Bone Children NKFguideline

K/DOQI Clinical Practice Guidelines for BoneMetabolism and Disease in Children

With Chronic Kidney DiseaseTables ............................................................................................................................... S1

Figures ............................................................................................................................. S1

Acronyms and Abbreviations ........................................................................................ S2

Algorithms ....................................................................................................................... S3

Work Group Members..................................................................................................... S4

K/DOQI Advisory Board Members................................................................................. S5

Foreword .......................................................................................................................... S6

Introduction ..................................................................................................................... S8

Guideline 1. Evaluation of Calcium and Phosphorus Metabolism ............................ S12

Guideline 2. Assessment of Bone Disease Associated with CKD................................ S18

Guideline 3. Surgical Management of Osteodystrophy ............................................. S23

Guideline 4. Target Serum Phosphorus Levels .......................................................... S26

Guideline 5. Management of Dietary Phosphorus Intake in Children with CKD ...... S29

Guideline 6. Use of Phosphate Binders in CKD ......................................................... S32

Guideline 7. Serum Calcium and Calcium-Phosphorus Product .............................. S39

Guideline 8. Prevention and Treatment of Vitamin D Insufficiency and Vitamin DDeficiency in CKD Patients ................................................................................... S48

Guideline 9. Active Vitamin D Therapy in CKD Patients .......................................... S53

Guideline 9A. Active Vitamin D Therapy in Patients with CKD Stages 2-4 ........... S53

Guideline 9B. Active Vitamin D Therapy in Patients on Dialysis (CKD Stage 5) ... S57

Guideline 10. Dialysate Calcium Concentrations...................................................... S64

Guideline 11. Recommendations for the Use of Growth Hormone for Childrenwith CKD .............................................................................................................. S68

VOL 46, NO 4, SUPPL 1, OCTOBER 2005

AJKD CONTENTSAmerican Journal ofKidney Diseases

Guideline 12. Aluminum Overload and Toxicity in CKD.......................................... S70Guideline 13. Treatment of Aluminum Toxicity ....................................................... S79Guideline 14. Treatment of Bone Disease in CKD ..................................................... S87

Guideline 14A. Hyperparathyroid (High-Turnover) Bone Disease ....................... S87Guideline 14B. Rickets/Osteomalacia.................................................................... S87Guideline 14C. Adynamic Bone Disease................................................................ S88

Guideline 15. Parathyroidectomy in Patients with CKD ........................................... S91Guideline 16. Metabolic Acidosis.............................................................................. S94Guideline 17. Bone Disease in the Pediatric Kidney Transplant Recipient ................ S96

Afterword ......................................................................................................................... S99

Biographical Sketches of Work Group Members ........................................................ S101

References....................................................................................................................... S103

TT

TTTT

TTTTTTTTT

T

TTTT

FFFFF

F

FF

F

A

Tables

able 1. Signs and Symptoms of Bone Disease in Children with CKD .......................................... S9able 2. Frequency of Measurement of PTH, Calcium, Phosphorus, Total CO2, and

Alkaline Phosphatase by Stage of CKD........................................................................... S12able 3. Target Range of Serum PTH by Stage of CKD................................................................ S12able 4. Histological Features of High-Turnover Renal Osteodystrophy...................................... S19able 5. Histological Features of Low-Turnover Renal Osteodystrophy ...................................... S19able 6. Representative Normal Values for Serum Phosphorus, Total Calcium, Blood

Ionized Calcium, and Alkaline Phosphatase Concentrations........................................... S26able 7. Dietary Reference Intakes of Phosphorus in Children ..................................................... S29able 8. Steps to Calculate the Initial Binder Prescription ............................................................ S33able 9. Phosphorus-Binding Compounds .................................................................................... S33able 10. Recommendations for Calcium Intake ............................................................................ S40able 11. Calcium Content of Common Calcium-Based Binders ................................................... S41able 12. Low-Phosphorus, High-Calcium Foods .......................................................................... S42able 13. Partial List of Calcium-Containing Supplements ............................................................ S43able 14. Determining Calcium Requirements in Adults Aged 19-30 Years .................................. S45able 15. Recommended Supplementation for Vitamin D Deficiency/Insufficiency in

Patients with CKD Stages 3-4 ......................................................................................... S48able 16. Serum Levels of PTH, Calcium, and Phosphate Required for Initiation of Oral

Vitamin D Sterol Therapy, and Recommended Initial Doses in Patients withCKD Stages 2-4 ............................................................................................................... S53

able 17. Initial Calcitriol Dosing Recommendations for Children on Maintenance Dialysis ....... S57able 18. Aluminum-Related Disorders: Features, Causes, and Considerations for Therapy ........ S71able 19. Frequency for Measurement of Serum Levels of Total CO2 ........................................... S94able 20. Frequency of Measurement of Calcium, Phosphorus, PTH, and Total CO2 after

Kidney Transplantation.................................................................................................... S96

Figures

igure 1. Relationship between Serum iPTH Levels and CCR......................................................... S13igure 2. Summary ROC Analysis of Erosions on X-Ray as Diagnostic for Osteitis Fibrosa .......... S14igure 3. Summary ROC Analysis of Intact PTH for Diagnosis of High-Turnover Bone Disease... S15igure 4. Summary ROC Analysis of Intact PTH for Diagnosis of Low-Turnover Bone Disease ... S16igure 5. Meta-Analysis of Size of Effect on Serum Phosphorus Levels of Calcium

Acetate versus Calcium Carbonate .................................................................................... S35igure 6. Meta-Analysis of Size of Hypercalcemic Effect of Calcium Carbonate versus

Other Phosphate Binders.................................................................................................... S35igure 7. Meta-Analysis of Oral versus Intravenous Calcitriol on PTH Suppression....................... S62igure 8. Individual Study and Summary Effect sizes for the Effect of DFO Therapy

on Bone Formation Rate .................................................................................................... S83igure 9. Individual Study and Summary Effect Sizes for the Effect of DFO Therapy on

