LRAns versus 90% na LRAs (p < 0.001). A mortalidade foi 38% e 39% na LRAs e DRCags vs. 16% e 0% na LRAns e DRCagns, respectivamente (p < 0.001). Conclusão: LRAs e DRCags têm pior prognóstico que a não séptica. O nefrologista ainda não é solicitado em grande parte dos casos com influência direta na mortalidade (p < 0.001), o débito urinário é consideravelmente prejudicado; o tempo de permanência na UTI, necessidade de VM e mortalidade são maiores quando há associação da sepse e LRA.

Resumo

Palavras-chave: Lesão Renal Aguda; Insu-ficiência Renal Crônica; Sepse; Nefrologia; Balanço Hídrico; Mortalidade.

Acute kidney injury (AKI) has an incidence rate of 5–6% among intensive care unit (ICU) patients and sepsis is the most frequent etiology. Aims: To assess patients in the ICU that developed AKI, AKI on chronic kidney disease (CKD), and/or sepsis, and identify the risk factors and outcomes of these diseases. Methods: A prospective observational cohort quantitative study that included patients who stayed in the ICU > 48 hours and had not been on dialysis previously was carried out. Results: 302 patients were included and divided into: no sepsis and no AKI (nsnAKI), sepsis alone (S), septic AKI (sAKI), non-septic AKI (nsAKI), septic AKI on CKD (sAKI/CKD), and non-septic AKI on CKD (nsAKI/CKD). It was observed that 94% of the patients developed some degree of AKI. Kidney Disease Improving Global Outcomes (KDIGO) stage 3 was predominant in the septic groups (p = 0.018). Nephrologist follow-up in the non-septic patients was only 23% vs. 54% in the septic groups (p < 0.001). Dialysis was performed in 8% of the non-septic and 37% of the septic groups (p < 0.001). Mechanical ventilation (MV) requirement was higher in the septic groups (p < 0.001). Mortality was 38 and 39% in the sAKI and sAKI/CKD groups vs 16% and 0% in the nsAKI and nsAKI/CKD groups, respectively (p < 0.001). Conclusions: Patients with sAKI and sAKI/CKD had worse prognosis than those with nsAKI and nsAKI/CKD. The nephrologist was not contacted in a large number of AKI cases, except for KDIGO stage 3, which directly influenced mortality rates. The urine output was considerably impaired, ICU stay was longer, use of MV and mortality were higher when kidney injury was combined with sepsis.

absTRacT

Keywords: Acute Kidney Injury; Renal In-sufficiency, Chronic; Sepsis; Nephrology; Water Balance; Mortality.DOI: 10.1590/2175-8239-JBN-2018-0240

https://orcid.org/0000-0001-8500-8439

https://orcid.org/0000-0003-3221-898X

https://orcid.org/0000-0002-7801-757X

https://orcid.org/0000-0003-2697-7357


Mortality on Septic Acute Kidney Injury

463

inTRoducTion

Acute kidney injury (AKI) is defined as a sudden reduction of renal function, increase of serum creatinine (sCr), and/or decrease of urine output (UO) and is a common complication in intensive care unit (ICU) patients1,2.

There is a strong association between prior chronic kidney disease (CKD) and AKI incidence during hospital stay; some authors describe prior CKD as a main risk factor for the development of AKI in the hospital3.

Sepsis is defined by the presence of infection associated with a systemic inflammatory response and has been the most important etiology for AKI in the ICU; this incidence can range from 11 to 70%1,4,5.

Therapeutic options that allow antibiotic therapy and maintenance of hemodynamic stability are still limited. The most important strategy is AKI prevention6.

Mortality in AKI is still extremely high and can affect 40–80% of ICU patients; the association between sepsis and AKI has a high mortality regardless of the primary diagnosis, whether sepsis or AKI, and the mortality increases significantly if there is need for renal replacement therapy (RRT)1,4,7-11.

Septic AKI is a great cause of mortality in ICU, it increases treatment costs, prolongs the length of stay in the hospital, worsens the prognosis of the patients, and increases the chance of CKD development1,4,5,12.

Information on septic AKI is still limited. Therefore, it is important to identify the profile of each hospital and the risk factors associated with the development of AKI or AKI on CKD (AKI/CKD). The aims of this research were to assess patients in the ICU that developed AKI, AKI on CKD, and/or sepsis and identify the risk factors and the outcomes of these diseases.

maTeRials and meThods

This prospective cohort observational quantitative study assessed all patients who stayed in the ICU for more than 48 hours at the State Public Hospital of São Paulo-HSPE/SP, a general tertiary and teaching hospital, from May to December 2013 and who developed AKI or AKI/CKD and/or sepsis.

Patients with an ICU stay < 48 hours and a history of dialysis-dependent CKD were excluded. A total of 1156 patients were admitted to the ICU during this period and finally 302 patients were included in the study.

This study was approved by the ethics committee of HSPE and signed informed consent was waived due to the observational nature of the study.

The population consisted of patients who stayed in the ICU for more than 48 hours and were diagnosed with AKI or AKI/CKD with or without sepsis and patients diagnosed with sepsis only or no sepsis and no AKI.

Sepsis was defined according to the International Guidelines for Management of Sepsis 201210.

AKI was defined in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) criteria as any of the following:

• Increase in sCr by ≥ 0.3 mg/dL within 48 hours;• Or increase in sCr to ≥ 1.5 times baseline,

which is known or presumed to had occurred within the prior 7 days;

• Or urine volume < 0.5 mL/kg/h for 6 hours.KDIGO stages were defined as follows:Stage 1, sCr 1.5 - 1.9 times baseline or ≥ 0.3 mg/dL

increase or urine output < 0.5 mL/kg/h for 6 - 12 hours; Stage 2, sCr 2.0 - 2.9 times baseline or urine output

< 0.5 ml/kg/h for ≥ 12 hours;Stage 3, sCr 3.0 times increase baseline or ≥ 4.0

mg/dL or urine output < 0.3 ml/kg/h for ≥ 24 hours or anuria for ≥12 hours or initiation of renal replacement therapy11.

Creatinine used for AKI diagnosis was the first sCr value measured during ICU stay or the previous sCr value before hospital admission registered in medical records.

Patients with pre-existing renal dysfunctions and a glomerular filtration rate < 60 mL/min were classified as having CKD13.

AKI/CKD was defined as worsening of renal function according to KDIGO13.

Daily assessments were performed to ensure that patients met the criteria for diagnosis of kidney injury and sepsis.

The patients were classified into six groups:1. nsnAKI, no sepsis and no AKI.2. S, sepsis without AKI or CKD.3. sAKI, septic AKI.4. nsAKI, nonseptic AKI.5. sAKI/CKD, septic AKI on CKD.6. nsAKI/CKD, nonseptic AKI on CKD.In some statistical analyses, the nsAKI and nsAKI/

CKD groups were merged with the nonseptic group, whereas the sAKI and sAKI/CKD groups were merged with the septic group (Figure 1).

Data was collected from patients daily ICU history and evolution charts. Age, sex, race, weight, personal history, type of admission, and hospital stay were



464

collected once. Minimum and maximum changes of vital signs, laboratory results, use of mechanical ventilation (MV), 6-, 12- and 24-h urine output, amount of fluid administered in 24 h, 24-h fluid balance, nephrologist follow-up, need for dialysis and its mode, and drugs and antibiotics were collected on a daily basis. Mortality was defined as death that occurred during ICU stay.

Data from the six groups underwent descriptive analysis: categorical variables were described by absolute (N) and relative (%) frequencies, and numerical variables were described by measures of central tendency (mean and median) and variability (interquartile range). A bivariate analysis was performed to compare the groups.

Association tests were performed to compare the groups regarding the numerical variables. A t-test was used for variables with normal distribution, and Kruskal-Wallis and Mann-Whitney tests were used for variables with non-normal distribution. For comparison of frequencies, the chi-square test and Fisher’s test were used. A p < 0.05 indicated

significant associations or differences. The SPSS 13.0 software was used for statistical analysis.

A chi-square test was performed with linear association between sepsis and KDIGO classification variables.

Two multivariate analysis were performed with the following explicative variables or associated factors: age, sex, type of admission, ICU stay, 24-h fluid balance, nephrologist follow-up, and mechanical ventilation. One model considered the development of AKI as the final and the second multivariable analysis included death as final event.

ResulTs

We observed that 94% of the cases developed some degree of kidney injury (AKI or AKI/CKD), 77% had sepsis (sepsis, sAKI, and sAKI/CKD groups) mostly associated with kidney injury, 48% had sAKI, 27% had sAKI/CKD, while only 2% developed non-AKI associated sepsis. These results indicated a

Figure 1. Sample Organization Diagram.



465

predominance of the combined diagnosis of sepsis and AKI (Figure 1).

Of the 302 patients included in the study, 54% were men and 89% were Caucasian; the median age was 71 years, 88% were emergency or urgent admissions, and the median ICU stay was 6 days (Table 1). The patients with sAKI (69 years) were younger than those with sAKI/CKD (76 years) (p < 0.001).

The sAKI/CKD group had the lowest diuresis values in 24 hours, with an adjusted diuresis value of 0.58 mL/kg/hr (p = 0.013), followed by the nsAKI/CKD (0.83 mL/kg/hr), sAKI (0.98 mL/kg/hr), and nsAKI (0.96 mL/kg/h) groups. The nsnAKI (1.70 mL/kg/h) and S (1.81 mL/kg/h) groups had the highest urine output in 24 hours (p < 0.001) (Table 2).

Decreased renal function was related with high 24-h fluid balance (FB) values, progressively greater accumulation in the S, nsAKI, sAKI, sAKI/CKD, and nsAKI/CKD groups, and a mean of 477 mL/24 h in the S group reaching 1162 mL/24 h in the nsAKI/CKD group (p = 0.020) (Table 2).

The sCr values did not show significant differences among groups (Table 2).

Emergency and urgent hospitalizations were significantly higher in the septic group (92%) compared to the non-septic group (77%) (p = 0.002)(Table 3). Additionally, the median ICU stay and total hospital stay were significantly greater in the septic groups and were double those in the nonseptic groups (p < 0.001) (Table 3). There was no difference in ICU stay between the sAKI and sAKI/CKD groups (Table 3).

Patients with sAKI and sAKI/CKD required significantly more MV compared to the septic patients without kidney injury (S) group (respectively, 90%, 88%, and 57%, p < 0.001).

The duration of MV was also greater in septic groups and was 2-fold that of the other groups (p < 0.001) (Table 2).

The comparison of the severity score (Simplified Acute Physiology Score II, SAPS II), among patients with sAKI (42) and nsAKI (35) showed a significant difference (p < 0.001), but there was no significant difference between sAKI/CKD (44) and nsAKI/CKD (45) (p = 0.325) (Table 2). Mortality was greater in the sAKI group (38%) and sAKI/CKD group (39%). This indicated that the combination of renal injury and sepsis increases ICU mortality. It is noteworthy that there was no death in the nsAKI/CKD group (Tables 2 and 3).

Patients with AKI were followed up by the nephrologist significantly fewer times than the AKI/CKD patients (42% in the sAKI group vs 75% in sAKI/CKD group (p = 0.009)) (Table 3). The septic group also required more RRT, especially patients with sAKI/CKD (45%). This group also presented a higher mortality (p < 0.001) (Table 3).

Most patients followed by the nephrologist were those diagnosed with KDIGO 3 in both the septic and nonseptic groups (80% and 38%, respectively) (p < 0.001). Septic patients in KDIGO 1 had only 8% of nephrologist follow-up vs 80% of those classified in KDIGO 3. The need of RRT and mortality were significantly greater in septic KDIGO 3 patients (65 and 59%, respectively) (p < 0.001) (Figure 2).

The bivariate analysis showed a linear trend between the severity of AKI and the incidence of sepsis, showing greater involvement of KDIGO 3 in septic patients (Table 4).

On multivariate analysis, type of admission, ICU stay, MV, and nephrologist follow-up were the determining factors for developing sAKI (Table 5).

The ICU stay of sAKI and sAKI/CKD was twice that of other patients. Each day of stay in the ICU increased in 33% the probability of developing sAKI (p < 0.001) (Table 5). The need of MV also increased the probability of developing sAKI (p = 0.027) and the absence of nephrologist assistance increased by 211% this probability (p = 0.003) (Table 5).

On multivariate analysis with death as the final event, the significantly associated factors were absence of nephrologist follow-up, MV, 24-h FB, and ICU stay (Table 5).

n = 302

Male (%[n]) 54 (162)

Caucasian (% [n]) 89 (270)

Age (years [IQR])* 71 (62 - 79)

Urg./Emerg. Admission (% [n]) 88 (265)

Pre-ICU Length of Stay (days [IQR])* 5 (1 - 18)

Length of Stay in ICU (days [IQR])* 6 (4 - 11)

Total Length of Stay (days [IQR])* 16 (8 - 27)

SAPS II [IQR]* 40 (32 - 50)* Values in median.

Table 1 dEmographic data of thE total casuistry



466

nsA

KI

sAK

In

sAK

I vs.

sA

KI

nsA

KI/C

KD

sAK

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sAK

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vs. s

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n =

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n =

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p va

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3n

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p va

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(16)

49 %

(71)

0,47

373

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% (5

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314

77%

(10)

29%

(2)

0,02

2C

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(%[n

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% (3

4)93

% (1

36)

0,44

693

% (1

4)82

% (6

8)0,

247

92%

(12)

86%

(6)

-Ag

e (y

ears

[IQ

R])*

73 (6

5 - 7

9)69

(59

- 78)

0,24

377

(63

- 82)

76 (6

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657

64 (5

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9)70

(55-

85)

0,00

1

Urg

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[n])

74 %

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92 %

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87 %

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454

% (7

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(day

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3 (1

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0,08

52

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0,03

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(3 -

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(5 -

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p <

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p <

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8 (5

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18 (1

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5 (5

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p <

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Urin

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(ml [

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78

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488)

1602

(919

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81)

0,16

813

29

(660

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75)

1338

(540

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17)

0,13

017

50

(895

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91)

2583

(1

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013

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12h

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IQR

])*66

9 (5

26 -

1017

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0 (3

36 -

800)

0,90

935

8 (2

25 -

625)

472

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503

867

(481

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31)

950

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63)

0,00

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213

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1 (1

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1135

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1459

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1162

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1912

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0 (4

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1609

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724

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Flui

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216

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13 (6

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203

9 (-1

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56 (0

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0,98

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97

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p <

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Diu

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74 (0

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0,72

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0,67

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1,32

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Diu

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96 (0

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27)

0,98

(0

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571

0,83

(0

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0) 0,

58 (0

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- 0,9

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013

1,70

(1

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468

discussion

AKI has a multifactorial etiology and is common in the ICU environment. It must be identified early and readily treated. In addition, aggravating factors must be identified and modified as soon as possible. Studies have suggested that even lighter degrees of AKI contribute to the development of CKD and in-crease in mortality2-9,11.

In this prospective study, 94% of ICU-admitted patients who stayed for a period longer than 48 h developed some degree of kidney injury; 75% of these patients had kidney injury and sepsis. This incidence is higher than that found in the literature in recent studies. Hoste (2015) shows an incidence of 54% on the 1st and 2nd day of ICU stay, and longer ICU stays can expose patients to a higher risk of AKI1,4,5,8.

Patients with AKI/CKD were older compared to the total sample (77 and 71 years, respectively) (Table 1), whereas the median age in the sAKI group was 69 years (Table 2), similar to the BEST Kidney study; age was not a factor associated with mortality1.

Pearson's Chi-square p = 0,006

Linear by Linear Association p = 0,026.

Table 4 chi-squarE tEst of Kdigo and sEpsis

KDIGO vs. Sepse

SepseTotal

No Yes

KDIGO

1 8 32 40

2 29 75 104

3 16 122 138

Total 53 229 282

sAKI Associated Factors p OR (I.C. 95%)

Nephrologist Follow-up 0,003 no 3,112 (1,462 - 6,622)

yes 1,000

Mechanical Ventilation 0,027 yes 2,417 (1,107 - 5,277)

no 1,000

Length of Stay in the ICU p < 0,001 1,336 (1,155 - 1,545)

Type of admission 0,061

urg/emer 2,377 (0,961 - 5,881)

elective 1,000

Constant p < 0,001 0,118

Death Associated Factors p OR (I.C. 95%)

Nephrologist Follow-up p < 0,001

no 5,361(3,013 - 9,539)

yes 1,000

Mechanical Ventilation 0,006

yes 4,800 (1,580 - 14,588)

no 1,000

24-hour Fluid Balance 0,045 1,000 (1,000 - 1,001)

Length of Stay in the ICU 0,073 1,039 (0,996 - 1,083)

Constant p < 0,001 0,024

multivariatE analysis of saKi and dEath associatEd Table 5

Figure 2. Nephrologist Follow-up.



469

In all groups, emergency and urgent hospitalizations prevailed in the sAKI (92%) and sAKI/CKD (93%) groups. Bagshaw et al. (2008) showed similar results8.

ICU stay was significantly longer when kidney injury was associated with sepsis; likewise, the total hospital stay showed that septic kidney injury increased ICU stay, reaching twice the admission period compared to that with non-septic kidney injury, showing that the increase in ICU stay is associated with sepsis7,14.

There was a high incidence of hypertension (H), diabetes mellitus (DM), heart failure (HF), and neoplasms, particularly in the CKD group compared to the other groups. Notably, DM was higher, which can be explained by the more advanced age of these patients. Neoplasms required attention in all studied groups as it was the fourth most frequently concomitant disease, with the exception of the sAKI/CKD group (electronic Annex 1).

In our study, there was a progressive decrease of UO in the nsAKI, AKI, and AKI/CKD groups, and a further decrease in the septic groups. UO was considerably more impaired when there was an association between kidney injury and sepsis. Simultaneously, there was a progressive increase in FB in the same groups reaching more than 1L in the sAKI/CKD group. Studies have shown that a positive FB can worsen the condition of critical patients and underestimate diagnosis due to sCr dilution, leading to increased mortality2,15.

The patients’ weight-adjusted 24-h FB was 7.5 mL/kg in the nsAKI group and 12 mL/kg in the sAKI group (Table 2). Although this difference was not statistically significantly, it is important in clinical practice15.

It has been difficult to determine whether fluid overload is a worsening marker for sAKI or the cause of mortality increase15. Studies have shown that volume resuscitation, outside the therapeutic window, is useless and may be harmful16,17.

Except for the nsAKI group, there was a predominance of the KDIGO 3 level in other groups.

The nephrologist was consulted more often in the follow-up of septic patients (sAKI, 42%; sAKI/CKD, 75%); however, this rate is still low if we consider that the diagnostic classification of AKI is familiar to the hospital’s intensive care physicians. Knowing that the changes of sCr and UO are not the best diagnostic markers for AKI, we can consider that KDIGO stage 1 is the ideal stage to consult the nephrologist. However, this often

occurred late, when the patient was in KDIGO stage 3, and in less than half of the patients, with the exception of the sAKI/CKD group (nsAKI, 13%; sAKI, 42%; nsAKI/CKD, 27%; sAKI/CKD, 75%). Although the follow-up was greater in the septic group, it was still only 54%.

Patients with CKD were also more likely to be followed up by the nephrologist, suggesting that the awareness of kidney disease brings attention to the need of follow-up; however, more than half of the AKI cases were still being managed by the intensivist exclusively. The absence of nephrologist follow-up was the main risk factor associated with increased mortality (OR = 5.3). Thus, the habit of requesting the nephrologist’s evaluation in the early stages of AKI still needs to be reinforced1,2,4.

Patients with sepsis required more RRT (37% of septic AKI vs 8% in non-septic AKI), used more frequently nephrotoxic drugs and combined antibiotics (electronic Annex 2), had a higher need for MV, presented with higher mortality, showing once again that sepsis and kidney injury combined lead to a worse prognosis4,18. Critical patients have a high incidence of infection and antimicrobial therapy can be a cause of AKI; likewise, AKI can facilitate infection development, making it difficult to understand the cause and effect relationship.

The use of nephrotoxic drugs averages a 19% contributing factor to AKI in critical patients. These can be identified and sometimes replaced after the nephrologist follow-up19. For example, hydroxyethylamide (Voluven®) was used by 5% of the patients in the nsAKI, sAKI, and sAKI/CKD groups during this study despite it being widely contraindicated in sepsis and renal failure cases, which could be prevented with the nephrologist follow-up19.

In this study, high rates of SAPS II were found in the sAKI/CKD (44), sAKI (42) groups, as well as in the nsAKI/CKD (45) group. Although mortality was high in the septic groups, in the nsAKI/CKD, which had high SAPS II index, had no death. Thus, CKD itself was not the decisive factor for increasing severity or mortality, but rather the combination of kidney injury with sepsis.

This can be observed also in the comparison of septic vs non-septic patients, where the non-septic group had lower SAPS II and mortality rates. Diverse studies point out that AKI is an independent risk



470

factor for mortality when associated with sepsis. It is worth emphasizing that mortality was progressively higher with higher KDIGO stages (KDIGO 3) and in patients with sAKI (Figure 2)2,4,6,7,20.

The main factors associated with the risk of developing sAKI were urgent or emergency admission, ICU stay, lack of nephrologist follow-up, and MV need. On multivariate analysis to evaluate mortality, the more strongly associated factors were KDIGO stage 3 AKI, MV need, and absence of nephrologist follow-up, with highly significant values and OR. MV use and 24-h fluid balance increase also showed a strong association with mortality. ICU stay, although quite different among groups, was not a determining factor (p = 0.073). It is worth discussing whether these factors lead to the development of LRAs or whether LRAs are responsible for increasing these parameters21.

conclusion

We conclude that sepsis was the main factor associated with AKI (75%) in this ICU study. AKI associated with sepsis had the worst outcomes (38% mortality) compa-red to non-septic AKI (16% mortality). Sepsis also wor-sened the prognosis of patients with AKI/CKD (39% mortality) compared to non-septic AKI/CKD (no death). Septic patients with no AKI had a more preserved UO compared to that in all groups with AKI or AKI/CKD. The need for mechanical ventilation was higher in the sAKI (90%) and sAKI/CKD (88%) groups compared to the nsAKI (61%) or nsAKI/CKD (67%) groups, as well as the duration of mechanical ventilation, (nsAKI, 1 day and nsAKI/CKD, 1 day vs. sAKI, 6 days and sAKI/CKD, 7 days). The nephrologist was not consulted in the first stages of AKI, showing that the need for consulting the nephrologist in the early stages of AKI must be highli-ghted. Patients with AKI/CKD were followed-up by ne-phrologists more often probably because of the previous knowledge of CKD.

limiTaTions of The sTudy

The limitations of this study were that it was con-ducted in a single center and had a large number of excluded patients.

auThoRs' conTRibuTion

Kellen Hyde Elias Pinheiro, Franciana Aguiar Azêdo, Kelsy Catherina Nema Areco, Ederlon Alves de Carvalho Rezende, Sandra Maria Rodrigues Laranja,

contributed substantially to the conception or design of the study; collection, analysis, or interpretation of data; writing or critical review of the manuscript; and final approval of the version to be published.

conflicTs of inTeResT

The authors declare that they have no competing interests.

supplemenTaRy maTeRial

The following online material is available for this article:

Annex 1.Annex 2.

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2. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380:756-66.

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4. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al.; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2007;2:431-9.

5. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 2015;41:1411-23.

6. Palomba H, do Amaral Campos PP, Corrêa TD, de Carvalho FB, Westphal G, Gusmão D, et al.; DETRAKI (DEfining and TReating Acute Kidney Injury) Study investigators. Defining and treating acute kidney injury patients in Brazilian intensive care units: Results from a cross-sectional nationwide survey. J Crit Care 2016;34:33-7.

7. Zarjou A, Agarwal A. Sepsis and Acute Kidney Injury. J Am Soc Nephrol 2011;22:999-1006.

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14.Challiner R, Ritchie JP, Fullwood C, Loughnan P, Hutchison AJ. Incidence and consequence of acute kidney injury in unselected emergency admissions to a large acute UK hospital trust. BMC Nephrol 2014;15:84.

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19. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al.; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901-11.

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472


AuthorsJuliana Carvalho Romagnolli Plastina1

Vitor Y. Obara1

Décio Sabbatini Barbosa2

Helena Kaminami Morimoto2

Edna Maria Vissoci Reiche2

Andrea Graciano3

Vinicius Daher Alvares Delfino4

1 Universidade Estadual de Londrina, Centro de Ciências da Saúde, Londrina, PR, Brasil.2 Universidade Estadual de Londrina, Departamento de Patologia, Análises Clínicas e Toxicológicas, Londrina, PR, Brasil.3 Hospital Evangélico de Londrina, Londrina, PR, Brasil.4 Universidade Estadual de Londrina, Departamento de Clínica Médica, Londrina, PR, Brasil.


Correspondence to:Juliana Carvalho Romagnolli Plastina.E-mail: [email protected]

Functional iron deficiency in patients on hemodialysis: prevalence, nutritional assessment, and biomarkers of oxidative stress and inflammationDeficiência funcional de ferro em pacientes em hemodiálise: prevalência, avaliação nutricional e de biomarcadores de estresse oxidativo e de inflamação

Introdução: A anemia na DRC pode ser di-vidida em anemia sem deficiência funcional de ferro e com deficiência funcional de ferro (ADFF). Diante do aumento dos casos de hemossiderose em pacientes em hemodiáli-se, atribuídos à reposição excessiva de ferro endovenoso, maiores conhecimentos sobre os fatores envolvidos na gênese da ADFF são importantes. Objetivos: documentar a prevalência de ADFF em renais crônicos em hemodiálise. Caracterizar clínica e laborato-rialmente os portadores de ADFF em HD e avaliar o estado nutricional, estresse oxidati-vo e inflamatório. Estudo transversal, amos-tra de conveniência, envolvendo 183 renais crônicos em hemodiálise no sul do Brasil. Após aplicação dos critérios de exclusão, os pacientes foram separados em dois grupos: portadores de anemia com e sem deficiên-cia funcional de ferro. Foram submetidos a questionário socioepidemiológico, à análise antropométrica e análise laboratorial dos marcadores de anemia, estresse oxidativo, inflamatórios e nutricionais. Análise esta-tística: programa GraphPad InStat versão 3.1. Foram aplicados os testes: Kolmogo-rov-Smirnov, qui-quadrado, t de Student e Mann-Whitney. Nível de significância ado-tado de 5%. Resultados: não houve diferen-ça significativa nos marcadores inflamató-rios entre os dois grupos. Houve diferença significativa nos marcadores de anemia e nutrição, significativamente menores nos pacientes com ADFF. Pacientes com ADFF receberam doses mais elevadas de ferro pa-renteral (p < 0,05). Discussão: ADFF esteve associada a menores valores de marcado-res nutricionais, mas não esteve associada a marcadores inflamatórios ou de estresse oxidativo aumentados, como relatado na literatura. Estudos adicionais sobre o tema são necessários.

Resumo

Palavras-chave: Insuficiência Renal Crô-nica; Anemia Ferropriva; Estresse oxida-tivo; Inflamação; Avaliação Nutricional.

Introduction: Anemic patients with chronic kidney disease (CKD) can be divided into anemic patients without or with functional iron deficiency (FID). The increase in the number of cases of hemosiderosis in patients on hemodialysis (HD) attributed to exces-sive intravenous iron replacement has called for the investigation of the factors involved in the genesis of FID. Objectives: This study aimed to describe the prevalence of FID in patients with CKD on HD, characterize the included individuals in terms of clinical and workup parameters, and assess their nutri-tional, oxidative stress, and inflammation statuses. This cross-sectional study assem-bled a convenience sample of 183 patients with CKD on HD treated in Southern Brazil. Patients meeting the inclusion and exclusion criteria were divided into two groups, one with anemic subjects with FID and one with anemic patients without FID. Participants answered a questionnaire probing into socio-epidemiological factors, underwent anthro-pometric measurements, and were tested for markers of anemia, oxidative stress, inflam-mation, and nutrition. Statistical analysis: The date sets were treated on software pack-age GraphPad InStat version 3.1. Variables were tested with the Kolmogorov-Smirnov, chi-square, Student’s t, and Mann-Whitney tests. Statistical significance was attributed to differences with a p < 0.05. Results: Markers of inflammation were not statistically differ-ent between the two groups. Markers of ane-mia and nutrition were significantly lower in patients with FID. Patients with FID were prescribed higher doses of parenteral iron (p < 0,05). Discussion: FID was associated with lower nutritional marker levels, but not to in-creased levels of markers of inflammation or oxidative stress, as reported in the literature. Additional studies on the subject are needed.

absTRacT

Keywords: Renal Insufficiency, Chronic; Anemia, Iron-Deficiency; Oxidative stress; Inflammation; Nutrition Assessment.DOI: 10.1590/2175-8239-JBN-2018-0092

https://orcid.org/0000-0002-7467-8901


Functional iron deficiency in patients on HD: prevalence, nutritional assessment, and biomarkers

473

inTRoducTion

Anemia appears in the early stages of chronic kidney disease (CKD) and prevalence increases as renal func-tion deteriorates. Oral or parenteral iron therapy and erythropoiesis-stimulating agents (ESA) are relevant elements in the care provided to patients with CKD, since anemia is one of the primary factors in the etio-logy of cardiovascular death in this group of patients.1

The etiology of anemia in patients with CKD is multifactorial. Primary contributing factors inclu-de absolute or functional iron deficiency; relative erythropoietin deficiency; deficiency of micronu-trients such as folic acid and complex B vitamins; chronic inflammation; infection; blood loss after ex-tracorporeal circulation; blood collected for workup purposes; and hemolysis.2 Chronic inflammation has been associated with decreased survival of patients with advanced-stage disease. Serum C-reactive pro-tein (CRP) and proinflammatory cytokine levels - in-cluding tumor necrosis factor alpha and interleukins 1 and 6 - are increased in 30-50% of the patients with CKD.1,2,3 IL-6 increases serum levels of hepci-din, a liver-derived peptide hormone that inhibits the duodenal absorption of iron and the mobilization of iron in the reticuloendothelial system.2 High hepcidin levels lead to iron sequestration and hypoferremia. Inflammation has also been implicated in decreased iron bioavailability for erythropoiesis and low albu-min levels, a sensitive marker of malnutrition.3,4

Although the guidelines for the treatment of ane-mia in patients with CKD favor a relatively liberal use of intravenous iron with the purpose of strengthening the action of erythropoietin (EPO), they fail to consi-der that high ferritin levels may induce hemosiderosis. Intravenous iron is prescribed to patients with ferritin levels ranging between 500 ng/dL and 1200 ng/dL. In healthy individuals, these levels might be indicative of hemosiderosis.5

This study aimed to describe the prevalence of FID in patients with CKD on HD, characterize the inclu-ded individuals in terms of clinical and workup para-meters, and assess their nutritional, oxidative stress, and inflammation statuses.

maTeRials and meThods

dEsign and population

This cross-sectional study was carried out in two hemodialysis units in Southern Brazil. Patients aged

18 years or older on hemodialysis with native arte-riovenous fistulae or grafts for at least three months were included in the study in June 2014. Individuals with temporary hemodialysis catheters, cancer, active infection or infection that caused hospitalization wi-thin 15 days of blood collection, hepatitis B or C, or infection by the human immunodeficiency virus we-re excluded. Two hundred patients met the inclusion criteria of the study. Twenty-four were excluded, four for having active infection, five due to inadequate blood collection, two for requiring hemodialysis ca-theters, seven for having anemia with absolute iron deficiency, and six for having died (Figure 1).

The remaining patients were divided into two groups, one with 65 patients with anemia and FID characterized by ferritin levels > 200 ng/dL and per-cent transferrin saturation < 20%, and another with 111 patients without FID and with iron overload and ferritin levels > 500ng/dL as per the guidelines of the KDOQI.

The patients underwent dialysis in sessions lasting for 210-240 minutes three times a week, with blood flow rates of 300-450 mL/min and dialysate flow rate set at 500 mL/min. Hemodialysis was performed wi-th medium flow polysulfone membrane filters, with a surface area matched to the body surface area of each patient. The water used in the hemodialysis ses-sions met the national criteria for water quality. The non-equilibrated target Kt/V was set at 1.2. Anemia was managed in accordance with the KDOQI guideli-nes. Patients were prescribed iron therapy with ferric hydroxide 100 mg/ampoule. Participants were provi-ded ample information on the study and gave written consent before joining the study. The Research Ethics Committee of the Londrina State University approved the study.

data collEction

Patient charts and interviews were used as sources of demographic and anthropometric data, in addi-tion to information on time on dialysis, comorbi-dities, and prescribed medication. Mean doses of erythropoietin and iron were calculated based on the prescriptions issued within 30 days of blood collection, with values described as U/kg/month and mg, respectively. Blood was collected before patient heparinization. Patients were asked about whether they smoked or drank alcohol. Race/eth-nicity was self-reported.



474

anthropomEtric mEasurEmEnts

The patients were asked to wear light clothing to have their dry weight (weight patients had at the end of hemodialysis sessions while feeling well and without edema) measured on a Filizzola scale with a reada-bility of 0.1 kg. Patients were asked to stand against a wall with feet together flat on the ground and had their height measured with a measure tape. Height was reported based on the nearest centimeter. The height of patients unable to undergo the measuring process was self-reported or reported by a relative.

The body mass index (BMI) was calculated as weight divided by height in meters squared.

Waist circumference was measured to the nearest centimeter with a flexible plastic tape measure pla-ced in the midpoint between the lowest rib and the anterior-superior portion of the iliac crest with the patient standing. The same plastic tape measure was used to measure the mid-upper circumference of the dominant arm (patients with an arteriovenous fistula in this area of the arm had the circumference of the non-dominant arm measured).

Figure 1. Horizontal Flowchart.



475


Biochemical analyses were performed at the labora-tory of the Londrina University Hospital, a member of quality control programs PELM and PNCQ. The patients were advised to fast for eight hours prior to blood collection. Patient blood samples of approxi-mately 20 mL were collected in anticoagulant-free vacuum tubes (Vacutainer®, Franklin Lakes, NJ, USA) during venipuncture at the start of the first hemodialysis session of the week. Intravenous iron was discontinued seven days before the collection of blood samples. The samples were centrifuged at 3000 rpm for 15 minutes. Blood serum was stored at -70ºC until the tests for biomarkers of inflammation and oxidative stress were carried out. Serum creatinine, urea before and after hemodialysis (to calculate dialy-sis adequacy - Kt/v), serum iron, ferritin, transferrin saturation, hematocrit, hemoglobin, parathyroid hormone (PTH), calcium, phosphorus, alkaline phos-phatase, and albumin levels were measured following standard laboratory practices. The intra and inter as-say coefficients of variation were less than 5% for all analytes.

inflammation paramEtEr mEasurEmEnt

Inflammation parameters were measured based on in-terleukin-6 (IL-6) and CRP levels.

Serum high-sensitivity CRP (hs-CRP) levels we-re determined by turbidimetric assay (ARCHITECT c8000, Architect, Abbott Laboratory, Abbott Park, IL, USA). The intra and inter assay coefficients of va-riation were less than 5%.

IL-6 levels were quantified with the aid of a com-mercially available kit from eBioscience. Results were expressed in pg/mL of serum. The intra and inter as-say coefficients of variation were less than 5%.

oxidativE strEss mEasurEmEnt

The following panel was used to measure oxidative stress: levels of nitric oxide metabolites - NOx; quan-tification of advanced oxidation protein products - AOPP; paraoxonase; sulfhydryl groups; total, redu-ced, and oxidized glutathione.

NOx levels were indirectly assessed via plasma nitrite levels based on an adaptation of the method described by Navarro-Gonzalez et al.6

Plasma AOPP was quantified based on the method described by Witko-Sarsatet al.7 The test was used to measure protein oxidation. AOPP reaction reads were

captured on a Thermo Spectronic® Helios-α spectro-photometer (Waltham, MA, USA) at a wavelength of 340 nm. AOPP levels were expressed in µmol/L of chloramine-T equivalents.

Total PON-1 activity was derived from the rate of phenyl acetate hydrolysis (phenol) based on the method described by Richter, Jarvink Furlong.8 The rate of phenyl acetate hydrolysis was determined with the aid of a Perkin Elmer® EnSpire microplate reader (Waltham, MA, USA) at a wavelength of 270 nm me-asured for four minutes (16 readings with 15-second intervals between them) at a temperature of 25ºC. Activity was expressed in U/mL based on the molar extinction coefficient of phenyl acetate (1.31mMol/Lcm-1).

Protein thiol groups in plasma were assessed with a spectrophotometer as described by Miao-Lin Hu.9 Analysis is based on the reaction between 5,5’-dithiobis-(2-nitrobenzoic acid) (DTNB) and a protein sulfhydryl group. Reaction readings were taken with a Thermo Spectronic® Helios-α spectro-photometer (Waltham, MA, USA) at a wavelength of 412 nm. Results were expressed in µM/mg of protein.

Erythrocyte glutathione was quantified based on the method described by Tietze et al. modified by Anderson.10,11 Intra and inter assay coefficients of va-riation were less than 10%.


The data sets were processed in software program Statistical Package for Social Sciences (SPSS, UK) ver-sion 20.0. A confidence interval of 95% and a level of significance of 5% (p < 0.05) were set in statistical tests.

Quantitative variables were expressed as mean values ± standard error or median values and inter-quartile intervals based on whether the data followed a normal distribution. The Kolmogorov-Smirnov test was used to check if the variables followed a normal distribution.

The chi-square test was used to compare between the proportions of patient subsets in terms of race/ethnicity, sex, smoking, alcohol intake, hypertension, diabetes, parathyroidectomy, prescription of non-cal-cium-based phosphate binders, angiotensin-conver-ting-enzyme (ACE) inhibitors, and/or angiotensin II receptor blockers (ARBs), statins, calcium carbonate or acetate, calcitriol, intravenous iron, and EPO.



476

Variables with a normal distribution - age, sul-fhydryl group, hematocrit, hemoglobin, and creati-nine - were compared through Student’s t-test. The Mann-Whitney test was used in the comparison of the following variables: time on hemodialysis, BMI, AOPP, NOx, total, reduced, and oxidized glutathio-ne, Kt/V, PTH, serum iron, ferritin, transferrin, total iron-binding capacity, percent transferrin saturation, serum calcium, serum phosphorus, alkaline phospha-tase, albumin, IL-6, waist circumference (WC), mid--upper arm circumference, dose of EPO and CRP.

Oxidative stress variables, AOPP, NOx, sulfhydryl group, and oxidized glutathione presented a trend to-ward having a correlation with ferritin levels or percent transferrin saturation. Multiple linear regression models were built to analyze the possible impact of these parame-ters on oxidative stress variables controlled for age, sex, BMI, time on dialysis, hypertension, diabetes, smoking, and use of statins. Only variables with a p ≤ 0.20 in biva-riate analysis were included in the final model.

ResulTs

The prevalence of anemia with functional iron de-ficiency in our study was 36.9%. The patients were divided into two groups after the analysis of test re-sults, one with 54 anemic individuals with FID and a second group with 111 patients with iron overload.

Table 1 shows the demographic, epidemiological, and clinical data of patients divided between individu-als with FID and anemic patients with iron overload.

No statistically significant difference was seen in terms of age, sex, time on hemodialysis, or Kt/V in the studied groups. No statistically significant diffe-rence was seen in the use of statins, ACE inhibitors/ARBs, calcium carbonate, calcitriol, or sevelamer between the groups. No statistically significant diffe-rence was seen in the proportions of smokers or indi-viduals drinking alcohol, patients with hypertension or diabetes, or individuals previously submitted to parathyroidectomy.

The groups were not statistically different in re-lation to the outcomes of lab tests for calcium, phos-phorus, alkaline phosphatase, PTH, ferritin, or crea-tinine. Hemoglobin levels were significantly lower in anemic individuals with FID.

Inflammation and oxidative stress parameters we-re not significantly different when patients with FID were compared to individuals with iron overload (Table 2).

Parameters serum iron, transferrin, total iron-bin-ding capacity, percent transferrin saturation, BMI, and serum albumin were statistically different betwe-en the groups.

Ferritin and nitric oxide were statistically correla-ted (Table 3).

Table 4 shows that the studied variables were una-ble to explain the mild negative correlation observed between ferritin and NOx.

discussion

This study aimed to verify the presence of increased oxidative stress and inflammation in patients with CKD and FID. FID has been associated with increased inflammation, oxidative stress, and malnutrition.12

Data analysis revealed that the levels of markers of inflammation and oxidative stress were similar be-tween the two groups (with or without FID).

However, monthly parenteral iron levels were sig-nificantly higher and percent transferrin saturation, serum albumin, hemoglobin, hematocrit, BMI, waist circumference, and mid-upper arm circumference we-re significantly lower in the group with FID. Although difficult to interpret in anemic patients and individu-als with anemia and CKD, the lower serum transfer-rin levels seen in this study may indicate diminished synthesis of the protein in question, a marker of nutri-tional status in children, patients in postop care, pa-tients on parenteral nutrition, and patients with CKD, to name a few.12,13

The lower serum albumin levels seen in the group of patients with FID, along with the lower levels of hemoglobin and hematocrit and smaller mid-upper arm circumference seem to indicate that, in the absen-ce of a difference in parameters of inflammation and oxidative stress between the two groups, the defini-tion of FID used in this study revealed an association between FID and type 1 malnutrition.

Classical studies on the synthesis of hemoglobin and hemeprotein, whose primary role is to transport oxygen from the lungs to tissues, revealed the impor-tance of having proper serum amino acid levels for the synthesis of the polypeptide chains of the globin chains present in this protein.14

The fact that patients with FID were prescribed hi-gher monthly doses of iron than individuals without FID is a concern and a reflection of a possible error in the prescription of iron therapy, since patients in this group have high serum ferritin levels and should therefore not



477

VariableFunctional iron

deficiency (n = 65)Iron overload

(n = 111)p

Females 19 (29.3%) 32 (28.8%) 0.9548

Males 46 (70.7%) 79 (71.2%) 0.9548

Race/ethnicity 0.3253

White 46 (63.0%) 70 (63.6%)

Black 10 (13.6%) 30 (27.2%)

Brown 6 (8.2%) 8 (7.2%)

Yellow 3 (4.1%) 3 (2.7%)

Age (years) (mean) (95%CI) 55.0 (51.0 - 59.1) 54.5 (21.6 - 57.4) 0.8230

Time on HD (months) (median) (IQR) 48.0 (12.0 - 75.0) 48.0 (24.0 - 81.0) 0.3992

KtV (median) (IQR) 1.370 (1.210-1.480) 1.390 (1.260-1.530) 0.4788

Creatinine (mean) (mg/dL) (95%CI) 8.83 (8.04-9.62) 9.30 (8.71-9.90) 0.3404

Albumin (median) (g/dL) (IQR) 4.05 (3.80-4.30) 4.20 (4.10-4.50) 0.0020§

BMI (median) (IQR) 23.1 (21.0 - 26.1) 25.1 (22.0 - 29.2) 0.0075§

Waist circumference (median) (cm) (IQR) 89.25 (82.00-99.75) 99.00 (87.25-108.00) 0.0036§

Mid-upper arm circumference (median) (cm) (IQR) 26.00 (24.00-29.00) 28.00 (26.00-30.50) 0.0076§

Diabetes 65 (89.0%) 97 (88.2%) 0.8583

Hypertension 58 (89.2%) 97 (87.4%) 0.9020

Smoking 8 (12.3%) 12 (10.8%) 0.9554

Alcohol drinking 10 (9.2%) 18 (16.2%) 0.8843

Previous PTX 13 (20.0%) 15 (23.1%) 0.3565

Use of calcium carbonate or acetate 37 (56.9%) 6 (62.2%) 0.5990

Use of sevelamer 27 (41.5%) 61 (55.0%) 0.1183

Use of calcitriol 23 (35.4%) 38 (34.2%) 0.8770

Use of ACEi/ARB 38 (58.5%) 55 (49.5%) 0.3238

Use of statins 21 (32.3%) 25 (22.5%) 0.2120

Serum calcium (mg/dL) (median) (IQR) 8.12 (7.83-8.41) 8.42 (8.21-8.64) 0.0963§

Serum phosphorus (median) (mg/dL) (IQR) 5.70 (4.30-6.60) 5.60 (4.70-7.20) 0.6097

Alkaline phosphatase (median) (U/L) (IQR) 126.0 (85.0-208.0) 161.0 (101.0-215.5) 0.1604

PTH (median) (pg/mL) (IQR) 326.8 (145.30-707.0) 462.7 (165.00-941.35) 0.2561

Table 1 dEmographic, EpidEmiological, clinical, and worKup charactEristics of patiEnts with cKd, functional iron dEficiEncy, and iron ovErload

receive higher parenteral doses of iron than anemic pa-tients with some degree of absolute iron deficiency on account of the risk of hemosiderosis. The regimen pres-cribed to these patients was based on the guidelines for the treatment of anemia in individuals with CKD present in Ordinance 226 issued by the Brazilian Ministry of Health on May 10, 2010.

Although described by a number of authors, the results presented in our study did not support the existence of an association between FID and mal-nutrition–inflammation complex syndrome.15,16 The broad panel with oxidative stress and inflammation

biomarkers, the numerous nutritional parameters, and the definition of FID used in our study15,16 sug-gested an association with markers of malnutrition, but not increased inflammation or oxidative stress. Differences among study populations including fac-tors such as ethnicity, mutations and polymorphisms in proteins involved in iron metabolism, income, so-cioeconomic status, nutritional patterns, vitamin sup-plementation, prevalence of anorexia and depression in dialysis services, anemia management guidelines, and definitions of FID may have contributed to these results.