Bone Surface Aluminum Stain........................................................................................... S83

merican Journal of Kidney Diseases, Vol 46, No 4, Suppl 1 (October), 2005: p S1 S1

S

Acronyms and Abbreviations1st PTH-IMA First-generation parathyroid hormone immunometric assay

2° HPT Secondary hyperparathyroidismAIs Adequate intakes

AVN Avascular necrosisBCG Bromocresol green methodBFR Bone formation rate

BMC Bone mineral contentBMD Bone mineral densityCaR Calcium-sensing receptors

CAPD Continuous ambulatory peritoneal dialysisCaXP Calcium-phosphorus productCCR Creatinine clearance rateCKD Chronic kidney diseaseCRF Chronic renal failureDBP Vitamin D-binding protein

DEXA Dual energy X-ray absorptiometryDFO Desferrioxamine

DOQI Dialysis Outcomes Quality InitiativeDRI Dietary Reference Intake

EBCT Electron beam computed tomographyEEG Electroencephalogram

ESRD End-stage renal diseaseGFR Glomerular filtration rate

GH, rhGH Growth hormone, recombinant human growth hormoneICMA Immunochemiluminometric assay

IGF Insulin-like growth factorIRMA Immunoradiometric assay

K/DOQI Kidney Disease Outcomes Quality InitiativeMCV Mean cell volume

MDRD Modification of Diet in Renal DiseaseMRI Magnetic resonance imagingNKF National Kidney FoundationPBM Peak bone massPTH Parathyroid hormoneQCT Quantitative computed tomographyRDA Recommended dietary allowanceRDI Recommended daily intake

ROC Receiver operating characteristicsSCFE Symptomatic proximal femoral slipped epiphyses

SD Standard deviationVDR Vitamin D receptor

VDRE Vitamin D receptor element, vitamin D-responsive element

American Journal of Kidney Diseases, Vol 46, No 4, Suppl 1 (October), 2005: p S22

AAAAA

AA

AA

A

Algorithms

lgorithm 1. Vitamin D Supplementation in CKD (Stages 2-4) .................................................................................. S49lgorithm 2. Management of CKD Patients (Stages 2-4) with Active Vitamin D Sterols ........................................... S54lgorithm 3. Managing Vitamin D Sterols Based on Serum Calcium Levels.............................................................. S59lgorithm 4. Managing Vitamin D Sterols Based on Serum Phosphorus Levels ........................................................ S60lgorithm 5. Managing Vitamin D Sterols Based on PTH Levels in Children Not

Receiving Growth Hormones ................................................................................................................. S61lgorithm 6. Evaluation of Aluminum Neurotoxicity.................................................................................................. S72lgorithm 7. Evaluation of Aluminum-Related Disorders: Considerations for DFO Test

and Subsequent DFO Treatment ............................................................................................................. S73lgorithm 8. DFO Treatment After PAl Rise between 50-300 �g/L ............................................................................ S80lgorithm 9. Subsequent DFO Treatment after PAl Rise �300 �g/L.......................................................................... S81

merican Journal of Kidney Diseases, Vol 46, No 4, Suppl 1 (October), 2005: p S3 S3

K/DOQI Clinical Practice Guidelines for Bone Metabolism andDisease in Children with Chronic Kidney Disease

Work Group Membership

Work Group Co-Chairs

Craig B. Langman, MDNorthwestern University Feinberg School of Medicine

Children’s Memorial Hospital
Chicago, IL
Work G

Philadelphia, PA

Consultants to the

Los Angeles, CA

Isidro B. Salusky, MDDavid Geffen School of Medicine at UCLA

Los Angeles, CA

roup

Larry Greenbaum, MD, PhDMedical College of Wisconsin

Milwaukee, WI

Harald Jueppner, MDMassachusetts General Hospital

Harvard Medical SchoolBoston, MA

Mary Leonard, MDChildren’s Hospital of Philadelphia

Pauline Nelson, RDUCLA Medical Center

Los Angeles, CA

Anthony Portale, MDUniversity of California San Francisco

San Francisco, CA

Bradley A. Warady, MDThe Children’s Mercy Hospital

Kansas City, MO

Work Group

Richard E. Bowen, MDAssistant Clinical Professor

David Geffen School of Medicine at UCLA

William L. Oppenheim, MDDavid Geffen School of Medicine at UCLA

Los Angeles, CA

GBPAPWALBCGKMCDDLRM

DMA

K/DOQI Advisory Board Members

Adeera Levin, MD, FACPK/DOQI Chair

Michael Rocco, MD, MS
K/DOQI Vice-Chair
Garabed Eknoyan, MD
K/DOQI Co-Chair Emeritus
aureen Michael, BSN, MBA

WJGRTBNCARNDWS

EJD

K/DOQI Guideline Dev

nthony Gucciardo

LK

Nathan Levin, MD, FACP
K/DOQI Co-Chair Emeritus
eorge Bailie, PharmD, PhDryan Becker, MDeter G. Blake, MD, FRCPC, MBB.Chllan Collins, MD, FACPeter W. Crooks, MDilliam E. Haley, MDlan R. Hull, MDawrence Hunsicker, MDertrand L. Jaber, MDynda Ann Johnson, MD, MBAeorge A. Kaysen, MD, PhDarren King, MSW, ACSW, LCSWichael Klag, MD, MPHraig B. Langman, MDerrick Latos, MDonna Mapes, DNSc, MSinda McCann, RD, LD, CSRavindra L. Mehta, MD, FACP

illiam Mitch, MDoseph V. Nally, MDregorio Obrador, MD, MPHulan S. Parekh, MD, MShakor G. Patel, MD, MACPrian J.G. Pereira, MD, DMeil R. Powe, MDlaudio Ronco, MDnton C. Schoolwerth, MDaymond Vanholder, MD, PhDanette Kass Wenger, MDavid Wheeler, MD, MRCPinfred W. Williams, Jr., MD

huin-Lin Yang, MD

x-Officioosephine Briggs, MD
avid Warnock, MD
elopment NKF Staff
onna Fingerhutargaret Fiorarancio
ori Morminoerry Willis, PhD

Teokppblbtstasioip

bbtmltitmrdaha

VOL 46, NO 4, SUPPL 1, OCTOBER 2005

AJKD American Journal ofKidney Diseases

S

Foreword

dpsnCoc

tNliptplr2tsml

grl2bsttabouba

HE DISCIPLINE OF pediatric nephrol-ogy is unique and challenging because it

ncompasses the widest developmental stagesf life, from in utero presentation of chronicidney disease (CKD) through kidney failureresenting in early adulthood. CKD in ouratients may arise from embryological distur-ances, genetic mutations, acquired glomeru-opathies and/or tubulopathies, systemic meta-olic diseases, immune-mediated diseases, orhose diseases that derive—in part—from life-tyle choices. The natural history of many ofhese diseases is being rewritten continually,s longevity for patients increases beyond thateen by our mentors before us. We see thenfluence of socio-demographic distributionsn disease expression and severity, and thensufficiencies of organ availability for trans-lantation on disease chronicity.In the pediatric population, body calcium

alance remains markedly positive to supportoth somatic growth and bone mineral accre-ion. The sine qua non of pediatric CKD is thearked change in these two processes that

eads to the devastating clinical disease that weerm “osteodystrophy.” We have come to real-ze that the disorder encompasses marked dis-urbances in mineral homeostasis with chronicetabolic acidosis, secondary hyperparathy-

oidism (2° HPT), insufficiency of 1,25-dihy-roxyvitamin D, and failure of linear growth inddition to extraskeletal disease. Thus, weave seen children, adolescents, and youngdults with an as yet undefined cardiovascular

© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4604-0101$30.00/0

bdoi:10.1053/j.ajkd.2005.07.024

American Journal of Kidney D6

isease associated with calcium in incorrectlaces within the vasculature, similar to thateen in adult patients who develop CKD deovo. We recognize the pervasive nature ofKD, and perhaps a more subtle manifestationf its osteodystrophy, in abnormal neurologi-al development of our youngest patients.

Although we were members of the commit-ee for the preparation and publication of theational Kidney Foundation K/DOQI Guide-

ines for bone metabolism and disease in CKDn adults, we recognized that the subject in thatopulation was filled with enough controversyhat recommendations for children could notroperly be placed within it. Therefore, theeaders of the K/DOQI process acceded to ourequest for a meeting in Chicago, in October002, to begin the arduous process of sortinghrough the literature to produce a pediatric-pecific set of K/DOQI guidelines for boneetabolism and disease in CKD with our col-

eagues and committee members.The task differed initially from the resultant

uidelines seen here; but with very limitedesources, and no external review of extantiterature by a third party, we decided late in003 to follow the structure of the adult-basedone metabolism and disease guidelines in-tead. We owe great thanks to that group forheir wisdom in allowing us to use some ofheir work, and adapt it where indicated for thespects unique to pediatric osteodystrophy. Itecame rather clear, quickly, that the area ofsteodystrophy in pediatric CKD is highlyninvestigated, and is a wonderful career-uilding opportunity for the generation of pedi-tric nephrologists who will follow the mem-
ers of this writing committee.
iseases, Vol 46, No 4, Suppl 1 (October), 2005: pp S6-S7

cawgi

wduektftFeMt

ats

wsdtrsosp

CWIW

FOREWORD S7

As Co-Chairs, we owe a deep gratitude to ourommittee members. Each worked long hours,cceded to our many requests on short noticeith a ‘can-do’ attitude, and worked in a colle-ial manner that allowed the project to succeedn a lofty manner.

With the successful completion of our task,e need to thank many of our colleagues whoid not serve on the committee, but who taughts much from their science, and from theirmpathetic care of patients. We hope we ac-nowledged, by attribution within our text,heir work and toil, and we take responsibilityor any mistakes of omission in this regard. Wehank the entire staff of the National Kidneyoundation for their excellent support, andspecially that of Mr. Anthony Gucciardo ands. Donna Fingerhut, who were tireless in

heir pursuit of our goals. Drs. Gary Eknoyan

nd Adeera Levin are to be commended forheir spiritual input to our project (and our-elves) during its long course.

As you, the Reader, use these guidelines, youill be quick to see its flaws and weaknesses, as all

uch guidelines possess. We welcome your inputirectly through the National Kidney Foundation tohose areas that need improvement, emendation, oremoval in subsequent iterations of the work. De-pite this caveat, we believe that regular attention tour patients’ osteodystrophy in a manner pro-cribed within the guidelines will lead to an im-roved outcome in every facet of the disease.

raig B. Langman, MDork Group Co-Chair

sidro B. Salusky, MDork Group Co-Chair

mfotratpfnbdutTtct

cddsstbtbbfmmspdtiP

S

Introduction

aOasomddoKfida

opiocpaIadrobrs(ltpelgb

atsaethm

GROWTH AND DEVELOPMENTOF THE SKELETON

During childhood and adolescence, totalskeletal calcium increases from approxi-

ately 25 g at birth to 900 g and 1,200 g in adultemales and males, respectively. Attainment ofptimal peak bone mass by young adulthood ishought to be the best protection against osteopo-osis later in life.1 Therefore, childhood anddolescence are particularly critical periods forhe establishment of life-long bone health. Whileeak bone mass is strongly influenced by geneticactors, full genetic potential is attained only ifutrition, growth, physical activity, and meta-olic and endocrine function are optimal in chil-ren. The clinical features of renal bone diseasenique to childhood relate to distinctions be-ween the growing and the fully-grown skeleton.he metabolic process of skeletal modeling

hroughout growth dictates that pediatric-spe-ific recommendations for the management ofhe bone disease of CKD be developed.