478

VariableFunctional iron

deficiency (n = 65)Iron overload

(n = 111)p

Hematocrit (%) (mean) (95%CI) 32.84 (31.47-34.22) 34.66 (33.70-35.62) 0.0288

Hemoglobin g/dL (mean) (95%CI) 11.09 (10.64-11.54) 11.83 (11.52-12.14) 0.0063

Serum iron (median) (µg/dL) (IQR) 47.40 (41.00-55.40) 90.70 (68.45-122.70) < 0.0001§

Ferritin (ng/mL) (median) (IQR) 1010.0 (568.3-1360.0) 1030.0 (739.4-1455.0) 0.2295

% transferrin saturation (median) (IQR) 0.170 (0.150-0.185) 0.310 (0.240-0.481) < 0.0001§

Transferrin (median) (mg/dL) (IQR) 208.0 (182.4-248.0) 233.3 (209.8-260.2) 0.0100§

TIBC (mg/dL) (median) (IQR) 260.0 (228.0-310.0) 291.6 (262.2-325.2) 0.0100§

Use of parenteral iron 44 (67.7%) 70 (63.1%) 0.6477

Monthly dose of parenteral iron (mg) (median) (IQR) 400 (200.0-400.0) 200 (200.0-400.0) 0.0027

Monthly dose of (IU) 32.000 (32.000-48.000)32.000

(24.000-48.000)0.7846

IL-6 (median) (pg/mL) (IQR) 6.78 (4.54-11.81) 6.96 (3.53-12.02) 0.6270

C-reactive protein (median) (mg/dL) (IQR) 9.10 (3.40-16.10) 6.30 (3.05-12.60) 0.1169

AOPP (µM of chloramine T equivalents) (median) (IQR) 175.28 (142.78-224.52) 187.70 (145.33-272.04) 0.2050

NOx (µM) (median) (IQR) 10.43 (8.36-15.16) 11.02(8.08-15.91) 0.7256

Sulfhydryl group (mM/mg of protein) (mean) (95%CI) 265.39 (249.83-280.95) 272.93 (261.47-284.39) 0.4340

Total glutathione (mM/g of Hb) 7.12 (5.99-8.22) 6.98 (6.17-7.95) 0.5188

Reduced glutathione (mM/g of Hb) 5.07 (4.37-5.90) 4.96 (4.28-5.64) 0.2786

Oxidized glutathione (mM/g of Hb) (median) (IQR) 0.94 (0.67-1.22) 0.99 (0.83-1.23) 0.7360

Paraoxonase (U/mL) (median) (IQR) 139.77 (105.48-164.76) 146.59 (124.25-175.49) 0.0919

Table 2 lEvEls of hEmoglobin and marKErs of iron mEtabolism, inflammation, and oxidativE strEss of patiEnts on hEmodialysis with functional iron dEficiEncy and iron ovErload

Median values (interquartile interval), §: Mann-Whitney test

Acronyms: FID: functional iron deficiency, CI: confidence interval, IQR: interquartile range, TIBC: total iron-binding capacity, EPO: erythropoietin, IL-6: interleukin-6, AOPP: advanced oxidation protein products, NOx: nitric oxide metabolites.

The cross-sectional design of our study, the rela-tively small patient sample, and the failure to measu-re cofactors in hemoglobin synthesis such as vitamin B12 and folic acid were some of the limitations en-countered in this study. For purposes of comparison, a previous study enrolling patients from the same dialysis centers involved in the present study revealed that supplementation with routinely recommended vitamins yielded mean acid folic and median vitamin B12 levels within the reference range in 186 patients on hemodialysis.15,16

Intravenous iron therapy requires careful atten-tion, so that doses are decreased and iron overload is prevented in patients on hemodialysis.17

Studies with a larger number of patients, more markers of oxidative stress and inflammation, and closer consideration to malnutrition are required to improve the knowledge and management of FID in patients on hemodialysis.

conclusion

Our study did not find significant correlations be-tween FID and inflammation and oxidative stress, as suggested in current literature. Our patients had high levels of inflammation and oxidative stress markers probably on account of uremia, and the prevalence of more pronounced inflammation or oxidative stress was 36.9%.

The association between FID and malnutrition verified by the observation of lower BMI, albumin, transferrin, waist circumference, and mid-upper arm circumference in this group seemed to indicate that protein-energy malnutrition might have been a factor.

FID may be caused by the accelerated production of red blood cells induced by the administration of ESA, and by low levels of transferrin secondary to malnutrition and/or lower mobilization of iron stocks in the reticuloendothelial system in contexts of inflam-mation or infection.17 This study aimed to associated



479

VariablesNon-adjusted coefficients

pAdjusted

coefficientsp

Beta Beta

Age - 0.016 0.84 ----

BMI 0.03 0.67 ----

Sex 0.11 0.13 0.14 0.07

Hypertension - 0.07 0.39 ----

Diabetes mellitus - 0.003 0.96 ----

Smoking 0.11 0.16 0.13 0.08

Time on dialysis - 0.03 0.67 ----

Use of statins 0.085 0.26 ----

Ferritin 0.02 0.78 ----

Percent ferritin saturation 0.002 0.97 ----

Table 4 multiplE linEar rEgrEssion: rEgrEssion coEfficiEnts aftEr bivariatE analysis (non-adjustEd coEfficiEnts) and multivariatE analysis (adjustEd coEfficiEnts) of thE studiEd variablEs and nox lEvEls in thE study population

Ferritin levels Percent ferritin saturation

VariablesSpearman's

rank correlation coefficient

p VariablesSpearman's

rank correlation coefficient

p

AOPP rS= 0.07 0.32 AOPP rS=0.14 0.06

NOx rS= - 0.18 0.01* NOx rS=-0.003 0.97

Sulfhydryl group rS= - 0.13 0.08 Sulfhydryl group rS=0.04 0.59

Total glutathione rS= 0.047 0.53 Total glutathione rS= 0.08 0.26

Reduced glutathione

rS= 0.058 0.45Reduced

glutathionerS=0.01 0.88

Oxidized glutathione

rS= -0.01 0.88Oxidized

glutathionerS= 0.13 0.08

Paraoxonase rS= -0.01 0.88 Paraoxonase rS=0.09 0.23

Table 3 corrElations bEtwEEn fErritin lEvEls and pErcEnt fErritin saturation and oxidativE strEss marKErs

FID with states of increased inflammation and oxida-tive stress, but found a consistent association between FID and protein-energy malnutrition.

A relatively small patient sample, failure to measu-re folic acid and vitamin B12 levels and red blood cell markers rank among the limitations present in our study. Nevertheless, the study was carried out with patients seen at centers with proper control of water quality, hemodialysis, and hemoglobin levels, aided by a relatively broad panel of biomarkers of oxidative stress and inflammation.

The fact that patients with FID were prescribed sig-nificantly higher monthly doses of iron than individuals without FID is a concern. This finding, along with the consideration that the guidelines issued by the Brazilian Ministry of Health ban the use of EPO when percent

transferrin saturation is less than 25% even when ferri-tin levels are above 500 ng/dL, raises questions over the recommendations in effect and may open room for a review of the Brazilian guidelines, since overprescription of iron therapy may lead to hemosiderosis.

According to Ordinance 226 issued by the Ministry of Health, treatment with parenteral iron must be dis-continued temporarily when percent transferrin satu-ration is greater than 50% or serum ferritin is abo-ve 800 ng/dL or higher than 1200 ng/dL in patients requiring epoetin alfa doses greater than 225IU/kg/week or 22,500IU/week. After serum ferritin levels have returned to 500 ng/dL or 800 ng/dL in patients requiring high doses of EPO or percent transferrin has decreased to less than 50%, parenteral iron can be restarted at half the previous dose.



480

Brazilian guidelines validate the indiscriminate use of parenteral iron therapy, since they allow it in pa-tients with low percent transferrin saturation regard-less of the presence of high ferritin levels, thus explai-ning the high doses of parenteral iron prescribed to the patients with FID.

The most recent international guideline (KDIGO 2012) states that parenteral iron must be discontinued with ferritin levels > 500 ng/dL, while the Brazilian guideline contained in Ordinance 226 issued by the Ministry of Health permits the use of parenteral iron in patients with ferritin levels of 500-1200 ng/dL.

Our study indicated the need to review the Brazilian guidelines and calls for stricter protocols for prescriptions of parenteral iron.

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2. Chawla LS, Krishnan M. Causes and consequences of inflam-mation on anemia management in hemodialysis patientes. He-modial Int 2009;13:222-34.

3. Porto G, Oliveira S, Pinto JP. Hepcidina: a molécula-chave na regulação do metabolismo do ferro. J Port Gastrenterol 2012;19:26-32.

4. Kaysen GA, Dubin JA, Müller HG, Mitch WE, Rosales LM, Levin NW. Relationships among inflammation, nutrition and physiologic mechanisms establishing albumin levels in hemo-dialysis patients. Kidney Int 2002;61:2240-9.

5. KDOQI; National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006;47:S11-145.

6. Navarro-Gonzálvez JA, García-Benayas C, Arenas J. Semiauto-mated measurement of nitrate in biological fluids. Clin Chem 1998;44:679-81.

7. Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen--Khoa T, Nguyen AT, Zingraff J, et al. Advanced oxidation protein products as a novel marker of oxidative stress in ure-mia. Kidney Int 1996;49:1304-13.

8 Richter RJ, Jarvik GP, Furlong CE. Determination of paraoxo-nase 1 status without the use of use of toxic organophosphate substrates. Circ Cardiovasc Genet 2008;1:147-52.

9. Hu ML. Measurement of protein thiol group and glutathione in plasma. Methods Enzymol 1994;233:380-5.

10. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: appli-cation to mammalian blood and other tissues. Anal Biochem 1969;27:502-22.

11. Anderson ME. Determination of glutathione and glutathione di-sulfide in biological samples. Methods Enzimol 1985;113:548-55.

12. Santos NSJ, Draibe AS, Kamimura MA, Cuppari L. Albumina sérica como marcador nutricional de pacientes em hemodiálise. Rev Nutr 2004;17:339-49.

13. Kalantar-Zadeh K, Kleiner M, Dunne E, Ahern K, Nelson M, Koslowe R, et al. Total iron-binding capacity-estimated trans-ferrin correlates with the nutritional subjective global assess-ment in hemodialysis patients. Am J Kidney Dis 1998;31:263-72.

14. Kruh J, Borsook H. Haemoglobin synthesis in rabbit reticulo-cytes in vitro. J Biol Chem 1956;220:905-915.

15. Vianna AC, Mocelin AJ, Matsuo T, Morais-Filho D, Largura A, Delfino VA, et al. Uremic Hyperhomocysteinemia: a rando-mized trial of folate treatment for the prevention of cardiovas-cular events. Hemodial Int 2007;11:210-6.

16. Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome -- the heart of the matter. Nephrol Dial Transplant 2002;17:28-31.

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481


AuthorsLenina Ludimila Sampaio de Almeida1

Luís Henrique Bezerra Cavalanti Sette2

Fernando Luiz Affonso Fonseca1

Leila Silveira Vieira da Silva Bezerra3

Francisco Hélio Oliveira Júnior3

Ronaldo Roberto Bérgamo1

1 Faculdade de Medicina do ABC, Departamento de Nefrologia, Santo André, SP, Brasil.2 Universidade Federal de Pernambuco, Departamento de Nefrologia, Recife, PE, Brasil.3 Universidade Federal do Cariri, Departamento de Nefrologia, Barbalha, CE, Brasil.


Correspondence to:Lenina Ludimila Sampaio de Almeida. E-mail: [email protected]

Metabolic and volume status evaluation of hemodialysis patients with and without residual renal function in the long interdialytic intervalAvaliação metabólica e volêmica no maior intervalo interdialítico de pacientes em hemodiálise com e sem função renal residual

Introdução: Não se sabe ao certo se a fun-ção renal residual (FRR) de pacientes di-alíticos pode atenuar o impacto metabólico do maior intervalo interdialítico (MII) de 68 horas, no qual ocorre acúmulo de vol-ume, ácidos e eletrólitos. Objetivo: Avaliar os níveis séricos de eletrólitos, balanço hí-drico e status ácido-básico de pacientes di-alíticos com e sem FRR ao longo do MII. Metodologia: Tratou-se de estudo unicên-trico, transversal e analítico, que comparou pacientes com e sem FRR, definida como diurese acima de 200 mL em 24 horas. Para tal, os pacientes foram pesados e sub-metidos à coleta de amostras séricas para análise bioquímica e gasométrica no início e fim do MII. Resultados: Foram avaliados 27 e 24 pacientes com e sem FRR, respec-tivamente. Pacientes sem FRR apresenta-ram maior aumento de potássio sérico du-rante o MII (2,67 x 1,14 mEq/L, p < 0,001) atingindo valores mais elevados no fim (6,8 x 5,72 mEq/L, p < 0,001); menor valor de pH no início do intervalo (7,40 x 7,43, p = 0,018), maior proporção de pacientes com bicarbonato sérico < 18 mEq/L (50 x 14,8 %, p = 0,007) e distúrbio ácido-básico misto (70,8 x 42,3 %, p = 0,042), além de maior ganho de peso interdialítico (14,67 x 8,87 mL/kg/h, p < 0,001) e menor natremia (137 x 139 mEq/L, p = 0,02) no fim do in-tervalo. A calcemia e fosfatemia não foram diferentes entre os grupos. Conclusão: Paci-entes com FRR apresentaram melhor con-trole dos níveis séricos de potássio, sódio, status ácido-básico e da volemia ao longo do MII.

Resumo

Palavras-chave: Insuficiência Renal Crônica; Diálise Renal; Hiperpotassemia; Acidose; Hiperfosfatemia.

Introduction: It is unclear whether resi-dual renal function (RRF) in dialysis pa-tients can attenuate the metabolic impact of the long 68-hour interdialytic interval, in which water, acid, and electrolyte ac-cumulation occurs. Objective: to evaluate serum electrolyte levels, water balance, and acid-base status in dialytic patients with and without RRF over the long inter-dialytic interval (LII). Methodology: this was a single-center, cross-sectional, and analytical study that compared patients with and without RRF, defined by diuresis above 200 mL in 24 hours. Patients were weighed and serum samples were collec-ted for biochemical and gasometric analy-sis at the beginning and at the end of the LII. Results: 27 and 24 patients with and without RRF were evaluated, respectively. Patients without RRF had a higher increa-se in serum potassium during the LII (2.67 x 1.14 mEq/L, p < 0.001), reaching higher values at the end of the study (6.8 x 5.72 mEq/L, p < 0.001) and lower pH value at the beginning of the interval (7.40 x 7.43, p = 0.018). More patients with serum bi-carbonate < 18 mEq/L (50 x 14.8%, p = 0.007) and mixed acid-base disorder (57.7 x 29.2%, p = 0.042), as well as greater in-terdialytic weight gain (14.67 x 8.87 mL/kg/h, p < 0.001) and lower natremia (137 x 139 mEq/L, p = 0.02) at the end of the interval. Calcemia and phosphatemia were not different between the groups. Conclu-sion: Patients with RRF had better control of serum potassium, sodium, acid-base sta-tus, and volemia throughout the LII.

absTRacT

Keywords: Renal Insufficiency, Chronic Renal; Dialysis; Hyperkalemia; Acidosis; Hyperphosphatemia.

DOI: 10.1590/2175-8239-JBN-2018-0171

http://orcid.org/0000-0002-2842-8493


Effects of residual renal function on the long interdialytic interval

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inTRoducTion

Dialysis patients have a higher risk of morbidity and mortality than the general population ¹. This risk appears to be increased in the long interdialytic in-terval (LII), a 68-hour period without hemodialysis (HD), to which patients undergoing conventional HD treatment three times a week are submitted and in which there is a greater number of hospitalizations and cardiovascular events2,3. Probably, this fact ste-ms from the greater accumulation of uremic toxins, acids, electrolytes, especially potassium, and fluids in this time interval4-8. Besides that, removal of these ele-ments in the first HD session subsequent to the LII, occurs more intensely, resulting in abrupt fluctuations of electrolytes and greater hemodynamic instability9.

In addition, the presence of residual renal func-tion (RRF), which can be defined as a 24-hour uri-ne output greater than 200 mL, is associated with a lower risk of morbidity and mortality in dialysis pa-tients10,11. In fact, patients with RRF have higher ex-cretion of sodium and water, with consequent lower interdialytic weight gain (IDWG) and more adequate blood pressure (BP) levels12,13. Besides that, they have better control of serum potassium, phosphate, and bi-carbonate levels 14-16.

Since dialytic patients with RRF have a greater ability to excrete electrolytes, acids, and fluid com-pared to patients without RRF, they are likely to have less body accumulation of these elements during the LII and exhibit a better metabolic and hemodynamic profile in this period. However, there are few studies comparing patients with and without RRF regarding serum electrolyte levels (sodium, potassium, calcium, and phosphate), acid-base status (pH, pCO2, and bi-carbonate) and water balance, specifically throughout the LII. We understand that obtaining these data is important, since it can encourage practices aimed at the preservation of RRF, in addition to promoting the-rapeutic strategies to minimize the deleterious effects of the LII in the population of patients without RRF. Thus, this study aims to evaluate the variation of elec-trolytes, acid-base status, and volume status over the LII in patients with and without RRF.

paTienTs and meThods

patiEnts

The study was performed with patients submitted to HD at the Raimundo Bezerra Hemodialysis Unit in

the city of Crato, Ceará. This unit has 289 patients distributed in three shifts: on Mondays, Wednesdays, and Fridays (MWF); and Tuesdays, Thursdays, and Saturdays (TTS). Patients were selected from the first and second shifts of MWF and the first shift of TTS. Patients on HD for less than three months, younger than 18 years, who had less than 12 hours of prescri-bed dialysis per week, and those unable to measure urinary volume were excluded from the study. The patients used polyethersulfone membrane dialyzers: Elisio-19 H and 21 H (Japan, 2016) and commercial dialysate with the following concentrations: sodium: 138 mEq/L, potassium: 2 mEq/L, calcium: 3.5 mEq/L, and bicarbonate: 32 mEq/L. The informed consent form was obtained from all patients. The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committee of the Faculty of Medicine of ABC - Santo André / São Paulo.

study dEsign

This was a single-center, cross-sectional, and analyti-cal study with the objective of evaluating the metabo-lic and hemodynamic changes over the LII in dialytic patients with and without RRF. In May 2017, 128 dialysis patients who met the inclusion criteria were questioned about the presence of RRF, defined as a 24-hour urinary output >200 mL. Of these, 42 pa-tients reported the presence of RRF and 86 its absen-ce. Thirty patients from each group were randomly selected by lot.

data collEction

Patients with RRF were instructed to collect 24 hour urine volume to measure urea and creatinine clea-rances. For those on a MWF schedule, the urine col-lection started from the time they first emptied their bladder on Sunday until the same time on Monday. Patients on a TTS schedule performed the same pro-cedure from Monday to Tuesday. Blood samples were collected at the beginning and at the end of the LII. Samples obtained after the last HD session prior to LII were collected at the end of the fourth hour of dialysis, through the arterial blood line of the HD circuit; the samples from the end of the LII were col-lected prior to the HD session, through the arterial line of the circuit after its connection to the patient. Two 3-mL samples were collected at each time point; one for biochemical analysis, in which urea, sodium,



483

creatinine from serum samples collected at the end of the interval. The values obtained were corrected to 1.73 m2 of body surface area and the mean urea and creatinine clearance were calculated.

Serum calcium level was corrected according to serum albumin by the formula:

Corrected (Ca) = Measured total (Ca) + (0.8 x (4 – serum albumin))

The expected pCO2 was estimated for each patient from the bicarbonate measured in blood gas analysis through the formula HCO3 + 1519. For patients with fistula, blood gases in which the oxygen saturation was > 95% were consider for analysis and PCO2 va-lues that were up to 5 mmHg higher or lower than the expected PCO2 were considered adequate. For pa-tients with catheter, 4 mmHg was subtracted from the PCO2 measured in blood gas analysis, since central venous PCO2 is about 4 mmHg higher than arterial PCO2, and resulting values that were up to 5 mmHg higher or lower than the expected PCO2 were consi-dered adequate5.

NPCR (normalized protein catabolic rate) was calculated by urea variation in the LII, taking in-to account urinary urea in the case of patients who had RRF20. As diuresis was collected in only one day of the interval, the same value of urine urea for the day not collected was considered for calculation. Values higher than 1.2 g/kg per day were considered adequate21.

IDWG <13 mL/kg/h, pre-HD systolic BP between 130 and 159 mmHg and diastolic BP between 60 and 89 mmHg were considered adequate22,23.


Descriptive statistics of central tendency, mean and stan-dard deviation were used for all continuous variables, and frequency distribution for categorical variables. The t-test for independent samples was conducted to evaluate possible differences between continuous variables of the two groups, and the chi-square association test (linear by linear) to verify possible differences between categorical variables. Values of p < 0.05 were considered significant. The Jasp program (Free Version 0.8.5.0) was used in all analyses.

ResulTs

Of the 30 patients initially allocated to each group, 7 (2 with RRF and 5 without RRF) were excluded

potassium, calcium, and phosphate were measured; and another, for blood gases, in which pH, bicarbo-nate, and pCO2 were measured. In order to determine plasma creatinine clearance, a serum creatinine mea-surement was performed at the end of the LII. Serum albumin was measured at the end of the interval for correction of serum calcium.

Information on the etiology of renal disease, me-dications used and KT/V were obtained through the patients’ electronic records.

Patients were weighted at the beginning and at the end of the LII and IDWG was calculated from the di-fference between the two values. Blood pressure was measured at the end of the LII using mercury sphyg-momanometer in sitting position after a 10-min rest period by trained professionals.


Biochemical samples were analyzed on Vitros 5600 Integrated System - Ortho Clinical Diagnostics (Johnson & Johnson, New Jersey, USA) using the Reflectance Spectrometer (Dry Chemistry) methodology.

Blood gases were analyzed on Gen Premier blood gas analyzer (Instrumentation Laboratory, Massachusetts, USA) using the potentiometric me-thod. The study followed good laboratory practices.

calculations and dEfinitions

Variation in electrolytes (potassium, sodium, cal-cium, and phosphate) and gasometric parameters (pH, pCO2 and bicarbonate) were calculated by the difference between the values found after and before the LII.

The KT/V value recorded in the electronic medical record was obtained using the Daugirdas formula17 in the month preceding the sample collection and values greater than or equal to 1.2 per session were conside-red adequate18.

Urea and creatinine clearances were calculated using the formula:

Urinary Urea or creatinine concentration (mg/dL) x Urinary voLUme (mL)

Urea or creatinine serum concentration (mg/dL) x 1440

Urinary urea and creatinine were obtained from the 24-hour urine collection and serum urea and



484

because they did not perform 12 hours of HD during the week of the study. One patient in the RRF group was excluded because he did not collect diuresis for analysis and 1 patient in the RRF group was excluded because he was in another city during the collection period. We then evaluated 27 and 24 patients with and without RRF, respectively.

Baseline characteristics of the patients are shown in Table 1. The measured mean urea and creatinine clearance was 3.6 mL/min in the RRF group. The

groups were similar, even in relation to Kt/V and type of vascular access for HD, presenting statistically sig-nificant difference only in relation to dialysis vintage (2.1 x 7.2 years in the groups with and without RRF, respectively; p < 0.001) and to the amount of calcium carbonate tablets used, higher in the group without RRF.

In relation to electrolyte changes, patients without RRF, despite starting from similar serum potassium values, presented a significantly higher increase (2.67

Table 1 clinical charactEristics of patiEnts on hEmodialysis in thE city of crato, cE

With residual function Without residual function p

N 27 24

Shift

MWF (%) 81.5 88 0.515 †

Age (years) 46. 81 ± 16.38 52.50 ± 17.16 0.232 #

Male (%) 48.5 70.8 0.100 †

Residual diuresis (mL) 930 ± 423.3

Urea clearance (mL/min) 2.61 ± 2.13 -

Creatinine clearance (mL/min) 5.42 ± 3.13

Mean urea and creatinine clearance (mL/min) 3.68 ± 2.12

Vascular access arteriovenous fistula (%) 87.5 95.8 0.739 †

Base Disease (%) 0.327 †

Hypertension 37 20.8

Diabetes 3.7 4.2

Glomerulonephritis 11.1 16.7

ADPKD 14.8 8.3

Obstructive Uropathy 18.5 12.5

Unknown 14.8 37.5

Hemodialysis vintage (years) 2.10 ± 1.91 7.20 ± 3.13 < 0.001#

KT/V 1.31 ± 0.36 1.22 ± 0.28 0.36 #

Adequate KTV (%) 74.1 70.8 0.79 †

Antihypertensive drugs that cause Hyperkalemia 0.395 †

(ACEI / ARB / Spironolactone / Beta-Blocker) (%)

None 33.3 50

One 59.3 41.7

Two 7.4 4.2

Three 0.0 4.2

Four 0.0 0.0

Diuretic (%) 18.5 8.3 0.291 †

Other Antihypertensives (%) 0.729 †

None 66.7 62.5

One 22.2 25

Two 7.4 12.5

Three 3.7 0.0

Erythropoietin (%) 0.528 †



485

x 1.14 mEq / L, p < 0.001) of the electrolyte serum le-vel throughout the LII, culminating in higher values at the end of the study period (Table 2 and Figure 1 A). In addition, they exhibited lower serum sodium levels at the end of the LII (Table 2 ), with a higher pro-portion of patients with natremia below 137 mEq/L (Figure 1 B), although they had similar serum levels at the beginning of the interval. Calcemia and phos-phatemia were similar in the groups with and without RRF over the LII (Table 2). There was no difference between the groups in relation to the proportion of patients with normal phosphatemia (between 2.5 and 4.5 mg/dL) at the end of the interval (44.4 x 66.6%, p = 0.11).

Regarding acid-base status, the group without RRF had a lower pH value at the beginning and a trend towards a lower value at the end of the inter-val (Table 3). Although serum bicarbonate level was similar between the groups over the interval (Table 3), the group without RRF had a higher proportion of patients with bicarbonate values lower than 18 mEq/L at the end of the LII (Figure 1C). There was no difference between the groups with and without RRF in relation to PCO2 values at baseline and at the end of the interval (Table 3). Mean PCO2 variation was

also similar between the groups (Table 3); however, in the non-RRF group there was a higher proportion of patients with pCO2 values inadequate for the bicarbo-nate values found, that is, with mixed acid-base disor-der at the end of the LII (Figure 1D). The respiratory disorder was found to be respiratory acidosis (pCO2 exceeding 5 mmHg the expected value) in 100% of patients with mixed acid-base disorder in the group without RRF and in 91.7% in the group with RRF (only one patient presented respiratory alkalosis asso-ciated with metabolic acidosis).There was no eviden-ce of metabolic alkalosis at the end of the LII in any of the study patients.

Patients without RRF had higher IDWG over the LII (14.67 x 8.87 mL/kg/h, p < 0.001), as well as hi-gher proportion of patients with inadequate IDWG, although blood pressure levels did not reach a sta-tistically significant difference between the groups (Table 4).

There was no difference between serum albumin levels and npcr between the two groups (Table 4).

discussion

Patients with RRF had more adequate serum sodium and potassium levels, better acid-base status and

Did not use 7.4 12.5

≤ 4000 U / week 44.4 25

Between 4000 and 8000 U / Week 11.1 16.7

> 8000 U / week 37 45.8

Sevelamer (%) 0.873 †


1 tablet/day 0.0 0.0

2 tablets /day 14.8 12.5

3 tablets/day 11.1 16.7

≥ 4 tablets/day 7.4 4.2

Calcium carbonate (%) 0.018 †

Do not use 74.1 62.5

1 tablet /day 14.8 0.0



≥ 4 tablets/day 0.0 29.2

Calcitriol 0.476 †





Table 1. Continued.

† X2 (linear by linear)#t-test for independent samples



486

Table 2 variation of ElEctrolytEs ovEr thE lii according to rrf

ElectrolyteWith RRF Without RRF

pn= 27 n=24

Potassium (meq/L)

Beginning of the LII 4.58 ± 0.91 4.12 ± 0.67 0.08 #

Mean variation 1.14 ± 1.26 2.67 ± 1.23 < 0.001 #

End of the LII 5.72 ± 0.96 6.8 ± 0.67 < 0.001 #

Sodium (mmol/L)

Beginning of the LII 139.03 ± 5.14 137.87 ±2.99 0.337 #

Mean variation 0.0 ± 5,1 - 0.8 ± 3.0 0.542 #

End of the LII 139.03 ± 3.00 137.08± 2.78 0.020 #

Phosphate (mg/dL)

Beginning of the LII 3.73 ± 0.84 4.43 ± 1.69 0.064 #

Mean variation 1.24 ± 1.61 1.12 ± 1.62 0.784 #

End of the LII 4.98 ± 1.54 5.55 ± 1.90 0.241 #

Corrected Calcium (mg/dL)

Beginning of the LII 10.85 ± 1,09 10.70 ± 0.67 0.55 #

Mean variation - 2.11 ± 0.95 -1.90 ±1.50 0.68 #

End of the LII 8.74 ± 0.62 8.73 ± 1.22 0.96 #

#t-test for independent samples.

Figure 1. Hydroeletrolytic and acid-base disorders after the long interdialytic interval according to residual renal function



487

lower IDWG over the LII when compared to patients without RRF. They also had a lower dialysis vinta-ge, as expected, since loss of RRF occurs with the passage of years after initiation of dialysis therapy15. To the best of our knowledge, this is the first article comparing the entire interdialytic interval in patients with and without residual renal function in relation to electrolytes and acid-base status (pH, pCO2, and bicarbonate).

Regarding potassium, the findings were similar to those found in prior studies. In fact, a 2009 Egyptian study comparing serum potassium levels of 400 dialy-sis patients with and without RRF at the beginning and end of the interdialytic interval also found higher potassium levels in the non-RRF group at the end of

the interval (5.89 x 5.12 mEq/L, p < 0.001), althou-gh, unlike our study, these authors evaluated patients in different dialytic intervals14. In contrast, potassium levels at the beginning of the interval were higher in the non-RRF group (4.29 x 3.60 mEq/L, p < 0.001), while in our study the values measured at this time were similar, which could have resulted from factors related to HD efficiency, not evaluated in the afore-mentioned study. The authors also did not compare the mean values of potassemia variation over the in-terval between the groups, in contrast to our study that found significantly higher values in the group without RRF.

Vilar et al.12 compared pre-HD serum potassium obtained in monthly collections from 650 English

Table 3 variation of acid-basE status ovEr thE lii according to rrf

With RRF Without RRFp

n= 27 n=24

pH

Beginning of the LII 7.43 ± 0.47 7.40 ± 0.04 0.018#

Mean variation -0.12 ± 0.05 -0.12 ± 0.08 0.940#

End of the LII 7.30 ± 0.05 7.27 ± 0.06 0.073#

Bicarbonate


Mean variation -6.71 ± 3.52 - 6.76 ± 3.48 0.959#

End of the LII 19.91 ± 2.85 19.24 ± 2.84 0.403#

pCO2


Mean variation - 0.60 ±4.08 -0.88 ± 4.70 0.821#

End of the LII 39.19 ± 6.24 41.04 ± 4.02 0.221#

#t-test for independent samples

Table 4 hEmodynamic changEs, npcr and albumin according to rrf

With residual function Without residual functionp

n= 27 n=24

Interdialytic weight gain (mL/kg/h) 8.87 ± 4.77 14.67 ± 4.80 < 0.001#

Adequate interdialytic weight gain (%) 70.3 ± 4.7 37.5 ± 4.8 0.019†

SBP at the end of the LII (mmHg) 141 ± 21.1 151 ± 24 .7 0.125#

DBP at the end of the LII (mmHg) 81 ± 10.59 85 ± 13.8 0.319#

Adequate BP at the end of the LII (%) 51.5 37.5 0.197†

nPCR (g/kg/day) 0.91 ± 0.33 0.86 ± 0.26 0.53#

Adequate nPCR (%) 33.3 29.2 0.57†

Albumin 3.89 ± 0.41 4.08 ± 0.37 0.09#

Data presented as mean ± standard deviation or %#t-test for independent samples† X2 (linear by linear)

SBP, systolic blood pressure; DBP, diastolic blood pressure; nPCR, normalized protein catabolic rate.



488

patients on hemodialysis with and without RRF, du-ring six months after onset of HD. The authors found significantly higher values in the group without RRF in the majority of months in which the electrolyte was dosed (5.37 x 5.10 mEq/L, p = 0.005, in the month with the highest serum level in both groups). However, unlike our study, there was no evaluation of the entire interdialytic interval and the criterion used to define RRF was the presence of a urea clearance greater than 1 mL/min/1.73 m2.

It should be noted that in the studies mentioned above, serum potassium levels at the end of the inter-dialytic interval were lower than in our study. One of the possible explanations for this is that these data, unlike ours, were not obtained exclusively after the LII, when serum potassium levels are generally hi-gher than in the middle of the week. In this regard, Yusuf et al.24 found a 2 to 2.4-fold higher prevalen-ce of hyperkalemia after the LII when compared to the short interval, in a cohort of American dialysis patients between 2007 and 2010. However, in the data obtained from DOPPS (Dialysis Outcomes and Practice Patterns Study, which assessed data from 20 countries between 1996 and 2015), the difference be-tween serum potassium levels obtained after the long and short interdialytic interval ranged from only 0.01 mEq/L in China to 0.19 mEq/L in Germany25.

It is important to emphasize two factors that de-monstrate the great vulnerability of patients without RRF during the LII. The first is related to the fact that the morbimortality associated with hyperkalemia in patients on HD is even more significant when potas-sium values are above 6 mEq/L, which occurred in 83% of patients without RRF in our study24,25. The second was the large variation of serum potassium levels in these patients throughout the LII, since, al-though starting from values similar to those of pa-tients with RRF at the beginning of the interval, they reached significantly higher values at the end, which exposed them to a higher electrolyte gradient during HD session and increased the risk of adverse events9. Although we have not evaluated serum potassium af-ter the rebound effect occurred within 6 hours after the end of dialysis, this effect is known to occur more intensely the higher the pre-dialytic serum potassium levels are, which could make patients without RRF even more vulnerable to it.26

Regarding acid-base balance disorders, patients with RRF presented higher pH values at the beginning

of the LII, maintaining this trend throughout the in-terval, although without statistical significance at the end of the period. Nonetheless, serum bicarbonate levels did not differ during the interval between the groups. In contrast, Suda et al.16, when comparing 41 patients from a dialysis center in Japan with and without RRF at the end of the LII, found significan-tly higher values of bicarbonate in the RRF group (19.5 x 18.2 mEq/L; p = 0.032), although they did not evaluate other gasometric parameters. However, although the mean bicarbonate value was not diffe-rent between the groups in our study, the prevalence of patients with serum bicarbonate < 18 mEq/L at the end of the LII was significantly higher (50 x 14.8%) in the group without RRF, emphasizing that this ran-ge of values was associated with higher mortality27. Similarly, Raikou et al.28 divided 52 dialytic patients into two groups according to their serum bicarbonate levels higher or lower than 22 mEq/L and found a positive association (log rank = 3.9, p = 0.04) between the absence of RRF and lower values of bicarbonate.

However, due to the conflicting results of studies on bicarbonate values and mortality in dialysis pa-tients, it is believed that their joint analysis with pH and pCO2 leads to a more adequate understanding of .patients’ acid-base status due to the high prevalence of mixed disorders in this population26,29. Thus, our study showed a significantly higher proportion of pa-tients with mixed disorder in the group without RRF (57.7 x 29.2%), represented by respiratory acidosis associated with metabolic acidosis in all patients in this group. This fact could show the lower capacity of these patients to compensate for variations of bicar-bonate, eliminating CO2 through respiration.

Our study suggests that patients without RRF are more likely to have lower bicarbonate levels (< 18 mEq/L) and inadequate respiratory response to meta-bolic acidosis. A possible explanation for this would be pulmonary congestion, since these patients also present a higher IDWG, as observed in our study.

We found no difference between nPCR and serum albumin in the two groups evaluated, contrary to li-terature findings, where RRF is associated with bet-ter nutritional parameters, possibly due to our small sample size.16 Patients in both groups had a mean nP-CR value below the adequate value, although it was higher than the critical value (0.8 g/kg per day); the mean serum albumin was higher than the recommen-ded minimum value (3.8 g/dL) and the mean Kt/V



489

value was adequate in both groups. It is possible that the low nPCR values found were related to the mean bicarbonate levels of the two groups considered be-low the recommended level (< 22 meq/L) or related to social issues or comorbidities not evaluated in our study.18

Serum phosphate levels were not different over the LII between the two groups. These results differ from those found in most studies in the literature15,30,31, al-though not in all31. It is possible that the small sample size as well as urea and creatinine clearance values of our study contributed to these findings. Indeed, Penne et al.31, in 2010, when evaluating the phosphatemia of 552 patients with and without RRF after the LII, found a higher proportion of patients with normal serum phosphate levels only in the subgroup who had mean urea and creatinine clearance higher than 4.13 mL/min compared to the subgroup of patients without RRF (64 x 48%, odds ratio 2.4, < 0.005). When comparing the subgroup with mean clearance below 4.13 mL/min, as in our study, with the sub-group of patients without RRF, there was no signi-ficant difference between the groups. Similarly, Rhee et al.15 evaluated 77 patients from a Korean dialysis center, showing lower phosphatemia values in the RRF group compared to the non-RRF group (4.32 x 5.32; p = 0.017), but the mean urea and creatinine clearance in the RRF group was also higher than ours (6.4 x 3,6 mL/min).

Serum calcium levels were similar in the two groups during the interval. The results in the litera-ture are controversial in this regard. Indeed, Shin et al.32, when comparing patients with urea clearance hi-gher and lower than 0.9 mL/min in three Korean HD units, also found no difference between the groups for serum calcium levels (8.7 x 8.6 mg/dL, p = 0.92). On the other hand, Wang et al.30 performed a single-cen-ter study with 134 Chinese patients who found lower calcium values in the RRF group (9.1 x 9.8 mg/dL; p < 0.001). The great variation of calcemia in dialysis patients, influenced by factors other than renal excre-tion, could explain these different results32.

As expected and reported by other studies, we found a significantly higher IDWG in patients without RRF when compared to patients with RRF, in addi-tion to a higher prevalence of patients with inadequa-te weight gain (> 13 mL/kg/h) in the first group 12,31. It is known that this excessive fluid accumulation, more

pronounced in the LII, is associated with both long--term cardiovascular morbidity, probably because it increases the risk of left ventricular hypertrophy, and to the probability of hypotension and cardiovascular instability during HD session 9,10.

Although there is a relationship between IDWG and BP increase in the LII, this relationship is not li-near34. Thus, we did not find a difference between the two groups regarding mean BP, proportion of patients with adequate BP levels at the end of the interval, and amount of antihypertensive drugs used, findings simi-lar to those reported in the literature12,30,32.

Finally, in relation to serum sodium levels, pa-tients without RRF presented significantly lower va-lues at the end of the LII, which could be associated with the higher IDWG evidenced in patients of this group35,36. However, Abalate et al.37, when evaluating 98 dialysis patients from a Spanish center in relation to natremia, found no difference in the proportion of patients who had RRF in the groups divided by serum sodium: na < 138 mEq/L, between 138 and 140, and > 142 mEq/L (25, 33.3, and 41.7%, respectively; p = not significant), although natremia had a negative relation with IDWG. In this study, natremia was not specifically evaluated in the LII, the period in which there is a greater difference in IDWG and possibly in natremia between patients with and without RRF. Nonetheless, lower sodium values are associated with higher mortality in dialysis patients in several studies, even when adjusted for other possible confounding factors, such as higher IDWG, heart failure, and RRF; natremia below 137 mEq/L was associated with grea-ter risk of negative outcomes in the study by Hecking et al.37, highlighting the greater proportion of patients in this range of values in the group without RRF (45 x 11%) in our study35,38.

Our study had limitations. One of them was the small sample size, which probably made it difficult to obtain statistically significant results in some analyzed variables. In addition, we did not evalua-te patients’ diet in the studied interval nor their co-morbidities, factors that could have interfered in the results. Although residual renal function can be me-asured through the mean of 24 hour urea and creati-nine clearance15, the ideal would be to collect diuresis throughout the entire interdialytic interval. Another point is that we defined FRR as a urinary volume gre-ater than 200 mL according to some studies, although



490

others consider 100 mL as cutoff point, which could also interfere with the results.

conclusion

Patients without residual renal function had greater accumulation of potassium and interdialytic weight gain throughout the long interdialytic interval, in addition to lower natremia and higher prevalence of mixed acid-base disorders at the end of the period when compared to patients with residual renal func-tion. More studies are needed about the long inter-dialytic interval, with a larger number of patients, in order to confirm these data and to find other possibly associations not evidenced by the small sample size.

acknowledgmenT

We thank the valuable contribution of João Halisson Lemos Carvalho and Jessica Lissandra Alves Leite responsible for laboratory technical support in the biochemical dosages included in the study and Paulo Felipe Bandeira, responsible for statistical support.

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2. Georgianos PI, Sarafidis PA, Sinha AD, Agarwal R. Adverse effects of conventional thrice-weekly hemodialysis: is it time to avoid 3-day interdialytic intervals? Am J Nephrol 2015;41:400-8.

3. Fotheringham J, Fogarty DG, El Nahas M, Campbell MJ, Far-rington K. The mortality and hospitalization rates associated with the long interdialytic gap in thrice-weekly hemodialysis patients. Kidney Int 2015;88:569-75.

4. Keshaviah PR, Nolph KD, Van Stone JC. The peak concen-tration hypothesis: a urea kinetic approach to comparing the adequacy of continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis. Perit Dial Int 1989;9:257-60.

5. Marano M, Marano S, Gennari FJ. Beyond bicarbonate: com-plete acid-base assessment in patients receiving intermittent he-modialysis. Nephrol Dial Transplant 2017;32:528-33.

6. Sigrist MK, Devlin L, Taal MW, Fluck RJ, McIntyre CW. Length of interdialytic interval influences serum calcium and phosphorus concentrations. Nephrol Dial Transplant 2005;20:1643-46.

7. Brunelli SM, Du Mond C, Oestreicher N, Rakov V, Spiegel DM. Serum Potassium and Short-term Clinical Outcomes Among Hemodialysis Patients: Impact of the Long Interdialytic Interval. Am J Kidney Dis 2017;70:21-9.

8. Agarwal R, Light RP. Arterial stiffness and interdialytic weight gain influence ambulatory blood pressure patterns in hemo-dialysis patients. Am J Physiol Renal Physiol 2008;294:F303-8.

9. Rhee CM, Kalantar-Zadeh K. Implications of the long inter-dialytic gap: a problem of excess accumulation vs. excess remo-val? Kidney Int 2015;88:442-4.

10. Moist LM, Port FK, Orzol SM, Young EW, Ostbye T, Wolfe RA, et al. Predictors of loss of residual renal func-tion among new dialysis patients. J Am Soc Nephrol 2000;11:556-64.

11. Obi Y, Streja E, Rhee CM, Ravel V, Amin AN, Cupisti A, et al. Incremental Hemodialysis, Residual Kidney Function, and Mor-tality Risk in Incident Dialysis Patients: A Cohort Study. Am J Kidney Dis 2016;68:256-65.

12. Vilar E, Wellsted D, Chandna SM, Greenwood RN, Farring-ton K. Residual renal function improves outcome in incre-mental haemodialysis despite reduced dialysis dose. Nephrol Dial Transplant 2009;24:2502-10.

13. Menon MK, Naimark DM, Bargman JM, Vas SI, Oreopoulos DG. Long-term blood pressure control in a cohort of perito-neal dialysis patients and its association with residual renal function. Nephrol Dial Transplant 2001;16:2207-13.

14. Khedr E, Abdelwhab S, El-Sharkawy M, Ali M, El Said K. Prevalence of hyperkalemia among hemodialysis patients in Egypt. Ren Fail 2009;31:891-8.

15. Rhee H, Yang JY, Jung WJ, Shin MJ, Yang BY, Song SH, et al. Significance of residual renal function for phosphate con-trol in chronic hemodialysis patients. Kidney Res Clin Pract 2014;33:58-64.

16. Suda T, Hiroshige K, Ohta T, Watanabe Y, Iwamoto M, Ka-negae K, et al. The contribution of residual renal function to overall nutritional status in chronic haemodialysis patients. Nephrol Dial Transplant 2000;15:396-401.

17. Daugirdas JT. The post: pre-dialysis plasma urea nitrogen ra-tio to estimate K.t/V and NPCR: mathematical modeling. Int J Artif Organs 1989;12:411-9.

18. KDOQI Clinical Practice Guidelines and Clinical Practice Re-commendations for 2006 Updates: Hemodialysis Adequacy, Peritoneal Dialysis Adequacy and Vascular Access. Am J Kid-ney Dis 2006;48:S1-322.

19. Marano M, D’Amato A, Marano S. A very simple formula to compute pCO2 in hemodialysis patients. Int Urol Nephrol 2015;47:691-4.

20. Jindal KK, Goldstein MB. Urea Kinetic Modelling in Chronic Hemodialysis: Benefits, Problems, and Practical Solutions. Se-min Dial 1988;1:82-5.

21. Tattersall J, Martin-Malo A, Pedrini L, Basci A, Canaud B, Fouque D, et al. EBPG guideline on dialysis strategies. Ne-phrol Dial Transplant 2007;22:ii5-21.