BONE FORMATION

Formation of the skeleton occurs by two pro-esses of ossification—intramembranous and en-ochondral. Intramembranous ossification is theirect mineralization of vascular connective tis-ue membrane in the plate-like bones of thekull, facial bones, mandible, and clavicle. Theransformation of mesenchymal cells into osteo-lasts and production of osteoid matrix converthe primitive mesenchyme into bone. In contrast,ones that involve joints and bear weight formy endochondral ossification. Endochondral boneormation is the result of ossification of an inter-ediate cartilage model that is derived fromesenchyme and represents the position and

hape of the bone to be formed at that site. Thisrovides a mechanism for the formation of boneuring growth. In the long bones of the extremi-ies, the primary center of ossification is locatedn the central portion of the cartilage model.roliferation and hypertrophy of chondrocytes

© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4604-0102$30.00/0

fdoi:10.1053/j.ajkd.2005.07.025

American Journal of Kidney Di8

nd elaboration of matrix result in linear growth.ssification proceeds toward the end of the bone

nd ultimately forms the growth plate (epiphy-eal plate or physis) that is the predominant sitef longitudinal bone growth. With continuedaturation, the growth plate thins and eventually

isappears with fusion of the epiphyseal andiaphyseal ossification centers. Epiphyseal unionccurs at an earlier age in females than males.nowledge about the appearance of various ossi-cation centers in the carpal bones is used toetermine a child’s maturational age, or “bonege.”

BONE MODELING

The shape and structure of bones are continu-usly modified and renovated by two differentrocesses during growth: modeling and remodel-ng. Both processes result in the replacement ofld bone tissue with new bone. The remodelingycle of bone resorption and formation takeslace throughout life and is vital for microdam-ge repair and maintenance of skeletal integrity.n contrast, modeling predominates during growthnd promotes formation of new bone at locationsifferent from the sites of bone resorption. Thisesults in increased bone mass and modificationf bone shape. For example, increases in corticalone diameter of the diaphysis are due to concur-ent bone formation on the periosteal (outer)urface and bone resorption on the endostealinner) surface. In contrast, as the bone grows inength, the wide metaphyseal region is convertedo a narrow diaphysis through resorption of theeriosteal surface and bone formation on thendosteal surface. Finally, long bones drift in aateral direction during growth due to relativelyreater resorption along the medial edge of theone and formation along the lateral edge.In conclusion, bone growth during childhood

nd adolescence involves the complex coordina-ion of varied cell activities on specific boneurfaces. Cartilage proliferation, bone modeling,nd epiphyseal closure are under the direct influ-nce of a variety of hormones and growth fac-ors, such as growth hormone (GH), thyroidormone, estrogen, testosterone, parathyroid hor-one (PTH), vitamin D, and insulin-like growth

actors (IGF).2 Each of these factors may be

seases, Vol 46, No 4, Suppl 1 (October), 2005: pp S8-S11

db

adrbcbotts

asm

CdITgaas

INTRODUCTION S9

isordered in CKD, with important effects onone structure and maturation.

CLINICAL MANIFESTATIONS OF BONEDISEASE IN CHILDREN WITH CKD

Renal osteodystrophy is an early, universal,nd pervasive consequence of CKD that mayevelop prior to any clinical manifestations ofenal failure. The clinical manifestations of renalone disease seen in adults may also appear inhildhood. However, the effects of abnormalone and mineral metabolism on endochondralssification during growth result in complica-ions in the epiphyseal region that are unique tohe children with CKD. The clinical signs and
ymptoms of bone disease in children with CKD t
re summarized in Table 1, highlighting thoseeen exclusively during growth and develop-ent.

GROWTH RETARDATION AND SKELETALMATURATION DELAY

Growth retardation is a frequent feature ofKD in children. Skeletal maturation is usuallyelayed commensurate with the growth deficit.n the 2002 North American Pediatric Renalransplant Cooperative Study Annual Report,rowth status is described in over 5,000 childrennd adolescents with CKD Stages 2-4. Use ofge- and gender-specific standard deviation (SD)cores revealed that more than one-third of pa-
ients had a height SD score of less than �1.88

(ahasdtmmSwml

tttiad(otbletc

avswidFdmmi

mrmdemdd

mpadptit

vmcdbstrvicodahchutmt

B

ktHdwrlbp

mrtodj

INTRODUCTIONS10

3rd percentile). Height deficits were observedcross all ages, from infants through adolescents;owever, the SD score deficits were greatestmong the children with early-onset and long-tanding CKD. Nevertheless, significant heighteficits were also observed in children with mildo moderate CKD. Among children with an esti-ated glomerular filtration rate (GFR) of 50-75L/min/1.73 m2 (Stages 2-3), 22% had a heightD score of less than �1.88; among childrenith an estimated GFR of 25-50 mL/min/1.732 (Stages 3-4), 38% had a height SD score of

ess than �1.88.The growth retardation and delayed matura-

ion in children with CKD is multifactorial. Po-ential contributing factors include prior steroidherapy, chronic metabolic acidosis, anorexia,nadequate nutrient (vitamins, trace minerals)nd caloric intake, hyposthenuria and sodiumepletion, inadequate insulin-like growth factor IIGF-I) availability due to increased serum levelsf IGF-binding protein 3 (IGFBP-3), inadequateestosterone and estrogen production during pu-erty, and bone disease, including severe rachitic-ike lesions. The contribution of renal bone dis-ase to growth failure is unclear; however,reatment with 25(OH) vitamin D3 therapy inhildren with CKD resulted in improved growth.3

MUSCULOSKELETAL DEFORMITIES

Clinical manifestations of the bone diseasessociated with CKD in children generally in-olve the musculoskeletal system. Nonspecificymptoms such as bone pain, muscle crampsith repetitive motion activities, and a decrease

n normal muscle functions used in activities ofaily living may be seen in children with CKD.ractures may occur in children with CKD witheformed bones subjected to the trauma of nor-al childhood activities. The evaluation and treat-ent of orthopedic complications are discussed

n greater detail in Guideline 3.During childhood and adolescence, bony defor-ities may develop, most commonly involving

apidly growing bones of the extremities. Vita-in D deficiency in CKD results in skeletal

eformities resembling vitamin D-deficient rick-ts, such as a rachitic rosary, widening of theetaphysis, frontal bossing, craniotabes, ulnar

eviation, and pes varus. Histologically, there is
isorganization in the growth plate and subjacent i
etaphysis. The hypertrophic zone of the growthlate demonstrates an increase in cell numbernd loss of the normal columnar cell pattern. Theisordered cartilage is resorbed and no longerrovides adequate scaffolding for bone deposi-ion. The subjacent metaphyseal fibrosis maynterfere with vascularization and maturation ofhe growth plate.

The growth plate in children with CKD isulnerable to injury; the hypertrophic zone isost vulnerable to shearing injuries. Morphologi-

al studies on the epiphyses have demonstrated aense fibrous tissue that disrupts the connectionetween the epiphyseal plate and the metaphy-is.4 These abnormalities, along with hyperpara-hyroid erosions of bone, result in an increasedisk for slipped epiphyses (physiolysis) and genualgum. Possible sequelae of slipped epiphysesnclude severe varus deformity, osteonecrosis,hondrolysis and degenerative joint disease. Therthopedic approach to correction of extremityeformities in children with CKD often requiresn osteotomy. It is clinically recognized thatealing of the bone after such a procedure pro-eeds poorly in the face of severe secondaryyperparathyroidism (2° HPT). Therefore, it isrged that biochemical control of the hyperpara-hyroidism be accomplished prior to perfor-ance of the osteotomy to enhance success of

he procedure.

ONE MINERAL ACCRETION AND PEAK BONEMASS

The impact of CKD on peak bone mass is notnown. However, increased bone resorption onhe periosteal and endosteal surfaces due to 2°PT may compromise bone microarchitecture,ensity, and dimensions. Biopsy studies in adultsith kidney disease have demonstrated a 40%

eduction in cortical bone mass5; therefore, it isikely that CKD during childhood compromisesone mineral accretion and results in inadequateeak bone mass.As outlined in these guidelines, the manage-ent of bone disease in children with CKD

equires careful monitoring for skeletal complica-ions in the growing child, and strategies toptimize bone mineral accretion. In addition,ual-energy X-ray absorptiometry (DXA) is sub-ect to several limitations that limit its usefulness
n children. These include the inadequacy of

ptitgm

lotaTd

E

Bm

G

a

pc

cmvmarf

RHC

st

ihnmc

tias

INTRODUCTION S11

ediatric reference data across varied matura-ional stages, ethnic groups, and gender groupsn healthy children, and difficulties in the interpre-ation of DXA results in children with impairedrowth, altered body composition, or delayedaturation due to childhood illness.

OVERVIEW OF PRIOR PEDIATRIC K/DOQIGUIDELINES: IMPACT OF RENAL FUNCTION,

GROWTH HORMONE, AND NUTRITION ONTHE MANAGEMENT OF BONE DISEASE IN

CHILDREN WITH CKD

Prior K/DOQI Pediatric Work Groups have pub-ished recommendations regarding the assessmentf renal function in children with CKD, the indica-ions and monitoring of growth hormone therapy,nd the unique nutritional needs of these children.hese guidelines impact the management of boneisease in CKD and are summarized here.

stimation of GFR in Children with CKD

Among children, the Schwartz and Counahan-arratt formulae provide clinically useful esti-ates of GFR.6,7

rowth and Nutrition in Children on Dialysis

Scheduled, interval measurements of growth
nd nutrition parameters should be obtained to u
rovide optimal care of the nutritional needs ofhildren on dialysis.

Supplemental nutrition support should beonsidered when a patient is not growing nor-ally (i.e., does not have a normal height

elocity) or fails to consume the Recom-ended Dietary Allowances (RDA) for protein

nd/or energy. Supplementation for the oraloute is preferred followed by enteral tubeeeding.

ecommendations for the Use of Recombinantuman Growth Hormone (rhGH) forhildren Treated with Maintenance Dialysis

Treatment with rhGH in children with CKDhould be considered under the following condi-ions:

Children who have (a) a height for chronolog-cal age more negative than 2.0 SD; or (b) aeight velocity for chronological age SD moreegative than 2.0 SD; (c) growth potential docu-ented by open epiphysis; and (d) no other

ontraindications for GH use.Prior to the consideration of the use of rhGH,

here should be correction of (a) insufficientntake of energy, protein and other nutrients; (b)cidosis; (c) hyperphosphatemia (the level oferum phosphorus should be less than 1.5X the
pper limit for age); and (d) 2° HPT.

1

1

tt

S

GUIDELINE 1. EVALUATION OF CALCIUM AND
PHOSPHORUS METABOLISM
aaTptodepmptl

rni(datsiC

.1 Serum levels of calcium, phosphorus, alka-line phosphatase, total CO2, and PTH—measured by a first-generation immuno-metric parathyroid hormone assay (1st

PTH-IMA)—should be measured in allpatients with CKD Stages 2 through 5.The frequency of these measurementsshould be based on the stage of CKD(Table 2). (OPINION)1.1.a Patients with known tubulopathies

in Stage 1 CKD should have serumphosphorus levels measured at leastyearly.