22. Flythe JE, Kimmel SE, Brunelli SM. Rapid fluid removal du-ring dialysis is associated with cardiovascular morbidity and mortality. Kidney Int 2011;79:250-7.

23. Turner JM, Peixoto AJ. Blood pressure targets for hemodialy-sis patients. Kidney Int 2017;92:816-23.

24. Yusuf AA, Hu Y, Singh B, Menoyo JA, Wetmore JB. Serum Potassium Levels and Mortality in Hemodialysis Patients: A Retrospective Cohort Study. Am J Nephrol 2016;44:179-86.

25. Karaboyas A, Zee J, Brunelli SM, Usvyat LA, Weiner DE, Ma-ddux FW, et al. Dialysate Potassium, Serum Potassium, Mor-tality, and Arrhythmia Events in Hemodialysis: Results From the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2017;69:266-77.

26. Niemczyk L, Szamotulska K, Niemczyk S, Paklerska E, Kla-tko W, SokalsKi A, et al. Hyperpotassemia after hemodialysis (HD) and hemodiafiltration (HDF) - is there any difference in rebound effect? Nefrol Dializ Pol 2009;13:58-62.

27. Misra M. Pro: Higher serum bicarbonate in dialysis patients is protective. Nephrol Dial Transplant 2016;31:1220-4.

28. Raikou VD, Kyriaki D. Association between Low Serum Bicarbonate Concentrations and Cardiovascular Disea-se in Patients in the End-Stage of Renal Disease. Diseases 2016;4:pii:E36.

29. Wu DY, Shinaberger CS, Regidor DL, McAllister CJ, Kopple JD, Kalantar-Zadeh K. Association between serum bicarbo-nate and death in hemodialysis patients: is it better to be aci-dotic or alkalotic? Clin J Am Soc Nephrol 2006;1:70-8.

30. Wang M, You L, Li H, Lin Y, Zhang Z, Hao C, Chen J. As-sociation of circulating fibroblast growth factor-23 with renal phosphate excretion among hemodialysis patients with resi-dual renal function. Clin J Am Soc Nephrol 2013;8:116-25.



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31. Penne EL, van der Weerd NC, Grooteman MP, Mazairac AH, van den Dorpel MA, Nubé MJ, et al. Role of residual renal function in phosphate control and anemia manage-ment in chronic hemodialysis patients. Clin J Am Soc Ne-phrol 2011;6:281-9.

32. Shin DH, Lee YK, Oh J, Yoon JW, Rhee SY, Kim EJ, et al. Vascular calcification and cardiac function according to residual renal function in patients on hemodialysis with urination. PLoS One 2017;12:e0185296.

33. Levitt H, Smith KG, Rosner MH. Variability in calcium, phosphorus, and parathyroid hormone in patients on he-modialysis. Hemodial Int 2009;13:518-25.

34. Agarwal R, Light RP. Chronobiology of arterial hyperten-sion in hemodialysis patients: implications for home blood pressure monitoring. Am J Kidney Dis 2009;54:693-701.

35. Waikar SS, Curhan GC, Brunelli SM. Mortality associated with low serum sodium concentration in maintenance hemodialysis. Am J Med 2011;124:77-84.

36. Albalate Ramón M, de Sequera Ortiz P, Pérez-García R, Ruiz--Álvarez MJ, Corchete Prats E, Talaván T, et al. Sodium set--point in haemodialysis: is it what we see clinically? Nefrologia 2013;33:808-15.

37. Hecking M, Karaboyas A, Saran R, Sen A, Inaba M, Rayner H, et al. Dialysate sodium concentration and the association with interdialytic weight gain, hospitalization, and mortality. Clin J Am Soc Nephrol 2012;7:92-100.

38. Hecking M, Karaboyas A, Saran R, Sen A, Hörl WH, Pisoni RL, et al. Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2012;59:238-48.

492


AuthorsChristine Zomer Zomer Dal Molin1

Thiago Mamoru Sakae1

Fabiana Schuelter-Trevisol1

Daisson Jose Trevisol1

1 Universidade do Sul de Santa Catarina, Tubarão, SC, Brasil.


Correspondence to:Thiago Mamoru Sakae.E-mail: [email protected]

Effects of sertraline in the prevention of low blood pressure in patients undergoing hemodialysis

Efeitos da sertralina na prevenção de hipotensão arterial em pacientes submetidos à hemodiálise

Introdução: A hipotensão intradialítica (HID) é uma das principais complicações da hemodiálise, com uma prevalência de cerca de 25% durante as sessões de hemodiálise, causando aumento da morbimortalidade. Objetivo: Estudar os efeitos da sertralina na prevenção da HID em pacientes em hemo-diálise. Métodos: Este foi um ensaio clínico duplo-cego, cruzado, comparando o uso de sertralina versus placebo para reduzir a hi-potensão intradialítica. Resultados: Dezes-seis pacientes completaram as duas fases do estudo durante um período de 12 semanas. A prevalência de HID foi de 32%. Uma comparação entre intervenções intradialíti-cas, sintomas intradialíticos (ID) e episódios de HID não revelou diferença estatística na redução dos episódios de HID (p = 0,207) entre os dois grupos de intervenção. No en-tanto, o risco de intervenções para HID foi 60% maior no grupo placebo em compara-ção com o grupo Sertralina, e o risco de sin-tomas ID foi 40% maior no grupo placebo em comparação com o grupo Sertralina. A análise de sobrevida utilizando o estimador de Kaplan-Meier corroborou os resultados deste estudo. A sertralina apresentou um número necessário para tratar (NNT) de 16,3 pacientes para prevenir um episódio de intervenção de HID e 14,2 pacientes para prevenir um episódio de sintomas intradia-líticos. Conclusão: Este estudo sugere que o uso de sertralina pode ser benéfico para re-duzir o número de sintomas e intervenções de HID, embora não tenha havido diferença estatisticamente significante nos níveis pres-sóricos.

Resumo

Palavras-chave: Diálise Renal; Hipotensão; Sertralina; Insuficiência Renal Crônica.

Introduction: Intradialytic hypotension (IDH) is a major complication of he-modialysis, with a prevalence of about 25% during hemodialysis sessions, caus-ing increased morbidity and mortality. Objective: To study the effects of sertra-line to prevent IDH in hemodialysis pa-tients. Methods: This was a double-blind, crossover clinical trial comparing the use of sertraline versus placebo to reduce intradialytic hypotension. Results: Six-teen patients completed the two phases of the study during a 12-week period. The IDH prevalence was 32%. A com-parison between intradialytic interven-tions, intradialytic symptoms, and IDH episodes revealed no statistical differ-ence in the reduction of IDH episodes (p = 0.207) between the two intervention groups. However, the risk of IDH inter-ventions was 60% higher in the placebo group compared to the sertraline group, and the risk of IDH symptoms was 40% higher in the placebo group compared to the sertraline group. Survival analysis us-ing Kaplan-Meier estimator supported the results of this study. Sertraline presented a number needed to treat (NNT) of 16.3 patients to prevent an episode from IDH intervention and 14.2 patients to prevent an episode from intradialytic symptoms. Conclusion: This study suggests that the use of sertraline may be beneficial to re-duce the number of symptoms and ID in-terventions, although there was no statis-tically significant difference in the blood pressure levels.

absTRacT

Keywords: Renal Dialysis; Hypotension; Sertraline; Renal Insufficiency, Chronic.

DOI: 10.1590/2175-8239-JBN-2018-0189

https://orcid.org/0000-0002-1481-836X

https://orcid.org/0000-0002-0603-3685

https://orcid.org/0000-0003-0997-1594

https://orcid.org/0000-0002-7053-9082


Sertraline for low blood pressure in hemodialysis

493

inTRoducTion

Chronic kidney disease is currently considered a pub-lic health problem because of its high prevalence1-4. The number of patients suffering from end-stage renal disease (ESRD) is expected to rise even more in devel-oping countries, as there is an increase in the elderly population, a higher prevalence of cardiovascular diseases and improvement in their treatment, as well as persistent high rates of hypertensive and diabetic patients1,5-7.

Hemodialysis (HD) is a widely used alternative therapy to treat ESRD patients6,8. HD imposes a great psychosocial overload on patients and their families and can be aggravated by the existence of comorbidi-ties, such as diabetes mellitus, cardiovascular disease, peripheric neuropathy3,9, and by the complications during hemodialysis, such as hypotension, fatigue, cramps, headache, and others10,11.

Intradialytic hypotension (IDH) is the most fre-quent complication among hemodialysis patients10-14. Estimates suggest that up to 75% of patients suffering from ESRD experience one or more episodes of hy-potension during hemodialysis within 6 months from initiation, with a prevalence of about 25% during he-modialysis sessions, depending on the definition used to describe IDH13.

Pathophysiology of IDH is complex and multi-factorial15, involving different systems and measures, such as osmolarity drop, dialysate temperature, mem-brane biocompatibility, the use of acetate as buffer, and endotoxin entry into the circulation10,16,17.

The main mechanisms involved in hypotension during a hemodialysis session include plasma volume, volume preservation during ultrafiltration (UF), and cardiovascular compensation16.

Usually when there is a low UF rate, blood pres-sure (BP) is maintained during HD through capillary refill, peripheral vascular resistance and cardiac out-put15,18,19 Other factors like plasma osmolarity, auto-nomic dysfunction, and increased vasodilator synthe-sis are also related to this hemodynamic instability.15

These events may lead to reduction of intravas-cular volume, increased release of vasodilatory sub-stances, and reduction in vasoconstrictors, as well as complement activation and cytokine release. In turn, these mechanisms lead to reduction of cardiac output and peripheral vascular resistance, with consequent reduction of arterial pressure16.

Factors such as body weight, degree of hydration of the interstitial space, osmolarity, and concentration of plasma proteins and variations in regional blood flow distribution during dialysis also contribute to the hypotensive episode16.

Non-modifiable patient-related demographic fac-tors include advanced age (≥ 65 years), female gender, Hispanic origin, and long dialysis18.

Comorbidities associated with increased risk of IDH include diabetic nephropathy, cardiovascular disease (including left ventricular hypertrophy, dia-stolic dysfunction, and systolic dysfunction. Patients with congestive heart failure and/or previous myocar-dial infarction), high weight gain between dialysis ses-sions (>3% of body weight), aneurysm patients and patients with autonomic dysfunction are at higher risk of developing IDH18,20,21. Other factors that con-tribute to IDH are: low blood pressure (BP) before the HD session (SPB less than 100 mmHg), hyperphos-phatemia, meals before dialysis, and others20,22.

Patients on regular hemodialysis who have mod-erate to severe IDH have a higher prevalence of car-diovascular events, such as myocardial ischemia and myocardial dysfunction7; in addition, there are other mechanisms involved, including neurological damage and intestinal bacterial translocation. Imaging stud-ies, such as magnetic resonance imaging of the skull, evidence cerebral ischemia, including cerebral infarc-tions, atrophy, and altered white matter, which is a risk factor for dementia and stroke. Bacterial translo-cation occurs due to organ edema and hypoperfusion, contributing to pro-inflammatory stimuli and aggra-vating the malnutrition of these patients18.

The prompt recognition by the hemodialysis team, associated with modifications in the patients’ dialysis therapy, has been adopted for the management and prevention of hypotensive episodes. However, despite these measures, IDH prevalence remains high13,14,17,18.

Previous studies have indicated that selective se-rotonin reuptake inhibitors have improved symptoms in orthostatic hypotension and neurocardiogenic syn-cope, and have been used as an alternative treatment in patients who develop intradialytic hypotension23-29. Ultrafiltration performed during hemodialysis seems to be the main factor for the activation of the sym-pathetic reflex and vasoconstriction, which has the purpose of preserving BP at normal levels. However, paradoxical inhibition of this pathway occurs due



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to the sudden increase of serotonin in the central nervous system, which causes hypotension and vasodilatation24.

Sertraline has been studied with the aim of improv-ing the response to the sudden increase of serotonin by sympathetic inhibition. Furthermore, it is widely used in the dialysis population30,31 at low cost and with high safety due to its pharmacokinetics and pharmacodynam-ics, efficacy, tolerability, and very few drug interactions24. The hypothesis of this study was that the use of sertra-line prevents hypotensive episodes during hemodialysis, with positive impacts on the quality of life, decrease in the number of interventions and interruptions of dialysis treatment, as well as improves patient compliance and laboratory test results.

Lastly, considering that previous reports on the ef-fect of serotonin reuptake inhibitors in the manage-ment of IDH episodes still need to be confirmed by further studies7,32, a double-blind, crossover trial was carried out to compare sertraline and placebo and as-sess the medication efficacy on the prevention of IDH episodes in hemodialysis patients.

meThods

A double-blind, crossover clinical trial was conducted to compare placebo and sertraline in reducing hypo-tension in patients undergoing hemodialysis. ESRD patients undergoing hemodialysis for at least 3 months were selected for the trial from a Hemodialysis Clinic of Southern Santa Catarina, Brazil16,33, from January to March, 2017.

The Open Epi software was used to calculate the sample size. For the statistical calculation, we used a 50% prevalence of exposed and 5% of unexposed treat-ed subjects, with an 80% study power, sample size ratio of 1:1, which resulted in a total of 30 subjects, based on the worldwide prevalence of nephropathy, as well as he-modialysis patients with IDH2,15,1618,20,32,34.

All patients underwent hemodialysis three times a week, with blood capillaries of biocompatible mate-rials (polysulfone or cellulose triacetate), in hemodi-alysis machines, using a dialysate bath containing 35 mEq/L bicarbonate, 138 mEq/L sodium, 3.5 mEq/L calcium, 2 mEq/L potassium, and 1 mEq/L magne-sium. The dialysate temperature was maintained at 37 degrees Celsius, the dialysate flow set at 500 to 600 mL/min and blood flow between 250 and 350 mL/min. Ultrafiltration volumes were removed con-stantly throughout the hemodialysis session.

The inclusion criteria were patients on hemodi-alysis three times a week, for at least three hours per day, and at least three months, aged 18 years or more, male or female according to previous study35. Patients should have presented intradialytic hypotension, characterized according to previous studies25-27,29 by the presence of an SBP decrease of at least 30 mmHg or pre-hemodialysis SBP less than or equal to 100 mmHg with any of the associated symptoms: head-ache, weakness, cramps, dizziness, blurred vision, nausea or vomiting, malaise; any SBP lower than 90 mmHg and/or DBP less than 40 mmHg; or symptoms previously mentioned that required intervention by the nursing team25,35.

Patients eligible for the study had IDH defined by the above criteria in at least 50% of the hemodialysis sessions of the last three months prior to the start of sertraline use26.

Patients with known hypersensitivity to sertraline, with known hemodynamic instability, such as system-ic infection, or unfavorable clinical conditions, such as advanced liver cirrhosis and decompensated heart failure, were excluded.

Patients with acute renal failure or those who pre-viously took antidepressants or serotonin reuptake blockers were excluded25,36.

All patients were also carefully evaluated for dry weight, clinical history, comorbidities, and if necessary, physical examination and chest X-ray to complement the common clinical examination. They were instructed not to take their antihyper-tensives before the sessions, to maintain their in-terdialytic weight gain (IDWG) between sessions, emphasizing salt and fluid restriction, according to the routine adopted among all patients in the Hemodialysis Clinic.

Previous studies have reported trials with ran-domization in two groups (placebo versus medica-tion)24,28. In this study, all participants received only a placebo at the beginning of the study for a 6-week period. After that, they received sertraline for another 6 weeks, which meant that the patients were their own controls (crossover trial), with a week washout period. Patients and their families, as well as physi-cians (not involved in the research), nursing staff, and other key personnel directly involved in the patient’s care were blinded to the use of sertraline or placebo. Only study investigators were not blinded to placebo or sertraline use.



495

The sertraline capsules were obtained from a spe-cialized laboratory after quality assurance through a certificate of analysis. The placebo capsules were manufactured and packaged in a similar way to the sertraline capsules by the same laboratory.

Pre- and post-dialytic dry weight, and need, num-ber, and type of interventions performed during IDH episodes were evaluated. The laboratory tests were evaluated according to the Hemodialysis Clinic rou-tine. During the hemodialysis sessions, blood pressure measurements were taken on at least three occasions to calculate mean arterial pressure29.

ResulTs

We selected 18 of 55 patients treated at the Hemodialysis Clinic of Araranguá, state of Santa Catarina, Brazil, at the time of the study, represent-ing an IDH prevalence of 32%. Two of the 18 pa-tients were excluded from the study. One requested his withdrawal because of his assistant cardiologist

advice, and the other patient died of unrelated causes before starting the use of placebo.

The remaining 16 patients participated in both phases of the study (placebo and sertraline), complet-ing 12 weeks of treatment. Regarding the demograph-ic data, the sample was composed of 8 women and 8 men; 10 patients were white and 6 were non-whites. The mean age of study participants was 61 years (SD=15.73). 9 patients had diabetes mellitus and 7 suffered from hypertension.

With regard to vascular access, 15 patients under-went hemodialysis through an arteriovenous fistula and one underwent hemodialysis through a double lumen catheter.

As the present study used a crossover design, in which the cases were their own controls, the sample size was 32.

The results of the laboratory tests for the 16 pa-tients are displayed in Table 1. Data represent the average of the three measurements of the exams col-lected during the study period.

Minimum score Maximum score Mean Standard deviation

Kt/V 1.4 1.6 1.54 0.058

URR 76 84 80.58 2.18

Ur pre 86 216 131.57 29.36

Ur pos 12 48 24.83 8.38

Ca 7.20 10.30 8.76 0.63

K 3.70 5.60 4.92 0.45

P 2.40 8.90 5.54 1.91

Ht 21.10 39.10 31.72 4.37

Hb 7.10 12.80 10.45 1.41

Vol UF 0.00 6.40 2.12 1.29

UF rate 0.00 1633.33 596.42 334.28

IDWG 0.00 7.90 2.14 1.42

Weight pre 48.85 112.60 76.12 15.32

Weight post 48.00 111.70 74.01 15.11Kt/V

URR - Urea reduction ratio (%)

Ur pre - Urea pre-dialysis (mg/dL)

Ur pos - Urea pos-dialysis (mg/dL)

Ca - calcium (mg/dL)

K - potassium (mEq/L)

P - phosphorus (mg/dL)

Ht - hematocrit (%)

Hb - hemoglobin (g/dL)

Vol UF - ultrafiltrate volume (L)

UF rate - ultrafiltration rate (mL/H)

IDWG - interdialytic weight gain (kg)

Weight pre - pre dialysis session weight (Kg)

Weight post - post dialysis session weight (Kg)

Table 1 Lab test resuLts of the study partiCipants



496

The majority of patients had adequate examina-tions, and the laboratory abnormalities were those expected for nephropathic patients on hemodialysis. There was no statistically significant difference be-tween the results of the tests during the use of placebo or sertraline. Thus, we present the data of the two groups together in Table 1.

A comparison between the placebo group and the sertraline group revealed a statistically significant difference (p < 0.05) between pre- (higher) and post-dialysis weight (lower). A significant difference (p < 0.05) was found in BP with a drop between pre- and post-hemodialysis in all SBP measurements (Table 2). A significant difference was found (p < 0.05) between the first and second DBP measurement, but not be-tween the second and third (p = 0.75), as shown in Table 2.

Comparisons between intradialytic interventions, intradialytic symptoms, and IDH episodes revealed no statistical difference in the reduction of IDH episodes (p = 0.207) between the two intervention groups. However, the risk of IDH interventions was 60% higher in the placebo group compared to the ser-traline group (RR = 1.59; 95% CI 1.03 to 2.48, p = 0.034). Likewise, the risk of ID symptoms was 40% higher in the placebo group compared to the sertra-line group (RR = 1.42; 95% CI: 1.02 to 2.02, p = 0.038).

Sertraline presented a NNT of 16.3 patients to prevent an episode of IDH interventions and 14.2 pa-tients to prevent an episode of ID symptoms.

Graphs 1 and 2 present a survival analysis by com-paring the study groups with the incidence of IDH interventions (Graph 1) and ID symptoms (Graph 2). Kaplan-Meier survival analysis (time on hemodialysis was the time variable) presented in graphs 1 and 2 cor-roborated the results of the bivariate analysis, show-ing differences in the incidence of IDH interventions

(log rank 4.38; p = 0.037) and ID symptoms (log rank 4.17; p = 0.041).

discussion

In the present study, there was a relatively high preva-lence of patients with IDH (32%) compared to the findings of several studies, in which the prevalence was approximately 20%2,10,13,15,16,18,20,32. The high prevalence of IDH may be due to their selection dur-ing the summer in the southern hemisphere (January through March 2017), a season in which the patients ingest larger amounts of liquids, leading to an increase of the dry weight and IDWG, thus contributing to an eventual higher need for UF during the HD process. It is known that an UF of 10–13 mL/kg/h is not as-sociated with increased mortality for most patients, except for those with heart failure37. Therefore, ele-vated IDWG generates higher UF rates, with a higher probability of IDH14,15. Furthermore, the mean age of the patients was 61 years and studies have shown a greater probability of IDH (up to 50%) among the elderly population10,32.

The majority of the patients in this study presented diabetes mellitus as a baseline disease, which was sim-ilar to the findings by Razeghi24, who found that 5 out of 12 patients had diabetes. This comorbidity is re-lated to a greater number of cardiovascular complica-tions3,9, and most of the studies that performed inter-ventions excluded diabetic patients, as it was reported in the study by Yalcin and colleagues27 in which the incidence was 11% (12 patients out of 108 chronic kidney disease subjects had IDH), but patients with diabetes mellitus or autonomic neuropathy were ex-cluded from the sample. Brewster26 has found an inci-dence of 26% of IDH using similar diagnostic criteria to our study. In a study by Tislér and colleagues38, pa-tients who improved SBP in Trendelemburg position

Intradialytic blood pressure measurements

Mean (SD) Confidence interval p-value

SBP 1 X SBP 2 9.58 (23.72) 7.64 a 11.56 < 0.05

SBP 1 X SBP 3 7.74 (25.21) 5.65 a 9.84 < 0.05

SBP 2 X DBP 2 -1.82 (20.04) -3.46 a -1.57 < 0.05

DBP 1 X DBP 2 4.08 (14.01) 2.91 a 5.24 < 0.05

DBP 1 X DBP 3 4.24 (14.05) 3.07 a 5.41 < 0.05

DBP 2 X DBP 3 0.14 (12.41) -0.85 a 1.18 0.77

Table 2 desCription of interdiaLytiC bLood pressure measurements

SBP - Systolic Blood Pressure

BDP - Diastolic Blood Pressure



497

Graph 1. Survival analysis of the incidence of interventions and intradialytic hypotension episodes.

Graph 2. Survival analysis of the incidence of interventions and symptoms during hemodialysis.

were not included as a frequent IDH subject, thus having a reduced incidence of about 10%.

In the present study, a larger number of white pa-tients presented IDH compared to non-whites, which corroborated most studies that found higher hyper-tension rates in non-white patients39–41.

One patient had double lumen catheter access and was not excluded from the present study, since there was no evidence of catheter infection or other altera-tions that could contribute as bias. In addition, the patient had vascular access failure, a case in which hemodialysis by AVF is difficult.

No significant difference was found among labo-ratory tests taken in three occasions, during the study

12-week period. However, when the laboratory tests were evaluated individually, an improvement was found in the parameters, especially in the anemia con-trol tests, reported as hemoglobin/hematocrit ratio (Hb/Ht). The improvement in these parameters may be attributed to the dialysis adequacy associated with medication dose adjustments, such as erythropoietin and intravenous iron.

In the present study, there was a statistical differ-ence (p < 0.05) between the pre- and post-dialysis weight correlation, probably due to the fact that pa-tients presented adequate UF during the hemodialysis session. SBP declined from the first to the second and from the second to the third measurement (Table 2). This finding corroborates the IDH presence among the study participants, which is in agreement with the findings of several studies that use SBP to assess IDH15,18,24-27,29.

Nonetheless, the comparison between the placebo and sertraline groups regarding the DBP levels, re-vealed a significant difference (p < 0.05) from the first to the second DBP measurement, and from the first to the third DBP measurement, whereas no statistically significant difference (p = 0.75) was found from the second to the third DBP measurement. This indicated that the diagnosis of IDH should be made through SBP level and drop, as well as by analyzing the mean arterial pressure decline using DBP as a factor14,37.

A statistically significant difference was found be-tween heart rate and respiratory rate measurements in the pre- and post-hemodialysis period. No reported findings indicate a correlation between vital signs and IDH, but we observed a significant difference that could be explained by the hemodynamic response to the BP drop using the formula BP = CD x PVR, in which CD is the cardiac output and PVR the periph-eral vascular resistance42. However, the respiratory rate (RR) and heart rate (HR) were not evaluated dur-ing the hypotensive episode itself, but in the pre- and post-hemodialysis periods. Consequently, the pres-ence of a compensatory hemodynamic response to the BP drop or the absence of bradycardia could not be verified in those patients with paradoxical sympa-thetic reflex inhibition 10,14,15,43.

Sertraline presented an NNT of 16.3 patients to prevent an episode of IDH interventions, and 14.2 patients to prevent an episode of ID symptoms. According to a meta-analysis by Cipriani and col-leagues44 in which a comparison between SSRIs



498

(sertraline vs. fluoxetine) was made for the treatment of major depressive disorder, sertraline was superior to fluoxetine, with an NNT of 12. This result can be attributed to the antidepressant effect of the medica-tion, as reported in the study by Dheenan29. Based on that study and the NNT of this study, the clinical use of sertraline is supported.

Yalcin25,27, Dheenan29 and Razeghi24, who have described a significant effect in the control of IDH, support the use of sertraline as an alternative to other medications or techniques for the treatment of ESRD patients mainly because of its low toxicity, although the use of sertraline is not yet established as a thera-peutic alternative to minimize the IDH disorder.

The present study showed that the blockade of serotonin reuptake is not efficient to minimize hy-potension episodes during hemodialysis; however, it decreased the incidence of IDH interventions and ID symptoms, corroborating other studies, such as the one by Razeghi24, in which the number of interven-tions was reduced.

The use of higher doses of sertraline, as shown in a study by Yalcin25 in which the daily dose was 100 mg, revealed different findings than those of our study, which can be explained by the following sampling differences: patients selected for psychiatric illnesses and using antidepressants38 and exclusion of patients suffering from autonomic neuropathy or diabetes mellitus25,27,29.

Dheenan and colleagues29 have reported that the antidepressant effect could cause a decrease in com-plaints and demand for nursing interventions. Perhaps the antidepressant effect of sertraline improves the patients’ quality of life, well-being, symptomatology and tolerance and, consequently, reduces complaints in the intradialytic period. Some surveyed patients reported at-home improvements in the post-dialysis period, despite the unchanged blood pressure levels.

Data from the literature have indicated that ser-traline takes four to six weeks to reach the maximum effect24,45. Most of the studies have analyzed a 4-week period of sertraline use24-27, and made suggestions to use it for a longer period to obtain better results and improve blood pressure levels. Dheenan29 has used sertraline during 6 to 12 weeks, with a 6-week moni-toring period, so, in our study, we opted to use each drug for a 6-week period. Furthermore, there were re-ports of studies being affected by the washout period,

which was avoided in our study, since we administered placebo to all patients as the first drug. However, de-spite the precautions taken from other studies, there was no improvement in BP levels during the 6-week period of sertraline use compared to placebo.

The main limitation of the present study (and oth-er previous studies) is the small number of patients in each group. Nonetheless, the sample size was ad-equate, based on previous studies, for the validity of the results.

We used a crossover study design because of the advantage of allowing the use of smaller samples, since the cases are their own controls.

conclusion

The present study showed that the number of IDH episodes per session was similar for patients using ei-ther sertraline or placebo. It also showed that demo-graphic data, laboratory tests, IDWG, and pre- and post-dialysis weight did not present a significant dif-ference between the placebo and sertraline groups, with only a slight improvement in anemia control in the sertraline group.

Although no difference was found between the placebo and sertraline groups in blood pressure lev-els, there was an improvement in patients’ symptoms (even in those with IDH) as well as in the number of medical and nursing interventions during the intra-dialytic period, with a risk of IDH interventions 60% higher in the placebo group. The risk of ID symp-toms, which was 40% higher in the placebo group compared to the sertraline group, was also signifi-cantly different. It would be necessary 16.3 patients using sertraline to prevent an episode of IDH inter-vention and 14.2 patients to prevent an episode of ID symptoms. This finding indicated that the sample size was adequate to test the efficacy of sertraline used in clinical practice.

In conclusion, sertraline may be beneficial in de-creasing the number of ID symptoms and interven-tions. Further studies should be conducted to examine its antidepressant effect and efficacy for IDH treat-ment. Future studies should consider a longer period of patient monitoring after starting the use of sertra-line, e.g., twelve weeks instead of six, and a larger number of participants for a better analysis of the hypotensive episodes.



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lisT of abbReviaTions

IDH - Intradialytic hypotensionSSRIs - selective serotonin reuptake inhibitorsBP - blood pressureSBP - systolic blood pressureDBP - diastolic blood pressureMAP - mean arterial pressureID - intradialyticNNT - number needed to treatESRD - chronic end-stage renal disease HD - hemodialysisUF - ultrafiltrationIDWG - Interdialytic weight gainSD - standard deviationDM - diabetes mellitusAVF - arteriovenous fistulaHb - hemoglobinHt - hematocritCD - cardiac outputPVR - peripheral vascular resistanceRR - respiratory rateHR - heart rate

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AuthorsEdward Mezones-Holguin1,2

Roberto Niño-Garcia2,3

Percy Herrera-Añazco1,4

Álvaro Taype-Rondan1

Josmel Pacheco-Mendoza1

Adrian V. Hernandez1,5

1 Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Lima, Peru.2 Epi-gnosis Solutions. Piura, Peru.3 Universidad Nacional de Piura, Facultad de Ciencias de la Salud, Sociedad Científica de Estudiantes de Medicina de la Universidad Nacional de Piura (SOCIEMUNP), Piura, Peru.4 Hospital Nacional 2 de mayo, Department of Nephrology, Lima, Peru.5 University of Connecticut/Hartford Hospital Evidence-based Practice Center, Hartford, CT, USA.


Correspondence to:Edward Mezones-HolguínE-mail: [email protected]@gmail.com

Possible association between dysnatremias and mortality during hospitalization in patients undergoing acute hemodialysis: analysis from a Peruvian retrospective cohort Possível associação entre distúrbios do sódio e mortalidade hospitalar em pacientes submetidos a hemodiálise aguda: análise de uma coorte retrospectiva peruana

Objetivo: Avaliar a associação entre distúrbios do sódio ou do cloro e mortalidade hospitalar de pacientes com insuficiência renal aguda (IRA) ou doença renal crônica (DRC) submetidos a hemodiálise aguda. Métodos: O presente estudo de coorte retrospectiva incluiu pacientes adultos submetidos a hemodiálise aguda com diagnóstico de IRA ou DRC em um hospital público de Lima, Peru. Os distúrbios do sódio foram classificados como hiponatremia (Na < 135mmol/L) ou hipernatremia (Na > 145mmol/L), enquanto os distúrbios do cloro foram classificados como hipocloremia (Cl < 98 mmol/L) ou hipercloremia (Cl > 109mmol/L). O desfecho de interesse foi mortalidade hospitalar. Utilizamos modelos de Poisson da família de modelos lineares generalizados com bootstrap não-paramétrico e correção de viés acelerado para estimar os riscos relativos na análise bruta (RR) e ajustada (RRa) para sexo, idade, HCO3 (para todos os pacientes) e escore de Liaño (apenas para IRA) com IC 95%. Resultados: Foram incluídos 263 pacientes (idade média 54,3 anos; 43% do sexo feminino), 191 com DRC e 72 com IRA. A mortalidade foi mais elevada nos pacientes com IRA (59,7%) do que nos indivíduos com DRC (14,1%). No geral, os pacientes com hipernatremia tiveram mortalidade hospitalar mais elevada do que os indivíduos com valores normais de sódio (RRa: 1,82; IC 95%: 1,17-2,83). Os pacientes com hiponatremia não apresentaram mortalidade diferente (RRa: 0,19; IC 95%: 0,69-2,04). Também identificamos que hipercloremia (RRa: 1,35; IC 95%: 0,83-2,18) e hipocloremia (RRa: 0,66; IC 95%: 0,30-14,78) não elevaram a mortalidade em comparação a indivíduos com níveis normais de cloro. Não foi encontrada associação entre distúrbios do sódio ou do cloro e mortalidade hospitalar nos subgrupos com DRC e IRA. Conclusões: Em nossa análise exploratória, apenas hipernatremia apresentou associação com mortalidade hospitalar em pacientes com IRA ou DRC submetidos a hemodiálise aguda.

Resumo

Objective: To evaluate the association between dysnatremias or dyschloremias and mortality during hospitalization in patients with acute kidney injury (AKI) or chronic kidney disease (CKD) undergoing acute hemodialysis. Methods: We carried out a retrospective cohort study on adult patients undergoing acute hemodialysis with AKI or CKD diagnosis at a public hospital in Lima, Peru. Dysnatremias were categorized as hyponatremia (Na < 135mmol/L) or hypernatremia (Na > 145mmol/L), and dyschloremias were defined as hypochloremia (Cl < 98 mmol/L) or hyperchloremia (Cl > 109mmol/L). The outcome of interest was mortality during hospitalization. We performed generalized lineal Poisson family models with bias-corrected and accelerated non-parametric bootstrap to estimate the risk ratios at crude (RR) and adjusted analysis (aRR) by gender, age, HCO3 (for all patients) and Liaño score (only for AKI) with CI95%. Results: We included 263 patients (mean age: 54.3 years, females: 43%): 191 with CKD and 72 with AKI. Mortality was higher in patients with AKI (59.7%) than in patients with CKD (14.1%). In overall, patients with hypernatremia had a higher mortality during hospitalization compared to those who had normal sodium values (aRR: 1.82, 95% CI: 1.17-2.83); patients with hyponatremia did not have different mortality (aRR: 0.19, 95% CI: 0.69-2.04). We also found that hyperchloremia (aRR: 1.35, 95% CI: 0.83-2.18) or hypochloremia (aRR: 0.66, 95% CI: 0.30-14.78) did not increase mortality in comparison to normal chloride values. No association between dysnatremias or dyschloremias and mortality during hospitalization was found in CKD and AKI subgroups. Conclusions: In our exploratory analysis, only hypernatremia was associated with mortality during hospitalization among patients with AKI or CKD undergoing acute hemodialysis.

absTRacT

DOI: 10.1590/2175-8239-JBN-2018-0243

https://orcid.org/0000-0001-7168-8613

https://orcid.org/0000-0003-4396-4224

https://orcid.org/0000-0003-0282-6634

https://orcid.org/0000-0001-8758-0463

https://orcid.org/0000-0002-2251-8092

https://orcid.org/0000-0002-9999-4003


Dysnatremias and mortality in acute hemodialysis

502

inTRoducTion

Electrolytes and their alterations have an important repercussion in health, and it supposed to be an im-portant challenge in clinical practice. These molecules contribute to maintaining human body homeostasis1. Chloride (Cl) and sodium (Na) and their alterations - called dyschloremias and dysnatremias, respectively - have been associated with several harmful events in acute and chronic clinical situations2–12. Patients with kidney diseases are a special population of interest.

These patients are more likely to have alterations of Na and Cl, and to produce deleterious effects on their health. These include changes of urine dilution and concentration in response to antidiuretic hormone, and alteration of water and Na and CI reabsorption and excretion13,14. Previous studies have reported that dysnatremias and hypochloremia are associated factors for mortality in patients with chronic kidney disease (CKD), with or without dialysis15–22. Thus, dyschloremias and dysnatremias have been proposed as potential useful factors for mortality prediction in this population15–22.

Dysnatremias and dyschloremias in patients with acute kidney injury (AKI) or CKD submitted to acute dialysis need special attention. It is plausible that in AKI patients there is an association between these alterations and mortality. However, there are a few studies reporting the associations between hyperchloremia13 or dysnatremias with mortality in AKI patients undergoing hemodialysis23. Likewise, we have not found publications about the association between Na and Cl alterations and mortality in patients with CKD undergoing acute hemodialysis.

Our study evaluated the association between dysnatremias or dyschloremias with hospital mortality in patients with AKI or CKD undergoing acute hemodialysis. Findings could be useful for the improvement of clinical management in these patients.

meThods

dEsign and participants

We carried out a retrospective cohort in adult pa-tients with a diagnosis of AKI or CKD undergoing

acute hemodialysis at the Nephrology Department of National Hospital 2 de Mayo, a public general hos-pital of Ministry of Health located in Lima, Peru, be-tween January 2015 and July 2017.

AKI or CKD diagnosis, as well as the indication for hemodialysis, were determined by an attending nephrologist based on clinical criteria proposed in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines24. We excluded patients admitted to dialysis without kidney disease (vg. methanol intoxication, etc.) and patients who had received dialysis in other hospitals (since we could not access to the laboratory results and clinical evaluation before initiating the hemodialysis). Acute hemodialysis was defined as the emergency dialysis in a patient who never have received dialysis before. Both groups of patients (AKI and CKD) had conventional hemodialysis. In average, they had three sessions per week with a duration of 3.5-4 hours, using low-flow biocompatible synthetic membranes (polysulfone).

ExposurE, outcomE, and othEr patiEnt variablEs

Dysnatremias and dyschloremias were the exposure va-riables. Electrolytes were measured using a dry chemical technique in the last sample obtained in 24 hours be-fore starting hemodialysis. Based on NA serum values, dysnatremias were categorized as hyponatremia (lower than 135 mmol/L) and hypernatremia (higher than 145 mmol/L). We also classified Dyschloremia in the func-tion of Cl serum values in two categories: hypochlore-mia (lower than 98 mmol/L) or hyperchloremia (higher than 109 mmol/L). Our outcome was mortality and it was defined as death during hospitalization.

We assessed age and sex as demographic variables. Also, we measured serum potassium (K, categorized in: < 3.5 mmol/L, 3.5 mmol/L to 5.5 mmol/L, and > 5.5 mmol/L) and bicarbonate (HCO3, categorized in: 24 mmol/L, 24 mmol/L to 25 mmol/L and > 25 mmol/L) within 24 hours before starting dialysis. The Anion Gap (AG) value was calculated by the formula: Na - (Cl + HCO3) and categorized as high (higher than 12) and normal (lower than 12). The ratio between AG delta (12 - AG from patients) and bicarbonate delta (24 - bicarbonate from patients) was used to define the triple disorder. A ratio < 1 implied coexistence

Keywords: Acute renal injury; Renal Insufficiency, Chronic; Dialysis; Chlorine; Sodium; Mortality.

Palavras-chave: Lesão Renal Aguda; Insuficiência Renal Crônica; Diálise; Cloro; Sódio; Mortalidade.



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of high AG metabolic acidosis with normal AG, and ratio > 2 defined the coexistence of high AG metabolic acidosis and metabolic alkalosis (AM).

In patients with AKI, we assessed the severity of their clinical condition using the Liaño severity index according the equation:25

Severity = 0.032* (age in decades) - 0.086* (male sex) - 0.109* (nephrotoxic) + 0.109* (oliguria) + 0.116* (hypotension) + 0.122* (jaundice) + 0.15 (coma) - 0.154* (normal consciousness) + 0.182* (assisted respiration) + 0.21.

We used the recommended ≥ 0.74 threshold based on the association with a higher mortality in a Peruvian cohort25. All variables were obtained from the epidemiological surveillance records of the Nephrology Department.

statistical analysEs

We used arithmetic means and standard deviations (SD), and frequencies and percentages to report nume-ric and categorical variables, respectively. When evalua-ting the best multiple regression model for current data, none of them fulfilled assumptions. Also, there were fewer observations in certain categories of variables. In view of this, we replaced the estimation of the associa-tion measures and their uncertainty by non-parametric bootstrap, a resampling technique that does not require the development and fulfillment of assumptions about the probabilistic structure of observations. To estimate the confidence intervals, 1000 replicates were perfor-med with the bias-corrected and accelerated method for generalized linear models of the Poisson family26. We estimated crude and adjusted risk ratios (RR and aRR) with 95% confidence intervals (CI) as association measure between exposure and outcome in all patients, and in AKI and CKD populations. Other variables were included in adjusted models based on epidemiological criteria (theoretical confounding factor) with measured variables27. Therefore, for all patients and CKD patients we adjusted for gender, age and HCO3 and in AKI pa-tients, we adjusted for gender, age, HCO3 and Liaño score ≥ 0.74.

Ethical considErations

This study is an analysis of epidemiological sur-veillance without sensitive patient information. The protocol was approved for the Institutional Research

and Training department of Hospital Nacional 2 de Mayo from Lima, Perú.

ResulTs

From 275 patients with diagnosis of AKI or CKD ad-mitted due to acute hemodialysis, we excluded 12 of them since they did not have sodium or chloride mea-surements. Finally, we included 263 patients: 72 with AKI and 191 with CKD.

The average age was 54.7 (± 17.6) years and 54.3 (± 15.3) in patients with AKI and CKD, respectively. Most patients were men (57%). The average sodium values were 140.1 (± 10.4) mmol/L and 137.8 (± 7.3) mmol/L in patients with AKI and CKD, respectively (p = 0.049). Low sodium levels (< 135 mmol/L) were more likely to occur in AKI (31.9%) than in CKD (28.3%) groups, whether hypernatremia (> 145 mmol/L) was more frequent in patients with AKI (30.6%) than in patients with CKD (11.0%) (p < 0.001). Average chloride values were 109.0 (± 9.5) mmol/L and 104.4 (± 8.9) mmol/L in patients with AKI and CKD, respectively (p < 0.001). Hypochloremia (< 98 mmol/L) was less frequent in patients with AKI (9.7%) than in patients with CKD (22.0%); in contrast, hyperchloremia (> 109 mmol/L) was more frequent in patients with AKI (47.2%) than in patients with CKD (29.3%) (p = 0.009). Average potassium values were 5.1 (± 1.2) mmol/L and 5.4 (± 1.2) mmol/L in patients with AKI and CKD, respectively (p = 0.025). The average anion gap values were 18.2 (± 7.1) mmol/L and 20.7 (± 6.5) mmol/L in patients with AKI and CKD, respectively (p = 0.001). Mortality during hospitalization was higher in AKI (59.7%) than CKD (14.1%) patients (p < 0.001). In Table 1, we showed demographic and clinical characteristics of the entire population, AKI and CKD populations. In Figure 1 we compared mortality among groups, according to chloride and sodium levels. We reported frequencies with a confidence interval to 95%.

When evaluating the association between dysnatremias or dyschloremias and mortality during hospitalization, crude and adjusted models showed differences in mortality among patients who had hypernatremia (aRR: 1.82, 95% CI: 1.17-2.83), but not in those with hyponatremia (aIRR: 1.19, 95% CI: 0.69 - 2.04) when compared to those who had normal sodium values. We found no differences in mortality during hospitalization among patients who had hyperchloremia (aRR: 1.35, 95% CI: 0.83-2.18) or hypochloremia (aRR: 0.66, 95% CI: 0.30-14.78) when compared to those who had normal chloride



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Note: SD: standard deviation; NA: Not applicable; AKI: Acute Kidney Injury; CKD: Chronic Kidney Disease.†: n = 264; ‡: n = 244; ¶: n = 72

* Estimated value is for the comparison between AKI and CKD patients.

dEmographic and clinical charactEristics of thE total, acutE KidnEy injury and chronic KidnEy disEasE populations

Table 1

VariableTotal Patients AKI patients CKD patients

p value*N = 263 N = 72 N = 191

Age (mean ± SD) 54.4 ± 15.9 54.7 ± 17.6 54.3 ± 15.3 0.890Sex, Female, n (%) 112 (42.6) 33 (45.8) 79 (41.36) 0.513Sodium (mmol/L) (mean ± SD) 138.5 ± 8.3 140.1 ± 10.4 137.8 ± 7.3 0.049Normal (135-145), n (%) 143 (54.4) 27 (37.5) 116 (60.7)

< 0.001Low (< 135), n (%) 77 (28.3) 23 (31.9) 54 (28.3)High (> 145), n (%) 43 (16.4) 22 (30.6) 21 (11.0)Chloride (mmol/L) (mean ± SD) 105.6 ± 9.3 109.0 ± 9.5 104.4 ± 8.9 < 0.001Normal (98-109), n (%) 124 (47.2) 31 (43.1) 93 (48.7)

0.009Low (< 98), n (%) 49 (18.6) 7 (9.7) 42 (22.0)High (> 109), n (%) 90 (34.2) 34 (47.2) 56 (29.3)Potassium (mmol/L) (mean ± SD) 5.3 ± 1.2 5.1 ± 1.2 5.4 ± 1.2 0.025Normal (3.5-5.5), n (%) 151 (57.4) 48 (66.6) 103 (53.9)

0.124Low (< 3.5), n (%) 9 (3.4) 3 (4.2) 6 (3.2)High (> 5.5), n (%) 103 (39.2) 21 (29.2) 82 (42.9)HCO3 (mmol/L) (mean ± SD)† 13.2 ± 4.7 13.4 ± 4.9 13.1 ± 4.7 0.694Normal (24 - 25) 3(1.2) 0 (0.0) 3 (1.7)

0.371Low (< 24) 245 (98.0) 70 (100.0) 175 (97.2)High (> 25) 2 (0.8) 0 (0.0) 2 (1.1)pH (mean ± SD) † 7.2 ± 0.5 7.1 ± 0.9 7.2 ± 0.2 0.116Normal (7.4-7.5), n (%) 24 (9.6) 9 (12.9) 15 (8.3)

0.276Low (<7.4), n (%) 226 (90.4) 61 (87.1) 165 (91.7)Anion Gap ‡ 20.0 ± 6.8 18.2 ± 7.1 20.7 ± 6.5 0.001< 8 7 (2.9) 3 (4.4) 4 (2.3)

0.0568 to 12 23 (9.4) 11 (15.9) 12 (6.9)> 12 214 (87.7) 55 (79.7) 159 (90.8)Liaño score (≥ 0.74), n (%) ¶ NA 35 (48.6) NA NA

Mortality, Yes, n (%) 70 (26.6) 43 (59.7) 27 (14.1) < 0.001

values. There was no association in the subgroups of AKI and CKD separately, as shown in Table 2.

discussion

Our findings showed that in a single general hospi-tal in Peru there was an association between hyper-natremia and mortality during the hospitalization of patients with AKI or CKD undergoing acute hemo-dialysis; nevertheless, there was no association in each group separately. Also, we found no association be-tween dyschloremias and mortality in these patients. Our analysis represents one of the first published se-ries regarding this topic in a developing country.