.2 These measurements should be made morefrequently if the patient is receiving con-comitant therapy for the abnormalities inthe serum levels of calcium, phosphorus,or PTH (Guidelines 4-10), is a transplantrecipient (Guideline 17), or is a patientbeing treated with rhGH (Guideline 11).1.2.a The target range of serum PTH, in

the various stages of CKD, are de-noted in Table 3. (OPINION)

BACKGROUNDA disorder of bone remodeling, the osteodys-

rophy of CKD, is a common complication. Byhe time patients require dialysis, nearly all are

American Journal of Kidney Dis12

ffected. The onset of the disorder is detectablebout the time 50% of kidney function is lost.8,9

here are multiple histological types of boneathology in patients with CKD. At the presentime, the ability to diagnose the exact type ofsteodystrophy of CKD without the pathologicalescription enabled by bone biopsy does notxist. Since high-turnover osteodystrophy can berevented,10,11 patients with CKD should beonitored for imbalances in calcium and phos-

hate homeostasis, and for 2° HPT, by determina-ion of serum calcium, phosphorus, and PTHevels.

Levels of intact PTH determined by immuno-adiometric assay (IRMA) or immunochemilumi-ometric assay (ICMA) are an adequate screen-ng tool to separate high-turnover bone diseaseosteitis fibrosa) from low-turnover bone disor-ers (adynamic bone disorder).12-17 While thebility to discriminate between the histologicalypes of osteodystrophy of CKD has been demon-trated with determination of blood levels ofntact PTH, the optimal target level for PTH inKD is not known due to limitations in the

© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4604-0103$30.00/0doi:10.1053/j.ajkd.2005.07.026

eases, Vol 46, No 4, Suppl 1 (October), 2005: pp S12-S17

atr1cmoaoaiatcFrc

cpeoCTpdmte(uodnmcb

ramBPdrDscw

eomet

npstetbrsiupHsnDqs

a(lmaato

GUIDELINE 1: EVALUATION OF CALCIUM AND PHOSPHORUS METABOLISM S13

vailable data, and the emerging consensus ishat those target levels may be lower than cur-ently thought.18 Recent studies demonstrate thatst PTH-IMA overestimate the levels of biologi-ally active PTH by detecting C-terminal frag-ents missing amino acids from the N-terminus

f the molecule, which may have an inhibitoryctivity. Newer 1st PTH-IMA have been devel-ped to overcome this problem by using anntibody that detects the first several amino acidsn a two-site assay, but sufficient research has notccumulated to establish the predictive power ofhese newer assays, and whether they will over-ome the shortfalls in the intact hormone assays.urthermore, the newer assays have not as yeteplaced the intact hormone assays as standardlinical tools.

The predictive power of PTH levels is in-reased by concomitant consideration of alkalinehosphatase levels,19 although insufficient dataxist to determine the sensitivity and specificityf alkaline phosphatase in osteodystrophy ofKD, or its concomitant use with PTH levels.hese studies were performed in the era of highrevalence of osteomalacia, and it remains to beetermined whether alkaline phosphatase deter-inations are additive to the newer 2nd genera-

ion PTH-IMA. Several other biochemical mark-rs of bone turnover have been developedosteocalcin, hydroxyproline) and are possiblyseful in the evaluation and management ofsteoporosis, but CKD affects each of theseeterminations, and no evidence of their useful-ess in this population exists.19 No bone imagingethods exist for measuring bone disease that

an be used diagnostically in place of boneiopsy for osteodystrophy of CKD.

RATIONALEIn adults, blood levels of intact PTH begin to

ise when GFR falls below 60 mL/min/1.73 m2,nd evidence of bone disease due to this 2° HPTay be present at Stage 3 of CKD (Figure 1).ased on data using a less sensitive assay forTH, it appears that 2° HPT can occur in chil-ren in Stage 2 CKD.20 Secondary hyperparathy-oidism progresses as kidney function worsens.uring this process, changes in blood levels of

erum phosphorus (hyperphosphatemia) and cal-ium (hypocalcemia) occur and contribute to the
orsening of hyperparathyroidism and bone dis- c
ase. Therefore, measurements of serum levelsf phosphorus, calcium, and PTH should beade when GFR falls below Stage 2 CKD lev-

ls, and these parameters should be monitoredhereafter in patients with CKD (Table 2).

Most children with CKD or those on mainte-ance dialysis have some form of osteodystro-hy. Despite considerable advances in under-tanding the pathophysiology, prevention, andreatment of osteodystrophy of CKD, an ad-quate substitute for bone biopsy in establishinghe histological type of osteodystrophy has noteen developed. In adults, standard bone radiog-aphy can reliably detect bone erosions, but has aensitivity of approximately 60% and a specific-ty of 75% for the identification of osteitis fibrosasing such erosions (Figure 2). Skeletal radiogra-hy is therefore an inadequate test to diagnose 2°PT. Sufficient data to assess the sensitivity and

pecificity of other imaging methods in the diag-osis of osteodystrophy of CKD do not exist.ata on the assessment of the usefulness ofuantitative computed tomography in the diagno-is of osteodystrophy of CKD are also insuffi-