The pathophysiology of the association between dysnatremias and mortality is limited and inconclusive. Although dysnatremias can be associated with brain

alterations, which can explain their association with mortality in critical patients12,28,29, it has not been determined that this mortality is due to dysnatremia or to an underlying disease9. In AKI patients in hemodialysis, only one study found an association between hypernatremia and mortality23, and hypernatremia was defined as serum Na > 156 mmol/L23. A study in the USA found an association between serum sodium level and mortality in patients with CKD on hemodialysis for sodium values < 138 mmol/L and ≥ 140 mmol/L, with a stronger association for values lower than 138 mmol/L17. This means that the association with mortality occurs at the extremes of sodium values17. To our knowledge, the current investigation represents a first report of the positive correlation between dysnatremia and mortality in patients in hemodialysis when including both groups (AKI and CKD).



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Figure 1. Distribution of mortality according Sodium and Chrolide levels in Acute Kidney Injury, Chronic Kidney Disease and all patients.

Variable Died n (%) Crude RR Adjusted RR

All Yes (n = 70) No (n = 193) n = 263 n = 251*

Sodium

Normal (135-145 mmol/L), n (%) 32 (22.4) 111 (77.6) Ref Ref

Low (< 135 mmol/L), n (%) 20 (26.3) 57 (74.0) 1.16 (0.67 - 1.99) 1.19 (0.69 - 2.04)

High (> 145 mmol/L), n (%) 18 (41.9) 25 (58.1) 1.87 (1.15 - 3.05) 1.82 (1.17 - 2.83)

Chloride

Normal (98- 109 mmol/L), n (%) 31 (25.0) 93 (75.0) Ref Ref

Low (< 98 mmol/L), n (%) 8 (16.3) 41 (83.7) 0.65 (0.30 - 1.42) 0.66 (0.30 - 14.78)

High (> 109 mmol/L), n (%) 31 (34.4) 59 (65.6) 1.38 (0.89 - 2.12) 1.35 (0.83 - 2.18)

CKD patients Yes (n = 27) No (n = 164) n = 191 n = 180**

Sodium

Normal (135 - 145 mmol/L), n (%) 16 (13.8) 100 (86.2) Ref Ref

Low (< 135 mmol/L), n (%) 7 (13.0) 47 (87.0) 0.94 (0.37 - 2.37) 0.93 (0.34 - 2.59)

High (> 145 mmol/L), n (%) 4 (19.0) 17 (81.0) 1.38 (0.00 - 2560.93) 1.61 (0.73 - 35.42)

Chloride


Low (< 98 mmol/L), n (%) 4 (9.5) 38 (90.5) 0.63 (0.03 - 14.53) 0.66 (0.02 - 21.22)

High (> 109 mmol/L), n (%) 9 (16.1) 47 (83.9) 1.07 (0.47 - 2.42) 1.14 (0.48 - 2.66)

AKI patients Yes (n = 43) No (n = 29) n = 72 n = 71***

Sodium

rElationship bEtwEEn chloridE or sodium lEvEls, with mortality in aKi and cKd patiEnts (non-paramEtric bca boostrap)

Table 2



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* Adjusted for gender, age, HCO3.

** Adjusted for gender, age and HCO3.

*** Adjusted for gender, age, HCO3 and Liaño score ≥ 0.74.


Low (< 135 mmol/L), n (%) 13 (56.5) 10 (43.5) 0.95 (0.58 - 1.58) 1.01 (0.59 - 1.71)

High (> 145 mmol/L), n (%) 14 (63.6) 8 (36.4) 1.07 (0.67 - 1.72) 1.00 (0.66 - 1.52)

Chloride

Normal (98-109 mmol/L), n (%) 17 (54.8) 14 (45.2) Ref Ref

Low (< 98 mmol/L), n (%) 4 (57.1) 3 (42.9) 1.04 (0.05 - 22.88) 1.03 (0.51 - 2.05)

High (> 109 mmol/L), n (%) 22 (64.7) 12 (35.3) 1.18 (0.78 - 1.78) 1.12 (0.70 - 1.80)

conTinued Table 2.

The pathophysiological mechanism about the association between dyschloremias and mortality is complex and not completely explained. In the case of hypochloremia, it is possibly associated with an abnormal neutrophil function30,31; hyperchloremic metabolic acidosis (normal AG) increases the pro-inflammatory response, with increased levels of nitric oxide and interleukin (IL) -6, - 10 or tumor necrosis factor (TNF)32,33. However, not all the studies have found an association between dyschloremia and mortality35, possibly due to differences of included patients. Studies that found an association between hyperchloremia and mortality were frequently conducted in patients with higher Cl load due to the use of saline solution (0.9% NaCl)2,4. Likewise, 0.9% NaCl use is associated with mortality in some studies in surgical patients34,35. In our study, we could not determine the frequency of the use of 0.9% NaCl and the Cl load, and our patients with hyperchloremia did not have coexistence of normal AG metabolic acidosis. This could explain why we did not find an association between hyperchloremia and mortality contrary to other studies36,37.

Some studies in critical patients without AKI have suggested that the association between hyperchloremia and mortality only happens if the CI collection was conducted 72 hours after admission 4, a situation different of our study, where Cl was measured on the first day of hospitalization. It is possible that the association between dyschloremia and mortality in a patient submitted to acute hemodialysis is not independent of confounders such as comorbidities and the critical condition5. In our study, among AKI patients, the results did not vary when adjusting the analysis according to the level of severity as per the Liaño score.

Our study has some limitations. First, we could not objectively evaluate the level of severity, cause of hospitalization, comorbidities and other clinical condition of patients undergoing acute hemodialysis,

which may be a confounding factor for our associations of interest. However, we defined our analysis as exploratory, thus our exposures have been cataloged as markers of a possible association with mortality. Second, we could not measure some factors that can affect the CI and Na values in each patient before initiating hemodialysis, such as the use of 0.9% NaCl, other solutions for parenteral hydration, diuretics and the state of blood volume or nutrition of the patient, among others. Third, the extrapolation of our results must be cautiously conducted, since protocols and clinical condition can differ from other centers for patients requiring acute hemodialysis. Fourth, this was not a representative AKI/CKD population, which could affect the external validity of the results. However, the main objective was to evaluate the existence of an association, and in this regard, it is considered that this can be done in non-representative populations38. Fifth, statistical power problems (the sample size is relatively small) may have happened especially when evaluating the association between hypernatremia in each group (AKI or CKD); and in the absence of a known population distribution it was decided to make nonparametric bootstrap26.

We suggest carrying out new studies that evaluate the causal effect of sodium and chlorine alterations in the mortality of patients with AKI and CKD, which include the measurement of other potentially confusing clinical variables with larger sample size.

conclusion

In this single-center cohort, there was an association between hypernatremia and mortality during the hos-pitalization of patients in acute hemodialysis; never-theless, no association was found with dyschloremias and mortality. In addition, no association was found in AKI or CKD populations separately. This infor-mation is relevant primary evidence that can inform the decision-making in these populations. Larger



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observational, prospective studies are necessary to confirm these findings.

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AuthorsMohamed Elsheikh1

Khaled A Elhefnawy1

George Emad1

Mabrouk Ismail1

Maher Borai2

1 Faculty of Medicine, Internal Medicine Department, Zagazig University, Egypt.2 Faculty of Medicine, Clinical Pathology Department, Zagazig University, Egypt.


Correspondence to:Khaled A Elhefnawy.E-mail: [email protected]

Zinc alpha 2 glycoprotein as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus

Zinco-alfa2-glicoproteina (ZAG) como biomarcador precoce de nefropatia diabética em pacientes com diabetes mellitus tipo 2

Introdução: Embora a microalbuminúria continue sendo o padrão ouro para a detec-ção precoce da nefropatia diabética (ND), ela não é um preditor suficientemente pre-ciso do risco de ND. Assim, novos bio-marcadores para prever mais precocemen-te o risco de ND e possivelmente evitar a ocorrência de doença renal terminal estão sendo investigados. Objetivo: Investigar a zinco-alfa2-glicoproteína (ZAG) como marcador precoce de ND em pacientes com debates mellitus tipo 2 (DM2). Métodos: Os 88 indivíduos incluídos foram divididos em quatro grupos: grupo controle (Grupo I), composto por voluntários saudáveis normais; e três grupos de pacientes com DM2 assim divididos: grupo normoalbu-minúria (Grupo II), subdivididos em TFG normal e TFG > 120 mL/min/1,73 m2), gru-po microalbuminúria (Grupo III) e grupo macroalbuminúria (Grupo IV). Todos fo-ram submetidos a urinálise e exames para determinar glicemia, HbA1c, função he-pática, creatinina sérica, ácido úrico, perfil lipídico, cálculo da TFG, relação albumina/creatinina (RAC) e dosagem urinária e séri-ca de ZAG. Resultados: Os níveis séricos e urinários de ZAG foram mais elevados nos pacientes com DM2 em comparação aos controles. Foi identificada diferença estatis-ticamente significativa entre os grupos estu-dados em relação aos níveis séricos e uriná-rios de ZAG. Os níveis urinários de ZAG foram positivamente correlacionados com a RAC. Ambos os níveis de ZAG foram ne-gativamente correlacionados com TFG. Os níveis urinários de ZAG no subgrupo com TFG ˃ 120 mL/min/1,73m2 foram maio-res do que no subgrupo com TFG normal. Conclusão: Constatamos que a ZAG séri-ca e urinária pode ser um útil biomarcador precoce para detecção de ND em pacientes com DM2, sendo detectável mais precoce-mente que microalbuminúria.

Resumo

Introduction: Although microalbumin-uria remains the gold standard for early detection of diabetic nephropathy (DN), it is not a sufficiently accurate predic-tor of DN risk. Thus, new biomarkers that would help to predict DN risk ear-lier and possibly prevent the occurrence of end-stage kidney disease are being in-vestigated. Objective: To investigate the role of zinc-alpha-2-glycoprotein (ZAG) as an early marker of DN in type 2 dia-betic (T2DM) patients. Methods: 88 per-sons were included and classified into 4 groups: Control group (group I), com-posed of normal healthy volunteers, and three patient groups with type 2 diabetes mellitus divided into: normo-albuminuria group (group II), subdivided into normal eGFR subgroup and increased eGFR sub-group > 120 mL/min/1.73m2), microalbu-minuria group (group III), and macroal-buminuria group (group IV). All subjects were submitted to urine analysis, blood glucose levels, HbA1c, liver function tests, serum creatinine, uric acid, lipid profile and calculation of eGFR, urinary albumin creatinine ratio (UACR), and measure-ment of urinary and serum ZAG. Results: The levels of serum and urine ZAG were higher in patients with T2DM compared to control subjects and a statistically sig-nificant difference among studied groups regarding serum and urinary ZAG was found. Urine ZAG levels were positively correlated with UACR. Both ZAG levels were negatively correlated with eGFR. Urine ZAG levels in the eGFR ˃ 120 mL/min/1.73m2 subgroup were higher than that in the normal eGFR subgroup. Con-clusion: These findings suggest that urine and serum ZAG might be useful as early biomarkers for detection of DN in T2DM patients, detectable earlier than microal-buminuria.

absTRacT

DOI: 10.1590/2175-8239-JBN-2018-0200 Palavras-chave: Nefropatias Diabéticas; Biomarcadores.

Keywords: Diabetic Nephropathies; Bio-markers.

http://orcid.org/0000-0002-2024-5449


Zinc alpha 2 glycoprotein in diabetic nephropathy

510

inTRoducTion

Diabetic nephropathy is associated with mortality and morbidity in patients with diabetes mellitus.1 The most common method of detecting the early signs of diabetic nephropathy is the measurement of microalbuminuria.2 However, pathological ab-normalities have been reported to occur before the onset of microalbuminuria.3 In chronic cases of dia-betic nephropathy, renal function correlates better with the degree of tubulointerstitial injury rather than with glomerular lesions, suggesting that rese-archers should look for tubular biomarkers in or-der to identify patients with diabetic nephropathy.4 There has been an increasing interest in identifying other biomarkers that might give a sensitive and rapid means of detecting the progression of diabe-tic nephropathy. In this aspect, biomarkers that re-flect tubular damage have been suggested by many investigators.5,6

Zinc-alpha-2-glycoprotein (ZAG) is a protein of interest because of its ability to play many important functions in the human body, including fertilization and lipid mobilization. Its structural organization and folding characteristics are similar to the MHC class I antigen-presenting molecule; hence, ZAG may have a role in the immune response. The function of ZAG under physiologic and cancerous conditions remains mysterious; however, it is considered a tumor bioma-rker for various carcinomas. There are several un-related functions attributed to ZAG, such as RNase activity, regulation of melanin production, hindering of tumor proliferation, and transport of nephritic by-products7.

ZAG is present in a variety of epithelia and is secreted into many body fluids.8 It was found that urine ZAG increased specifically in patients with diabetes and it may be used as a biomarker for spe-cific and accurate analysis of diabetic nephropathy.9 Immunohistochemical analyses have shown that ZAG is expressed mainly in the tubules of the human kidney.10

We hypothesized that the urine and serum con-centrations of ZAG might increase earlier than mi-croalbuminuria in diabetic nephropathy. This stu-dy aimed to determine the role of ZAG in the early diagnosis of diabetic nephropathy by estimating the

concentrations of urine and serum ZAG in patients with type 2 diabetes mellitus (T2DM), according to their levels of albuminuria.

subjecTs and meThods

study dEsign:

This was a case-control study carried out in the Internal Medicine and Clinical Pathology depart-ments, Faculty of Medicine, Zagazig University, from December 2017 to August 2018.

participants and groups:

A total of 88 persons were included after their written informed consent and classified into 4 main groups. Control group (group I) were normal healthy volun-teers (n = 22). The three T2DM patient groups were divided according to urinary albumin/creatinine ra-tio (UACR) into: normo-albuminuria group (group II) (UACR < 30 mg/g, n = 22, further subdivided according to eGFR into 2 subgroups: normal eGFR subgroup and increased eGFR subgroup > 120mL/min/1.73m2), DN group with microalbuminuria (group III, UACR from 30 to 300 mg/g, n = 22) and DN with macroalbuminuria (group IV, UACR > 300 mg/g, n = 22). All groups were matched for age, sex, and body mass index.

Exclusion critEria:

Patients with hepatic diseases, heart failure, thyroid disorders, autoimmune diseases, inflammatory con-ditions and sepsis, malignancy, renal impairment of known origin, urinary tract infections, past history of rapidly progressive renal failure, any type of glomeru-lonephritis, and patient with polycystic kidney were excluded from the study.

physical Examination and mEasurEmEnts:

All subjects in the study were subjected to A) assess-ment of medical history and thorough clinical exami-nation according to patients’ records; B) routine in-vestigations according to the methods applied in the clinical pathology laboratories of Zagazig University hospitals including urine analysis, complete blood count, fasting and random blood glucose levels, HbA1c, liver function tests, serum creatinine, urea, uric acid, lipid profile and calculation of eGFR. The



511

modification of diet in renal disease (MDRD) equa-tion was used for eGFR (mL/min/1.73 m2): 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female)11. The uri-ne albumin was divided by 100 to convert mg/dL to g/L and then the urine albumin value was divided by the urine creatinine value to albumin creatinine ra-tio (UACR) (mg/g) (urine albumin (mg/L) x100/ uri-ne creatinine (mg/dL)). UACR was reported as (mg albumin/g creatinine)12. C) Specific investigations in-cluded measurement of urinary and serum ZAG by human ZAGp1 (Zinc-alpha-2-glycoprotein) ELISA Kit (Spanbiotec, Guandong, China). D) Other inves-tigations included electrocardiogram and abdominal ultrasound.


The collected data were computerized and statis-tically analyzed using SPSS program (Statistical Package for Social Science) version 18.0. Qualitative data were presented as frequencies and relative per-centages. Chi-square test was used to calculate diffe-rence between qualitative variables. Quantitative data were presented as mean ± SD (standard deviation). Independent T-test was used to compare differences between quantitative variables in two groups with normally distributed data. ANOVA F-test test was used to compare differences between quantitative va-riables in more than two groups with normally distri-buted data. Kruskal Wallis test was used to compare differences between quantitative variables in more than two groups with non-normally distributed data. Pearson correlation coefficient was used to calculate correlation between quantitative variables. Receiver operating characteristic (ROC) curve analysis was used to identify optimal cut-off values of Vnn-1 with maximum sensitivity and specificity for prediction of the disease. Accuracy was measured by the area under the ROC curve. p-values > 0.05 indicated non-signifi-cant results, < 0.05 indicated significant results and < 0.01 indicated highly significant results.

ResulTs

Our results showed that there was no significant di-fference among groups regarding age, weight, and sex while there was a significant difference regarding the duration of diabetes mellitus (Table 1). We found sig-nificant differences among groups regarding fasting

blood glucose (FBG), random blood glucose (RBG), HbA1C, serum creatinine, eGFR, urinary albumin/creatinine ratio, serum albumin, and total plasma proteins (Table 2). There were significant differen-ces among groups regarding both urinary and serum ZAG and estimated GFR (Table 3). Table 3 shows the number and percentage of subjects according to eGFR in all groups. There was a significant positive correlation between both urinary and serum ZAG and duration of DM, UACR, and with each other, while a negative significant correlation was found between both urinary and serum ZAG and serum albumin, to-tal plasma proteins, and eGFR (Table 4). There was a significant increase in serum and urinary ZAG in cases with eGFR > 120 mL/min when compared to cases with normal eGFR (90 to 120 mL/min) in the normoalbuminuric group II (Table 5). The accuracy of urinary ZAG was 95.5%, and that of serum ZAG was 90.9%; considering both of them, the accuracy was 95.5% (Table 6 & Figure 1).

discussion

Microalbuminuria is considered the earliest clinical manifestation of DN.3 DN affects all cellular compo-nents in the glomeruli and renal tubular interstitium.4 As glomerular damage usually results in proteinuria, much research has been undertaken on glomerular damage in patients with T2DM.13 However, some patients with diabetes can have a decrease in eGFR and may progress to end-stage renal disease without having any significant albuminuria.14 Some patients with microalbuminuria have advanced renal patholo-gical changes for which therapy is less effective than one might usually expect for those with early stage disease.13,14 The correlation between albuminuria and eGFR has been found to be weak and urinary albu-min lacks both sensitivity and specificity to detect ear-ly stages of DN.14

Several tubular biomarkers that can predict renal damage in patients with early diabetic nephropathy have been investigated, such as neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, and li-ver fatty acid binding protein.7

Our study aimed to investigate the role of ZAG in early diagnosis of DN by estimating the concen-trations of urine and serum ZAG in patients with T2DM, according to their levels of albuminuria.



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p-value < 0.05 is significant. DM: diabetes mellitus, SD: standard deviation

VariableGroup I (n = 22)

Group II (n = 22)

Group III (n = 22)

Group IV (n = 22)

F p

Age (years) Mean ± SD

51 ± 6.62 51 ± 6.91 51 ± 6.29 51 ± 5.76 0.01 0.99

Weight (Kg): Mean ± SD

80.36 ± 7.65 79.59 ± 9.42 81.18 ± 9.12 80.95 ± 6.59 0.16 0.92

DM Duration (years) Mean ± SD

------- 4.59 ± 0.95 7.91 ± 0.97 12.68 ± 2.82 111.62 < 0.001

Variable No % No % No % No % χ2 p

Sex

Male 13 59.1 11 50 12 54.5 13 59.10.51 0.92

Female 9 40.9 11 50 10 45.5 9 40.9

Table 1 comparison of diffErEnt variablEs among thE study groups

Table 2 comparison of diffErEnt variablEs among thE study groups


Group II (n = 22)

Group III (n = 22)

Group IV (n = 22)

F p

FBG: (mg/dl) Mean ± SD

79.89 ± 13.51 131.36 ± 56.65 141.82 ± 73.37 150.89 ± 94.83 6.354 0.001

RBG: (mg/dl) Mean ± SD

92.07 ± 8.23 160.93 ± 93.86 194.64 ± 98.85 180.14 ±66.26 10.020 < 0.001

HbA1c: (%) Mean ± SD

5.19 ± 0.335 7.77 ± 1.74 8.64 ± 1.49 8.49 ± 1.18 18.428 < 0.001

S. uric acid: (mg/dl) Mean ± SD

5.28 ± 1.09 4.63 ± 1.03 4.71 ± 1.07 4.97 ± 1.17 1.59 0.2

S. Cr: (mg/dL) Mean ± SD

0.882 ± 0.136 1.13 ± 0.533 3.48 ± 1.16 5.45 ± 2.91 45.749 < 0.001

eGFR: (mL/min) Mean ± SD

108.73 ± 7.11 124.09±11.23 98.86 ± 3.85 82.36 ± 4.87 125.43 < 0.001

UACR: (mg/g) Mean ± SD

20.4 ± 5.11 20.72 ± 5.37 77.74 ± 28.93 383.55 ± 61.59 569.05 < 0.001

Albumin: (g/dL) Mean ± SD

4.53 ± 0.66 4.15 ± 0.54 4.19 ± 0.58 3.31 ± 0.08 22.06 < 0.001

T. protein: (g/dL) Mean ± SD

7.26 ± 0.55 7.12 ± 0.52 7.21 ± 0.54 6.39 ± 0.09 16.85 < 0.001

FBG: fasting blood glucose, RBG: random blood glucose, HbA1C: glcosylated hemoglobin, S. Cr: serum creatinine, eGFR: estimated glomerular filtration rate, UACR: urinary albumin creatinine ratio, p-value < 0.05 is significant.


Group II (n = 22)

Group III (n = 22)

Group IV (n = 22)

F p

Urinary ZAG: (mg/g) Mean ± SD

26.91 ± 2.41 36.86 ± 3.76 46.09 ± 2.31 56.73 ± 2.62 444.93 < 0.001

Serum ZAG: (mg/l) Mean ± SD

20.27 ± 1.52 24.55 ± 1.68 32.23 ± 2.11 40.82 ± 1.89 545.43 < 0.001

eGFR: No % No % No % No % χ2 p

< 90 0 0 0 0 0 0 19 86.4

90 - 120 22 100 8 36.4 22 100 3 13.6 119.7 < 0.001

> 120 0 0 14 63.6 0 0 0 0

Table 3 comparison of Egfr, and urinary and sErum Zag among thE studiEd groups

ZAG: zinc-alpha-2-glycoprotein, eGFR: estimated glomerular filtration rate, p-value < 0.05 is significant.



513

VariableUrinary ZAG

(n = 66)Serum ZAG

(n = 66)

r p r p

Age (years) 0.06 0.63 0.002 0.98

Weight 0.13 0.31 0.07 0.56

Duration of DM (years) 0.88 < 0.001 0.86 < 0.001

Albumin (g/dL) -0.51 < 0.001 -0.52 < 0.001

Total protein (g/dL) -0.49 < 0.001 -0.47 < 0.001

FBS: (mg/dL) 0.04 0.74 0.03 0.84

RBG: (mg/dL) -0.02 0.9 -0.02 0.99

HbA1c: (%) -0.08 0.51 -0.02 0.86

eGFR: (mL/min) -0.78 < 0.001 -0.87 < 0.001

Uric acid: (mg/dL) 0.16 0.2 0.12 0.34

Creatinine:(mg/dL) 0.15 0.23 0.08 0.46

UACR: (mg/g) 0.86 < 0.001 0.89 < 0.001

Urinary ZAG: (mg/g) ----- ------ 0.93 < 0.001

Serum ZAG: (mg/L) 0.93 < 0.001 ------ -----

Table 4 corrElation bEtwEEn both urinary and sErum Zag and diffErEnt variablEs among thE thrEE patiEnts groups

DM: diabetes mellitus, FBG: fasting blood glucose, RBG: random blood glucose, HbA1C: glycosylated hemoglobin, S.Cr: serum creatinine, eGFR: estimated glomerular filtration rate, UACR: urinary albumin creatinine ratio, ZAG: zinc-alpha-2-glycoprotein, p-value < 0.05 is significant.

Table 5 rElation bEtwEEn urinary and sErum Zag and Egfr in group ii and group iv

VariableGroup II

t pGFR 90 - 120 (n = 8)

GFR > 120 (n = 14)


32.63 ± 2.77 39.29 ± 1.14 7.99 < 0.001

Serum ZAG: (mg/L) Mean ± SD

24.38 ± 1.51 26.44 ± 1.82 2.71 0.01

VariableGroup IV

t pGFR < 90 (n = 19)

GFR 90 - 120 (n = 3)


56.63 ± 2.69 57.33 ± 2.52 0.42 0.78

Serum ZAG: (mg/L) Mean ± SD

40.37 ± 1.61 41.67 ± 0.58 1.36 0.19

ZAG: zinc alpha 2 glycoprotein, p-value < 0.05 is significant

Table 6 validity of urinary and sErum Zag in prEdiction of albuminuria

Variable Cutoff AUC Sens. Spec. +PV -PV Accuracy p-value

Urinary ZAG ≥ 28.5 0.99 98.5 86.4 95.6 95 95.5 < 0.001

Serum ZAG ≥ 22.5 0.99 97 72.7 91.4 88.9 90.9 < 0.001

Both -- 0.99 97 90.9 96.9 90.9 95.5 < 0.001ZAG: zinc alpha 2 glycoprotein, NPV: negative predictive value, PPV: positive predictive value, p-value < 0.05 is significant.



514

Because our groups were matched regarding age, body weight and sex, the effect of these factors on the results of urinary and serum ZAG in our study were excluded. A significant difference was found re-garding the duration of T2DM which is in agreement with other studies that found a significant difference between normo- and microalbuminuric groups regar-ding duration of diabetes mellitus.15-17

The results for FBG, RBG, HbA1C, serum creati-nine, eGFR, urinary albumin/creatinine ratio, serum albumin and total plasma proteins were in agreement with another study, which documented a significant difference between both diabetic groups regarding the previous parameters.18 Another study reported that progression of diabetic nephropathy was accom-panied by declining GFR and increasing urinary al-bumin excretion.19 We found that serum albumin in Group IV was statistically decreased compared to the other groups, which is in line with another study that found that serum albumin was significantly lower in the macroalbuminuric group of DN patients20.

A significant difference between control and nor-mo-albuminuric groups was found as for GFR by MDRD. These results were demonstrated by other studies21-23. This can be explained by the pathogenesis

of diabetic nephropathy, as there is hyperfiltration in stage 1 due to an imbalance in afferent and efferent arteriolar resistance, resulting in increased glomerular hydrostatic pressure and hyperfiltration. Activation of the renin-angiotensin system (RAS) increases an-giotensin II levels, leading to efferent arteriolar vaso-constriction and production of proinflammatory and profibrotic molecules through multiple mechanisms.24

Regarding GFR, other studies also found signifi-cant difference between control and normo-albumi-nuric patients (high eGFR subgroup), being lower in the normoalbuminuric group.25,26 On the other hand, our study found significant differences regarding GFR by MDRD between control and micro-albuminuric groups, which is in line with another study that repor-ted that albuminuria is the strongest risk factor for fast annual eGFR decline.27

In our study, a significance differences was found among studied groups in both urinary and serum ZAG levels. The increase of urinary ZAG in diabetic groups is the result of the proximal tubules in the kidneys being particularly susceptible to diabetes-associated injury, as they are subjected to prolonged exposure to various metabolic and hemodynamic disturbances.28 In prolonged cases of DN, renal function correlates

Figure 1. Roc curve for Validity of urinary and serum ZAG in prediction of albuminuria.



515

better with the degree of tubulointerstitial injury than the degree of glomerular lesions.29

As ZAG is mainly expressed in the proximal con-voluted and straight tubules,10 the changes in ZAG urine concentrations observed in our study might be indicative of the tubular damage that is present in ear-lier stages of diabetic nephropathy, preceding those that result in microalbuminuria.

Another study reported that the concentration of ZAG in urine was higher than that in serum, espe-cially in patients with T2DM, which suggests that the increased urine concentrations of ZAG were mainly due to increased ZAG secretion by tubular epithelial cells.30 Other studies demonstrated that urine ZAG levels were progressively increased in diabetic patients with normo-, micro-, and macroalbuminuria indica-ting that it is positively related with diabetes nephro-pathy progression.31

Moreover, other studies indicated that the appea-rance of ZAG in albumin-negative urine samples pre-ceded the appearance of albumin in T2DM patients from South Asia, suggesting that ZAG may be an ear-ly novel urinary biomarker useful for the screening of non-albuminuric DN.32

In our study there were significant positive corre-lations between both urinary and serum ZAG and du-ration of DM, UACR, and with each other. Negative significant correlation was found between both uri-nary and serum ZAG and albumin, total plasma pro-teins and eGFR, in contrast with another study that reported an inverse relationship between ZAG levels and plasma proteins.33

We found that urine concentrations of ZAG were significantly increased in patients with T2DM with higher eGFR compared with T2DM patients with normal eGFR.

The serum ZAG concentration was positively cor-related with eGFR but not with glucose levels, body weight and serum creatinine, which is in agreement with another study.30

conclusion

The strong positive association between urinary ZAG concentrations and UACR, and the earlier appearan-ce of urine ZAG compared with albuminuria, suggest that ZAG might be a useful biomarker for the early diagnosis of DN in patients with T2DM.

Large-scale prospective studies are needed to comprehensively understand the potential

pathophysiological role of ZAG in DN and to deter-mine the cause-effect relationship between urine and serum concentrations of ZAG and DN.

acknowledgmenTs

The authors thank all participants of the study, and colleagues and staff of the department.

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AuthorsAída Fernanda Batista Rocha1

Marcus Villander Barros De Oliveira Sá2

Ubirace Fernando Elihimas Junior3

1 Universidade Federal de Pernambuco, Hospital das Clínicas, Recife, PE, Brasil.2 Real Hospital Português, Recife, PE, Brasil.3 Real Hospital Português, Unidade de Nefrologia, Recife, PE, Brasil.


Correspondence to:Aída Fernanda Batista RochaE-mail: [email protected]

Hyponatremia in elderly patients with fragility fractures of the proximal femur: a cross-sectional study

Hiponatremia em pacientes idosos com fratura proximal de fêmur por fragilidade: um estudo transversal

Introdução: Fratura de fêmur proximal tem impacto na mortalidade e morbidade de idosos. Estudos recentes vêm demonstrando associação entre fratura por fragilidade e hi-ponatremia, um distúrbio hidroeletrolítico comum na prática médica. Objetivos: Inves-tigar a ocorrência de hiponatremia em pa-cientes com fratura proximal de fêmur por fragilidade. Metodologia: Foram coletados dados a partir de prontuários de pacientes admitidos na emergência do Real Hospi-tal Português devido à fratura proximal de fêmur por fragilidade, entre 2014 e 2017, e aqueles com natremia disponível no pron-tuário eletrônico foram incluídos no estudo. Resultado: Dentre os 69 pacientes com fra-tura de fêmur proximal, houve uma ocor-rência de 14 pacientes com hiponatremia, o que corresponde a 20,3%. Os principais fatores associados à hiponatremia no estudo foram doença pulmonar, uso de amiodarona e antidepressivos. Conclusão: Em idosos, a fratura de fêmur proximal por fragilidade pode estar correlacionada com hiponatre-mia, principalmente quando estão sob uso de amiodarona ou antidepressivos.

Resumo

Palavras-chave: Hiponatremia; Fraturas Ósseas; Fêmur; Idoso.

Introduction: Proximal femur fractures affect the mortality and morbidity of el-derly individuals. Recent studies have shown an association between fragility fractures and hyponatremia, a common fluid and electrolyte balance disorder. Objectives: This study aimed to inves-tigate the occurrence of hyponatremia in patients with fragility fractures of the proximal femur. Methods: The authors looked into the data from the medical re-cords of patients admitted to the emergen-cy unit of the Real Hospital Português for fragility fractures of the proximal femur from 2014 to 2017. The study included patients with serum sodium levels recor-ded in their charts. Results: Fourteen of 69 (20.3%) patients with proximal femur fractures had hyponatremia. The main factors linked to hyponatremia were lung disease, and prescription of amiodarone and/or antidepressants. Conclusion: In el-derly individuals, fragility fractures of the proximal femur may correlate with hypo-natremia, particularly among patients on amiodarone or antidepressants.

absTRacT

Keywords: Hyponatremia; Fractures, Bone; Femur; Aged.

DOI: 10.1590/2175-8239-JBN-2019-0019

inTRoducTion

Hyponatremia is the most common fluid and electrolyte balance disorder.1 Some authors have described a correlation be-tween hyponatremia and proximal femur fractures.2,3,4 Patients with asymptomatic hyponatremia are at higher risk of falling on account of gait disorders.5 Additionally, hyponatremia may also stem from decre-ased bone mineral density secondary to osteoclast activation.2 In 2011, Barsoni

et al. submitted that hyponatremia might induce oxidative stress on osteoclasts, in a proposition known as the theory of oxida-tive stress on ascorbic acid transporters.6 In 2016, Fibbi et al. described hypona-tremia as a regulator of the expression of genes MCP-1 (Monocyte chemoattractant protein-1) and CXCL-12 (C-X-C Motif Chemokine Ligand 12) connected to os-teoclastogenesis - the osteoclastogenesis modulation theory.7

https://orcid.org/0000-0002-1263-5287

https://orcid.org/0000-0003-1257-6958

https://orcid.org/0000-0001-5426-4253


Hyponatremia in proximal femur fractures

518

The etiology of hyponatremia must be defined before specific medical treatment is prescribed.8 Hyponatremia may be categorized based on the volu-me status of the patient as hypovolemic, euvolemic, or hypervolemic.9 Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) ranks as one of the main causes of euvolemic hyponatremia.8 SIADH may occur secondarily to malignant lung, mediastinal, gas-trointestinal, and genitourinary tumors. SIADH may originate from asthma, cystic fibrosis, chronic obstruc-tive pulmonary disease (COPD), and infectious lung diseases such as viral or bacterial pneumonias, tuber-culosis, aspergillosis, and lung abscesses. SIADH may be caused by other neurologic factors including vascu-lar malformations, mass lesions, stroke, head trauma, and infections such as encephalitis, meningitis, mala-ria, acquired immunodeficiency syndrome, and brain abscesses. SIADH may still occur in association with the use of medications such as vasopressin analogues, antidepressants, antipsychotics, anticonvulsants, can-cer drugs, opioids, proton pump inhibitors, amiodaro-ne, and non-steroid anti-inflammatory drugs.10

Falling is a common incident among the elderly that impacts their morbidity and mortality. An estimated 30% of the individuals aged 65+ years fall every ye-ar (Yale Health Project 1988),11 an event responsible for approximately 5% of the hospitalizations of el-derly persons.12 Hip fractures are placed among the most severe consequences of falling, with reported one-year mortality ranging between 26% and 33%.13 Several instruments have been developed to identify individuals at risk of fracture, such as the Fracture Risk Assessment Tool (FRAX) of the World Heath Organization published in 2008,14 and the QFracture algorithm developed for the British population. Since fractures significantly affect the quality of life of elder-ly individuals and impose a sizable financial burden on healthcare systems, it is only fitting to recognize, prevent, and address risk factors such as hyponatre-mia. This study aimed to investigate the occurrence of hyponatremia in patients with fragility fractures of the proximal femur.

meThods

This cross-sectional study was carried out at a tertiary referral hospital in the Brazilian city of Recife to in-vestigate the occurrence of hyponatremia in patients with proximal femur fractures.

The study enrolled elderly patients (individu-als with ages ≥ 60 years, as per the definition of the Brazilian Ministry of Health)15 hospitalized for pro-ximal femur fractures (femoral neck, transtrochan-teric, or subtrochanteric fractures)16 caused by falls from standing height or less that would not result in fractured bones in the majority of healthy individuals (fragility or low energy fractures).14 Additionally, in-cluded patients were required to have serum sodium levels recorded in their charts at the time of admission to the emergency unit or at some point in the three months preceding hospitalization.

The patients were analyzed based on the following data: age; sex; serum sodium levels (mild hyponatre-mia < 135 mmol/L; moderate hyponatremia < 130 mmol/L; or severe hyponatremia < 125 mmol/L);17 prescribed medication (amiodarone, benzodiazepi-nes, antidepressants, anticonvulsants, antipsychotics, diuretics, proton pump inhibitors); and comorbidities (systemic hypertension, diabetes mellitus, lung dise-ase, hypothyroidism, heart failure, osteoporosis, his-tory of stroke, dementia, history of bone fracture).

The authors examined the data collected from the charts of patients seen at the emergency unit of the Real Hospital Português from January 1, 2014 to December 31, 2017. The subjects included in the study were divided into two groups based on their serum sodium levels. Group 1 featured patients with hyponatremia (serum sodium < 135 mmol/L), while Group 2 enrolled individuals without hyponatremia (serum sodium ≥ 135 mmol/L). Statistical analyses were performed on software package R-project 3.4.2. Bartlett’s test was used to test the homogeneity of va-riances. Distribution normality was assessed via the Shapiro-Wilk test. Categorical variables were expres-sed as frequencies and proportions. Fisher’s exact test was used to evaluate the association between cate-gorical variables and hyponatremia, and p-values < 0.05 were deemed significant. Numerical variables were expressed as mean values ± standard error (SE). Statistical differences between the groups with and without hyponatremia were analyzed with the aid of the Mann-Whitney U test and significance was attri-buted to differences with a p-value < 0.05.

The Research Ethics Committee of the University of Pernambuco approved this study and assigned it permit CAE 94620518.7.0000.5207 on November 6, 2018.



519

ResulTs

A total of 212 patients were admitted to the emer-gency unit of the Real Hospital Português from January 1, 2014 to December 31, 2017 for proximal femur fractures. Forty-two were excluded for having ages of less than 60 years. Two patients with bone fractures for being hit by automobiles were also ex-cluded. Ninety-nine were excluded for not having their serum sodium levels measured at admission or in the three months preceding hospitalization for a fractured femur. Therefore, the study population ad-ded up to 69 patients (Figure 1).

Nearly four fifths (79.7%) of the 69 included pa-tients did not have hyponatremia. In the group with hyponatremia (20.3%), mild, moderate, and severe hyponatremia was seen in 78.6%, 14.3%, and 7.1% of the patients, respectively.

Table 1 shows that there was no statistically sig-nificant difference in the sex (p = 0.527) of age (p = 0.317) distributions of the two groups.

The mean serum sodium level seen in Group 1 was statistically different from the level

Table 2 lists the comorbidities observed in the two groups of patients and shows that the individu-als in Group 1 had lower serum sodium levels and

Figure 1. Patient selection flowchart



520

Variables

Group 1

< 135 mmol/L

(N = 14)

Group 2

≥ 135 mmol/L

(N = 55)

p-value

Serum sodium 131.1 ± 3.7 SE (120 - 134) 141.3 ± 4.3 SE (136 - 161) < 0.001

Sex 0.527

Female 57.1% 69.1%

Male 42.9% 30.9%

Age 83.9 ± 7 DP (67 - 95) 82 ± 7.8 DP (63 - 100) 0.317Note: the serum sodium levels considered were the most recent in the three months leading to hospitalization or the levels measured at admission

Table 1 charactEristics of thE patiEnts with fragility fracturEs of thE proximal fEmur in groups 1 (sErum na < 135 mmol/l) and 2 (sErum na ≥ 135 mmol/l) admittEd to thE EmErgEncy unit of thE rEal hospital português from january 1, 2014 to dEcEmbEr 31, 2017.

Comorbidities p-valueNa < 135 mmol/L Na ≥ 135mmol/L

(N = 14) (N = 51)*

Hypothyroidism 21.40% 3.90% 0.063

Systemic hypertension 71.40% 68.60% 1

Coronary artery disease 0.00% 2.00% 1

Osteoporosis 21.40% 21.60% 1

Diabetes mellitus 21.40% 33.30% 0.521

Dementia 28.60% 21.60% 0.721

Lung disease 28.60% 5.90% 0.034

History of fragility fracture 0.00% 5.90% 1

Cancer 0.00% 9.80% 0.576

Without bone metastases 0.00% 60.00%

With bone metastases 0.00% 40.00%

Heart failure 21.40% 15. 7% 0.691

History of stroke 0.00% 11.80% 0.327

Table 2 comorbidity analysis - group 1 vs. group 2. EldErly patiEnts with fragility fracturEs of thE proximal fEmur admittEd to thE EmErgEncy unit of thE rEal hospital português from january 1, 2014 to dEcEmbEr 31, 2017.

* Note: four patients were excluded for having incomplete data.

significantly greater involvement by lung disease (p = 0.034). Three quarters of the patients with lung dise-ase in Group 1 had COPD and one quarter was diag-nosed with idiopathic pulmonary fibrosis. A third of the patients with lung disease in Group 2 had asthma, a third had COPD, and a third was diagnosed with bronchiectasis.

Statistical analysis indicated the existence of a correlation between hyponatremia and amiodarone (p = 0.007) and hyponatremia and prescription of antidepressants (p = 0.042), as seen in Table 3. The patients included in the study were on the following antidepressants: escitalopram (25.00%), mirtazapine

(20.83%), sertraline (12.50%), desvenlafaxine (8.33%), trazodone (8.33%), duloxetine (8.33%), fluoxetine (4.17%), paroxetine (4.17%), fluvoxa-mine (4.17%), citalopram (4.17%), and venlafaxine (4.17%), as seen in Figure 2.

discussion

This study aimed to investigate the occurrence of hy-ponatremia in patients with proximal femur fractu-res. Similarly to prior studies,2-4,18-22 fourteen (20.3%) of the 69 patients with proximal femur fractures had hyponatremia. The main findings associated with



521

Medication

Group 1 Group 2

p-valueNa < 135 mmol/L Na ≥ 135 mmol/L

(N = 14) (N = 50)**

Amiodarone 28.6% 2.0% 0.007

Diuretics 21.4% 26.0% 1.000

Benzodiazepines 28.6% 28.0% 1.000

Antidepressants 14.3% 44.0% 0.042

Anticonvulsants 7.1% 14.0% 0.673

Proton pump inhibitors 21.4% 22.0% 1.000

Antipsychotics 7.1% 16.0% 0.670** Note: five patients were excluded for having incomplete data.

Table 3 a comparison bEtwEEn thE mEdications prEscribEd to individuals in groups 1 (sErum na < 135) and 2 (sErum na ≥ 135) admittEd to thE EmErgEncy unit of thE rEal hospital português for fragility fracturEs of thE proximal fEmur from january 1, 2014 to dEcEmbEr 31, 2017

Figure 2. Number of patients in each of the prescribed antidepressants.

hyponatremia were lung disease and prescription of amiodarone and/or antidepressants.

Hyponatremia may be categorized based on the duration of the disorder as acute (< 48 hours) or chro-nic (> 48 hours).23 In chronic hyponatremia, the brain adjusts to the hypotonic environment and clinical ma-nifestations are not quite as exuberant.17 Patients with chronic hyponatremia are generally asymptomatic or present with mild clinical anomalies such as attention deficit, gait disorders, falls, and impaired recovery from bone fractures.24,25

Upala and Sanguankeo published a meta-analysis featuring 12 trials and observed the existence of a sig-nificant association between bone fractures and oste-oporosis in individuals with hyponatremia, with an odds ratio (OR) for fracture of 1.99 [95% confidence interval (CI); 1.50 - 2.63; p < 0.001] in studies repor-ting odds ratios, and increased relative risk (RR) of fracture of 1.62 (95%CI; 1.28 - 2.05; p < 0.001) in studies reporting risk measurements.2

Ayus et al. analyzed a retrospective cohort of 31,527 patients - 0.9% diagnosed with chronic hypo-natremia - and found that the absolute risk of having a hip fracture was 3.07% in patients with chronic hyponatremia and 1.31% in individuals with normal serum sodium levels. Patients with hyponatremia had increased adjusted RR of having a hip fracture [4.52 (95%CI 2.14-9.6)]. The adjusted RR seen for the sub-set of patients with moderate hyponatremia (< 130 mmol/L) was even higher [7.61 (95%CI 2.8–20.5)].3

Gankam Kengne et al. looked into the prevalen-ce of hyponatremia (serum sodium < 135 mmol/L) of 513 elderly patients with bone fractures and compa-red them against controls without fractures matched for sex and age. The prevalence of hyponatremia was significantly higher among individuals with bone frac-tures than controls (13% vs. 3.9%), with an adjusted OR of 4.16 (95%CI 2.24 - 7.71). In the cited study, hyponatremia was primarily caused by medication - diuretics (36%) and selective serotonin re-uptake inhibitors (17%) - and SIADH (37%).18

In a similar study, Sandhu et al. compared the in-cidence of hyponatremia in 364 elderly patients ad-mitted to an emergency unit for bone fractures (hip/pelvis/femur) against another group of 364 elderly patients without bone fractures admitted to the same service within the same time period. The incidence of hyponatremia was significantly higher in the group with bone fractures (9.1% vs. 4.1%). The mean serum sodium level of the individuals in the fracture group was 131 ± 2 mEq/L. More than three quarters (75.3%) of the indivi-duals in the bone fracture group were females. Nearly a quarter (24.2%) of the patients with bone fractures and



522

hyponatremia were on antidepressants, 75% of which were selective serotonin re-uptake inhibitors (SSRIs). None of the patients in the fracture-free group was on antidepressants.19

Jamal et al. reviewed the data from the Osteoporotic Fractures in Men (MrOS) trial to elicit possible rela-tionships between hyponatremia and bone fractures in 5,122 males aged 65 and older. The relative risk for hip fracture was 3.48 (95%CI: 1.76-6.87).20 Kinsella et al. looked into the data from 1,408 females sub-mitted to bone densitometry and found that 18% had bone fractures. The incidence of hyponatremia was greater in the group with fractures (8.7%) than in the fracture-free group (3.2%).21

Rittenhouse et al. investigated 2,370 cases of trau-ma involving elderly individuals and found a preva-lence of hyponatremia of 12.4% (OR: 1.81; 95%CI: 1.26-2.60; p = 0.001).22 Aicale et al. reported a preva-lence of hyponatremia of 19% in a population of 334 elderly individuals with hip fractures.4

Amiodarone-induced hyponatremia is a rare com-plication, with only 17 cases described in the literatu-re.26 The first case report was published in 1996.27 The mechanism by which amiodarone induces SIADH is still unclear.28 Iovino et al. suggested that amiodarone causes SIADH by stimulating anti-diuretic hormone secretion by the magnocellular neurons in the supra-optic and paraventricular nuclei of the hypothalamus or through the expression of water channel aquapo-rin-2 (AQP2) in the collecting ducts.29

More than a quarter (28.6%) of the individuals with hyponatremia included in our study were on amiodarone, suggesting that SIADH secondary to amiodarone prescription might not be that rare.

Prescription of antidepressants has been associated with increased risk of falling and fracture.30 Tricyclic antidepressants and mirtazapine have been linked to increased risk of falling on account of their effects in the ability to concentrate and balance, orthostatic hypotension, and sedative effects.31 SSRIs reportedly cause dizziness and increase the risk of fractures by decreasing bone mineral density.32

Macri et al. showed that subjects on antidepressants were at increased risk of falling when compared to in-dividuals off antidepressants [5.2% vs. 2.8%; adjusted OR: 1.9, (95%CI: 1.7-2.2). The authors did not find sta-tistically significant differences between antidepressant classes SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs) and trazodone.33

Antidepressants increase the risk of falling via se-veral different mechanisms,30 and have been conside-red to cause SIADH.17 The results of our study seem to indicate the existence of an association between antidepressants and proximal femur fractures (p = 0.042). However, we found more patients on antide-pressants in the group with bone fractures without hyponatremia (44% of the subjects in Group 2 were on antidepressants vs. 14.3% in Group 1). A third (33.33%) of the 69 patients included in our study were on antidepressants. More than half (54.71%) of the patients included in our study were on SSRIs; 20.83% were on SNRIs; 20.83% were on mirtazapi-ne; and 8.33% were on trazodone.

There seems to exist a relationship between hypo-natremia and fragility fractures of the proximal femur in elderly patients, although recent studies2–4 have pu-blished new information connecting hyponatremia to falls5 and bone fractures.6 Serum sodium levels have been underreported for elderly patients admitted for falls. In the study period, only 69 of the 168 elder-ly individuals admitted for proximal femur fractures had serum sodium levels recorded in their charts - and a meager 45 had serum sodium levels measured upon admission.

Our study showed that amiodarone might be linked to hyponatremia. However, this inference can only be verified through a prospective stu-dy designed to establish a causal link between amiodarone and hyponatremia.

Lung diseases such as COPD and asthma or in-fectious conditions such as tuberculosis, aspergillosis, and bacterial pneumonia have been described as pos-sible causes of SIADH.34 Some authors have described hyponatremia in COPD exacerbation.35,36 Although the mechanism by which hyponatremia occurs in COPD has not been fully elucidated, it has been su-ggested that hypercapnia decreases renal blood flow, thereby increasing the retention of water and sodium and causing edema and hyponatremia.37

Our study found a significant correlation between hyponatremia and lung disease. The lung diseases for which our patients were tested were COPD, asthma, idiopathic pulmonary fibrosis, and bronchiectasis. Few studies have described a relationship between COPD or asthma and hyponatremia. Further studies enrolling larger populations are required to verify the existence of an association between hyponatremia and the lung diseases analyzed herein.



523

SIADH secondary to amiodarone might be un-derdiagnosed in emergency and trauma centers. We believe that elderly patients on amiodarone or antide-pressants should have serum sodium levels measured not only upon admission, but also during regular visits with their physicians. Additional attention is required in the presence of the following triads of findings: falls in the elderly/hyponatremia/amiodarone and falls in the elderly/hyponatremia/antidepressants. When these triads are present, physicians or medical teams with expert knowledge on the matter should further inves-tigate patients for SIADH.

Our study had its share of limitations. The cross--sectional nature of the study and the relative lack of data - only 69 of 168 elderly patients with fragility fractures were included - decreased the sample space. Additionally, the study was carried out in only one regional private tertiary referral hospital.

More studies are needed to assess a possible corre-lation and the causal links between fragility fractures of the proximal femur and hyponatremia in elderly individuals. Our study found associations betwe-en some comorbidities and prescribed medication. Significant associations were found with amiodarone and antidepressants (SSRIs, SNRIs, mirtazapine, and trazodone). In the realm of comorbidities, lung disea-ses in general (asthma, COPD, idiopathic pulmonary fibrosis, and bronchiectasis) had a relevant role.

author’s contribution

Aída Fernanda Batista Rocha, Marcus Villander Bar-ros De Oliveira Sá, Ubirace Fernando Elihimas Junior contributed substantially to the conception or design of the study; collection, analysis, or interpretation of data; writing or critical review of the manuscript; and final approval of the version to be published.

conflict of intErEst

The authors declare that they have no conflict of in-terest related to the publication of this manuscript.

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AuthorsManish Kumar1

Jaypalsing Ghunawat1

Diganta Saikia1

Vikas Manchanda1

1 Chacha Nehru Bal Chikitsalaya, Department of Pediatrics and Microbiology, New Delhi, Delhi, India.


Correspondence to:Manish Kumar.E-mail: [email protected].

Incidence and risk factors for major infections in hospitalized children with nephrotic syndrome

Incidência e fatores de risco para infecções graves em crianças hospitalizadas com síndrome nefrótica

Introdução: Crianças com síndrome nefrótica apresentam maior risco de infecções devido ao próprio status da doença e ao uso de vários agentes imunossupressores. Em grande parte, as infecções desencadeiam recidivas que exigem hospitalização, com risco aumentado de morbidade e mortalidade. Este estudo teve como objetivo determinar a incidência, o espectro e os fatores de risco para infecções graves em crianças hospitalizadas com síndrome nefrótica. Métodos: Todas as crianças hospitalizadas consecutivamente entre 1 e 12 anos de idade com síndrome nefrótica foram incluídas no estudo. Crianças com nefrite aguda, síndrome nefrótica secundária, bem como aquelas admitidas para biópsia renal diagnóstica e infusão intravenosa de ciclofosfamida ou rituximabe foram excluídas. Resultados: Foram cadastradas 148 crianças com 162 internações. A incidência de infecções graves em crianças hospitalizadas com síndrome nefrótica foi de 43,8%. A peritonite foi a infecção mais comum (24%), seguida por pneumonia (18%), infecção do trato urinário (15%) e celulite (14%), contribuindo com dois terços das principais infecções. Streptococcus pneumoniae (n = 9) foi o organismo predominantemente isolado em crianças com peritonite e pneumonia. Na análise de regressão logística, a albumina sérica < 1,5gm / dL foi o único fator de risco independente para todas as infecções (OR 2,6; 95% CI, 1,2-6; p = 0,01), especialmente para peritonite (OR 29; IC95% 3 –270, p = 0,003). Houve quatro mortes (2,5%) em nosso estudo, todas devido a sepse e falência de múltiplos órgãos. Conclusões: A infecção continua sendo uma importante causa de morbimortalidade em crianças com síndrome nefrótica. Como o Pneumococo foi a causa mais prevalente de infecção nessas crianças, deve-se atentar para a imunização pneumocócica em crianças com síndrome nefrótica.

Resumo

Palavras-chave: Infecção; Peritonite; Síndrome Nefrótica.

Introduction: Children with nephrotic syndrome are at increased risk of infections because of disease status itself and use of various immunosuppressive agents. In majority, infections trigger relapses requiring hospitalization with increased risk of morbidity and mortality. This study aimed to determine the incidence, spectrum, and risk factors for major infections in hospitalized children with nephrotic syndrome. Methods: All consecutive hospitalized children between 1–12 years of age with nephrotic syndrome were enrolled in the study. Children with acute nephritis, secondary nephrotic syndrome as well as those admitted for diagnostic renal biopsy and intravenous cyclophosphamide or rituximab infusion were excluded. Results: A total of 148 children with 162 admissions were enrolled. Incidence of major infections in hospitalized children with nephrotic syndrome was 43.8%. Peritonitis was the commonest infection (24%), followed by pneumonia (18%), urinary tract infection (15%), and cellulitis (14%), contributing with two thirds of major infections. Streptococcus pneumoniae (n = 9) was the predominant organism isolated in children with peritonitis and pneumonia. On logistic regression analysis, serum albumin < 1.5gm/dL was the only independent risk factor for all infections (OR 2.6; 95% CI, 1.2–6; p = 0.01), especially for peritonitis (OR 29; 95% CI, 3–270; p = 0.003). There were four deaths (2.5%) in our study, all due to sepsis and multiorgan failure. Conclusions: Infection remains an important cause of morbidity and mortality in children with nephrotic syndrome. As Pneumococcus was the most prevalent cause of infection in those children, attention should be paid to the pneumococcal immunization in children with nephrotic syndrome.

absTRacT

Keywords: Infection; Peritonitis; Ne-phrotic Syndrome.DOI: 10.1590/2175-8239-JBN-2019-0001

https://orcid.org/0000-0002-7936-221X

https://orcid.org/0000-0001-7380-6943

https://orcid.org/0000-0002-2409-8108

https://orcid.org/0000-0002-3969-5167


Infection in children with nephrotic syndrome

526

inTRoducTion

Nephrotic syndrome (NS) is one of the commonest chronic renal diseases in children, characterized by se-lective proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Majority of cases of nephrotic syndrome are without underlying secondary etiology and termed idiopathic nephrotic syndrome (INS). Based on response to therapy, these cases are further classified as steroid sensitive (SSNS) and steroid resistant nephrotic syndro-me (SRNS). More than 50% cases of SSNS show fre-quent relapses or become steroid-dependent requiring repeated courses of steroid and other immunosuppres-sive drugs as steroid sparing agent.1 SRNS cases, at the other end, are at additional risk of renal failure. Among the important risk factors for infection are urinary loss of immunoglobulins and alternative complement pa-thway factors B and I, presence of edema, and treat-ment with prednisolone and other cytotoxic agents.2 Peritonitis, pneumonia, urinary tract infection (UTI), cellulitis, meningitis and tuberculosis have been re-ported as major infections in these children.3-11 Data are limited on incidence and risk factors for major infections in children with NS from north India. This study aimed to estimate the incidence, pattern, and risk factors for major infections in hospitalized chil-dren with INS.

maTeRial and meThods

This prospective observational study was conducted at a tertiary care pediatric hospital in Delhi from June 2014 to December 2015. All consecutive hospitalized children between 1–12 years of age with diagnosis of NS were screened. NS and associated complications were defined as per guidelines from Indian Pediatric Nephrology Group.12 Children with NS were admit-ted in presence of one or more of the following condi-tions: anasarca, suspected major infections, or hypo-volemia. Major infections were defined as those with disseminated or deep seated infections requiring hos-pitalizations and treatment with parenteral antibio-tics, and were the following: peritonitis pneumonia, cellulitis, meningitis, unexplained pyrexia and infec-tive diarrhea.12 Children were subjected to complete blood counts, kidney and liver function tests, lipid profile and urine routine microscopic examination. Ascitic and cerebrospinal fluid cytology, biochemis-try, and culture were performed in children with sus-pected peritonitis and meningitis respectively. Chest

X-ray and blood and urine culture were performed as and when required. The exclusion criteria were: features of nephritis, secondary NS, as well as tho-se admitted for diagnostic renal biopsy and infusion therapy (cyclophosphamide or rituximab). The study was approved by Institutional Ethics Committee.

Based on previous studies,6-8 the average incidence of major infections in children with NS was assumed to be 35%. Sample size was calculated by the formula 4p (1–p)/d2, where p is the prevalence of major in-fections and d is the precision. A sample size of 91 children was calculated at 95% confidence interval and 7% precision (d). Assuming a 10% loss to follow up, we planned to enroll a minimum of 100 children.

Data were analyzed using SPSS version 23. Incidence of major infections was measured as a pro-portion of children diagnosed with major infections out of total episodes of hospitalizations with NS. Independent sample t-test and Chi square or Fischer’s exact tests were used to test the significance of diffe-rence between two means and proportions respecti-vely. Mann-Whitney U-test was used to test the sig-nificance of difference between two medians, where data were skewed. Risk factors for infections were analyzed by logistic regression analysis.

ResulTs

A total of 199 episodes of hospitalizations with diagnosis of NS were screened, out of which 37 were excluded. Finally, 148 children with 162 episodes of hospitaliza-tions were enrolled (Figure 1). Baseline characteristics of the study population are depicted in Table 1. Indications for hospitalization were isolated anasarca (n = 81), ana-sarca with suspected infection (n = 59), suspected infec-tion without anasarca (n = 12), hypovolemia (n = 7), tetany (n = 2), and hypertensive encephalopathy (n = 1). None of the children had received pneumococcal vaccine in the past. There were four (2.5%) deaths in our study population, all due to multi-organ failure resulting from major infections.

Baseline demographic, clinical, and laboratory characteristics of admitted children with and without infections are shown in Table 2. Age, gender, dura-tion of NS, remission status, type of NS, immunosup-pressive treatment, and biochemical parameters were not significantly different between the two groups. Duration of hospital stay in children with infection was significantly higher in comparison to children wi-thout infection (12 versus 8 days, p < 0.001).



527

Figure 1. Study flow chart.

There were 71 episodes of major infections out of 162 hospitalizations, amounting to 43.8% incidence of major infections in hospitalized children with NS. Out of 71 episodes of major infections, bacterial pe-ritonitis (n = 17, 24%), pneumonia (n = 13, 18%), urinary tract infection (n = 11, 15%), and cellulitis (n = 10, 14%) accounted for the majority (71%), follo-wed by acute diarrhea (n = 4), acute viral hepatitis (n = 4), tuberculosis (n = 3), typhoid (n = 3), measles, va-ricella, malaria, and sepsis (n = 1 each). Streptococcus pneumoniae was the predominant organism isolated from blood and ascitic fluid (n = 9, 8 in blood and one in ascitic fluid). E. coli was the commonest organism isolated from urine (n = 7), followed by Enterococcus faecium (n = 2), Klebsiella (n = 1) and Proteus (n = 1).

Nocardia and Cryptococcus neoformans were isola-ted from pleural and cerebrospinal fluid respectively from one child each (Table 3).

On logistic regression analysis, serum albumin < 1.5 g/dL was found as the only risk factor for major infections (OR 2.6; 95% CI, 1.2–6; p = 0.01) as well as peritonitis (OR 29; 95% CI, 3–270; p = 0.003). Age, gender, duration of disease, types of NS, immu-nosuppressive therapy and high serum cholesterol were not associated with increased risk of major in-fections and peritonitis (Table 4).

discussion

In our study, incidence of major infections in hospitali-zed children with NS was 43.8%, peritonitis being the



528

Parameters (n = 162)

Age in years, means and SD 5.3 ± 3.0

Age in years, median (IQR) 4.5 (3-8)

Age of onset of disease (years) 3.5 ± 2.3

Duration of nephrotic syndrome (years), median, IQR 1 (0-2.5)

Male, n (%) 86 (53%)

Type of NS, n (%)

Initial episode 49 (30.2)

IFRNS 33 (20.4)

FRNS/ SDNS 50 (31)

SRNS 30 (18.5)

Remission status

Remission 11 (7)

Relapse 102 (63)

Initial episode 49 (30)

Treatment received

No treatment 36 (22.2)

Only prednisolone 88 (54.3)

Prednisolone with Levamisole 6 (3.7)

Prednisolone with cyclosporine 15 (9.3)

Prednisolone with cyclophosphamide 12 (7.4)

Prednisolone with MMF 3 (1.9)

Rituximab 2 (1.2)

Weight (Kg) 18.8 ± 9.1

Height (cm) 104 ± 20

Hb (g/dL) 11.5 ± 2.1

S. Creatinine (mg/dL) 0.58 ± 0.3

S. Albumin (g/dL) 1.5 ± 0.5

S. Cholesterol (mg/dL) 473 ± 151

Types of infections, n (% out of total number of infections)

Peritonitis 17 (24.2)

Pneumonia 13 (18.5)

UTI 11(15.7)

Cellulitis 10 (14.2)

Acute diarrhea 4 (5.7)

Typhoid 3 (4.3)

Hepatitis 4 (5.7)

Tuberculosis 2 (2.8)

Meningitis 2 (2.8)

Varicella 1 (1.4)

Measles 1 (1.4)

Malaria 1 (1.4)

Sepsis 2 (2.8)

Death, n (%) 4 (2.5)

Duration of hospital stay (days) 10 ± 6.8

Table 1. basElinE charactEristics of study population

IQR: interquartile range; NS: nephrotic syndrome; IFRNS: Infrequently relapsing nephrotic syndrome; FRNS: frequently relapsing nephrotic syndrome; SDNS: steroid dependent nephrotic syndrome; SRNS: steroid resistant nephrotic syndrome; MMF: mycophenolate mofetil; UTI: urinary tract infection.



529

Parameters Infection (n = 71)Without

infection (n = 91)p value; RR, 95% CI

Age (years) 5.4 ± 3.1 5.2 ± 2.9 0.67

Age of onset of disease (years) 3.4 ± 2.2 3.6 ± 2.3

Duration of nephrotic syndrome (years), median IQR 1 (0.5-3) 0.8 (0-2) 0.46

Male, n (%) 38 (53%) 48 (53%)

Type of NS, n (%) 0.49

Initial episode 17 (24) 32 (35)

IFRNS 16 (23) 17 (19)

FRNS/SDNS 23 (32) 27 (30)

SRNS 15 (21) 15 (16)

Remission status 0.30

Remission 6 (9) 5 (6)

Relapse 48 (67) 54 (59)

Initial episode 17 (24) 32 (35)

Treatment received 0.09

No treatment 13 (19) 23 (24)

Only prednisolone 41 (57) 47 (52)

Prednisolone with Levamisole 0 (0) 6 (6.6)

Prednisolone with cyclosporine 9 (13) 5 (5.5)

Prednisolone with cyclophosphamide 6 (9) 6 (6.6)

Prednisolone with MMF 1 (2) 2 (2.2)

Rituximab 1 (2) 2 (2.2)

Weight (Kg) 19.1 ± 9.4 18.6 ± 9 0.79

Height (cm) 103.6 ± 20 104 ± 20 0.84

Hb (g/dL) 11.6 ± 2.2 11.5 ± 2 0.66

S. Creatinine (mg/dL) 0.5 ± 0.3 0.6 ± 0.3 0.23

S. Albumin (g/dL) 1.5 ± 0.5 1.6 ± 0.5 0.28

S. Cholesterol (mg/dL) 447 ± 145 488 ± 133 0.06

Death, n (%) 4 (5.6) 0 0.03*; 2.4 (1.9-2.8)

Duration of hospital stay (days) 12 ± 8 8 ± 5 0.001*

Table 2. basElinE clinical and hEmatological charactEristics in nEphrotic childrEn with and without.

RR: relative risk; IQR: interquartile range; NS: nephrotic syndrome; IFRNS: Infrequently relapsing nephrotic syndrome; FRNS: frequently relapsing nephrotic syndrome; SDNS: steroid dependent nephrotic syndrome; SRNS: steroid resistant nephrotic syndrome; MMF: mycophenolate mofetil. * p value significant.

Culture site Samples screened Sample positive for

growth, n (%)Organism identified, n (%)

Blood 148 12 (8)

Streptococcus pneumoniae: 8 (66)

Salmonella typhi: 3 (25)

Pseudomonas: 1(9)

Urine 85 11 (13)

E. coli: 7 (64)

Enterococus fecium: 2 (18)

Klebsiella: 1 (9)

Proteus: 1 (9)

Ascitic fluid 34 1 (3) Streptococcus pneumoniae, 1 (9)

Pleural fluid 1 1 Nocardia, 1 (9)

CSF 2 1 Cryptococcus Neoformans,1 (9)

Table 3. microorganism growth pattErn in major infEctions in childrEn with nEphrotic syndromE

CSF- cerebrospinal fluid.



530

commonest infection, followed by pneumonia and UTI. Serum albumin level less than 1.5 g/dL was the only inde-pendent risk factor for major infections including perito-nitis. Duration of hospital stay was significantly higher in children with infections in comparison to without infec-tion. There were four deaths (2.5%) in our study, all due to sepsis with multiorgan failure.

Major infections in children with NS have been re-ported from different parts of India and neighboring countries, with incidence varying from 20–38%.3-8 The relatively higher incidence of infection in our stu-dy population can be explained by referral bias and high index of clinical suspicion for infections in these children. In contrast, studies where minor infections were included as well 9-15, like upper respiratory tract infections, reported very high incidence of infection varying from 76% to 84%.

Peritonitis (24%) was the commonest infection in our study, similar to studies from other parts of the country.4-8 Studies have shown incidence of peritonitis in childhood NS ranging from 2.6–26%.7-9,13 Differently

from our study, where Streptococcus pneumoniae was the only organism isolated from children with peritoni-tis, Senguttuvan et al.7 observed E.coli and Klebsiella as predominant organisms in peritonitis. None of the chil-dren in our study were immunized with pneumococcal vaccine. Given that pneumococcal vaccine is not inclu-ded in our national immunization schedule, the majo-rity of children coming to public sector hospitals are at risk of invasive pneumococcal diseases. However, revi-sed guidelines on the management of NS from Indian Pediatric Nephrology Group suggest that all children with NS should receive vaccination against pneumococ-cal infections.12

In our study, UTI was the 3rd most common in-fection, comprising 15% of all major infections. In contrast, studies on infections in NS from two diffe-rent parts of India reported UTI as the commonest infection, with incidence varying from 13.7 to 46%.3,7 In another study from Saudi Arabia, UTI was the most common major infection, comprising 25% of total in-fections.14 In one of the largest retrospective analysis

Risk factors for infection

Parameters Odds Ratio (OR) 95% CI p value

Male 1.3 0.6-3 0.45

Age 1 0.8-1.3 0.58

Duration of disease 1 0.8-1.2 0.78

Serum Albumin < 1.5 g/dL 2.6 1.2-6 0.01*

Serum Cholesterol > 500 mg/dL 0.6 0.2-1.3 0.22

Platelets > 500 cells/mm3 0.8 0.4-1.8 0.66

FRNS/SDNS 4.5 0.8-26 0.09

IFRNS 5 0.8-32 0.08

SRNS 6.6 0.9-46 0.06

Immunosuppressant therapy 0.3 0.05-2 0.22

Risk factors for peritonitis

Parameters Odds Ratio (OR) 95% CI p value

Male 2.8 0.7-10.3 0.10

Age 0.9 0.7-1.2 0.80

Duration of disease 1.2 0.9-1.8 0.18

Serum Albumin < 1.5 g/dL 29 3-270 0.003*

Serum Cholesterol > 500 mg/dL 0.2 0.05-1.2 0.08

Platelets > 500 cells/mm3 2.1 0.6-8.3 0.25

FRNS/SDNS 1.5 0.2-19 0.74

IFRNS 3.1 0.2-42 0.38

SRNS 11.1 0.8-157 0.07

Immunosuppressant therapy 1.8 0.08-40 0.71

Table 4. risK factors for major infEctions and pEritonitis in childrEn with nEphrotic syndromE

IFRNS: Infrequently relapsing nephrotic syndrome; FRNS: frequently relapsing nephrotic syndrome; SDNS: steroid dependent nephrotic syndrome; SRNS: steroid resistant nephrotic syndrome; CI: confidence interval.



531

in children with NS to determine the incidence of UTI, 15% of children were found to have UTI, with more than 50% being asymptomatic and diagnosed as a part of screening investigations for relapse and non-respon-se.15 This highlights the importance of screening for UTI in all children with NS with relapse or non-response to steroids, as symptoms may be masked because of anti--inflammatory action of steroids.

Very few studies have assessed risk factors for ma-jor infections in children with NS. In concordance wi-th the literature, we found hypoalbuminemia as a risk for peritonitis in our study.2,3,13 Severity of hypoalbu-minemia serves as a marker for urinary loss of im-munoglobulins and complement factors required for opsonization, phagocytosis, and host defense. We did not find hypercholesterolemia as a risk factor for in-fection, in contrast to a study from south India,8 whe-re serum cholesterol > 400 mg/dL was found to be an independent risk factor for peritonitis. In contrast to earlier studies,3,8,11 we did not observe a higher risk of infection in children suffering from more severe types of NS in comparison to initial episodes. Senguttuvan et al,7 showed higher risk of infection in children re-ceiving a combination of prednisolone and cyclophos-phamide. However, we did not find increased risk of infection in children receiving prednisolone alone or in combination with any other immunosuppressive agent in comparison to no treatment, confirming that these children remain in a state of immunosuppres-sion and increased risk of infection irrespective of im-munosuppressive therapy.

In our study, four children (2.5%) died of sepsis with multiorgan failure. The International Study of Kidney Disease in Children (ISKDC) followed almost 389 chil-dren with minimal change disease for 5–10 years and reported ten deaths, of which six were due to infection.16 In contrast, Srivastava et al.4 reported a very high death rate with 13% of children dying of infection, mostly wi-thin 24 hours of admission, indicating fulminant nature of infections associated with NS. The fewer deaths in our study can be explained by early presentation, high index of suspicion for infections and prompt institution of treatment.

To conclude, infections are common in hospitali-zed children with NS resulting in significant morbidity and mortality. Hypoalbuminemia was an independent risk factor for major infections, including peritonitis. As pneumococcus was the most prevalent cause for infections in our study population, attention should

be paid to pneumococcal immunization in children with NS. These children should receive recommended doses of pneumococcal conjugate vaccine (PCV-13), followed by pneumococcal polysaccharide vaccine (PPSV-23) early in the course of disease.17

Limitations of our study include not measuring serum immunoglobulin as well as complement levels. Our study did not have adequate power for assessing risk factors for infection. Adequately powered studies with larger sample sizes are needed to assess risk fac-tors for major infections and peritonitis in nephrotic children.

auThoRs’ conTRibuTions

MK and DS conceptualized the study. JG enrolled the patients, collected the data, and was involved in patient management. MK prepared the initial draft, and performed the analysis and interpretation of da-ta. MK, DS and VM revised the draft. All the authors approved the final version of the manuscript. MK will act as a guarantor for the manuscript.



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1. Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet. 2018 Jul 7;392(10141):61-74.

2. Hingorani SR, Weiss NS, Watkins SL. Predictors of peritonitis in children with nephrotic syndrome. Pediatr Nephrol. 2002 Aug;17(8):678-82.

3. Gulati S, Kher V, Gupta A, Arora P, Rai PK, Sharma RK. Spec-trum of infections in Indian children with nephrotic syndrome. Pediatr Nephrol. 1995 Aug; 9(4):431-4.

4. Srivastava RN, Moudgil A, Khurana O. Serious infections and mortality in nephrotic syndrome. Indian Pediatr. 1987 Dec;24(12):1077-80.

5. Wei CC, Yu IW, Lin HW, Tsai AC. Occurrence of infection among children with nephrotic syndrome during hospitaliza-tions. Nephrology (Carlton). 2012 Nov;17(8):681-8.

6. Krishnan C, Rajesh TV, Shashidhara HJ, Jayakrishnan MP, Geeta MG. Major infections in children with nephrotic syndro-me. Int J Contemp Pediatr. 2017 Mar/Apr;4(2):346-50.

7. Senguttuvan P, Ravanan K, Prabhu N, Tamilarasi V. Infections encountered in childhood nephrotics in a pediatric renal unit. Indian J Nephrol. 2004;14:85-8.

8. Ajayan P, Krishnamurthy S, Biswal N, Mandal J. Clinical spec-trum and predictive risk factors of major infections in hospita-lized children with nephrotic syndrome. Indian Pediatr. 2013 Aug;50(8):779-81.

9. Alwadhi RK, Matthew JL, Rath B. Clinical profile of children with nephrotic syndrome not on glucocorticoid therapy, but presenting with infection. J Paediatr Child Health. 2004 Jan/Feb;40(1-2):28-32.

10. Moorani KN, Raj M. Spectrum of infections in children with newly diagnosed primary nephrotic syndrome. Pak J Med Res. 2012 Jan/Mar;51(1):10-14.



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11. Sinha A, Hari P, Sharma PK, Gulati A, Kalaivani M, Mantan M, et al. Disease course in steroid sensitive nephrotic syndro-me. Indian Pediatr. 2012 Nov;49(11):881-7.

12. Indian Pediatric Nephrology Group, Indian Academy of Pedia-trics, et al. Management of steroid sensitive nephrotic syndro-me: revised guidelines. Indian Pediatr. 2008 Mar;45(3):203-14.

13. Uncu N, Bülbül M, Yildiz N, Noyan A, Koşan C, Kavukçu S, et al. Primary peritonitis in children with nephrotic syndro-me: results of a 5-year multicenter study. Eur J Pediatr. 2010 Jan;169(1):73-6.

14. Alfakeekh K, Azar M, Sowailmi BA, Alsulaiman S, Makdob SA, Omair A, et al. Immunosuppressive burden and risk factors of infection in primary childhood nephrotic syndrome. J Infect Public Health. 2018 Jan/Fev;12(1):90-94.

15. Narain U, Gupta A. Urinary Tract Infection in Children With Nephrotic Syndrome. Pediatr Infect Dis J. 2018 Feb;37(2):144-146.

16. International Study of Kidney Disease in Children. Minimal change nephrotic syndrome in children, deaths occurring during the first 5 to 15 years’ observation. Pediatrics. 1984 Apr;73(4):497-501.

17. Nuorti JP, Whitney CG, Centers for Disease Control and Pre-vention (CDC). Prevention of pneumococcal disease among infants and children - use of 13-valent pneumococcal con-jugate vaccine and 23-valent pneumococcal polysaccharide vaccine recommendations of the Advisory Committee on Im-munization Practices (ACIP). MMWR Recomm Rep. 2010 Dec;59(RR-11):1-18.

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AuthorsGuilherme Palhares Aversa Santos¹

Luis Gustavo Modelli de Andrade¹

Mariana Farina Valiatti¹

Mariana Moraes Contti¹

Hong Si Nga¹

Henrique Mochida Takase¹

1 Universidade Estadual Paulista, Faculdade de Medicina de Botucatu, Departamento de Clínica Médica, Botucatu, SP, Brasil.


Correspondence to:Guilherme Palhares Aversa SantosE-mail: [email protected]

Kidney transplantation with donors in severe acute kidney injury. Should we use these organs? Retrospective Case SeriesTransplante renal com doadores em lesão renal aguda severa. Devemos utilizar esses órgãos? Série de casos retrospectiva

Introdução: O número de pacientes incidentes e prevalentes em diálise tem aumentado, assim como o número de candidatos ao transplante renal no Brasil, sem um aumento proporcional do número de doadores de órgãos. O uso de rins expandidos, quanto à função renal, pode ser uma alternativa para aumentar a oferta de órgãos. Objetivo: discutir a viabilidade do uso de rins expandidos quanto à função renal, que estejam em lesão renal aguda severa. Métodos: foram avaliados todos os casos de transplante renal de doador falecido realizados no Hospital das Clínicas de Botucatu da UNESP, de janeiro de 2010 a junho de 2018, totalizando 732 casos. Selecionou-se os casos com creatinina final do doador maior do que 6 mg/dL. Resultados: quatro pacientes foram selecionados, dos quais todos os doadores estavam em lesão renal aguda (LRA) severa. Esses doadores apresentavam rabdomiólise como provável causa de LRA severa, eram jovens, sem comorbidades e apresentavam diminuição de volume urinário nas últimas 24 horas. A evolução clínica de todos os receptores foi satisfatória, com taxa de filtração glomerular após o transplante variando entre 48 a 98 mL/min/1,73m². Conclusão: essa série de casos mostra a possibilidade de utilização de doadores renais em LRA severa, desde que respeitadas as condições seguintes: idade do doador, rabdomiólise como causa de LRA e achados de biópsia favoráveis à implantação. Estudos adicionais com melhores desenhos, maior número de pacientes e maiores tempos de seguimento são necessários.

Resumo

Palavras-chave: Transplante de Rim; Doadores de Tecidos; Função Retardada do Enxerto; Lesão Renal Aguda.

Introduction: The number of incident and prevalent patients on dialysis has increased, as well as the number of candidates for renal transplantation in Brazil, without a proportional increase in the number of organ donors. The use of expanded kidneys, as to renal function, may be an alternative to increase the supply of organs. Objective: to discuss the feasibility of using expanded kidneys for renal function, which are in severe acute renal injury. Methods: All cases of renal transplantation of deceased donors performed at the Hospital das Clínicas de Botucatu of UNESP, from January 2010 to June 2018, totaling 732 cases were evaluated. Cases with final donor creatinine greater than 6 mg/dL were selected. Results: four patients were selected, of whom all donors were in severe acute kidney injury (AKI). These donors presented rhabdomyolysis as a probable cause of severe AKI, were young, with no comorbidities and had decreased urinary volume in the last 24 hours. The clinical evolution of all the recipients was satisfactory, with a glomerular filtration rate after transplantation ranging from 48 to 98 mL/min/1.73 m². Conclusion: this series of cases shows the possibility of using renal donors in severe AKI, provided the following are respected: donor age, rhabdomyolysis as the cause of AKI, and implantation-favorable biopsy findings. Additional studies with better designs, larger numbers of patients and longer follow-up times are needed.

absTRacT

Keywords: Kidney Transplantation; Tissue Donors; Delayed Graft Function; Acute Kidney Injury.

DOI: 10.1590/2175-8239-JBN-2018-0264

https://orcid.org/0000-0002-4853-3506

https://orcid.org/0000-0002-0230-0766

https://orcid.org/0000-0001-9744-9274

https://orcid.org/0000-0003-1267-4312

https://orcid.org/0000-0002-1993-0254

https://orcid.org/0000-0002-6815-0588


Renal transplant with donors in severe acute kidney injury

534

inTRoducTion

In recent years, the number of incident and prevalent dialysis patients has increased, as has the number of renal transplant candidates in Brazil,¹ without a proportional increase in the number of organ donors. The use of renal donors with expanded criteria is a measure that may help in solving this problem and has been increasingly adopted.² Kidneys of donors with acute kidney injury (AKI) - KDIGO III, considered expanded kidneys as to renal function, are frequently discarded³ but its use may contribute to a greater supply of organs.

The objective of this series of cases was to discuss the feasibility of expanded kidneys with severe acute renal injury being used for renal function.

meThod

This is an observational, retrospective, case-series study. All cases of renal transplantation performed at the Hospital das Clínicas of UNESP from January 2010 to June 2018 were reviewed. Our goal was to evaluate the most severe and more challenging cases of AKI donors for the transplantation under the clinical viewpoint, in this eight-year period, we selected all patients transplanted from a deceased donor with a final creatinine level greater than 6 mg/dL. This creatinine cutoff value was based on the retrospective study carried out by Heilman et al., in which the maximum final creatinine of donors with AKI was 6.29 mg/dL.4

ResulTs

A total of 732 transplant recipients from deceased donors were found in the period, of which 4 fulfilled the selection criteria. Clinical and laboratory data are described below.

Case 1. Female, 44 years old, having granuloma-tosis with polyangeitis as baseline disease, peritoneal dialysis for 2 years and 11 months, residual diure-sis of 600 mL, antibody reactivity panel (ARP) of 0. Donor: female, 37 years old, cause of death, traumat-ic HSA after severe head injury, without comorbidi-ties, three days of hospitalization in Intensive Care Unit (ICU), using Clavulanic acid to treat an infec-tive pulmonary focus and noradrenaline 1.8 mcg/kg/min, diuresis of 300 mL in the past 24 hours, initial creatinine of 1.1 mg/dL, final creatinine of 7.4 mg/dL, CPK of 8,688 U/L, Kidney Donor Profile Index

(KDPI) of 46%. Uptake renal biopsy with signs of ATN. Cold ischemia duration (CID) of 23 hours and 30 minutes, induction therapy with methylpredniso-lone 500 mg and thymoglobulin 3 mg/kg and main-tenance therapy with tacrolimus, everolimus and prednisone. The transplantation occurred without problems, with no urologic or vascular complica-tions. The patient had delayed graft function (DGF) in the postoperative period, with progressive im-provement of nitrogenous waste and urinary output from the second week after transplantation. She was discharged from the hospital on the 30th postopera-tive day. Currently, with two years and eight months of transplantation, she has creatinine of 1.0 mg/dL and TFG (by CKD-epi) of 67 mL/min/1.73 m².

Case 2. Male, 38 years old, unknown baseline disease, without residual diuresis, in renal replace-ment therapy for 9 years and 5 months, under he-modialysis, ARP of 0. The donor is the same as that of Case 1 patient. TIF of 25 hours and 5 minutes, induction therapy with methylprednisolone 500 mg and thymoglobulin 3 mg/kg and maintenance ther-apy with tacrolimus, everolimus and prednisone. Transplantation occurred without intercurrences, with no urologic or vascular complications. He developed DGF, with partial improvement of the waste and urine output from the 14th day of hos-pitalization. On account of prolonged DGF, he was biopsied at the 18th postoperative day, with pa-thology compatible with ATN. He was discharged in the 28th postoperative day. C urrently, with the same time of transplantation as the patient of case 1, he has a GFR of 58 mL/min/1.73 m².

Case 3. Female, 52 years old, unknown base-line disease, on hemodialysis for 4 years and 11 months, residual diuresis of 500 mL, ARP of 34%. The donor, A 43-year-old male smoker, had acute subdural hematoma after traumatic head injury as the cause of death, two days of ICU, using nor-adrenaline 0.8 mcg/kg/minute, vasopressin 6 IU/hour, diuresis in the last 24h of 120 mL, initial cre-atinine of 1.1 mg/dL and final creatinine of 12.2 mg/dL, CPK of 58,124 U/L, 54% KDPI. The up-take renal biopsy presented ATN. TIF of 22 hours and 46 minutes, induction therapy with methyl-prednisolone 500 mg and thymoglobulin 4.5 mg/kg (divided into 1.5 mg/kg initiated on anesthetic induction, and then 1 mg/kg for 3 more days) and therapy with tacrolimus, mycophenolate and



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prednisone. Surgery occurred without complica-tions, with no vascular or urologic complications. Patient evolved with DGF, being biopsied in the 13th postoperative due to prolonged DGF, histo-pathologically compatible with ATN. There was an increase in urine output and progressive waste formation from the 21st day of hospitalization. He presented several infectious intercurrences (UTI, esophageal moniliasis, cytomegalovirus infection); he was discharged from the hospital in the 46th postoperative day. Currently, after 5 months and 13 days of transplantation, he has a creatinine lev-el of 0.8 mg/dL and GFR of 98 mL/min/1.73 m².

Case 4. Male, 35 years, unknown baseline dis-ease for 1 year and 5 months, residual diuresis of 1000 mL, ARP of 0. Male donor, 35 years old, traumatic HI as cause of death, chronic alcoholic, 6 days of ICU, diuresis of 350 mL in the last 24 hours using noradrenalin 0.16 mcg/kg/min, ini-tial creatinine of 1.1 mg/dL and final of 6.5 mg/dL, CPK of 11,922 IU/L, 33% KDPI. Uptake re-nal biopsy ATN-compatible. TIF of 20h33 min-utes. Induction therapy with 500 mg of methyl-prednisolone and thymoglobulin 4.5 mg/kg, and maintenance with tacrolimus, mycophenolate and prednisone. Surgery occurred without complica-tions, with no urologic or vascular complications. He evolved with DGF, underwent a biopsy on the 15th postoperative day with ATN findings. As of the 21st postoperative day, there was a renal func-tion improvement, and he was discharged on the 29th POD. Currently, after 6 months and 12 days of transplantation, he has creatinine of 1.8 mg/dL and GFR of 48 mL/min/ 1.73 m².

Table 1 depicts clinical and laboratory data from donors and recipients.

discussion

In this retrospective series of four cases, we evaluated the experience of a tertiary care hospital with kidney transplantation from donors in KDIGO III AKI and with final creatinine higher than 6 mg/dL.

All donors in this series are considered to be of the standard category according to the classic criteria of United Network for Organ Sharing (UNOS)5 expanded donors, but we can consider them to be borderline in renal function. Donors in this series were young, were on KDIGO III AKI and had renal biopsy of the ATN uptake (with no significant histological changes in the glomerular, tubule-interstitial and vascular compartments). The most likely renal insults were ischemic and nephrotoxic by rhabdomyolysis, with good prospects for recovery.

Regarding renal donors with altered creatinine, Kayler et al., in a retrospective study using the American transplant registry system, showed that, for standard criteria donors, the increase in serum creatinine in the donation was not associated with a decrease in survival graft, despite a higher percentage of DGF. In addition, for standard donors, the presence of final creatinine greater than 2 mg/dL increased the risk of organ rejection 7 fold,3 showing an underuse of these organs.

Boffa et al., In a retrospective study, analyzed the UK transplant registration system between 2003 and 2013. The presence of AKI in the donor increased the likelihood of kidney discarding, and the longer the stage of AKI, the greater the risk of not using the organ. In kidney donors with AKIN III AKI, the risk of organ rejection increased from 3 to 20 fold.6 There was little difference in graft survival comparing kidneys from donors with AKI and those without AKI (91% vs. 89%, p = 0.02). However, when compared with the

Cr (1) Cr (2) Cr (3) Cr (4) Cr (7)Uptake biopsy

Donor age

C.P.K. (UI/mL)

ARP (%)

UO (mL)

Case 1 6.3 6.4 4.4 2 1.1 ATN 37 8688 0 300

Case 2 8.6 13.7 9.1 5.1 1.6 ATN 37 8688 0 300

Case 3 8.3 3.5 6.1 1.8 0.8 ATN 43 58124 34 120

Case 4 9.8 15.6 7.7 4.4 2.2 ATN 35 11922 0 350

Table 1. clinical and laboratory data from donors and rEcipiEnts

Note: C.P.K: creatine phosphokinase. Cr (1): cr in the 1st week, Cr(2): cr in the 2nd week, Cr(3): cr in the 3rd week, Cr(4): cr in the 4th week, Cr(7): cr in the 7th. UO: Donor’s urinary output in the past 24h. ARP: antibodies reaction panel. ATN: Acute Tubular Necrosis.



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survival of patients in the queue for transplantation or on dialysis, this small difference does not have clinical relevance. In this study, there was an association between donors with a higher stage of AKI (AKIN III) and a higher rate of non-functioning primary organs; however, the number of donors with AKIN III AKI was small in the sample studied.

Zheng et al., in a systematic review and meta-analysis of 2018 with 14 cohort studies, involving 15,345 donors, did not find a significant difference in relation to graft survival and in relation to primary non-functioning organs, when comparing kidney recipients from AKI donors with those without AKI.7 Graft survival was assessed within one to ten years after transplantation. In addition, GFR and episodes of acute rejection were similar between the groups. In patients with AKI, there was longer hospital stay and a higher incidence of DGF.

Heilman and colleagues retrospectively assessed the outcomes of 162 kidney recipients from AKI donors over a period of about 9 years. Of these recipients, 139 received kidneys considered standard according to UNOS. It is noteworthy that among these standard kidney donors, 50% were oligoanuric, 71% with AKIN III stage AKI and 21% required renal replacement therapy. The final maximum creatinine in this group of standard donors in AKI was 6.29 mg/dL. However, with the exception of DGF, which was higher in the group of patients with AKI, there was no difference in the incidence of acute rejection and graft survival in one year compared to patients who transplanted in the same period and received kidneys from donors who were not in AKI.4

Donor age, one of the criteria for considering an offered kidney as borderline, is well established as a condition that requires histological evaluation of the kidney to be implanted.5,8 This characteristic is also important to consider in cases of renal donation whose donor is in AKI, the age of the donor, rather than the final creatinine value has a greater association with outcome and worsening renal function in 6 months.9

The histological assessment of the AKI kidneys is fundamental, as it shows their viability before implantation. The absence or discrete histological lesions correlate with good graft survival in one year, favoring the use of the organ offered; while the presence of moderate to severe lesions correlates with poor graft survival, making transplantation unwise.10,11 Kyler and colleagues reviewed 597 renal

donor biopsies performed between 1987 and 2006; arteriosclerosis, or moderate arteriolosclerosis, defined as a decrease in vascular lumen equal to or greater than 25%, were independently associated with poorer graft survival at one, three, and five years for both standard and marginal donors.10

Regarding the clinical course of AKI, these three donors were in a clear phase with oliguria, and the possibility of acute renal support could be considered, except for the condition of brain death. Such a clinical evolution could have led to organ rejection in many transplantation centers.