Fig 1. Relationship between Serum iPTH Levelsnd CCR. Values on the y-axis are serum iPTH levelspg/mL). Values on the x-axis are CCR in mL/min. Theines fitted to the data set are based on 4 different

athematical functions (power, linear, exponential,nd logarithmic), rather than on any assumptions aboutn underlying physiological mechanism. The horizon-al line represents the upper limit of the normal rangef serum iPTH levels. Reproduced with permision.21

ient. Standard radiography is more useful in the

do

bhfCagraidte861acah

�s1t

Iucfrdactmoi1cft

ffiTsbpe sa wa(

GUIDELINE 1: EVALUATION OF CALCIUM AND PHOSPHORUS METABOLISMS14

etection of vascular calcification than it is forsteodystrophy.In children and adults, multiple studies have

een performed using 1st PTH-IMA to diagnoseigh-turnover bone disorders and distinguish themrom low-turnover disorders. In children withKD Stage 5, data suggest that PTH levels ofpproximately 200 pg/mL are useful for distin-uishing patients with low-turnover lesions ofenal osteodystrophy from those with 2° HPTnd high-turnover disease.22,23 A receiver operat-ng characteristics (ROC) analysis (in essence, aiagnostic meta-analysis) of using 1st PTH-IMAo diagnose high-turnover disorders revealed anstimate of the sensitivity at 93% (95% CI,7%-97%) and a specificity of 77% (95% CI,2%-87%), using threshold PTH levels between50-200 pg/mL. In children, the combination ofserum PTH level �200 pg/mL and a serum

alcium value �10 mg/dL was 85% sensitivend 100% specific for identifying patients with

Fig 2. Summary ROC Analysis of Erosions on X-Rarom four individual studies assessing the diagnosticbrosa. Values on the y-axis are the diagnostic sensithe more effective the test is as a diagnostic, the cloummary ROC curve and its 95% confidence intervalased on the meta-analytically combined results fromoint estimate of the sensitivity and specificity of erorosions on x-ray as a tool for diagnosing osteitis fibro95% CI: 63.2-85.2).

igh-turnover bone lesions. Serum PTH values P

200 pg/mL were 100% sensitive but only 79%pecific for patients with adynamic bone.22 Thus,st PTH-IMA is a useful test in detecting high-urnover bone disorders (Figure 3).

In adults, studies performed using 1st PTH-MA to diagnose low-turnover bone disordersse levels of 60 pg/mL as the threshold. In thisase, the estimated sensitivity and specificityrom the ROC analysis were 70% and 87%,espectively. Thus, 1st PTH-IMA is also useful iniagnosing low bone turnover (Figure 4). Newerssays specific for 1-84 PTH have recently be-ome available and will likely refine and updatehis information. In the diagnosis and manage-ent of osteodystrophy of CKD, the usefulness

f these newer assays for PTH is being exam-ned. The normal range for the new assay for-84 PTH is 7-36 pg/mL (0.77-3.96 pmol/L),ompared to 16-65 pg/mL (1.76-7.15 pmol/L)or 1st PTH-IMA. Thus, the relationship betweenhe two assays is about 1:2 (1-84 PTH to 1st

iagnostic for Osteitis Fibrosa. Summary ROC derivedteristics of erosions on X-ray for diagnosis of osteitisnd values on the x-axis are the diagnostic specificity.falls to the upper left hand corner of the graph. Thee a summary estimate of the performance of the testr studies. The mean threshold point is our best singleon x-ray. In this case, the sensitivity for presence ofs 59.8% (95% CI: 44.9-73.2) and specificity was 79.9%

y as Dcharacivity aser itprovidall fousions

TH-IMA). The differences in the levels be-

ttd1

nas

ntbdws

ps3cl(wtaslpal

dhdcbah


ween the two types of assays are a reflection ofhe levels of circulating PTH fragments that areetected by the 1st PTH-IMA but not by the new-84 PTH assay.Current data are insufficient to assess the diag-

ostic utility of bone markers such as osteocalcinnd serum pyridinoline compounds in the diagno-is of high- versus low-turnover bone disease.

STRENGTH OF EVIDENCEExtensive review of the literature revealed

umerous gaps in the available database, necessi-ating that some aspects of this Guideline beased upon opinion. For instance, there were noata indicating the appropriate frequency withhich parameters of osteodystrophy of CKD

Fig 3. Summary ROC Analysis of Intact PTH for Derived from six individual studies assessing the diaigh-turnover bone disease. Values on the y-axis areiagnostic specificity. The more effective the test is aorner of the graph. The summary ROC curve and 95%ased on the meta-analytically combined results from adiamond icon) is the best point estimate of the sen

igh-turnover bone disease.

hould be followed. o

Four studies in adults and one in children thatrovided GFR data showed an inverse relation-hip between serum PTH levels and GFR (Figure). The two studies that presented creatininelearance data in adults showed that serum PTHevels increase as creatinine clearance decreasesFigure 1). A similar finding was seen in childrenith CKD. It was not possible to find a function

hat best described the relationship between GFRnd PTH levels, or the relationship betweenerum creatinine or creatinine clearance and PTHevels. Despite this difficulty, these data stillermit one to make clinically relevant decisionsbout when to begin screening for high serumevels of PTH. Based on these studies, it is the

sis of High-Turnover Bone Disease. Summary ROCic characteristics of iPTH levels for the diagnosis ofagnostic sensitivity and values on the x-axis are thegnostic tool, the closer it falls to the upper left handide a summary estimate of the performance of the test

studies. The mean threshold (indicated in the graph byy and specificity of iPTH levels for the diagnosis of

iagnognostthe dis a diaCI provll fivesitivit

pinion of the Work Group that measurements of

si

tpssRthaCposoe

soisctttwTu(t

dldtod sitivityl

GUIDELINE 1: EVALUATION OF CALCIUM AND PHOSPHORUS METABOLISMS16

erum PTH levels in CKD patients should benitiated when CKD Stage 2 is reached.