Tomita et al. Reported their experience with eight cardiac arrest donors who presented KDIGO III AKI, with creatinine greater than 10 mg/dL, prior to renal uptake. However, unlike the present series of cases, at the time of collection, patients already had adequate urine output and recovery of renal function. Most of these patients had good renal function after the first month of transplantation, as occurred with our patients, and adequate long-term graft survival.12

It is possible to argue that all three donors in this study had AKI for rhabdomyolysis. In a retrospective observational study carried out by Chen et al., they analyzed 30 patients diagnosed with KDIGO III AKI kidneys during rhabdomyolysis, compared to 90 patients who received standard kidneys, and they reported that there was no statistical difference in relation to creatinine and GFR at months 2, 6, 12 and 24; there was also no difference in the incidence of rejection,13 showing good graft function in the long term.

All patients reported in this series had DGF, as expected, since the percentage of graft delay in renal donors with AKI is high.6,7,8,9 The main risk factor and probable etiological factor for DGF is the KDIGO III AKI diagnosis validity prior to donation. Other risk factors include the long dialysis time prior to transplantation in the first case and the 25-hour CID in the third case.

The results and outcomes of this series of cases should be considered according to the nature of this study, that is, with limited power of association and generalization. Studies with more patients and longer follow-up are necessary.

conclusion

This case series shows the possibility of using KDIGO III AKI donor kidneys with high final creatinine;



537

observing the donor age conditions, kidney biopsy without histological lesions or discrete lesions and ischemic AKI with rabdomyolysis. Further studies, with better designs and larger numbers of patients are needed in order to assess the true possibility of using these kidneys.

authors' contributions

Guilherme Palhares Aversa Santos, Luis Gustavo Modelli de Andrade, Mariana Farina Valiatti, Mariana Moraes Contti, Hong Si Nga, Henrique Mochida Takase contributed substantially to the conception or design of the study; collection, analysis, or interpretation of data; writing or critical review of the manuscript; and final approval of the version to be published.

conflict of intErEst

The authors declare that they have no conflict of interest related to the publication of this manuscript.

RefeRências

1. Sociedade Brasileira de Nefrologia (SBN). Censo da Sociedade Brasileira de Nefrologia 2017. São Paulo: Sociedade Brasilei-ra de Nefrologia; 2018 [cited 2018 Oct 20]. Available from: https://sbn.org.br/o-censo-2017-foi-publicado-confira/

2. Querard AH, Le Borgne F, Dion A, Giral M, Mourad G, Gar-rigue V, et al. Propensity score-based comparison of the graft failure risk between kidney transplant recipients of standard and expanded criteria donor grafts: Toward increasing the pool of marginal donors. Am J Transplant 2018;18:1151-7. DOI: https://doi.org/10.1111/ajt.14651

3. Kayler LK, Garzon P, Magliocca J, Fujita S, Kim RD, Hemming AW, et al. Outcomes and utilization of kidneys from deceased donors with acute kidney injury. Am J Transplant 2009;9:367-73. DOI: https://doi.org/10.1111/j.1600-6143.2008.02505.x

4. Heilman RL, Smith ML, Kurian SM, Huskey J, Batra RK, Chakkera HA, et al. Transplanting Kidneys from Deceased Donors With Severe Acute Kidney Injury. Am J Transplant 2015;15:2143-51. DOI: https://doi.org/10.1111/ajt.13260

5. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Mer-ion RM. Expanded criteria donors for kidney transplantation. Am J Transplant 2003;3:114-25. DOI: https://doi.org/10.1034/j.1600-6143.3.s4.11.x

6. Boffa C, van de Leemkolk F, Curnow E, Homan van der Heide J, Gilbert J, Sharples E, et al. Transplantation of Kidneys From Donors With Acute Kidney Injury: Friend or Foe? Am J Transplant 2017;17:411-9. PMID: 27428556 DOI: https://doi.org/10.1111/ajt.13966

7. Zheng YT, Chen CB, Yuan XP, Wang CX. Impact of acute kid-ney injury in donorson renal graft survival: a systematic review and Meta-Analysis. Ren Fail 2018;40:649-56. DOI: https://doi.org/10.1080/0886022X.2018.1535982

8. Remuzzi G, Cravedi P, Perna A, Dimitrov BD, Turturro M, Locatelli G, et al.; Dual Kidney Transplant Group. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006;354:343-52. PMID: 16436766 DOI: https://doi.org/10.1056/NEJMoa052891

9. Si Nga H, Takase HM, Bravin AM, Garcia PD, Contti MM, Kojima CA, et al. Good Outcomes in Kidney Transplantation With Deceased Donor With Acute Kidney Injury: Donor's Age and Not Acute Kidney Injury Predicts Graft Function. Trans-plant Proc 2016;48:2262-6. PMID: 27742275 DOI: https://doi.org/10.1016/j.transproceed.2016.06.004

10. Kayler LK, Mohanka R, Basu A, Shapiro R, Randhawa PS. Correlation of histologic findings on preimplant biopsy with kidney graft survival. Transpl Int 2008;21:892-8. DOI: https://doi.org/10.1111/j.1432-2277.2008.00681.x

11. Ugarte R, Kraus E, Montgomery RA, Burdick JF, Ratner L, Haas M, et al. Excellent outcomes after transplantation of deceased donor kidneys with high terminal creatinine and mild patholog-ic lesions. Transplantation 2005;80:794-800. PMID: 16210967 DOI: https://doi.org/10.1097/01.TP.0000173801.33878.BF

12. Tomita Y, Iwadoh K, Ogawa Y, Miki K, Kai K, Sannomiya A, et al. Single Graft Utilization From Donors With Se-vere Acute Kidney Injury After Circulatory Death. Trans-plant Direct 2018;4:e355. DOI: https://doi.org/10.1097/TXD.0000000000000768

13. Chen CB, Zheng YT, Zhou J, Han M, Wang XP, Yuan XP, et al. Kidney transplantation from donors with rhabdomyolysis and acute renal failure. Clin Transplant 2017;31. DOI: https://doi.org/10.1111/ctr.13021

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rEviEw articlE | artigo dE rEvisão

AuthorsNatasha Silva Constancio1,5

Maria Lucia Gomes Ferraz2,4

Carmen Tzanno Branco Martins5

Angiolina Campos Kraychete5

Paulo Lisboa Bitencourt4

Marcelo Mazza do Nascimento3,5

1 Associação Renal Vida Rio do Sul, Rio do Sul, SC, Brasil.2 Universidade Federal de São Paulo, São Paulo, SP, Brasil.3 Universidade Federal do Paraná, Curitiba, PR, Brasil.4 Sociedade Brasileira de Hepatologia, São Paulo, SP, Brasil.5 Sociedade Brasileira de Nefrologia, São Paulo, SP, Brasil.


Correspondence to:Marcelo Mazza do Nascimento.E-mail: [email protected]

Hepatitis C in Hemodialysis Units: diagnosis and therapeutic approach

Hepatite C nas Unidades de Hemodiálise: diagnóstico e abordagem terapêutica

De acordo com os dados do último censo da Sociedade Brasileira de Nefrologia (SBN), a prevalência de portadores do vírus da hepa-tite C (HCV) nas unidades de hemodiálise (UH) no Brasil é de 3,3%, cerca de três vezes maior do que é observado na população ger-al brasileira. Muitas vezes, os profissionais que trabalham nas UH deparam-se com situ-ações clínicas que demandam rápido diag-nóstico do HCV, a fim de evitar uma trans-missão horizontal dentro das unidades. Por outro lado, a cura dos pacientes portadores do HCV, tanto na população geral como na portadora de doença renal crônica e a erradi-cação da doença, em virtude do desenvolvim-ento de novas drogas antivirais, parecem ser objetivos bastante factíveis, a ser alcançados em futuro próximo. Nesse cenário, a SBN e a Sociedade Brasileira de Hepatologia apresen-tam neste artigo de revisão uma proposta de abordagem do HCV dentro das UH.

Resumo

Palavras-chave: Hepatite C; Diálise Re-nal; Insuficiência Renal Crônica; Vírus de Hepatite; Antivirais.

According to data from the last census of the Brazilian Society of Nephrology (SBN), the prevalence of hepatitis C vi-rus (HCV) in Brazilian hemodialysis units (HU) is 3.3%, about three times higher than what is reported for the Brazilian general population. Often, profession-als working in HU are faced with clinical situations that require rapid HCV diagno-sis in order to avoid horizontal transmis-sion within the units. On the other hand, thanks to the development of new antivi-ral drugs, the cure of patients with HCV, both in the general population and in patients with chronic kidney disease and the disease eradication, appear to be very feasible objectives to be achieved in the near future . In this scenario, SBN and the Brazilian Society of Hepatology present in this review article a proposal to approach HCV within HUs.

absTRacT

Keywords: Hepatitis C; Renal Dialysis; Renal Insufficiency, Chronic; Hepatitis Viruses; Antiviral Agents.

DOI: 10.1590/2175-8239-JBN-2018-0177

inTRoducTion

Since its identification in 1989 by Choo et al.,1 the hepatitis C virus (HCV) has been causing concern in the scientific commu-nity because of the development of both acute and chronic liver disease, significan-tly increasing the risk of cirrhosis and he-patocellular carcinoma. Epidemiological data indicate that about 170 million people have chronic HCV infection.2-4 Regardless of country of origin, hepati-tis C prevalence is higher in hemodialy-sis (HD) patients,5-7 and its prevalence in different geographic regions vary widely, from 4% in England to more than 70%

in regions such as Kuwait and Cuba.7 According to data from the last SBN cen-sus of 2017, the prevalence in Brazil is 3.3%, about three times higher than that reported in the Brazilian general popula-tion,8,9 although a study that specifically evaluated the C virus epidemiology and genotyping in dialysis patients in Brazil has shown an even higher prevalence of 8.4%.10 Although high, these percentages are well below the 15.4% prevalence de-tected in this population 16 years ago.11 Still in agreement with US data available on the Centers for Disease Control (CDC) website, more than half of the hepatitis C

http://orcid.org/0000-0001-5442-8289

http://orcid.org/0000-0002-9602-4247


Hepatitis C in dialysis units

539

outbreaks from 2008 to 2015 occurred in HU settin-gs,12 noting that the risk of HCV infection increases as patient stay more time in HD.6

Unlike hepatitis B, the development of a hep-atitis C vaccine has not yet been possible.4 The challenge is even greater for many nephrologists because of the difficulty in diagnosing chronic C virus infection in dialysis patients because of the lower sensitivity of the diagnostic tests in this pop-ulation.7 Significant progress has been made in the last decade, culminating in a marked improvement in the treatment of HCV infection. Levels above 90% of sustained virological response (SVR) have been reached, including in the CKD population.13,14 Today there is a real promise of eliminating hepa-titis C in the next 15 to 20 years, but although we are experiencing a new era in relation to this disease, better knowledge about the number and characteristics of infected patients is needed to plan strategies for its eradication.3

Therefore, the Brazilian Society of Nephrology and the Brazilian Society of Hepatology propose in this article a guideline for HCV screening, the adop-tion of preventive measures within Dialysis Units (HU) and the therapeutic approach of dialysis pa-tients in our country.

discussion

diagnostic tEsts

SeroLogicaL teStS

HCV is an RNA virus that has 6 genotypes and mul-tiple subtypes (Figure 1). The prevalence of each ge-notype varies according to geographic region, with genotypes 1a and 1b being the most prevalent in the United States and Europe, followed by genotypes 2 and 3; whereas in Egypt the genotype 4 is the pre-ponderant one; in South Africa, genotype 5; and the genotype 6 in Southeast Asia.15 In Brazil, genotypes 1, 2 and 3 predominate.16

After cloning the HCV genome, scientists man-aged to determine the various viral proteins and an-tigenic regions and epitopes. Recombinant proteins and synthetic peptides, containing these dominant epitopes, were used in the development of immunoas-says, which enable the detection of the anti-HCV IgG immunoglobulin. The currently used 3rd generation immunoenzymatic assays (IEA) determine specific-ity of up to 99% and reduction in the immunological window period by approximately 5 weeks compared to 1st generation assays.17

RIBA (recombinant immunoblot assay) assays have emerged as more specific alternatives for anti-HCV detection than immunoassays, based on recom-binant peptides from specific antigenic regions, but they are not used in routine clinical practice, since, like the ELISA tests, they do not enable the differen-tiation between active and resolved infection, and its cost is high.

rna anaLySiS teStS

Even if 3rd generation tests are performed, immuno-assays may present false negative results in immuno-compromised and in HD patients.17 HCV nucleic acid (HCV-RNA) detection remains the gold standard in the diagnosis of active infection. Despite the excellent sensitivity and specificity, it is a more expensive and not always available test.

Detection of HCV-RNA by nucleic acid (NAT) as-says, by the polymerase chain reaction (PCR) or tran-scription-mediated amplification (TMA) method, can rapidly detect HCV infection, within approximately 1 week post-exposure by comparison to 10 weeks of the 3rd generation IEA. All NAT-based tests approved for clinical use have specificity above 99% for the 6 geno-types and viral load detection levels from 12 IU/mL and 10 IU/mL for PCR and TMA, respectively. Studies to confirm the phenomenon of intermittent viremia oc-curring in hemodialysis patients have demonstrated the importance of diagnostic evaluation in more than one determination using molecular methods in patients ini-tially considered non-viraemic.18 Serum HCV-RNA can be significantly reduced during hemodialysis sessions; therefore, blood sample collection should always be per-formed before the dialysis session.19,20

hcv TRacking in The dialysis Room

Screening for hepatitis C should be performed in all patients who initiate the dialysis program or are

Figure 1. Hepatitis C virus genome and structure.



540

transferred from other centers, initially with immuno-assay, and if positive, confirmed by NAT. However, in countries with a high hepatitis C prevalence, metho-ds for the detection of HCV-RNA may be considered as the initial examination.21,22 Figures 2 and 3 depict suggestions for conducting the initial assessment and serological follow-up of patients in HD program.

Hepatitis C diagnosis in patients with chronic kidney disease (CKD) is difficult due to some rea-sons, such as: presence of nonspecific clinical signs and symptoms, being often asymptomatic; normal or discrete (often fluctuating) levels of the alanine aminotransferase (ALT) enzyme in almost half of the patients with HCV infection; presence of possibly false-negative serology, in addition to the low viremia seen in these patients.23 ALT levels should be checked on admission to the dialysis unit and then monthly.

Recently infected patients may have elevated ALT levels prior to seroconversion, which warrants moni-toring levels for early detection of new infections.19 Patients with unwarranted alteration of ALT, even if discrete elevations, should be investigated for hepa-titis B and C. The validity or usefulness of monthly ALT dosing in patients with chronic hepatitis C infec-tion resolved is unknown and there are no specific recommendations for this subgroup.21,22

It has been shown that dialytic patients may have lower aminotransferase levels than individuals with normal renal function, but the reasons for this fact remain uncertain. The main hypotheses for this re-duction is the hemodilution (which would alter the dosage of liver enzymes) or the reduced levels of pyridoxine or elevated homocysteine.24,25 On the other hand, HCV-infected HD patients have higher

Figure 2. Initial HCV serological assessment flowchart after admission to the Dialysis Unit.



541

Figure 3. Follow-up serum flowchart in the Hemodialysis Unit.



542

aminotransferase levels than their uninfected counter-parts. A study conducted to evaluate the predictive value of ALT dosing for HCV infection in HD patients showed inadequate accuracy of the test, although widely used, with sensitivity and specificity for new infections of 83% and 90%, respectively. Changes in the cut-off value may help to improve accuracy, but the adequate value has not yet been defined, ranging from 45% to 70% of the upper limit of normality.20,26 In order to improve the diagnostic performance of the enzyme, studies suggest that the value of ALT found in patients on hemodialysis be increased by 50% of its baseline value.27

Some factors may reduce the production of an-tibodies against HCV surface antigens, such as the immunosuppressive effect of chronic uremia, high concentrations of proinflammatory cytokines and di-abetes, which may explain the false negative serologi-cal tests, even when this occurrence is rare.28 Another point of concern is the phenomenon of intermittent viremia, which is not only epidemiological, but also an inconvenience in the control of nosocomial trans-mission, since the results can be misinterpreted, clas-sifying a patient with active infection as non-vire-memic.18,20,29,30 The use of molecular tests with low detection levels should always be recommended.

Currently, the Ministry of Health recommends that all patients who initiate HD should be submit-ted routinely to monthly ALT analysis and serological profile analysis by performing anti-HCV upon dialy-sis onset, and every six months thereafter. In the year 2018, Kidney Disease Improving Global Outcomes (KDIGO) published the recommendations regarding the management of HCV in patients with CKD on di-alysis: all patients not infected by HCV with negative anti-HCV tests should be monitored every 6 months in relation to their serological profile; while HCV-RNA negative and HCV-positive patients (infection resolved but at risk of reinfection) should be moni-tored by NAT every six months or whenever there is an ALT elevation.19 The same guideline indicates that positive anti-HCV patients should be submitted to the NAT every six months, to look for viremia.

Although some studies have shown benefits in performing molecular tests for the early detection of acute C virus infection in a dialysis unit, this recom-mendation becomes difficult to apply in our country, taking into account its high cost to detect virus RNA. Data available since 1999 shows a prevalence of less

than 2% of HCV-RNA positive patients with anti-HCV negative testing; with more recent studies show-ing even lower false-negative rates, ranging from 0.1 to 0.86%, confirming that immunoassay is a reliable method to be used as screening.7,23 The NAT test is al-ways indicated in cases of a positive anti-HCV result. It is recommended that patients with anti-HCV posi-tive and HCV-negative RNA necessarily need screen-ing (or follow-up in the HU) using NAT.31

Acute HCV infection should be reported to the local Epidemiological Surveillance team. Acute cases are those with negative anti-HCV or HCV-RNA se-rology and subsequent positive serological examina-tion. A mild elevation of ALT is often the first sign of an acute infection, and should be appreciated. A new case in a dialysis unit should immediately trigger ac-tions to identify additional cases, with serological re-assessment of all uninfected. The screening frequency on this unit should also be changed for a set time. One suggestion is to reduce the anti-HCV testing fre-quency in all susceptible to monthly for 3 months or NAT in the patients on the same dialysis session and who initially showed a 50% transaminase elevation in relation to their baseline values. If there is no se-roconversion, retest in 3 months. In the absence of any new cases identified, the HD routine of six-month serology can be returned.18,23

pRevenTive measuRes

HCV is transmitted parenterally through percuta-neous exposure to contaminated blood. Rigorous screening policies in blood donors and widespread use of erythropoiesis have reduced the incidence of blood transfusion, and today the main route of trans-mission is nosocomial.22 According to data from the Centers of Disease Control, more than 50% of ou-tbreaks of hepatitis C in the United States between 2008 and 2015 were related to HU.12

Studies published in the early 2000s have shown significant declines in the incidence of HCV infection horizontal transmission through only the adoption of universal measures in many European clinics that did not isolate patients with hepatitis C.8,12,22 Jadoul et al. demonstrated in one study the possibility of complete-ly eradicating the C virus transmission within dialysis units through the adoption of universal precaution-ary measures, after reaching a 54-month follow-up with zero incidence of new cases of seroconversion contamination.8,32,33



543

Currently, nosocomial transmission is the main source of the C virus transmission, and several stud-ies are devoted to finding the reasons for transmis-sion in dialysis units.34 There are several hypotheses and, although it is not possible to exclude those re-lated to the dialysis equipment and reuse, most of the data points to failures in following infection con-trol protocols, such as preparation of medication at a contaminated site, reuse of medication in multiple patients, inadequate surface disinfection and failure to exchange gloves between patients. Inadequate hand washing, shorter shift time, and reduced num-bers of technicians per patient also increase the risk of transmission.22,35 In addition, studies have shown that outbreaks of seroconversion occurred in patients who shared the same environment and not necessarily the same hemodialysis machine, emphasizing the pos-sibility of transmission by healthcare professionals.28

The higher the number of years the patient has been in hemodialysis, the greater the risk of acquiring an HCV infection, taking into account the multiple exposures to the treatment during the week. It is im-portant to stress that even if there is no visible blood on the surface, the HCV virus can remain potentially infectious on the surface for at least 16 hours. Studies analyzing the presence of non-visible blood and HCV-RNA on surfaces show high indices in several devices, such as hemodialysis machines, connectors, patient trays and fistula lavage sinks.28 In an epidemiological study with more than 4,000 patients from different dialysis units in the United States, they demonstrated a direct correlation between the incidence of hepati-tis C and patient care by the healthcare team. After analysis, the main factors suspected as triggers of this episode were: inadequate cleaning of capillary boxes between uses, preparation of medications or stock of materials in areas where material contaminated with blood was handled and transport of injectable medications in mobile carts between patients.33,36 The CDC publishes on its website several checklists of in-fection control practices, all of which are important in reducing HCV transmission (Figure 4).37

The low compliance to universal precautionary measures is a constant in HUs around the world. A multicenter Spanish study with 9 Dialysis Units showed that in 93% of the opportunities, gloves are used, but only 36% of the staff sanitizes the hands af-ter contact with the patient and 14% before contact. No differences in compliance to hygiene measures

were observed among “white room” and isolation room staff.38 Similar data can be found in other observational studies from different localities and cultures.39,40

isolaTion

The isolation of patients with HCV infection emerged as an extension of the measures adopted for the isola-tion of patients infected with HBV, which, considering the characteristics of the two diseases, has no clinical basis. The 2008 KDIGO recommendations no lon-ger advocate isolation of patients suspected of HCV infection. Strict compliance to HU infection control measures is best indicated as a preventive measure for contamination of other patients.19,41 Other protocols, such as the United Kingdom Renal Association and European Renal Best Practice, do not recommend iso-lation as a preventive measure.42,43

A recent Cochrane systematic review44 showed that the quality of evidence for or against isolation is very poor. Of the 123 papers evaluated, only one Randomized Controlled Trial (RCT) was found,45 and even in that study the level of evidence was considered low. In the single RCT carried out by Shamshiraz et al., which included 593 patients, there was no differ-ence in the reduction of the HCV infection incidence with the use of exclusive machines; however, there are details in their methodology not described in this study that limit its use as a conclusive source stating the isolation ineffectiveness. Other publications adopt different isolation strategies that could be adopted and could be used in combination or separately, such as the exclusive use of machines, rooms, staff and shifts. Some of them show benefits from patient isola-tion; however, they are all observational studies and with inadequate evidence quality. In most of them, the study design is based on the intervention of isola-tion compared to its own historical controls, which creates a bias about the real reason for reducing inci-dence if it is directly related to the strategy or to the indirect effect of increased surveillance.19,44

The strategy of optimizing and strengthening uni-versal care seems to be quite effective in controlling HCV infection, so many specialists suggest it as a primary measure, and the isolation is necessary when these practices are flawed. Observational studies show that isolation did not protect against HCV in-fection, and in the latter CDC guidelines such an atti-tude is not recommended.12 Favorable arguments for



544

Figure 4. Universal precaution measures for safety in dialysis Source: Centers for Disease Control and Prevention. Control, C.f.D. and prevention, dialysis safety: audit tools, protocols and checklists, 2013.

not isolating include the fact that the measure is not protective of other infections and creates, with segre-gation, a falsely protected environment against par-enteral transmission; (HBV + HCV +, HBV + HVC-, HBV-HCV +, HBV-HCV-), the separation of patients

with HBV and HCV can create logistic problems in the HUs. the isolation may predispose to reinfection by a second C virus genotype; the incubation period of HCV is long, and therefore many patients in the immunological window could be deemed uninfected;



545

Finally, the creation of separate rooms increases the costs of dialysis, a sector that is already under-funded and has been struggling financially in recent years.19

The use of isolated machines is also not effective because, according to several studies with phylogenet-ic analysis, the highest risk of HCV is in patients who dialyze close to the infected patient, not in the same machine, emphasizing the importance of hygiene care between shifts, since the mechanism of transmission by single pass hemodialysis equipment makes the pos-sibility of transmitting the virus by internal pathways remote, since it is not possible to pass through the in-tact membrane of the dialyzer. Therefore, the absence or failure to disinfect the surface of machines, arm-chairs and other equipment commonly used among patients is frequently identified as factors in the analy-sis of HCV outbreaks in HUs.7,19,46

In Brazil, by determination of the National Agency of Health Surveillance (ANVISA), there is no indica-tion of a dedicated machine or isolation for HCV seropositive patients in a chronic hemodialysis pro-gram, who may remain in the same environment as their seronegative counterparts. Since 2014, all mate-rial used in the treatment must be used only once and discarded; In addition, disinfection and cleaning of surfaces between shifts is recommended in the HUs, in addition to general precautionary measures.47

TReaTmenT

Until recently, treatment possibilities for both he-modialysis and renal transplant patients are limited; dialysis patients often have low tolerance to interfe-ron (IFN) and ribavirin (RBV) regimens, mainly due to anemia, while in renal transplant patients the use of IFN has been associated with the possibility of graft rejection.48,49

With the new direct acting antiviral drugs (DAA) and the free IFN regimens, a new perspective has been opened for patients with chronic kidney disease, en-abling the achievement of high rates of sustained vi-rological response (SVR) with very few adverse events and fewer drug interactions.50 When considering the use of DAA in interferon-free regimens, the degree of renal dysfunction of the patient should first be as-sessed, since not all drugs have evidence of being safe to use in patients with advanced renal dysfunction and in hemodialysis.

The recommendations are based on the glomerular filtration rate (GFR), which can be measured or

estimated. If the estimated glomerular filtration rate (GFR) is used, the suggestion is to use the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for the calculation.19 Patients with CKD in conservative treatment and with GFR greater than 30 mL/ min may be treated with any of the drugs that are incorporated into the hepatitis C treatment regimens in our country: sofosbuvir, simeprevir, da-clatasvir, ledipasvir, ombitasvir/veruprevir/dasabuvir combination (3D) and the combination grazoprevir/elbasvir, at the usual doses recommended for each genotype, in the same way as patients without renal dysfunction.

However, patients with GFR of less than 30 mL/min are restricted to the use of sofosbuvir, a renal elimination drug. To date, there is a limitation on the use, as indicated in the package insert, when the GFR is below 30 mL/min,51 due to the buildup of a metab-olite (GS-3310007), which toxicity potential has not yet been fully elucidated. New studies will evaluate its use in more severe renal dysfunctions, identifying the best dose to be used and the possible dose interval, so that up to now the use of sofosbuvir in patients with GFR <30 mL/min should be done with caution, especially in pre-dialytic patients. In cases where there is an option for the use of sofosbuvir, it seems more appropriate to use the drug at a full dose (400 mg/day), associated with another antiviral (simeprevir, daclatasvir or ledipasvir, according to the genotype), since half dose or full dose on alternate days may be insufficient for treatment. For patients with genotype 3, the option is sofosbuvir associated with daclatasvir, for 12 weeks for non-cirrhotic patients, and for 24 weeks for cirrhotic patients.

Fortunately, there are other fairly safe options for patients with genotype 1 on dialysis. There are studies showing the safety of using the 3D combina-tion in stage 5 chronic kidney disease on dialysis.52 Treatment for 12 weeks achieved 90% SVR in 20 patients who received the regimen. The regimen was safe, especially in patients with genotype 1b, who did not require the use of ribavirin. In studies with fewer patients with genotype 1a, the drug was also highly efficient without the use of ribavirin.53

Another very safe, effective and well studied regi-men in patients with dialytic CKD is the grazoprevir and elbasvir association for 12 weeks. In the study with this combination, 115/116 patients obtained SVR, showing that this is an excellent option for the



546

treatment of patients with genotype 1.54 For patients with genotype 3, since there is no alternative scheme without the use of sofosbuvir, it is recommended to use sofosbuvir associated with daclatasvir, with careful patient follow-up, although there is already enough data from the literature showing the safety of using this medication.55-57

A new combination of pangenotype drugs is in the final phase of incorporation into the treatment pro-tocol in our country (Glecaprevir/Pribentasvir) and will also provide safety to dialysis patients with high response rates.54,58

The treatment regimens for hemodialysis patients adopted in Brazil are depicted on Tables 1, 2 and 3. In patients on dialysis, RBV should be used with great caution, starting at a dose of 250 mg/week, progres-sively, and in most cases it should not exceed the dose of 3 tablets of 250 mg/week.

Whatever the treatment schedule, the curing crite-rion is HCV-RNA negativity documented 3 months after the end of treatment.7,15,55 Despite the lack of consistent data in the literature, it seems reasonable to recommend that all cured patients could be allo-cated under the same conditions as the seronegative for hepatitis C and do without the need for dialyzer disposal, although there is no clear policy on this

approach. What can be recommended is that cured patients who continue dialyzing in the same shift as untreated patients should perform the NAT every six months to detect possible reinfection.19

conclusion

The hepatitis C virus is still a frequent problem faced by nephrologist physicians within the dialysis units in our country, who are faced day by day with the in-terpretation of serological tests and the institution of measures that will protect any patients at risk of HCV contamination. This paper presents the SBN and SBH stances regarding points that should be debated in our routine, such as the need to extend and make feasible the diagnosis of HCV, not only for serology interpre-tation, but also for viral RNA analysis, which should be made available in our healthcare network in the specific situations described herein. In addition, grea-ter synergism is needed between nephrologists and he-patologists, so that we can make available new drugs for the treatment of HCV in patients with CKD, espe-cially those on dialysis, leading to cure and radically modifying the clinical outcome with respect to the re-sults of renal transplantation and the development of chronic liver disease.

Time in treatment Time in treatment Time in treatment

No cirrhosis With cirrhosis Child A With cirrhosis Child B/C

Elbasvir+Grazoprevir 12 weeks 12 weeks Regimen not indicated

Regimen 3D 12 weeks + RBV 24 weeks + RBV Regimen not indicated

Glecaprevir+Paritaprevir 8 weeks 12 weeks Regimen not indicated

Table 1 trEatmEnt of patiEnts with typE 1a gEnotypE undEr dialysis

RBV: ribavirin; 3D: ombitasvir/veruprevir/dasabuvir



Elbasvir+Grazoprevir 12 weeks 12 weeks Regimen not indicated

3D Regimen 12 weeks 12 weeks + RBV Regimen not indicated


Table 2 trEatmEnt of patiEnts with typE 1b gEnotypE undEr dialysis

RBV: ribavirin; 3D: ombitasvir/veruprevir/dasabuvir




Table 3 trEatmEnt of patiEnts with typE 2 and 3 gEnotypEs undEr dialysis



547

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updatE articlEs | artigo dE atualiZação

AuthorsBernard Canaud1,2

Charles Chazot3

Jeroen Koomans4

Allan Collins5,6

1 Montpellier University, Montpellier, France.2 Senior Medical Scientist, Global Medical Office, FMC Deutschland, Bad Homburg, Germany.3 Head of Clinical Governance, NephroCare France, Fresnes, France.4 Maastricht University Medical Center, Department of Internal Medicine, Division of Nephrology, Netherlands.5 University of Minnesota, Minneapolis Minnesota, USA.6 Senior Medical Scientist, Global Medical Office, FMC North America, Waltham, MA, USA.


Correspondence to:Prof Bernard Canaud.E-mail: [email protected]

Fluid and hemodynamic management in hemodialysis patients: challenges and opportunities

Manejo hídrico e hemodinâmico em pacientes em hemodiálise: desafios e oportunidades

DOI: 10.1590/2175-8239-JBN-2019-0135

Fluid volume and hemodynamic man-agement in hemodialysis patients is an essential component of dialysis adequacy. Restoring salt and water homeostasis in hemodialysis patients has been a permanent quest by ne-phrologists summarized by the ‘dry weight’ probing approach. Although this clinical approach has been asso-ciated with benefits on cardiovascular outcome, it is now challenged by re-cent studies showing that intensity or aggressiveness to remove fluid during intermittent dialysis is associated with cardiovascular stress and potential or-gan damage. A more precise approach is required to improve cardiovascular outcome in this high-risk population. Fluid status assessment and monitor-ing rely on four components: clinical assessment, non-invasive instrumental tools (e.g., US, bioimpedance, blood volume monitoring), cardiac biomark-ers (e.g. natriuretic peptides), and al-gorithm and sodium modeling to esti-mate mass transfer. Optimal manage-ment of fluid and sodium imbalance in dialysis patients consist in adjust-ing salt and fluid removal by dialysis (ultrafiltration, dialysate sodium) and by restricting salt intake and fluid gain between dialysis sessions. Mod-ern technology using biosensors and feedback control tools embarked on dialysis machine, with sophisticated analytics will provide direct handling of sodium and water in a more precise and personalized way. It is envisaged in the near future that these tools will support physician decision making with high potential of improving car-diovascular outcome.

absTRacT

Keywords: Water-Electrolyte Balance; Hemodynamic Monitoring; Blood Pres-sure; Cardiovascular Deconditioning; Re-nal Dialysis; Treatment Outcome.

O volume de fluidos e o controle hemodinâ-mico em pacientes em hemodiálise é um com-ponente essencial da adequação da diálise. A restauração da homeostase do sal e da água em pacientes em hemodiálise tem sido uma busca constante por parte dos nefrologistas, no que condiz à abordagem do “peso seco. Embora essa abordagem clínica tenha sido associada a benefícios no desfecho cardiovas-cular, recentemente tem sido questionada por estudos que mostram que a intensidade ou agressividade para remover fluidos durante a diálise intermitente está associada a estres-se cardiovascular e dano potencial a órgãos.para remover fluidos durante a diálise intermi-tente está associada a estresse cardiovascular e dano potencial a órgãos. Uma abordagem mais precisa é necessária para melhorar o des-fecho cardiovascular nessa população de alto risco. A avaliação e monitorização do estado hídrico baseiam-se em quatro componentes: avaliação clínica, ferramentas instrumentais não invasivas (por exemplo, US, bioimpedân-cia, monitorização do volume sanguíneo), biomarcadores cardíacos (e.g. peptídeos na-triuréticos), algoritmos e modelagem de só-dio para estimar a transferência de massa. O manejo otimizado do desequilíbrio hídrico e de sódio em pacientes dialíticos consiste em ajustar a remoção de sal e líquido por diálise (ultrafiltração, dialisato de sódio), e restringir a ingestão de sal e o ganho de líquido entre as sessões de diálise. Tecnologia moderna que utiliza biosensores e ferramentas de controle de feedback, hoje parte da máquina de diáli-se, com análises sofisticadas, proporcionam o manejo direto sobre o sódio e a água de uma maneira mais precisa e personalizada. Prevê--se no futuro próximo que essas ferramentas poderão auxiliar na tomada de decisão do médico, com alto potencial para melhorar o resultado cardiovascular.

Resumo

Palavras-chave: Equilíbrio Hidroeletrolíti-co; Monitorização Hemodinâmica; Pressão Sanguínea; Descondicionamento Cardio-vascular; Diálise Renal; Resultado do Tra-tamento.

https://orcid.org/0000-0001-6854-2816


Fluid and hemodynamic management in hemodialysis patients

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fluid and hemodynamic managemenT in he-modialysis paTienTs: an idenTified modifiable caRdiovasculaR Risk facToR

Optimal fluid volume management in dialysis pa-tients is an essential component of dialysis adequacy but amplitude of volume fluctuation is still a quite challenging clinical condition1. Restoring salt and water homeostasis in hemodialysis patients has been a permanent Holy Grail quest by nephrologists from the sixties2. Salt and water management in dialysis patients is frequently summarized by the ‘dry weight’ approach3,4. Although this clinical approach has been associated with benefits on cardiovascular outcome, it is now challenged by recent studies showing that in-tensity or aggressiveness to remove fluid during con-ventional thrice-weekly dialysis might induce exces-sive hemodynamic stress and potential organ damage with potentially deleterious consequences on the long term5,6. In brief, ‘dry weight’ policy is necessary from a clinical perspective but it is not sufficient from a pathophysiologic perspective to ensure a fully cardio-protective effect in dialysis patients. A more balanced and precise approach is required to improve cardio-vascular outcome in this high-risk population. To sat-isfy this unmet need, it is time to move to a broader approach embracing the whole hemodynamic man-agement of dialysis patients rather than focusing only on their fluid management7.

Intermittent renal replacement therapy exposes dialysis patients to continuous and repetitive hemodynamic stress conditions (Figure 1). By nature this is due to intermittency of treatment exposing patients to up (interdialytic period) and down (intradialytic period) fluid volume changes. This is best summarized by the “unphysiological profile” of short intermittent dialysis treatment8,9. From a mechanistic approach, one can identify two different stress conditions: firstly, a chronic hemodynamic stress phase, which reflects extracellular fluid accumulation, often superimposed on a status of chronic fluid expansion during the interdialytic period; secondly, an acute hemodynamic stress phase, which reflects intravascular fluid depletion induced by dialysis session (ultrafiltration and sodium removal) marked by critical hypovolemia leading eventually to hypotensive episodes and impaired organ perfusion10.

Sodium and fluid accumulation that may occur in dialysis patients over time due to repetitive positive fluid imbalance is responsible for chronic extracellular fluid overload (Figure 2) with its adverse effects and cardiovascular consequences leading to poor outcomes11. Extracellular fluid overload and poor fluid management are the basic fundament of cardiovascular complications in hemodialysis patients12,13. Hypertension as part of this constellation of disorders is widely

Figure 1. Hemodynamic Stress in HD Patient : Acute vs. Chronic Cardiovascular Stress.



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Figure 2. Chronic Hemodynamic Stress: Chronic Fluid Overload and Its Consequences.

recognized as a leading cause for left ventricular cardiomyopathy and accelerated atherosclerosis including coronary artery disease, peripheral artery disease, and cerebrovascular disease14,15,16. Interestingly, as shown in a recent large cohort study, the presence of fluid overload per se has an independent and additive deleterious effect on blood pressure (either low or high blood pressure) in dialysis patient outcomes, which increases the global negative impact of blood pressure per se17. Hyponatremia, for reasons not entirely understood, is also associated with poor outcome in dialysis patients18,19,20. Management of sodium and fluid excess to restore fluid status homeostasis, (Figure 3) either by moderate or high ultrafiltration rate, or high plasma-to-dialysate sodium concentration gradient leading potentially to critical hypovolemia, is also associated with increased risk of mortality21,22,23,24,25,26. Combination of these characteristics increases significantly the negative impact of each one on patient outcome27,28,29,30. In this context, salt and fluid management of dialysis patients represents a major challenge for clinicians.

fluid and hemodynamic managemenT in hemodialysis paTienTs: challenges

Assessing fluid status of dialysis patients is not an easy task from a clinical perspective. In that context, it is interesting to note that over time several tools have been proposed (Figure 4) to assess salt and water status in hemodialysis patients with a common ob-jective of monitoring and guiding caregivers in their prescription31,32.

1. Clinical assessment focusing on fluid status, hemodynamic stability, and patient perception was the first attempt to address this issue in developing the concept of ‘dry weight’33,34. It relates in fact to the post-dialysis weight at which dialysis the patient has - in theory - no sign of fluid imbalance (neither excess nor depletion), blood pressure values in normal range for his or her clinical condition, and feels comfortable without functional limitations35. ‘Dry weight’ is probed over time by clinicians and reassessed periodically according to the patient conditions, changes, and/or intercurrent events in order to keep its fluid status balance over time36. Further work has led investigators to refine assessment of the ‘dry weight’ concept37.



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Figure 3. Acute Hemodynamic Stress : Excessive or Aggressive Fluid Depletion.

Figure 4. Fluid and Hemodynamic Monitoring in HD Patients - Usual Workflow.

Subsequently, several tools have been proposed to help physicians in refining clinical acumen and defining more objectively ‘dry weight’ of dialysis

patients38,39. In brief, they utilize either instrumental tools or biomarkers40,41,42.



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2. Instrumental or technology-based tools use various non-invasive ways to assess volemia, fluid status, or hemodynamic surrogate indicators.

Inferior vena cava diameter (IVCD) and collapsibility has been proposed to monitor intravascular volume and right atrial pressure or central venous pressure in dialysis patients with interesting findings43,44,45. However, the practical difficulty in implementing these methods in a dialysis facility and the poor predictive value on blood pressure response in probing dry weight have precluded its generalizability46. However, recent data in critically ill patients showed that IVCD collapsibility had reasonable value (c-statistic 0.72) in predicting tolerance to fluid removal47.

Relative blood volume change (RBV) and refilling rate capacity during dialysis assessed by online blood volume sensor has been also proposed for fluid management48. In expert hands, this tool provides useful information on individual patient volume status to facilitate hemodynamic guidance49. Furthermore, blood volume monitoring has been shown helpful to set individual patient critical volemia beyond which occurrence of severe intradialytic hypotension is likely to occur50. Despite the fact that most studies using blood volume monitoring (BVM) devices are reporting positive feedback on blood pressure control and hemodynamic stability51, their clinical benefit is still matter of controversy52. Furthermore, in a randomized controlled trial (CLIMB Study) comparing BVM guided treatment versus standard of care had negative results that were associated with adverse outcomes53. In a more recent study, BVM guided feedback did not result in an improvement in intradialytic hemodynamic stability although also no evidence of harm was found54. Absolute blood volume measurement, based on non-invasive measurement either by dilution or online calculation, has been proposed recently for a better assessment of this crucial parameter55,56,57. To date, no study has explored the clinical benefits of monitoring precisely this parameter.

Bioimpedance approach has been proposed over the last few years as a more objective way to assess fluid status in dialysis patients58,59. Several approaches (segmental versus total body, single versus multifrequency) using various devices and algorithms have been developed with interesting results60. In a systematic review, multifrequency bioimpedance

spectroscopy (BIS) analysis [NICE, UK; CADTH, Canada] was recognized as the most precise and reliable tool in a clinical setting for guiding fluid management in dialysis patients at present available, although its use has not entered clinical guidelines yet61,62. In addition, extensive use of BIS in clinical studies has generated substantial evidences showing that BIS was able to detect subtle fluid volume variation63,64,65 and to support the notion that more precise fluid management might improve intermediate outcomes and dialysis patient endpoints66,67,68. Few prospective clinical trials in advanced kidney disease or dialysis patients are ongoing to define more precisely the value of BIS in managing fluid status and its impact on preservation of residual kidney function and on cardiovascular outcomes69,70.

More recently, it has also been proposed to extend the use of lung ultrasound in chronic hemodialysis patients for tracking silent fluid accumulation in the lung interstitium (extravascular edema). Interlobular septa thickening due to water accumulation reflects US beam and generates visible B line bundles (comet-like tail). A simple counting of these B lines provides an estimate of lung water excess and predictive value for patient outcomes71,72.

Sodium MRI has been introduced quite recently in the field of sodium and fluid assessment in chronic kidney disease patients in dialysis to assess tissue sodium accumulation73. Tissue sodium, namely ‘free-water sodium’ or ‘sodium bound to proteoglycans’, accumulates in chronic kidney disease and modulates lymphangiogenesis and blood pressure via proinflammatory resident cells74,75. Recent studies have shown that tissue sodium might contribute to systemic toxicity via local tissue and organ damage76,77. Left ventricular hypertrophy is positively associated with the amount of tissue sodium storage independent from blood pressure78. Vascular stiffness is also associated with sodium intake and sodium tissue storage independent from mechanical stress79,80. Furthermore, sodium tissue accumulation might contribute to metabolic and inflammatory disorders (e.g., insulin resistance, protein energy wasting) that increase cardiovascular risk. Due to its complex setting and limited number of scanning devices, sodium MRI remains an experimental tool with quite restricted access. However, it is envisioned that in the near future the dedicated extremity sodium MRI device, such as in rheumatologic field, could be used



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in a more systematic way to assess salt tissue content in dialysis patients81.

3. Cardiac and vascular biomarkers have been used extensively in an attempt to disentangle fluid status and cardiac dysfunction in dialysis patients. Atrial natriuretic peptides (ANP, BNP, and NT-proBNP) are the most popular ones for assessing fluid overload82,83 while, on the other hand, copeptin (a vasopressin precursor) is more reflective of fluid depletion84. Cardiovascular biomarkers reflecting cardiac or endothelium injury are also of interest to set a more precise and personalized fluid management approach. Sensitive troponin family markers (troponin I and T) have been used to detect critical myocardial hypoperfusion. In this context, troponins (I and/or T) reflecting cardiac injury appear to be the most appealing ones being correlated with hemodynamic stress intensity, bearing a high predictive value for future cardiac events85,86,87,88. Several other cardiac and endothelial biomarkers (e.g., ADMA, FG23, ROS, NO pathways) appear promising either isolated or combined in assessing cardiovascular risk but deserve further studies to define their exact place in fluid management strategy since they reflect tissue remodeling, uremic byproducts, inflammation, or oxidative stress mechanisms89,90,91. Although these cardiac biomarkers have been shown to be quite useful for patient risk stratification, their predictive (specificity and sensitivity) and/or clinical value in term of fluid status management has remained limited to clinical cases management92. Interpretation and clinical application of these cardiac biomarkers should be done with caution and be integrated in strategic care planning of dialysis patients since their circulating levels reflect not only fluid status but also kidney function deterioration and cardiac remodeling93,94. Multi-markers approach and time trend analysis of these biomarkers have been proposed to better support physician decision in stratifying cardiovascular risk but raising a cost issue95,96.

4. In recent past years, several researchers have develop algorithms to quantify sodium and water mass transfer during hemodialysis sessions using either mass balance equations based on the law of conservation of mass within the dialysis/patient system97,98 or by modeling sodium mass transfer using ionic dialysance with dialysate and plasma sodium concentrations99. Interestingly, on one hand, these studies have confirmed the validity of such

an approach by direct dialysis quantification using partial or total dialysate collection. On the other hand, it has been clearly shown that sodium and water mass transfer and kinetics might be considered as a patient profile characteristic; in other words, intra-individual variability was relatively narrow while inter-individual variability was tremendously high100. Several putative causal factors are associated with individual sodium and water profile (sodium or osmotic set-point) but most likely reflecting life style and diet observance101,102,103. In addition, it has been shown that acting on sodium and water mass transfer by individualizing dialysis sodium prescription it was possible to alter patient perception (reduce thirst, and sodium and water intake), reduce interdialytic weight gain, and modify outcomes (reduce dry weight and arterial blood pressure)104,105,106. However, this approach is hampered by the need for frequent lab sampling, which is cumbersome for clinical practice.

fluid and hemodynamic managemenT in hemodialysis paTienTs: oppoRTuniTies

Optimal management of fluid and sodium imbalance in dialysis patients is achieved by adjusting salt and fluid removal through dialysis and salt intake restric-tion, and fluid gain between dialysis sessions107. This is the conventional approach obtained by adjusting ‘dry weight’ according to clinical judgment and com-plementary tools including dialysate sodium prescrip-tion adaptation described earlier. However, this ap-proach may be hampered by the discontinuous nature of the HD treatment and/or patient intolerance to flu-id and sodium removal. An obvious solution would be to increase time and/or frequency of dialysis ses-sions in patients with high inter-dialytic weight gains and/or intolerance for fluid removal, as this has been shown to reduce intradialytic hemodynamic stress108. However, this approach will not always be possible for financial or logistic reasons, or because of the wish of the patient.

Modern technology using biosensors and sophisticated analytics provide tools for handling directly sodium and water during hemodialysis session in a more precise and personalized way that have potential for improving patient outcome109. In this context, the use of calibrated conductivity meters or microsensors placed on dialysis fluid paths both inlet and outlet have been used to develop specific algorithms able to determine the precise contribution



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of sodium salt among the bulk of electrolytes110,111. Furthermore, the disposition of sensors on the dialysate path offers a means to ensure a precise mass balance due to a closed circuit112. In addition, the combined use of advanced analytics embedded in the central processor unit provides a way to ensure direct handling of sodium and water according to the targeted prescription and patient baselines. Artificial intelligence has been recently proposed for clinical guidance and decision-making support in adapting dialysis prescription (e.g., ultrafiltration rate, dialysate sodium, treatment time) to ensure an optimal fluid status control and to minimize hemodynamic stress113. The added value of these tools needs to be assessed in the future by clinical studies.

Complementary clinical studies on a large scale should help to better characterize dialysis patients in term of diet sodium intake over prolonged time period and explore effects of this precise sodium and fluid management approach on patients intermediary and clinical endpoint outcomes.

Take home message

Dialysis adequacy concept has evolved over time and based on patient outcomes. Due to more efficient hemodialyzers, more technically advanced hemodi-alysis machines, and wider use of ultrapure dialysis fluid, efficiency and biocompatibility of renal replace-ment therapy have improved tremendously114,115,116. Cardioprotective hemodialysis requires further deci-sive actions in which sodium and fluid management are top ranking117. However, restoring homeostasis of extracellular volume, achieving adequately blood pressure control, and preserving hemodynamic equi-librium of dialysis patients still remains a matter of concern118,119. Restoring sodium and fluid mass bal-ance of dialysis patients is moving from an over sim-plistic ‘dry weight’ approach to a more precise fluid management approach with support of new diag-nostic and monitoring tools and will enter in a new era with availability of smart hemodialysis machines with direct dialysis sodium and water handling op-tions and with the support of advanced technology and analytics.

auThoRs’ conTRibuTions

Bernard Canaud, Charles Chazot, Jeroen P. Kooman, and Allan J. Collins contributed equally to the con-ception or design of the study; collection, analysis, or

interpretation of data; writing or critical review of the manuscript; and final approval of the version to be published.



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74. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH, et al. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Phy-siol Heart Circ Physiol. 2004 Jul;287(1):H203-8.

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77. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009 May;15(5):545-52.

78. Schneider MP, Raff U, Kopp C, Scheppach JB, Toncar S, Wan-ner C, et al. Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD. J Am Soc Nephrol. 2017 Jun;28(6):1867-1876.

79. Safar ME, Temmar M, Kakou A, Lacolley P, Thornton SN. So-dium intake and vascular stiffness in hypertension. Hyperten-sion. 2009 Aug;54(2):203-9.

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81. Jordan CD, McWalter EJ, Monu UD, Watkins RD, Chen W, Bargerter NK, et al. Variability of CubeQuant T1ρ, quantitati-ve DESS T2, and cones sodium MRI in knee cartilage. Osteoar-thritis Cartilage. 2014 Oct;22(10):1559-67.

82. Wang AY, Lai KN. Use of cardiac biomarkers in end-stage re-nal disease. J Am Soc Nephrol. 2008 Sep;19(9):1643-52.

83. Hickman PE. Biomarkers and cardiac disease in patients with end-stage renal disease on dialysis. Clin Biochem Rev. 2011 May;32(2):115-9.

84. Kim JS, Yang JW, Chai MH, Lee JY, Park H, Kim Y, et al. Copeptin in Hemodialysis Patients with Left Ventricular Dys-function. Yonsei Med J. 2015 Jul;56(4):976-80.

85. McIntyre CW. Effects of hemodialysis on cardiac function. Kidney Int. 2009 Aug;76(4):371-5.

86. Breidthardt T, Burton JO, Odudu A, Eldehni MT, Jefferies HJ, McIntyre CW. Troponin T for the detection of dialysis-induced myocardial stunning in hemodialysis patients. Clin J Am Soc Nephrol. 2012 Aug;7(8):1285-92.

87. Drexler B, Heinisch C, Balmelli C, Lassus J, Siirilä-Waris K, Arenja N, et al. Quantifying cardiac hemodynamic stress and cardiomyocyte damage in ischemic and nonischemic acute heart failure. Circ Heart Fail. 2012;5(1):17-24.

88. Vaduganathan M, Bhatt DL. Elevated Troponin Levels in Sta-ble Patients Undergoing Hemodialysis: A Red Flag or a Red Herring?. Am J Nephrol. 2016;43(3):170-2.

89. Aucella F, Maas R, Vigilante M, Tripepi G, Schwedhelm E, Margaglione M, et al. Methylarginines and mortality in pa-tients with end stage renal disease: a prospective cohort study. Atherosclerosis. 2009 Dec;207(2):541-5.



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91. Niizuma S, Iwanaga Y, Yahata T, Miyazaki S. Renocardiovas-cular Biomarkers: from the Perspective of Managing Chronic Kidney Disease and Cardiovascular Disease. Front Cardiovasc Med. 2017 Mar 6;4:10.

92. Chazot C, Van CV, Zaoui E, Vanel T, Hurot JM, Lorriaux C, et al. Fluid overload correction and cardiac history influence brain natriuretic peptide evolution in incident haemodialysis patients. Nephrol Dial Transplant. 2011 Aug;26(8):2630-4.

93. D'Marco L, Bellasi A, Raggi P. Cardiovascular biomarkers in chronic kidney disease: state of current research and clinical applicability. Dis Markers. 2015;2015:586569.

94. Savoj J, Becerra B, Kim JK, Fusaro M, Gallieni M, Lombardo D, et al. Utility of Cardiac Biomarkers in the Setting of Kidney Disease. Nephron. 2019;141(4):227-235.

95. Bargnoux AS, Morena M, Jaussent I, Maurice F, Chalabi L, Le-ray-Moragues H, et al. A combined index of cardiac biomarkers as a risk factor for early cardiovascular mortality in hemodialy-sis patients. Clin Chem Lab Med. 2013 Sep;51(9):1865-74.

96. Ishii J, Takahashi H, Kitagawa F, Kuno A, Okuyama R, Ka-wai H, et al. Multimarker approach to risk stratification for long-term mortality in patients on chronic hemodialysis. Circ J. 2015;79(3):656-63.

97. Santos SF, Peixoto AJ. Sodium balance in maintenance hemo-dialysis. Semin Dial. 2010 Nov/Dec;23(6):549-55.

98. Lambie SH, Taal MW, Fluck RJ, McIntyre CW. Online con-ductivity monitoring: validation and usefulness in a clinical trial of reduced dialysate conductivity. ASAIO J. 2005 Jan/Feb;51(1):70-6.

99.Odudu A, Lambie S, Taal MW, Fluck RJ, McIntyre CW. Use of online conductivity monitoring to study sodium mass balan-ce in chronic haemodialysis patients: prospects for treatment individualisation. Kidney Blood Press Res. 2011;34(6):439-46.

100.Basile C, Libutti P, Lisi P, Vernaglione L, Casucci F, Losurdo N, et al. Sodium setpoint and gradient in bicarbonate hemodialy-sis. J Nephrol. 2013 Nov/Dec;26(6):1136-42.

101.Keen ML, Gotch FA. The association of the sodium "setpoint" to interdialytic weight gain and blood pressure in hemodialysis patients. Int J Artif Organs. 2007 Nov;30(11):971-9.

102.Song JH, Park GH, Lee SY, Lee SW, Lee SW, Kim MJ. Effect of sodium balance and the combination of ultrafiltration profi-le during sodium profiling hemodialysis on the maintenance of the quality of dialysis and sodium and fluid balances. J Am Soc Nephrol. 2005 Jan;16(1):237-46.

103.Penne EL, Levin NW, Kotanko P. Improving volume status by comprehensive dietary and dialytic sodium management in chronic hemodialysis patients. Blood Purif. 2010;30(1):71-8.

104.Raimann JG, Thijssen S, Usvyat LA, Levin NW, Kotanko P. Sodium alignment in clinical practice - implementation and im-plications. Semin Dial. 2011 Sep/Oct;24(5):587-92.

105.Basile C, Lomonte C. A neglected issue in dialysis practice: haemodialysate. Clin Kidney J. 2015 Aug;8(4):393-9.

106.Chevalier L, Tielemans C, Debelle F, Vandervelde D, Fume-ron C, Mandart L, et al. Isonatric Dialysis Biofeedback in He-modiafiltration with Online Regeneration of Ultrafiltrate in Hypertensive Hemodialysis Patients: A Randomized Control-led Study. Blood Purif. 2016;41(1-3):87-93.

107.Tomson CR. Advising dialysis patients to restrict fluid in-take without restricting sodium intake is not based on evi-dence and is a waste of time. Nephrol Dial Transplant. 2001 Aug;16(8):1538-42.

108.Jefferies HJ, Virk B, Schiller B, Moran J, McIntyre CW. Fre-quent hemodialysis schedules are associated with reduced levels of dialysis-induced cardiac injury (myocardial stunning). Clin J Am Soc Nephrol. 2011;6(6):1326-32.

109.Daugirdas JT, Tattersall JE. Automated monitoring of hemo-dialysis adequacy by dialysis machines: potential benefits to patients and cost savings. Kidney Int. 2010 Nov;78(9):833-5.

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pErspEctivEs/opinion | pErspEctivas/opinião

AuthorsJosé A. Moura-Neto1

Katherine Barraclough2,3

John W. M. Agar4

1 Grupo CSB, Salvador, Bahia, Brasil.2 Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia.3 University of Melbourne, Parkville, Australia.4 Renal Unit, University Hospital Geelong, Victoria, Australia.


Correspondence to:José A. Moura-Neto.E-mail: [email protected]

A call-to-action for sustainability in dialysis in Brazil

Um apelo pela sustentabilidade na diálise no Brasil

DOI: 10.1590/2175-8239-JBN-2019-0014

inTRoducTion

The planet has experienced major changes in the past decades as a result of human activities. Humans are now present on every continent and have had direct im-pact on more than 80% of the planet’s surface1; living, interacting globally with the environment, bringing developments to humankind, but also doing some harm.

Relevant to the medical community, climate change has been identified as the greatest human health threat of this centu-ry. It is increasingly leading to alterations in the patterns of diseases, including renal disease.2 This brings some threats, but al-so an opportunity while there is still time to critically evaluate our actions and look at current healthcare practices in order to mitigate the environmental impact.

discussion

The healthcare sector, paradoxically, has a significant and negative environmental impact. Its contribution to greenhouse gas emissions, for example, is estimated to be between 5 and 10%. In the United States of America (USA), the healthcare sector produces more than 8% of the national carbon dioxide (CO2) emissions3, while in the United Kingdom, the National Health Service (NHS) is responsible for approxi-mately 5%.4 The healthcare sector is re-sponsible for an estimated 35,772 kt of CO2 emissions in Australia5, which cor-responds to 7% of all national emissions.

The nephrology specialty, and especial-ly the dialysis sector, is among one of the most environmentally harmful within the healthcare system. More than 3,000,000

Human-induced climate change has been an increasing concern in recent years. Nephrology, especially in the dialysis setting, has significant nega-tive environmental impact worldwide, as it uses large amounts of water and energy and generates thousands of tons of waste. While our activities make us responsible agents, there are also sev-eral opportunities to change the game, both individually and as a society. This call-to-action intends to raise aware-ness about environmentally sustainable practices in dialysis and encourages this important discussion in Brazil.

absTRacT

Keywords: Hemodialysis Units, Hospital; Renal Dialysis; Environment and Pub-lic Health; Conservation of Natural Re-sources; Peritoneal Dialysis; Nephrology.

A mudança climática induzida pela ativida-de humana tem sido foco de preocupações crescentes nos últimos anos. A nefrologia, particularmente a diálise, produz significati-vos impactos ambientais em todo o mundo em virtude da grande utilização de água e energia e da geração de milhares de tonela-das de resíduos. Embora nossas atividades nos tornem agentes responsáveis, há várias oportunidades para mudar esse cenário, tanto individualmente como em sociedade. O presente artigo pretende ampliar a cons-cientização sobre práticas ambientalmente sustentáveis em diálise e estimular essa im-portante discussão no Brasil.

Resumo

Palavras-chave: Unidades Hospitalares de Hemodiálise; Diálise Renal; Meio Ambiente e Saúde Pública; Conservação dos Recursos Naturais; Diálise Peritoneal; Nefrologia.

https://orcid.org/0000-0003-1339-3731


Green dialysis in Brazil

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patients worldwide are estimated to be on mainte-nance dialysis programs. This number is projected to more than double in the next years and to exceed 7,000,000 patients by 2030. Despite the impressive-ness of this number, it would be at least two times bigger if equal and adequate access to healthcare were globally available and dialysis were universally pro-vided. Unfortunately, what is known as the “renal re-placement therapy gap” caused between 2.3 and 7.1 million premature deaths because of lack of access to renal replacement therapy.6-8

In dialysis, water usage is one of the most waste-ful aspects. Patients undergoing conventional hemo-dialysis (HD), in a 4-hour thrice-weekly regimen, are estimated to use around 500 liters of water per treat-ment. This estimate is based on the assumption that each HD treatment, with an average dialysate flow rate of 500 mL/min, requires around 125 L of water per patient, which represents only one-third of the to-tal water used — most reverse osmosis systems reject approximately two-thirds of the total water. In addi-tion to this value, we must add the volume of steril-ization, pre-HD priming, and post-HD rinsing, which may reach 500 L per treatment. In addition, it is im-portant to note that this value may vary depending not only on the frequency and length of sessions, but also on the reverse osmosis system and HD machine type.9,10

Remarkably, this represents an annual water us-age of around 78,000 L per patient, compared with the average annual domestic water consumption per capita of approximately 42,500 L in Brazil 11, 54,500 L in Australia12, and 55,000 L in France13. We can estimate an HD water consumption of more than 200 billion liters globally based on the total number of patients receiving HD treatment.14,15

Peritoneal dialysis (PD), the renal replacement therapy utilized by around 10% of patients world-wide16 and 8% in Brazil17, probably wastes less water, requiring between 6 to 12 liters per PD dialysate per day.9,14 However, there is no study that estimates the amount of water necessary to produce this sterile flu-id, and the total water usage in PD is probably much greater than 12 liters per day.

In addition to water waste, hemodialysis is esti-mated to consume approximately 2 billion kWh of power annually15 and 1 million tons of disposable waste — which includes dialyzers, lines, needles, and other single-use equipment.18 Taken together, these

numbers turn dialysis into one of the greatest waste-producing and resource-demanding practices in the healthcare sector.

The question that we should ask ourselves is: what can be done with this scenario? How can we act to reduce our environmental impact as care pro-viders? The answers come partially from eco-dialysis or green dialysis initiatives, which have been gaining force worldwide. The main idea of this initiative is to discuss ways to minimize the environmental impact of dialysis practices. Although it is recent, some nations, such as Australia, the Netherlands, and the United Kingdom, are far beyond others and have already made interesting moves towards more sustainable di-alysis practices. In the United Kingdom, for example, the National Health Service Sustainable Healthcare program established the Green Nephrology initiative in 2009, which has successfully changed practices and attitudes throughout the region.19 However, even in these countries, there is still an opportunity to further adopt sustainable practices in the dialysis setting. In Australia, a recent survey of 71 public dialysis facili-ties in the state of Victoria showed that only 10% of the units used renewable sources of energy, solar in these cases, and 25% recycled reverse osmosis reject water for use elsewhere, such as to water gardens or flush toilets.20 Although these countries are likely much ‘greener’ than other countries for which we do not have this baseline data yet, there is still much to be improved.

During the American Society of Nephrology 2018 Conference (San Diego, USA), a global meeting on “Green Nephrology” was held for the first time. The meeting, which was supported by the International Society of Nephrology (ISN), was attended by ne-phrologists and representatives from various medi-cal societies around the world and discussed several ways to engage the renal community worldwide. The meeting led to the following initiatives: the proposal of Green Nephrology as a topic for a scientific ses-sion at the 2020 World Congress of Nephrology and the elaboration of an ISN position statement by this group, headed by Dr Katherine Barraclough. All these recent events are very positive and possibly an indica-tion that sustainability may be a future trend in renal replacement therapy globally, as is already the case in other areas.

Basically, there are three major targets for an ini-tial approach in the green dialysis setting. We shall



561

first focus on power, water usage, and dialysis waste management.9 There are already several publica-tions that address ways to reduce water waste10,21-23 and encourage the use of solar energy.10,24 Power-off practices, the use of natural light, and lighting choices (incandescent, fluorescent or light-emitting diode - LED) are several options to reduce the overall use of energy.14 Other possibilities of sustainable practices for dialysis facilities exist, such as reducing the use of paper and printed files, encouraging staff to share automobiles (car-pooling) or use bikes, and using telemedicine or teleconferencing for patient consulta-tions and meetings to avoid carbon emissions from travel. Most of these practices are economically vi-able and even profitable for dialysis facilities, which makes convincing the board of directors and inves-tors to support a sustainable approach much easier. In a scenario in which the costs of renal replacement therapy around the world are an increasing concern and our capability as a healthcare system to univer-sally provide this therapy is at risk25,26, this are indeed excellent news. After all, green dialysis is a win-win initiative; advantageous for the environment, society, and dialysis facilities.

Although beneficial to the environment, as it re-duces the risks and cost of infectious-risk dialysis waste disposal, it is important to note that the reuse of equipment raises concerns related to the quality of the dialysis performed and the clinical staff’s chemi-cal exposure. In fact, reuse of dialyzers and lines is discouraged and illegal in some countries, such as Australia, Japan, New Zealand, France, Italy, and Germany. However, it is still practiced in the USA and Brazil - which has been a matter of increasing debate.14,27,28

In Brazil, there are 758 dialysis facilities and 126,583 chronic patients receiving maintenance di-alysis.29 This number increases each year and repre-sents an important impact to the environment. If we consider that 92.1% of the patients are under HD17 and a total of 116,583 chronic HD patients in Brazil performing 156 HD sessions annually each, then we can conservatively estimate a total of approximately 9 billion L/year of water used for HD in Brazil alone (500 L/patient/treatment x 116.583 patients x 156 treatments/year). Most of this amount, approximate-ly two-thirds, is constituted of reusable and potable water - usually discarded in the drain.14 Additionally, if we consider that each patient on thrice-weekly he-modialysis maintenance annually generates 323 kg of

waste30, we can estimate that hemodialysis generates a total of 37,656 tons of waste in Brazil (116,583 pa-tients x 323 kg/patient/year).

Furthermore, with a better healthcare system, this number will probably increase because more patients will have access to renal replacement therapy, which is a current trend in developing countries. Therefore, it is important to discuss ways to reduce the environ-mental impact of dialysis practice. However, there is still a paucity of discussion about this subject in Brazil.31

conclusion

As healthcare providers, one of our ultimate goals must be “primum non nocere”, which means, “first, to do no harm”.32 Dialysis is an established treat-ment that, while saving millions of lives, paradoxi-cally causes great negative impact to the environment that may affect the health and wellbeing of billions of people. Sooner or later, climate change will force us to redesign our practices and reduce the harm we cause through governmental laws and regulations. We must anticipate this move and be proactive; under these cir-cumstances, it is better to lead than to be led.33

Green or eco-dialysis is still little discussed in Brazil, and nephrologists and stakeholders are uncer-tain about what this really means. The first step for a change in current practice is to spread the word of the necessity of sustainability in dialysis throughout the country to create a collective consciousness. Green dialysis is not only a concept or a theoretical discus-sion. Quite the opposite, there are many tangible and practical opportunities available - as outlined above - to effectively reduce our environmental footprint. We hope that this “Call-to-Action” may cause an epiph-any in relation to the harm we have been causing as nephrologists and be a turning point for developing an environmentally positive attitude towards a sus-tainable future.

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casE rEport | rElato dE caso

AuthorsNara Thaisa Tenório Martins Braga1

Adriana Banhos Carneiro2

Kathia Liliane da Cunha Ribeiro Zuntini2,3

Flávio Bezerra de Araújo1

Elizabeth De Francesco Daher1,4

1 Hospital Geral de Fortaleza, Departamento de Nefrologia, Fortaleza, CE, Brasil.2 Hospital Infantil Albert Sabin, Departamento de Pediatria, Fortaleza, CE, Brasil.3 Hospital Infantil Albert Sabin, Departamento de Nefropediatria, Fortaleza, CE, Brasil.4 Universidade Federal do Ceará, Faculdade de Medicina, Departamento de Medicina Clínica, Fortaleza, CE, Brasil.


Correspondence to:Nara Thaisa Tenório Martins Braga.E-mail: [email protected]

Takayasu arteritis: differential diagnosis in a teenager with severe acute kidney injury - a case report

Arterite de Takayasu: diagnóstico diferencial em adolescente com lesão renal aguda grave - relato de caso

A Arterite de Takayasu (AT) é uma doença inflamatória crônica, granulomatosa, de causa desconhecida, que afeta grandes vasos, principalmente a aorta e seus ramos, incluindo artérias carótidas, coronárias, pulmonares e renais, sendo a artéria subclávia esquerda o vaso mais acometido. A estenose da artéria renal é relatada em 23-31% dos casos e pode resultar em hipertensão maligna, insuficiência renal por isquemia, descompensação cardíaca e morte prematura. O acometimento bilateral de artérias renais é incomum, sendo rara a presença de anúria súbita e lesão renal aguda como sintoma inicial da doença, com poucos relatos na literatura. O caso reporta uma adolescente de 15 anos com sintomas constitucionais durante um ano de evolução, associados a problemas como cefaleia, náuseas e vômitos, com idas frequentes a serviços de emergência, sem adequada investigação clínica. Após 6 meses do início dos sintomas, a paciente evoluiu de forma grave, com quadro de edema agudo de pulmão, oligúria, lesão renal aguda e hipertensão arterial de difícil controle, sendo necessário suporte em Unidade de Terapia Intensiva e hemodiálise. A ultrassonografia inicial mostrava rins normais e artérias renais sem sinais de estenose. Após 30 dias de internamento, paciente permanecia anúrica, sendo realizada biópsia renal que se mostrou dentro dos padrões da normalidade. Angiotomografia de aorta abdominal evidenciou oclusão bilateral de artérias renais. A paciente descrita fechou critérios diagnósticos para arterite de Takayasu e manifestou uma complicação grave pouco descrita na literatura: estenose bilateral de artérias renais, ainda na fase aguda da nefropatia isquêmica.

Resumo

Palavras-chave: Arterite de Takayasu; Hipertensão Arterial; Lesão Renal Aguda.

Takayasu arteritis (TA) is a chronic granulomatous inflammatory condition of unknown cause that involves large vessels - particularly the aorta and its branches - such as the carotid, coronary, pulmonary, and renal arteries. The left subclavian artery is the most frequently involved vessel. Stenosis of the renal artery has been reported in 23-31% of the cases and may result in malignant hypertension, ischemic renal disease, decompensated heart failure, and premature death. Involvement of both renal arteries is uncommon. Early onset anuria and acute kidney injury are rare and have been reported only in a few cases in the literature. This report describes the case of a 15-year-old female with constitutional symptoms evolving for a year, combined with headache, nausea, and vomiting, in addition to frequent visits to emergency services and insufficient clinical examination. The patient worsened significantly six months after the onset of symptoms and developed acute pulmonary edema, oliguria, acute kidney injury, and difficult-to-control hypertension, at which point she was admitted for intensive care and hemodialysis. Initial ultrasound examination showed she had normal kidneys and stenosis-free renal arteries. The patient was still anuric after 30 days of hospitalization. A biopsy was performed and revealed her kidneys were normal. Computed tomography angiography scans of the abdominal aorta presented evidence of occlusion of both renal arteries. The patient met the diagnostic criteria for Takayasu arteritis and had a severe complication rarely described in the literature: stenosis of the two renal arteries during the acute stage of ischemic renal disease.

absTRacT

Keywords: Takayasu Arteritis; Hyperten-sion; Acute Kidney Injury.

DOI: 10.1590/2175-8239-JBN-2018-0174

http://orcid.org/0000-0001-5842-0567


Takayasu arteritis in the differential diagnosis of acute kidney injury

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inTRoducTion

Takayasu arteritis (TA) is a chronic inflammatory condition of unknown cause that involves large and medium caliber arteries, including the aorta and its main branches, and the coronary and pulmonary ar-teries.1,2,5 TA is seen more commonly in individuals of Asian descent, aged between 10 and 30 years, and females (80-90%). Incidence in the USA and Europe ranges from 1 to 3 cases per million population a year.15

Transmural granulomatous inflammation charac-teristically seen in TA may cause stenosis, occlusion, dilation, and/or the formation of aneurysms in the in-volved arteries.4,12 Genetic causes, infectious agents, and autoimmune factors may be connected to the progression of TA, in addition to a possible link be-tween TA and infection by Mycobacterium tubercu-losis (MT) as indicated in tuberculin purified protein derivative (PPD) tests.10,12 The insidious onset of TA often means patients are diagnosed at later stages of the disease. Progression is divided into three stages: the first revolves around systemic involvement, in which patients present with unspecific signs lasting for weeks and even months, usually left unchecked; the second stage consists of inflammation of the ves-sels, leading to stenosis or the formation of aneurys-ms; the third stage, also known as fibrotic/late-stage disease, includes manifestations resulting from limb or organ ischemia due to the narrowing or obstruc-tion of large vessels.7,17

TA is diagnosed based on the criteria set out by the American College of Rheumatology, which inclu-de the following: age 40 or younger at the onset of symptoms; claudication of an extremity; decreased brachial artery pulse; > 10 mmHg difference in sys-tolic blood pressure between arms; a bruit over the subclavian arteries or the aorta; and arteriographic evidence of narrowing of occlusion of the entire aor-ta, its primary branches, or large arteries in the proxi-mal upper of lower extremities. The presence of three or more of these criteria confirm the diagnosis of TA with specificity and sensitivity above 90%.3,8,12

Treatment must be initiated with glucocorticoids 1-2 mg/kg/day for one to three months, followed by gradual decreases in dosage after 30 days combined with immunosuppressant therapy, with methotrexate as the first choice followed by azathioprine and myco-phenolate mofetil; cyclophosphamide and infliximab are spared for severe and refractory cases.4,7

The specific effects of renal artery stenosis on the survival of patients with TA have not been described, since most studies focused on brachiocephalic invol-vement. However, severe hypertension is a known in-dependent predictor of premature death and greater risk of adverse events in individuals with TA, leading to 5-year survival rates below 60%.7

case RepoRT

A 15-year-old unmarried female student and Jehovah’s witness born and residing in Fortaleza, Ceará, Brazil, ar-rived at our unit complaining of myalgia, asthenia, and lower back pain irradiating toward her left leg lasting for a year. Her pain had been managed with dipyro-ne and ibuprofen. The patient reported having intense holocranial headaches associated with nausea and vo-miting for six months. She sought care several times at emergency services. Her symptoms were treated in iso-lation and she was diagnosed as having migraines and anxiety, which led to a prescription of fluoxetine 20 mg/day. She took the prescribed medication for six mon-ths, but her symptoms never subsided. A month prior to being hospitalized she had a dry cough and pleurisy associated with orthopnea and paroxysmal nocturnal dyspnea, which prompted her to seek care. Physical exa-mination revealed she was tachypneic, with low oxygen saturation levels on pulse oximetry, and increased blood pressure (BP) (200/120 mmHg). Lung auscultation re-vealed she had diffuse bilateral crackles. She did not im-prove after initial measures, which included oxygen the-rapy, morphine, nitrate, and diuretics, and progressed to acute respiratory failure. The patient was then intubated and placed on a ventilator.

She was referred to the intensive care unit at Hospital Infantil Albert Sabin with anuria and signs of pulmonary edema. Her tests on admission showed hi-gh levels of nitrogenous wastes, and she was prescribed hemodialysis. Physical examination showed her right brachial artery pulse was decreased and a difference greater than 10 mmHg in BP between arms. The pa-tient denied she had had previous diseases or hospita-lizations. She had a family history of anxiety disorder (her mother and brother) and a cousin with pulmonary tuberculosis. After a few hemodialysis sessions with ultrafiltration, her respiratory condition improved and she was sent to a ward, although she still presented wi-th difficult-to-control hypertension, anuria, hypercata-bolism, repeated episodes of acute pulmonary edema, and indication for daily hemodialysis.



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Her workup showed she had iron-deficiency ane-mia, increased C-reactive protein (CRP) levels, and an elevated erythrocyte sedimentation rate (ESR) (Table 1); transaminase levels and thyroid function were within normal range. Serology tests for hepatitis B, C, HIV, toxoplasmosis, cytomegalovirus, parvovi-rus, EBV, and syphilis were negative. A transthoracic echocardiogram revealed she had diffuse hypokinesis and a moderately dilated and dysfunctional left ven-tricle with an ejection fraction of 42%. No alterations were seen in the Doppler ultrasound examination of the carotid and vertebral arteries. Tests for ANA, lupus anticoagulant, anticardiolipin antibodies, an-ticentromere antibodies, anti-Scl 70 antibodies, anti-neutrophil cytoplasmic antibodies (ANCA), anti-Ro/SSA and anti-La/SSB antibodies, anti-Sm antibodies, and anti-DNA antibodies were negative; anti-β2 glycoprotein I IgM and IgG antibodies were negati-ve; CH50, C3, and C4 were normal. Demonstration of AARB (gastric lavage) was negative. The PPD skin test read 14 mm of induration.

Multi-slice computed tomography angiography of the chest showed nodular opacity on the upper lobe of the left lung without vascular alterations. Initial ultrasound examination of the urinary pathways sho-wed kidneys with a normal structural pattern and lo-cation; the right kidney measured 9.3 x 4.7 x 4.1 cm with a parenchymal thickness of 14.3 mm; the left kidney measured 9.0 x 4.3 x 4.3 cm with a paren-chymal thickness of 16.4 mm. Doppler flowmetry showed normal peaks of systolic and diastolic velo-city and resistive index. Multi-slice computed tomo-graphy angiography of the abdominal aorta showed absence of flow in the proximal segments of the two renal arteries (Figure 1) indicating stenosis/occlusion;

multiple sites with focal luminal narrowing and sites with segmental dilatation in the area where the ce-liac trunk emerges and in the proximal third of the superior mesenteric artery; and minor segmental lu-minal narrowing of the abdominal aorta in the infra-renal area 6.0 cm from the celiac trunk. Large- and medium-vessel vasculitis indicated the presence of Takayasu arteritis.

A kidney biopsy performed on day 30 of hospitali-zation showed 13 glomeruli characterized as normal, global glomerulosclerosis (1/13), focal tubular atro-phy with mild interstitial fibrosis, and negative immu-nofluorescence (Figures 2 and 3).

Table 1 Laboratory workup

Hemoglobin (mg/dL) 9.4 Urea (mg/dL) 120

Hematocrit (%) 29.3 Creatinine (mg/dL) 3.5

MCV (fL) 78 ESR (mm) 52

MCHC (g/dL) 32.1 CRP (mg/L) 132

Leukocytes (/mm3) 9200 LDH 935

Segmented (%) 63 Direct Coombs negative

Rod (%) 0 PTH (pg/mL) 13.2

Lymphocytes (%) 29 25-hydroxyvitamin D (ng/mL) 23.2

Platelets (mil/mm3) 365 Total bilirubin 0.33

Iron 6 Direct bilirubin 0.05

Transferrin sat. (%) 21.3 Albumin (mg/dL) 3.9

Figure 1. Multi-slice computed tomography angiography of the abdominal aorta showing absence of flow in the renal arteries.



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The patient was started on pulse therapy with methylprednisolone 1 g for three days followed by oral prednisone 60 mg/day. Due to the severity of her vascular involvement, she was prescribed cyclophos-phamide and prophylactic isoniazid for tuberculosis. Revascularization was not indicated on account of disease activity and because she refused blood trans-fusions for religious reasons. Another biopsy was performed (six months after the onset of anuria) and the results showed 14 glomeruli with diffuse ischemic glomerular retraction, degenerative tubule epithelial cell alterations with signs of atrophy and moderate interstitial fibrosis, and multifocal tubulointerstitial nephritis, with negative immunofluorescence (Figures 4 and 5). The choice was made for conservative ma-nagement on account of signs consistent with chro-nic kidney disease and the time of progression of the disease.

After a year on hemodialysis, the patient underwent a deceased-donor kidney transplant at Hospital Geral de Fortaleza. She was prescribed thymoglobulin for induction immunosuppression therapy and tacroli-mus, everolimus, and prednisone for maintenance therapy. She progressed satisfactorily and was on fewer antihypertensive drugs and improved cardiac function as shown by normal electrocardiograms a year after transplantation. Her final creatinine level was 0.7 mg/dL.

discussion

TA was described for the first time in 1908 by the Japanese ophthalmologist Mikito Takayasu, who reported the case of a 21-year-old young woman with sudden loss of eyesight, arteriovenous anasto-moses around the optic disc, and no radial pulse.2,7

Figure 2. Optical microscopy image of a PAS-stained kidney biopsy specimen, 400x magnification: glomerulus with conserved cellularity and regular capillary loops.

Figure 3. Optical microscopy image of a Jones Silver-stained kidney biopsy specimen, 400x magnification: capillary loops with regular contours.

Figure 4. Optical microscopy image of a PAS-stained kidney biopsy specimen, 100x magnification: glomerulus with retracted tuft and relatively increased urinary space.

Figure 5. Optical microscopy image of a Jones Silver-stained kidney biopsy specimen, 400x magnification: retracted, tortuous capillary loops.



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In recent years, an association has been described be-tween TA and infection by MT. Clemente et al. des-cribed positive tuberculosis tests in 43.1% of the in-dividuals included in a study. Our patient had a latent infection by MT evinced by a 14-mm induration on the PPD test and nodular opacity in the upper lobe of the left lung, in addition to positive epidemiology.11

Studies carried out in Asia found that renal artery injury associated with TA including dilatation, aneu-rysm, and stenosis, was reported in 30-35% of the cases. Stenosis accounted for the majority of these in-juries with 23-31% of the cases.5 The progression of stenosis is directly linked to worsening hypertension and deterioration of renal function secondary to is-chemic renal disease. Therefore, renal artery stenosis is an important prognostic factor for TA.9

The patient described in this report met four of the criteria for TA, had had constitutional symptoms for a year, and presented severe complications such as di-fficult-to-control hypertension, cardiac dysfunction, and acute kidney injury requiring dialysis, all of whi-ch indicative of renal hypertension. Renal hyperten-sion - defined by the combination of hypertension and significant stenosis of the renal artery - is the main potentially curable cause of high blood pressure. By frequency of occurrence, the main etiologies are athe-rosclerosis and fibromuscular dysplasia, followed by other less common causes such as TA. Patients with severe refractory hypertension, hypertension starting before 20 or after 50 years of age, and hypertension associated with renal failure must be suspected for re-nal hypertension.6,14

Prolonged ischemia leads to gradual atrophy and loss of kidney structural integrity. The parameters around the minimum amount of stenosis required for the onset of renal ischemia have not been established, but stenosis involving more than 75% of the diameter of the renal artery has been associated with poorer outcomes. Few studies have examined the structural and functional effects of chronic decreases of perfu-sion pressure on renal tissue after vascular stenosis. Renal ischemia causes the release of cytokines, which by their turn trigger immune and inflammatory res-ponses. The perpetuation of this mechanism induces renal fibrosis, with glomerular hyalinization and pro-gressive kidney atrophy.18

Renovascular disease may be treated clinically, surgically, or by percutaneous procedures (with or without stent grafts). Calcium channel blockers,

angiotensin-converting-enzyme inhibitors, angioten-sin II type 1 receptor blockers, and beta blockers have been effectively used to treat systemic hypertension associated with renal artery stenosis. Percutaneous procedures or revascularization surgery are indicated in cases of resistant, accelerated, or malignant hyper-tension; progressive loss of renal function with bilate-ral stenosis or stenosis in individuals with one kidney; congestive heart failure or repeated episodes of acute pulmonary edema.6,16

Endovascular approaches such as angioplasty wi-th or without stenting and revascularization surgery may be employed in individuals with critical stenosis, but these procedures should be carried out only af-ter the patient has been in remission, since negative outcomes may occur in individuals with active dise-ase.10,15 Recent publications on renovascular disease associated with TA have included few subjects given the low prevalence of this condition. The evidence available indicates renal angioplasty has yielded bet-ter outcomes. The immediate outcome of angioplasty is generally good, but sustaining vascular patency re-lies on the good management of the disease’s inflam-matory activity.15 Treatment failure occurs primarily in cases of involvement of the aorta associated with proximal renal artery involvement.6

Similarly to our case, Tumeleiro et al. reported on a 25-year-old patient presented with vomiting, heada-ches, acute pulmonary edema, hypertension (200/140 mmHg), mildly increased creatinine level, and cardiac dysfunction. Her arteriogram revealed a 60% obs-truction on the ostium of the right renal artery and se-vere obstruction on the ostium of the left renal artery. She had stents placed in her renal arteries (initially on the left renal artery and three years later on her right renal artery when she had an 80% obstruction) and evolved well to fewer clinical and echocardiogram signs of aortic regurgitation, normal creatinine levels, controlled BP (140/60 mmHg), and prescription of fewer antihypertensive drugs.13

This report described the case of a 15-year-old female with severe acute kidney injury, difficult--to-control hypertension, and cardiac dysfunction secondary to stenosis of the renal arteries by TA. Surgery was contraindicated at first for reasons of disease activity and severe anemia. After she became clinically stable, ultrasound examination of the uri-nary pathways and kidney biopsy revealed she had progressed to chronic kidney disease.



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AuthorsCatarina Pereira Eusébio1

Sofia Correia2

Filipa Silva2

Manuela Almeida2

Sofia Pedroso2

La Salete Martins2

Leonídio Diais2

José Queirós2

Helena Pessegueiro3

Ramon Vizcaíno4

António Castro Henriques2

1 Serviço de Nefrologia do Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila Real, Portugal.2 Serviço de Nefrologia e Transplantação Renal do Centro Hospitalar do Porto, Porto, Portugal.3 Serviço de Gastroenterologia do Centro Hospitalar do Porto, Porto, Portugal.4 Serviço de Anatomia Patológica do Centro Hospitalar do Porto, Porto, Portugal.


Correspondence to:Catarina Isabel Pereira Eusébio.E-mail: [email protected]

Refractory ascites and graft dysfunction in early renal transplantation

Ascite refratária e disfunção do enxerto no pós-transplante renal precoce

A ocorrência de ascite no pós-Transplante Renal (TR) é infrequente, podendo ser consequência de complicações cirúrgicas ou médicas. Caso clínico: 61 anos, mas-culino, antecedentes de hipertensão arte-rial, carcinoma da língua e hábitos alco-ólicos 12-20g/dia. Doença renal crônica secundária à doença renal poliquística autossômica dominante, sem poliquisto-se hepática. Submetido a TR de doador cadáver em setembro de 2017. Atraso na função de enxerto por estenose da artéria renal, corrigida cirurgicamente. Internado em janeiro de 2018 por ascite de novo, sem resposta a diuréticos. Circulação co-lateral abdominal visível. Disfunção do enxerto, tacrolinemia adequada. Sedi-mento urinário inocente. Anemia ligeira, sem trombocitopenia. Albumina sérica 4,0g/dL. Bioquímica hepática normal. Líquido peritoneal com características de transudado e gradiente sero-ascítico de albumina > 1,1. Ecografia com hepato-megalia, eixos vasculares permeáveis, sem esplenomegalia. Suspendeu micofenolato mofetil, reduziu restante imunossupres-são. Manteve ascite refratária: excluídas etiologias infecciosas, metabólicas, autoi-munes e neoplásicas. Sem proteinúria ne-frótica e sem insuficiência cardíaca. RM: micronódulos compatíveis com quistos biliares. EDA sem varizes gastroesofági-cas. Linfocintigrafia abdominal normal. Submetido a laparoscopia exploradora com biópsia hepática: cirrose septal in-completa de provável etiologia vascular, alguns ductos biliares dilatados. Manteve disfunção progressiva do TR, reiniciou hemodiálise. Proposta medição direta da pressão portal, protelada por resolução da ascite. Recuperação posterior da fun-ção de enxerto. Discussão: A cirrose sep-tal incompleta é uma causa incomum de hipertensão portal não cirrótica. A sua definição é morfológica e a fisiopatologia,

Resumo

The occurrence of ascites after Renal Transplant (RT) is infrequent, and may be a consequence of surgical or medical com-plications. Case report: 61 year-old, male, history of arterial hypertension, tongue car-cinoma and alcoholic habits 12-20g/day. He had chronic kidney disease secondary to autosomal dominant polycystic kidney disease, without hepatic polycystic disease. He underwent cadaver donor RT in Sep-tember 2017. He had delayed graft func-tion by surgically corrected renal artery stenosis. He was admitted in January 2018 for ascites de novo, with no response to di-uretics. HE had visible abdominal collater-al circulation. Graft dysfunction, adequate tacrolinemia, Innocent urinary sediment, mild anemia, without thrombocytopenia. Serum albumin 4.0g / dL. Normal hepatic biochemistry. Peritoneal fluid with tran-sudate characteristics and serum albumin gradient > 1.1. Ultrasound showed hepato-megaly, permeable vascular axes, without splenomegaly. Mycophenolate mofetil was suspended, with reduced remaining immu-nosuppression. He maintained refractory ascites: excluded infectious, metabolic, autoimmune and neoplastic etiologies. No nephrotic proteinuria and no heart failure. MRI: micronodules compatible with bile cysts. Upper Digestive Tract Endoscopy did not show gastroesophageal varicose veins. Normal abdominal lymphoscintigraphy. He underwent exploratory laparoscopy with liver biopsy: incomplete septal cir-rhosis of probable vascular etiology some dilated bile ducts. He maintained progres-sive RT dysfunction and restarted hemodi-alysis. The proposed direct measurement of portal pressure was delayed by ascites resolution. There was further recovery of the graft function. Discussion: Incomplete septal cirrhosis is an uncommon cause of non-cirrhotic portal hypertension. Its defi-nition is not well known, morphological

absTRacT

DOI: 10.1590/2175-8239-JBN-2018-0175

http://orcid.org/0000-0002-4055-7116


Refractory ascites after renal transplantation

570

inTRoducTion

The term “ascites” refers to a pathological buildup of fluid in the peritoneal cavity. It is associated with symptoms and changes in the physical examination when the volume is greater than 1.5 L, with smaller volumes being diagnosed through image studies.1,2 In its etiology, conditions that directly involve the peri-toneum (infection, neoplasia) may be a consequence of changes in another organ, or systemic changes. In the West, cirrhosis is the main cause of ascites (75%), followed by peritoneal neoplasia (12%), heart failure (5%) or peritoneal tuberculosis (2%).3 Ascites can al-so be classified as associated with portal hypertension (such as liver cirrhosis, heart failure or Budd-Chiari syndrome) or not associated with portal hypertension (peritonitis or peritoneal metastases).4 Another etiol-ogy, uncommon in Western countries, is idiopathic non-cirrhotic portal hypertension, and it is rarely con-sidered in the differential diagnoses.5 Little is known about the pathophysiology of this entity, which is de-fined by the presence of clinical signs and symptoms of portal hypertension in the absence of known cir-rhosis or liver disease.6

In a patient with ascites as its initial clinical condi-tion, one should perform a detailed clinical history and physical examination as well as analytical and image assesments.2 Diagnostic paracentesis is the test that alone offers more information and should be performed early.1 A serum albumin (SA) greater than 1.1 g/dL has 97% diagnostic accuracy for ascites sec-ondary to portal hypertension.2,3

The occurrence of ascites in the post-renal trans-plantation is rare and may occur with either preserved graft function or in situations of its dysfunction.4 There are reports of cases associated with problems such as rejection, graft decapsulation, urinary or vascular leakage, lymphocytosis, transudation, or infection.7,8 In rare cases, ascites and hepatotoxicity is associated with immunosuppressive drugs such as

and pathophysiological. We have not found published cases of post-RT ascites secondary to this pathology, described as possibly associated with drugs, immune alterations, infections, hypercoagulability and genetic predisposition.

Keywords: Renal transplantation; Ascites; Incomplete septal cirrhosis; Drugs.

Palavras-chave: Transplante renal; Ascite; Cirrose septal incompleta; Fármacos.

pouco conhecida. Não encontramos publicados casos de ascite pós-TR secundária a esta patologia, descrita como possivelmente associada a fármacos, alterações imunitárias, infecções, hipercoagulabilidade e predis-posição genética.

mycophenolate mofetil, azathioprine and sirolim-us.7,9,10 Nephrogenic ascites should also be considered in cases of advanced or terminal renal dysfunction. Its pathophysiology is unknown, but it is assumed that there is an increase in the permeability of the perito-neal membrane with consequent exudation, charac-terized by SA less than 1.1 g/dL.11

clinical case

A 61-year-old male, with a history of arterial hyper-tension, tongue carcinoma, had been submitted to partial glossectomy 8 years earlier. He had inactive smoking habits and alcoholic habits of about 12-20 g/day. Personal and family history of chronic renal disease secondary to dominant Autosomal Polycystic Kidney Disease, with no hepatic impairment diag-nosed. He was in hemodialysis for four years, without adversities. He underwent nephrectomy of the right kidney in preparation for renal transplantation (RT). No known history of blood transfusion or hypersensi-tizing events. He underwent RT from a cadaver donor four months before the current situation, with three HLA Class I and one Class II incompatibilities, with-out anti-doping antibodies. Donor and recipient with previously acquired immunity to CMV (IgG positive for both serologies).

He underwent induction immunosuppression with Basiliximab, tacrolimus, mycophenolate mofetil (MMF) and methylprednisolone. His delayed graft function by renal artery stenosis was surgically cor-rected in the immediate post-RT. At the time, he had high serum creatinine (CrS) 2.6 mg/dL. No need for transfusion of erythrocyte concentrate in the post-RT period. She maintained outpatient follow-up, with basal CrS of 2.6-2.8 mg/dL. He had been regularly medicated with tacrolimus, prednisolone, mycophenolate mofetil, pantoprazole, furosemide, amlodipine, carvedilol, lisinopril, tamsulosin, folic acid, B vitamins and erythropoietin analogue. He was



571

hospitalized as a result of ascites again, progressive aggravation, without response to an increase in di-uretic therapy. He had no dyspnea, no orthopnea, had visible abdominal collateral circulation and a slight peripheral edema on physical examination, with no other noticeable changes. Analytically, the graft func-tion worsened (CrS 4.5 mg/dL), with adequate tacroli-mus levels (Tacrolimus 8.9 ng/mL). Light anemia (Hb 10.7 g/dL), no thrombocytopenia (platelets 154,000). Serum albumin 4.0 g/dL, LDH 266 U/L. Unchanged hepatic biochemistry (TGO 24 U/L, TGP 15 U/L, GGT 32 U/L, alkaline phosphatase 55 U/L, total biliru-bin 0.25 mg/dL); normal coagulation panel. Innocent urinary sediment, with a P/CrU ratio of 0.33. The patient was submitted to diagnostic and evacuation paracentesis, with peritoneal fluid drainage (PF), with a slightly milky aspect but no diagnostic cellularity of peritonitis, with biochemical transudate characteris-tics (total protein and LDH), SA > 1.1 g/dL and tri-glycerides in the upper limit of normality (210 mg/dL, the upper limit being 200 mg/dL), which could jus-tify the macroscopic appearance of PF. Abdominal ultrasound showed hepatomegaly (16.3 cm; patient height 165 cm), with liver with regular contours and increased parenchyma echogenicity, pervious vascular axes and no splenomegaly. He suspended MMF and reduced the remaining immunosuppression. He main-tained refractory ascites, requiring frequent evacua-tion paracentesis and drainage higher than 3 L (ad-ministered i.v. albumin when ≥ 5 L).

Graft dysfunction was interpreted in the con-text of effective intravascular volume depletion by losses to the third space and marked increase of intra-abdominal pressure (high volume asci-tes under tension), which is corroborated by the transient improvement in graft function, objec-tified immediately after performing evacuation paracenteses (CrS minimum 3.1 mg/dL). The re-sults of the PF microbiological, mycological and mycobacteriological exams were negative. Viral hepatitis and HIV serologies were negative. He had negative alpha-fetoprotein, copper, cerulo-plasmin, alpha-1-antitrypsin and hepatic autoim-munity markers. His ferritin was slightly increased (467 mg/dL). He also had peripheral blood flow cytometry and normal PF. He showed negative stool parasitological examination. His contrast

CT scan revealed scattered millimetric hypervascu-lar hepatic nodules and small simple biliary cysts. His MRI with hepato-specific contrast showed multiple micronodules with features suggestive of biliary cysts. His upper gastrointestinal endoscopy showed no gastroesophageal varices. His abdomi-nal lymphoscintigraphy had no changes, and his transthoracic echocardiogram showed no relevant changes.

We discussed this case at a multidisciplinary team meeting: due to the lack of diagnostic data, explor-atory laparoscopy was suggested. Intraoperatively, the liver had a nodular macroscopic appearance. In the same surgical procedure, we performed a surgi-cal wedge biopsy. The anatomopathological exam re-vealed incomplete septal cirrhosis of probable vascu-lar etiology (veno-occlusive disease) and dilated bile ducts in some portal spaces (Figures 1 and 2). The patient evolved with progressive RT dysfunction and required regular hemodialysis. In a later gastroenter-ology consultation, a direct measurement of portal pressure was proposed, with a view to the eventual placement of a transjugular intrahepatic portal-sys-temic shunt, which was, however, delayed because of the complete ascites resolution. Given the favor-able evolution, the hypercoagulability disorder study was also not performed. After one month on regu-lar dialysis, the patient recovered graft function and maintained stable RT function, with CrS 1.9mg/dL, under double immunosuppression (tacrolimus and prednisolone). At 6 months of follow-up, the ascites did not recur.

Figure 1. Liver histology. Reticulin staining 100x. Fibrous septa are observed which incompletely resemble a nodule.



572

discussion

The term incomplete septal cirrhosis (ISC) was first introduced by Popper in 1966.12 Liver biopsy studies revealed a ISC frequency of 0.74-1.4%.13 Histologically, it is characterized by of hepatic pa-renchyma nodularity, vascularized septa, reticulin buildup between hyperplastic parenchyma zones, si-nusoidal dilatation and hepatocyte hyperplasia.14 One of the pathophysiological mechanisms suggested was the existence of obliterative portal venopathy, with consequent heterogeneity in the hepatic parenchyma portal irrigation.

ISC is one of the histological presentation pat-terns of idiopathic non-cirrhotic portal hypertension (INCPH), and it is considered by several authors as a stage of disease manifestation.12,15 The inter-national nomenclature of INCPH is ambiguous. In Asia, where it is most frequent, it is known as non-cirrhotic portal fibrosis (India) and idiopathic portal hypertension (Japan). In the West, it has been dubbed hepatorenal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia.15

The main etiologies proposed for INCPH are: in-fectious (bacterial infections of the gastrointestinal tract and umbilical pyemia with repeated septic em-bolization for portal circulation, schistosomiasis and HIV); (systemic sclerosis, systemic lupus erythema-tosus, hypogammaglobulinemia); exposure to drugs and toxins (arsenic, azathioprine); prothrombotic states.16 Still, there are rare forms of genetic and fa-milial predisposition described.14,15

The diagnostic criteria for INCPH are the pres-ence of a clinical sign of portal hypertension

(splenomegaly/hyperpesplenism, esophageal varicose veins, ascites, increase in the hepatic venous pressure gradient or presence of portal venous collaterals), af-ter cirrhosis, vascular thrombosis of the portal and hepatic veins, and conditions that may be associated with chronic liver disease (infectious, autoimmune, metabolic, etc.).15,17

In the clinical case described here, the appear-ance of ascites seems to be temporally related to RT. Therefore, late surgical complications were excluded by imaging exams. The PF biochemical analysis re-vealed a SA > 1.1 g/dL, which is suggestive of portal hypertension and is corroborated by the presence of exuberant collateral venous circulation in the abdom-inal wall, and hepatomegaly. Although splenomegaly and esophageal varices did not coexist, the clinical picture, at the time of diagnosis, showed little evo-lution time, which may justify the absence of these findings. A SA > 1.1 g/dL makes unlikely etiologies such as ascites secondary to infectious, nephrogenic or neoplastic peritonitis, which were also investigated and ruled out. The intra-abdominal vascular axes thrombosis, hepatic cirrhosis or liver disease (meta-bolic, autoimmune and viral), as well as heart failure or nephrotic syndrome that could justify the clinical picture.

The authors thus reached the histological diag-nosis of incomplete septal cirrhosis after exploratory laparoscopy and surgical liver biopsy. The main causes that are thought to be associated with this entity were described above and also mostly excluded during the diagnostic investigation. However, it remains the hy-pothesis that the ISC, in the case of our patient, may be associated with the pharmacological exposure to the MMF. There is only one reported case of refrac-tory ascites in the literature, after kidney-pancreas transplantation, which association with mycopheno-lic acid was confirmed after ascites resurgence of with its reintroduction. However, in this case, no liver bi-opsy was performed.9

Veno-occlusive disease, which has been described as a possible etiology of hepatic septal cirrhosis. In our clinical case, it is characterized by loss of sinusoi-dal wall integrity and obliterative venulitis, and has been widely described as associated with myeloabla-tive regimens used in hematopoietic cell transplan-tation. However, it has also been described as sec-ondary to other chemotherapy, radiotherapy, teas/herbal products and other pharmacological therapies,

Figure 2. Liver histology. Masson trichrome 200x. We see central lobular vein with changes suggestive of veno-occlusive disease.



573

among which the antimetabolite drug Azathioprine is highlighted, with interest in our case.18,19

In our patient, after one month in a regular hemo-dialysis program, we achieved ascites resolution and graft function recovery. After 6 months of follow-up, with double immunosuppression (prednisolone and tacrolimus [low tacrolinemia, 5-6 ng/mL]), the pa-tient had no evidence of ascites relapse, confirmed by imaging, which is more in favor of the possible association between MMF, refractory ascites and in-complete septal cirrhosis/ INCPH, described in this clinical case.

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AuthorsRenato Demarchi Foresto1,2

Daniel Wagner de Castro Lima Santos3

Maria Amélia Aguiar Hazin1,2

Alejandro Túlio Zapata Leyton1,2

Nayara Cordeiro Tenório2

Laila Almeida Viana2

Marina Pontello Cristelli2

Hélio Tedesco Silva Júnior1,2

José Osmar Medina Pestana1,2

1 Universidade Federal de São Paulo, Escola Paulista de Medicina São Paulo, SP, Brasil.2 Hospital do Rim, Divisão de Nefrologia, São Paulo, SP, Brasil.3 Hospital do Rim, Divisão de Doenças Infecciosas, São Paulo, SP, Brasil.


Correspondence to:Renato Demarchi Foresto.E-mail: [email protected]

Chikungunya in a kidney transplant recipient: a case report

Chikungunya em um receptor de transplante renal: relato de caso

Em 2004, um surto global de Chikungunya af-etou a maioria das regiões tropicais e subtrop-icais do mundo. Em 2016, um surto ocorreu no Nordeste do Brasil com centenas de casos documentados. Receptores de transplantes de órgãos sólidos têm uma resposta imune modi-ficada à infecção, e o curso clínico é geralmente diferente daquele em pacientes imunocompe-tentes. O diagnóstico pode ser desafiador nessa população. A maioria dos relatos descreve pacientes residentes em áreas endêmicas, em-bora devamos enfatizar a importância do diag-nóstico diferencial em viajantes transplantados renais que visitam regiões endêmicas, como o Nordeste do Brasil. Aqui, nós relatamos o caso de um receptor de transplante renal que adquir-iu febre Chikungunya após uma viagem a uma região endêmica no Nordeste do Brasil durante o surto de 2016, com uma boa evolução clíni-ca. Também apresentamos recomendações de alerta para viajantes em áreas endêmicas, como medidas adicionais para prevenir surtos de doenças.

Resumo

Palavras-chave: Vírus Chikungunya; Transplante de Rim; Infecções por Arbovirus, Tolerância Imunológica.

In 2004, a global spread of Chikungunya fever affected most tropical and subtropi-cal regions of the world. In 2016, an ou-tbreak occurred in Northeast Brazil with hundreds of cases documented. Solid or-gan transplant recipients have a modified immune response to infection and the clini-cal course is usually different from immu-nocompetent patients. The diagnosis can be challenging in this population. Most re-ports describe patients residing in endemic areas, although we must emphasize the im-portance of differential diagnosis in kidney transplanted travelers who visit endemic regions, such as Northeast Brazil. Here, we reported a case of a kidney transplant reci-pient that acquired Chikungunya fever af-ter a trip to an endemic region at Northeast Brazil during the outbreak in 2016, with a good clinical evolution. We also present warning recommendations for travelers to endemic areas as additional measures to prevent disease outbreaks.

absTRacT

Keywords: Chikungunya virus; Kidney Transplantation; Arbovirus Infections; Immune Tolerance.

DOI: 10.1590/2175-8239-JBN-2018-0196

inTRoducTion

Chikungunya fever is a disease caused by the arbovirus Chikungunya (CHIKV), belonging to the Togaviridae Family and the Alphavirus genus. CHIKV is trans-mitted by the bite of the mosquito vec-tors Aedes aegypti or Aedes albopictus1. The name “Chikungunya” comes from the Makonde language in Tanganyika (Tanzania) and means “bended person” or “the one who stoops”, describing the posture caused by the severe arthralgia present in patients with Chikungunya fe-ver2. CHIKV is endemic in certain parts of

West Africa, East Asia, and Latin America, and some outbreaks of Chikungunya dis-ease have occurred in Brazil in the last years. Autochthonous cases in Brazil started in 2014, with a major outbreak in the Northeast region in mid-20163.

After a short period of incubation of 3 to 7 days, the main symptoms begin abruptly with severe polyarthralgia, fe-ver above 39°C, diffuse maculopapular rash, asthenia, myalgia, and headache, with self-limiting duration of around 7 to 10 days. Polyarthralgia and myalgia can last several weeks to even months, leading to chronic weakness. The most common

https://orcid.org/0000-0001-9370-0265

https://orcid.org/0000-0003-4946-911X

https://orcid.org/0000-0002-1445-5546

https://orcid.org/0000-0002-4719-4020

https://orcid.org/0000-0002-5887-6211

https://orcid.org/0000-0002-5064-9735

https://orcid.org/0000-0002-2813-0400

https://orcid.org/0000-0002-9896-323X

https://orcid.org/0000-0002-0750-7360


Chikungunya in transplant

575

serum abnormalities are lymphopenia, thrombocyto-penia, elevated CPK, mild elevated liver enzymes, and mild to moderate acute kidney injury4.

Although Chikungunya is not a disease of high lethality, it has an endemic behavior with a high mor-bidity rate associated with persistent arthralgia, re-sulting in low quality of life. Severe manifestations in-clude septic shock, myocarditis, meningoencephalitis, hepatic failure, respiratory distress, renal failure, and cryoglobulinemia. Although these complications and death are rare, they occur more often in patients over 65 years of age5,6. Chronic joint symptoms may occur in 25-35% of non-transplanted patients1. The clinical manifestations have a specific evolution in patients who received immunosuppressive drugs, as solid or-gan transplant recipients, with a few cases described in literature7,8. Supportive care is the standard treat-ment to Chikungunya fever and specific antivirals are not available.

Chikungunya infection in kidney transplant recipi-ents presents atypical clinical evolution and prognosis compared to infection in immunocompetent patients. Despite the occurrence of an outbreak of the disease in 2016, there are few reported cases in transplant recipients, notably in transplanted travelers, probably a consequence of underdiagnosis and underreporting. This case report corroborates the clinical findings of the Chikungunya infection described in kidney trans-plant patients, and alerts on the recommendations for those patients traveling to endemic areas.

case RepoRT

A 42-year-old woman, submitted to living donor kidney transplantation 7 years before, was admitted to the hospital due to fever (up to 40°C) since the day before admission, associated with severe pain in knees and right shoulder, and one episode of diar-rhea 5 days before. She referred a trip to the coun-tryside of Paraiba, at Northeast of Brazil, 20 days be-fore admission, where there was a local outbreak of Chikungunya. Physical examination revealed no signs of arthritis, cutaneous rash and respiratory distress. Neurological exam was normal.

Results of exams collected at admission revealed: creatinine 1.64 mg/dL (baseline 1.00 mg/dL); hemo-globin 12.1 g/dL; hematocrit 36.7%; leukocytes 7,000/µL (differential counts of neutrophils 6,230/µL; lym-phocytes 280/µL; basophils 0/µL; eosinophils 0/µL; monocytes 490/µL), platelets 125,000/µL; C-reactive protein 8.08 mg/dL; creatine phosphokinase 143 U/L;

alanine aminotransferase (ALT) 81 U/L; aspartate aminotransferase (AST) 55 U/L; NS1 rapid test for dengue was negative; serology for Chikungunya IgM was positive, and qualitative reverse transcription polymerase chain reaction (RT-PCR) was detectable. The patient was taking a combination of immunosup-pressive drugs with prednisone 5 mg once a day, ta-crolimus 5 mg bid, and mycophenolate 720 mg bid.

During hospitalization, after the diagnosis of Chikungunya fever, the dose of mycophenolate was reduced to 360 mg bid and the sulfamethoxazole-trimethoprim for pneumocystosis prophylaxis was stopped due to lymphopenia. The patient received ve-nous and oral hydration, with recovery of graft func-tion. The medical team opted not to increase corticoid dose. The patient had a good clinical evolution, with return to baseline graft function and clinical improve-ment. After a 2-year follow-up, the patient remained with good renal function (creatinine of 0.92 mg/dL), but with complaints of body cramps until 1 year after the infectious episode. The patient had no bone defor-mation or chronic arthritis.

discussion

CHIKV and other arboviruses such as Dengue, Zika and Yellow fever (YF) can infect people living in or traveling to endemic areas in Latin America, Africa, and East Asia. There are few data about arboviruses in solid organ transplant recipients, but the real inci-dence of these infectious diseases is probably greater than we think9,10. There is no reported case of YF transmitted by blood transfusion or organ trans-plantation, probably due to the vaccine against YF. Transmission of the other arboviruses by these routes is anecdotic11.

Since the global spreading of CHIKV in 2004, ma-ny countries situated in tropic and subtropic regions have endemic CHIKV circulation. In Brazil, Aedes aegypti is disseminated in all regions and widely dis-persed in urban areas, where cases of Chikungunya fever have already been documented12.

Mosquitoes become infected when they feed on a person infected by the virus, which reaches its sali-vary glands and is inoculated in the next person bit-ten by the insect. The virus life cycle involves human and other primates that live in the jungle, although urban transmission can occur due to mosquito hab-its. The vectors Aedes aegypti and Aedes albopictus also transmit Zika virus and Dengue virus, so they have the same endemic areas of transmission, and



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coinfections have been documented10,13. CHIKV may also be transmitted via maternal-fetal blood infection and rarely via solid organ transplantation, only if vi-remia is above 104-109 RNA copies/mL and the re-cipient has a lack of specific IgM and IgG response14.

CHIKV infection should be suspected in patients with acute onset of fever and polyarthralgia, and doc-umented epidemiologic exposure. The laboratory di-agnosis opportunity depends on the period of the in-fection. During the viremic period, usually up to one week from the onset of the symptoms, the diagnosis of the acute infection is based on direct methods, such as RT-PCR. Reported sensitivity and specificity of the CHIKV-IgM ELISA assay (Euroimmun®) are 98 and 97.5%, respectively15.

Chikungunya infection can be a cause of acute kidney injury (AKI) in severe cases, mainly secondary to pre-renal lesion (20%), but there are few reports of AKI due to rhabdomyolysis and acute interstitial ne-phritis16,17. Our patient had a mild transient KDIGO 1 AKI attributed to pre-renal lesion, with complete response after intravenous fluids. Rhabdomyolysis was discarded.

The patient described above was a kidney transplant recipient infected by a mosquito bite. Autochthonous cases in Brazil started in 2014, with a major outbreak in the Northeast region in mid-2016, probably when the described patient acquired the disease. Two articles published by Pierotti et al. and Girão et al. describe 4 and 9 cases, respectively, of Chikungunya fever in kidney transplant recipients, all of them with good evolution, without severe symp-toms, such as in the case presented above7,8.

The literature has conflicting data about the clini-cal course of persistent polyarthralgia in patients us-ing immunosuppressive drugs. These symptoms are generally incapacitating and have a negative impact in the quality of life of this population. In a cohort of 180 patients in the general population, 60% had severe persistent arthralgia or joint swelling at 3 years after the acute infection18. Economopoulou et al. in 2009 described a cohort of 610 atypical cases with only 3 of them having kidney transplants, and Kee et al. in 2010 described 2 cases of Chikungunya fever with atypical course and bacterial coinfections16,19.

Previously published data showed that patients who underwent immunosuppression, like kidney transplant recipients, were more likely to have bac-terial coinfections and poor clinical results16,20,21. However, some recent retrospective cohorts demon-strate that solid organ transplant recipients have a

good clinical course of Chikungunya fever, with less incidence of severe manifestations and persistent ar-thralgia, possibly due to the use of corticosteroids for immunosuppression, as suggested by other authors7,8.

The two main symptoms of the disease are fever and arthralgia. Both are associated to the synthesis of cytokines such as interleukin-1b, IL-6, and tumor necrosis factor-alpha, which are known pyretics and cause inflammation or destruction of cartilage, syno-vial, and bone tissues. It has also been shown that interferon (IFN) produced by CHIKV-infected fi-broblasts induce high expression of prostaglandins in these patients. Immunosuppressive drugs such as calcineurin inhibitors decreases the expression of genes encoding proinflammatory cytokines (interfer-on, TNF-alpha). Corticosteroids inhibit lymphocyte proliferation and cytokine synthesis, and mycophe-nolate exhibit a marked antiproliferative effect in all mononuclear cells, inhibiting the production of IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Thus, it is possible that anti-rejection drugs may cause a blockage of cyto-kines production that cause inflammatory responses in Chikungunya fever, decreasing the expression of symptoms and the severity of cases22,23.

Some guidelines recommend a short period of corticosteroids for treating inflammatory manifes-tations of CHIKV, like polyarthritis, during 1 to 2 months, with low-dose prednisone (5-10 mg)24-26. Rheumatologists recommend the use of hydroxy-chloroquine or meloxicam for persistent polyarthral-gia instead of other nonsteroidal anti-inflammatory drugs26, but there is no evidence of benefit in solid organ transplant recipients. In addition, the use of NSAIDs is strongly contraindicated in kidney transplant recipients, due to the risk of acute graft dysfunction.

No antiviral has been approved for treatment of CHIKV fever, but the combination of doxycycline and ribavirin showed a potential effect on inhibiting entry and replication of CHIKV in culture of kidney epithelial cells extracted from monkeys, and also re-duced viral infectivity in vitro and in vivo27. Human vaccine against CHIKV is not yet available for clinical practice; notwithstanding, inactivated and attenuated vaccine candidates have been studied in phase I/II tri-als, and engineered vaccines have proven to be safe and immunogenic in mouse and nonhuman primate models28.



577

Further studies are needed to determine a suitable treatment for both the eradication of serum CHIKV circulation and the management of chronic symp-toms. Meanwhile, environmental measures already implemented in campaigns to combat Aedes aegypti proliferation can help control and prevent CHIKV epidemics in tropical countries, such as Brazil. The Brazilian Ministry of Health recommends as preven-tion measures for travelers to endemic areas the use of repellents in exposed skin areas, keeping doors and windows closed if possible, wearing clothing that pro-tects skin surface, such as pants and a long-sleeved shirt, socks, and closed shoes, avoiding environments with mosquitoes without the above protective mea-sures, and looking for areas of mosquito breeding nearby and notifying the person responsible for their proper elimination. If a traveler develops the disease, he or she becomes a potential reservoirs of infection for other people and should maintain the above pro-tective measures to avoid disease spreading. Most importantly, the person should seek medical advice immediately and avoid self-medication29.

Here, we alert clinicians and nephrologists about the paucity of symptoms of arbovirosis like Chikungunya fever and advise early suspicion and correct treatment. Furthermore, patients traveling to areas at risk should be instructed to maintain clinical surveillance and seek medical attention in the event of fever, arthralgia, rash, headache, and fatigue for up to 7 days after the trip.

conclusion

We presented a case of an immunosuppressed kidney transplant recipient with Chikungunya fever, with a non-specific clinical course, demonstrating that this disease should be part of the differential diagnosis of febrile syndrome and polyarthralgia in transplanted patients in an endemic country. We have also given recommendations for travelers to endemic areas as additional measures to prevent disease outbreaks.

auThoR’s conTRibuTion

Renato Demarchi Foresto, Daniel Wagner de Castro Lima Santos, Maria Amélia Aguiar Hazin, Alejandro Túlio Zapata Leyton, Nayara Cordeiro Tenório, Laila Almeida Viana, Marina Pontello Cristelli, Hélio Tedesco Silva Júnior, José Osmar Medina Pestana contributed substantially to the conception or design of the study; collection, analysis, or interpretation of

data; writing or critical review of the manuscript; and final approval of the version to be published.



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AuthorsNey Arencibia Pérez1

María Luisa Agüera Morales1

Rafael Sánchez Sánchez2

Rosa María Ortega Salas2

Rafael Ángel Fernández de la Puebla3

Mario Espinosa Hernández1

1 Reina Sofia University Hospital, Nephrology, Av. Menendez Pidal, s/n Córdoba, Spain.2 Reina Sofia University Hospital, Pathological Anatomy, Cordoba, Spain.3 Reina Sofia University Hospital, Internal Medicine, Cordoba, Spain.


Correspondence to:Ney Arencibia Pérez.E-mail: [email protected]

Endothelial lesion and complement activation in patients with Scleroderma Renal Crisis

Lesão endotelial e ativação do complemento em pacientes com crise renal esclerodérmica

Nas revisões de biópsias renais, a crise renal esclerodérmica (CRE) é caracterizada por lesões endoteliais vasculares, depósitos de C4d em vasos peritubulares e lesões agudas e crônicas que coexistem na mesma bióp-sia. Os sinais clínicos de microangiopatia trombótica (MAT) são descritos na escle-rose sistêmica (ES); no entanto, não foram relacionados às lesões agudas descritas nas biópsias renais. Relatamos um caso de CRE em um paciente com síndrome de super-posição de esclerodermia-dermatomiosite, que também apresentou dados clínicos e histopatológicos de MAT. No exame de fundo do olho, foi encontrada uma retino-patia hipertensiva aguda grave. A biópsia renal mostrou lesão endotelial grave com alargamento das células mucoides ao nível da íntima, proliferação concêntrica focal na maioria das pequenas arteríolas e depósitos de C3, C4d e IgM ao longo das paredes dos capilares. O estudo genético do complemen-to mostrou apenas a presença de haplótipos de risco da proteína cofator de membrana (PCM), sem outros distúrbios genéticos do complemento. Entendemos que em um pa-ciente com MAT e ES, o dano renal seria fundamentalmente endotelial e do tipo agu-do; além disso, observaríamos evidências claras de ativação do complemento. Uma vez que novos estudos correlacionam dados clínico-analíticos com estudos anatomopa-tológicos, é provável que sejamos forçados a redefinir o conceito de CRE, enfocando a relação entre dano endotelial agudo e ativa-ção do complemento.

Resumo

Palavras-chave: Esclerodermia Localizada; Microangiopatia trombótica; Esclerose Sis-têmica; Retinopatia Hipertensiva; Endoté-lio; Ativação do Complemento.

In kidney biopsies reviews, scleroderma renal crisis (SRC) is characterized by vascular endothelial injuries, C4d depos-its on peritubular vessels, and acute and chronic injuries coexisting on the same biopsy. The clinical signs of thrombotic microangiopathy (TMA) are described in systemic sclerosis (SSc), nevertheless, it has not been related to acute injuries described on kidney biopsies. We report a case of SRC in a patient with scleroder-ma-dermatomyositis overlap syndrome, which also showed clinical and histo-pathological data of TMA. On fundus examination, a severe acute hypertensive retinopathy was found. The kidney bi-opsy showed severe endothelial damage with widening of mucoid cells at the level of the intima, focal concentric prolifera-tion on most small arterioles, and C3, C4d, and IgM deposits along the capillary walls. The genetic study of complement only showed the presence of membrane cofactor protein (MCP) risk haplotypes, without other genetic complement disor-ders. We understand that in a patient with TMA and SSc, the kidney damage would be fundamentally endothelial and of an acute type; moreover, we would observe clear evidence of complement activation. Once further studies correlate clinical-analytical data with anatomopathological studies, it is likely that we will be forced to redefine the SRC concept, focusing on the relationship between acute endothelial damage and complement activation.

absTRacT

Keywords: Scleroderma, Localized; Thrombotic Microangiopathy; Systemic Sclerosis; Hypertensive Retinopathy; En-dothelium; Complement Activation.

DOI: 10.1590/2175-8239-JBN-2018-0202


http://orcid.org/0000-0002-8878-8263


Scleroderma Renal Crisis and complement

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Classically, scleroderma renal crisis (SRC) is defined as the association of acute renal injury, normal uri-nalysis or mild proteinuria, and hypertension (often malignant hypertension), typically associated with plasma renin increase1,2,3.

SRC is an uncommon complication but between 20 and 30 percent of patients do not recover renal function4,5,6. Although it is a severe disease, to this day there are only a few histological descriptions of kid-ney biopsies.

In kidney biopsies reviews, SRC is characterized by vascular endothelial injuries, C4d deposits on pe-ritubular vessels, and acute and chronic injuries co-existing on the same biopsy6. The clinical signs of thrombotic microangiopathy (TMA) are described in systemic sclerosis (SSc); nevertheless, TMA has not been related to acute injuries described on kidney biopsies.

We present a clinical case with SRC, including the anatomopathological observations and clinical findings, and demonstrate the role of complement activation.

case RepoRT

A 50-year-old man was transferred to the emer-gency unit of our hospital due to progressive loss of vision in the previous 5 days. He had a 2‐ye-ar history of Raynaud syndrome treated with pentoxifylline 600 mg/24 h. Two weeks prior to admission, his rheumatologist suspected of a der-matomyositis and scleroderma overlap syndrome because the patient started with dysphagia and constitutional syndrome, and previously, he had Gottron nodules.

On arrival at the emergency unit, his blood pres-sure was 220/120 mmHg. Laboratory studies showed creatinine (Cr) of 1.7 mg/dL (two months before, Cr was 0.9 mg/dL) associated with a lactate dehy-drogenase (LDH) of 1252 U/L, creatine phosphoki-nase (CPK) of 3984 U/L, hemoglobin of 10.9 g/dL, platelet count of 149,000/uL (two months before was 326,000/uL), schistocytes at 2.5% and decreased lev-els of haptoglobin (13 mg/dL). Uroanalysis showed protein/Cr ratio of 0.3 and microscopic hematuria with 13 red blood cells/mL. Renal ultrasonography and Doppler study were normal.

We were getting results from the blood tests dur-ing his hospitalization. ANA test was positive (1/640) but anti-dsDNA was negative, C3 and C4 were de-pressed (C3 was 65.6 mg/dL and C4 was 11.5 mg/dL), anticentromere, ANCA-MPO, ANCA-PR3 and anti-GBM antibodies were negative. Protein electro-phoresis with immunofixation and quantification of serum immunoglobulins (IgG, IgM and IgA) were normal, as well as blood levels of vitamin B12 and fo-lic acid. Tests for HIV, hepatitis C virus, and hepatitis B virus were negative.

Regarding severe hypertension, fundus examina-tion showed a severe acute hypertensive retinopathy characterized by papillary edema with serous multifo-cal retinal detachments on the posterior pole of both eyes (Figure 1). Plasma renin level was increased to 320.1 pg/mL (1.8–59.4). Plasma cortisol, 24-hour urine fractionated catecholamines, and plasma aldo-sterone were normal.

Due to increased CPK, Raynaud syndrome, scapular waist muscle weakness, and anti-Ro/SSA and anti-PM-scl-75/PM-scl-100 positivity, a nailfold capillaroscopy and electromyographic study were performed.

Nailfold capillaroscopy demonstrated significant dropout (loss of capillary loops), lower density, and dilatation and tortuosity of capillaries, which are re-lated to dermatomyositis. Electromyogram showed a pattern of diffuse myopathic involvement of inflam-matory features. With these findings, and the Gottron nodules, the diagnosis of scleroderma-dermatomyosi-tis overlap syndrome was confirmed7,8,9.

Within the context of this disease, associated with acute renal injury and microangiopathic hemolytic anemia, a renal biopsy was performed. Direct coombs test was negative and blood activity of ADAMTS13 was normal.

The histopathology report stated a severe endo-thelial damage with widening of mucoid cells at the level of the intima, slight tubular atrophy, and focal concentric proliferation on most small arteries and ar-terioles. On direct immunofluorescence (IF) there was C3 and IgM deposits along the capillary walls in the mesangium and small vessels. Immunohistochemistry was positive for C4d on small-caliber arteries (Figure 2).

Regarding the genetic-molecular complement study, we observed low serum C3 and C4 levels,



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Figure 1. A1. Dilated fundus examination showing multi-foci serous retinal detachment. A2: Fluorescent angiography showing multiple hypofluorescent foci on the posterior pole. B: Macular optical coherence tomography at the 1st day of admission, C, 3rd day of admission, and D, 10th day of admission (progressive improvement of retinal detachment is observed).

indicating an activation of the classical and alterna-tive complement pathways. Antibodies to comple-ment factor H were negative, and serum factor H, membrane cofactor protein (MCP), and FI levels were normal. The genetic study only showed the presence of MCP risk haplotypes, without other genetic com-plement disorders.

Three months after admission, after controlling for blood pressure with angiotensin-converting en-zyme (ACE) inhibitors, the patient continued with as-thenia but without evidence of hemolytic anemia and renal failure (Cr 0.8 mg/dL without proteinuria and hematuria.). Furthermore, he recovered from vision loss and muscle weakness10,11.

discussion

Our patient had renal failure associated with seconda-ry TMA due to SSc overlapped with a dermatomyo-sitis. In general, renal replacement therapy (RRT) is required in approximately 50% of patients with se-condary TMA and acute renal injury12. In cases of secondary TMA due to SSc, RRT is required in 20-25% of cases4,5,6. In this patient, early diagnosis and

management provided a complete recovery of renal function and other systemic manifestations.

Until now, kidney biopsies are not routinely in-dicated for all SRC. However, when SRCs are as-sociated to other systemic diseases, kidney biopsy is particularly recommended3, and takes on even great-er importance to assess the levels of chronicity and endothelial injury, allowing the estimation of the re-versibility degree. In our patient, the kidney biopsy took on greater relevance because it was obtained at early stages of the disease, with only few mild chronic injuries.

Although several reviews have reported that en-dothelial damage is the underlying problem in TMA, in the case of SSc, the physiopathogenic mechanisms that produce endothelial damage are unclear. In early stages, a SRC may produce an acute endothelial dam-age and with time, give rise to mucopolysaccharide deposits and myointimal proliferation or fibrinoid necrosis due to a persistent vascular remodeling, es-tablishing chronic endothelial damage. The result is a retraction and necrosis of the glomeruli3.

In our patient, we uphold that there was a direct as-sociation between endothelial injury and complement

https://www.uptodate.com/contents/renal-involvement-in-the-mitochondrial-cytopathies?search=renal+involvement&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1



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Figure 2. A (100×) and B (200×): HE staining of arterioles with intimal proliferation and thickening that leads to obliteration of the vascular lumen and degraded red blood cells (image B, red star). C: Red arrow indicating arteriole with concentric "onion-skin" hypertrophy (methenamine silver stain, 100×). D: Arterioles with mucoid intimal thickening (Masson trichrome, 200×). E: Granular and focal immunostaining of small caliber artery (C4d, 200×). F: C3 and IgM (top right) immunodeposits along capillary walls and in te mesangium.

activation (classical and alternative complement path-ways). We observed low plasma C3 and C4 levels, and C3 and C4d deposits on dIF and immunohisto-chemistry respectively, suggesting a systemic TMA with complement activation13.

In the complement genetic study, we did not iden-tify any mutation in the regulatory genes, however, the patient had risk haplotypes in MCP, of which, to this day, the pathogenic role is unknown.



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The patient was treated early with ACE inhibi-tors, prior to the establishment of chronic kidney damage3,4,5,6. The initial therapy with eculizumab in SRC with TMA could be an alternative, but the avail-able data are based on small case series. Results from a Spanish study showed that short treatments with eculizumab were beneficial in patients with second-ary TMA, but two cases with SRC did not respond to treatment12.

In summary, this is a clear case of SRC with clinical and histopathological data of acute endo-thelial damage and complement activation. TMA in a patient with SSc would lead to kidney dam-age of an endothelial and acute type; moreover, we would observe clear evidence of complement activation (C4d positive on the vascular wall, C3 on dIF, and low plasma levels of C3 and C4). However, this needs to be corroborated by case series and experimental evidence and then, once we correlate clinical-analytical data with anato-mopathological studies, it is likely that we will be forced to redefine the SRC concept, focusing on the relationship between acute endothelial damage and complement activation.

RefeRences

1. Shapiro AP, Medsger TA Jr. Renal involvement in systemic scle-rosis. In: Schrier R, Gottschalk C, eds. Diseases of Kidney. 4th ed. Boston: Little, Brown; 1988.

2. Donohoe JF. Scleroderma and the kidney. Kidney Int 1992;41:462-77.

3. Chabtini L, Mounayar M, Azzi J, Bijol V, Bastacky S, Rennke HG, et al. Scleroderma Renal Crisis. In: Radstake T, ed. Syste-mic Sclerosis - An Update on the Aberrant Immune System and Clinical Features. London: Intech; 2012.

4. Guillevin L, Bérezné A, Seror R, Teixeira L, Pourrat J, Mahr A, et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls. Rheumatology (Oxford) 2012;51:460-7.

5. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133:600-3.

6. Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007;100:485-94.

7. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344-7.

8. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292:403-7.

9. Bohan A, Peter JB, Bowman RL, Pearson CM. Computer-as-sisted analysis of 153 patients with polymyositis and derma-tomyositis. Medicine (Baltimore) 1977;56:255-86.

10. Steen VD, Syzd A, Johnson JP, Greenberg A, Medsger TA Jr. Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol 2005;32:649-55.

11. Denton CP, Lapadula G, Mouthon L, Müller-Ladner U. Re-nal complications and scleroderma renal crisis. Rheumatology (Oxford) 2009;48:iii32-5.

12. Cavero T, Rabasco C, López A, Román E, Ávila A, Sevillano Á, et al. Eculizumab in secondary atypical haemolyticuraemic syndrome. Nephrol Dial Transplant 2017;32:466-74.

13. Batal I, Domsic RT, Shafer A, Medsger TA Jr, Kiss LP, Randha-wa P, et al. Renal biopsy findings predicting outcome in sclero-derma renal crisis. Hum Pathol 2009;40:332-40.

https://www.uptodate.com/contents/eculizumab-pediatric-drug-information?source=see_link

https://www.linguee.es/ingles-espanol/traduccion/evidence.html

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lEttEr | carta

AuthorsFábio Humberto Ribeiro Paes Ferraz1

Cibele Isaac Saad Rodrigues2

Giuseppe Cesare Gatto3

Natan Monsores de Sá4

1 Fundação de Ensino e Pesquisa em Ciências da Saúde, Escola Superior de Ciências da Saúde, Departamento de Graduação em Medicina, Brasília, DF, Brasil.2 Pontificia Universidade Católica de São Paulo. Faculdade de Ciências Médicas e da Saúde, Departamento de Medicina, Programa Mestrado Profissional em Educação nas Profissões de Saúde, Sorocaba, SP, Brasil.3 Universidade de Brasília, Hospital Universitário de Brasília, Unidade de Transplante, Brasília, DF, Brasil.4 Universidade de Brasília, Faculdade de Ciências da Saúde, Cátedra Unesco de Bioética, Brasília, DF, Brasil.


Correspondence to:Fábio Humberto Ribeiro Paes FerrazE-mail: [email protected]

Nephrologists and patients: between vulnerability and equityNefrologistas e pacientes: entre a vulnerabilidade e a equidade

DOI: 10.1590/2175-8239-JBN-2019-0060

Dear editorThe word “vulnerability” derives from the Latin term vulnerabilis, or from the Greek vulnus, and means “to hurt”.1 It was first ad-ded to the field of Bioethics in 1978, after the publication of the document called Belmont Report, which aimed to outline the ethical principles guiding research with human bein-gs in the United States.1

Since then, the term “vulnerable” has been used in caring ethics, and can be attributed to individuals, patients, family members, caregivers, health professionals or populations that are incapable of consent and/or reduced autonomy.

The vulnerability among chronic renal patients is multifactorial and multi-faceted, as these patients are deprived of their autonomy, requiring the availability, access and adherence to various forms of renal replacement therapy (RRT) for the maintenance of one’s life.

In this context, Obregón et al.’s2 paper is quite original, since it reverses the traditional viewpoint, concentrating not on the vulnerability of the patient, but rather on nephrologists themselves, regarding the technological, economic and professional contingencies that affect their field of work, their medical fees and their labor ties.2

A recent paper produced by our group sought to expand the view on vulnerability in the developing countries that make up the BRICS (Brazil, Russia, India, China and South Africa).3These countries account for 40% of the world population, 25% of the World’s Gross Product and 40% of the Global Burden of Disease.3 Through documentary analysis and systematic bibliographic research,

the objective was to analyze the main bioethical issues in accessing the various forms of RRT in these countries.

Regarding renal transplantation, there were permissive legislation on organ tourism (South Africa), the occurrence of renal transplants with deceased donors without prior consent (China), a high number of kidney transplants involved with evidence of commercialization of organs (India), difficulty concerning extra-official data in the international literature (Russia) and regional disparities in access to renal transplantation (in all).3 About dialysis, we find the most sensitive bioethical issues: prioritization of dialysis only for patients eligible for renal transplantation (South Africa), lack of government funding for dialysis and high-cost drugs (India), and inequalities in the provision of dialysis (all).3

While equity is a bioethical concept distinct from vulnerability, based on the Aristotelian premise that “unequal must be treated unequally,” promoting a fair provision of RRT to the most vulnerable countries, especially developing countries, would bring an improvement to the individuals’ vulnerabilities, as a bioethical reference, both for patients (due to better accessibility to treatment) and for nephrologists themselves (who often need to make difficult ethical choices in the context of scarce resources). The “Kidney Health for All” theme for the celebrations for the 2019’s World Kidney Day is an invitation to such a reflection. In fact, issues related to inequality in access to renal health are increasingly common in the world literature.5

https://orcid.org/0000-0001-8214-8778

https://orcid.org/0000-0001-9490-7997

https://orcid.org/0000-0001-6587-5949

https://orcid.org/0000-0002-0293-8460


Nephrologists, patients and vulnerability

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auThoR’s conTRibuTion

All authors participated in the preparation of the letter to the reader.

conflicT of inTeResTs

There is no conflict of interest on the part of any author.All authors participated in the preparation of the

letter to the reader.

RefeRences

1. Neves MP. Sentidos da vulnerabilidade: característica, condição, princípio. Rev Bras Bioética 2006;2:157-72.

2. Obregón JMV, Anjos MF. Nephrologists between power and vulnerability in times of technology. J Bras Nefrol 2018;40:403-9.

3. Ferraz FHRP, Rodrigues CIS, Gatto GC, Sa NM. Differences and inequalities in relation to access to renal replacement therapy in the BRICS countries. Ciênc Saúde Coletiva 2017;22:2175-85.

4. Wolf U. A “Ética a Nicômaco” de Aristóteles. São Paulo: Edições Loyola; 2010.

5. Crews DC, Bello AK, Saadi G; World Kidney Day Steering Committee. Burden, Access, and Disparities in Kidney Disease. Kidney Int Rep 2019;4:372-9.

https://www.ncbi.nlm.nih.gov/pubmed/?term=Crews%20DC%5BAuthor%5D&cauthor=true&cauthor_uid=30899864

https://www.ncbi.nlm.nih.gov/pubmed/?term=Bello%20AK%5BAuthor%5D&cauthor=true&cauthor_uid=30899864

https://www.ncbi.nlm.nih.gov/pubmed/?term=Saadi%20G%5BAuthor%5D&cauthor=true&cauthor_uid=30899864

https://www.ncbi.nlm.nih.gov/pubmed/?term=World%20Kidney%20Day%20Steering%20Committee%5BCorporate%20Author%5D

https://www.ncbi.nlm.nih.gov/pubmed/?term=World%20Kidney%20Day%20Steering%20Committee%5BCorporate%20Author%5D

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