The most robust available data were related tohe use of PTH levels as a marker of osteodystro-hy of CKD. In this instance, there were seventudies in adults that met the defined criteriaelected for meta-analysis and derivation of anOC curve.14,17,24-26 These data demonstrated

he usefulness of PTH levels for predicting bothigh- and low-turnover bone disease (Figure 3nd Figure 4, respectively). Data in children withKD Stage 5 allow PTH levels also to serve as aredictor of bone turnover based on bone bi-psy.22 The ability of bone imaging methods toubstitute for bone biopsy in the diagnosis ofsteodystrophy of CKD has only been ad-

Fig 4. Summary ROC Analysis of Intact PTH forerived from five individual studies assessing the dia

ow-turnover bone disease. Values on the y-axis areiagnostic specificity. The more effective the test is as ahe graph. The summary ROC curve and its 95% CI provn the meta-analytically combined results from all fiviamond icon) is the best point estimate of the sen

ow-turnover bone disease.

quately studied in the case of erosions demon- s

trated in standard X-rays as a diagnosis ofsteitis fibrosa, or in the demonstration of ricketsn growing children. A meta-analysis of fivetudies met the criteria to perform an ROCurve.14,27-30 The best single-point estimates ofhe sensitivity and specificity of erosions as aool to diagnose osteitis fibrosa were 60% sensi-ivity and 76% specificity. Thus, standard X-raysere not considered an adequate diagnostic tool.here were no adequate studies evaluating thesefulness of quantitative computed tomographyQCT), dual photon absorptiometry, or DXA inhe diagnosis of osteodystrophy in CKD patients.

LIMITATIONSThe application of modern techniques for as-

sis of Low-Turnover Bone Disease. Summary ROCic characteristics of iPTH levels for the diagnosis ofgnostic sensitivity and values on the x-axis are theostic, the closer it falls to the upper left hand corner ofummary estimate of the performance of the test basedies. The mean threshold (indicated in the graph by a

and specificity of iPTH levels for the diagnosis of

Diagnognost

the diadiagn

ide a se stud

essing bone turnover from biochemical markers

ootAadtonD2

I

tcmmo

mtmgio


r imaging is severely limited in osteodystrophyf CKD by the effects of CKD on the testshemselves and by the lack of sufficient studies.s a result, accurate diagnosis and management

re difficult. The most robust currently availableata, using 1st PTH-IMA, permit a general distinc-ion to be made between high- and low-turnoversteodystrophy, but recent studies suggest theeed for more accurate assays of PTH levels.ata on PTH and bone disease in CKD Stages-4 are missing in children.

CLINICAL APPLICATIONSThese Guidelines promote the use of 1st PTH-

MA in the diagnosis and management of os- t

eodystrophy in patients with CKD. They indi-ate the limited usefulness of other biochemicalarkers related—in large part—to lack of infor-ation. Inadequate data exist for the utilization

f imaging techniques.

RESEARCH RECOMMENDATIONSMuch work is needed to relate biochemicalarkers of bone turnover to growth and osteodys-

rophy in CKD. The role of new PTH assaysust be further defined. Optimal clinical practice

uidelines await outcome studies on the monitor-ng of osteodystrophy of CKD, and validatingutcome data of the recommendations made in
hese Guidelines.

2

2

2

2

otPtgcoothascts

S

GUIDELINE 2. ASSESSMENT OF BONE DISEASE
ASSOCIATED WITH CKD
B

mtdsPwalacsitcis

tllctnhwtH4tetcaa

mmbbsdlatTt

.1 The most accurate diagnostic test fordetermining the type of bone disease asso-ciated with CKD is iliac crest bone biopsywith double tetracycline labeling and bonehistomorphometric analysis. (EVI-DENCE)

.2 It is not necessary to perform bone biopsyfor most situations in clinical practice.However, a bone biopsy should be consid-ered in patients with kidney failure (Stage5) who have:2.2.a Fractures with minimal or no

trauma (pathological fractures);(OPINION)

2.2.b Suspected aluminum bone disease,based upon clinical symptoms orhistory of aluminum exposure;(OPINION) (See Guideline 12)

2.2.c Persistent hypercalcemia with PTHlevels between 400-600 pg/mL.

.3 Bone radiographs are indicated in pa-tients with clinical manifestations sugges-tive of avascular necrosis (AVN), symp-tomatic proximal femoral slippedepiphyses (SCFE), rickets, or for the as-sessment of skeletal maturation. (EVI-DENCE)

.4 Dual-energy X-ray absorptiometry (DXA)should not be used to monitor bone min-eral density (BMD) in children with CKD.(OPINION)

BACKGROUNDThe renal bone diseases represent a spectrum

f skeletal disorders that range from high-urnover lesions to low-turnover osteodystrophy.atients may change from one histological sub-

ype to another over time, according to the de-ree of renal insufficiency and the type of spe-ific treatment of renal osteodystrophy. The usef bone biopsy has contributed substantially tour current understanding of the different sub-ypes of renal bone diseases. Indeed, quantitativeistomorphometry of bone provides informationbout the status of skeletal mineralization, thetructural characteristics of cancellous and corti-al bone, the levels of osteoclastic and osteoblas-ic activities, and the presence of marrow fibro-
is. f

one Biopsy

Determinations of bone formation are esti-ated by the use of the technique of double

etracycline labeling. Patients are given eitheremeclocycline or tetracycline HCl; the doseshould not exceed 10 mg/kg/day in a tid dosage.hosphate-binding agents should not be givenhile patients are receiving the antibiotic. The

ntibiotics are given on 2 consecutive days, fol-owed by a 10- to 20-day interval when nontibiotic is given and then a second, 2-dayourse of antibiotics is given; the bone biopsyhould be performed within 3-7 days after finish-ng the second course of antibiotics. In additiono the bone histomorphometry, special stainingan be used for identification of aluminum orron in bone. Iliac crest bone biopsy can be doneafely with minimal morbidity.

Patients with histological features of high-urnover renal osteodystrophy may have a boneesion defined as osteitis fibrosa or the mildesion of 2° HPT. Osteitis fibrosa is the mostommon high-turnover lesion of renal osteodys-rophy in pediatric patients treated with mainte-ance dialysis. The disorder is characterized byistological evidence of active bone formationith increase in the number and size of os-

eoclasts and in the number of resorption bays, orowship’s lacunae within cancellous bone (Table). Fibrous tissue is found immediately adjacento bony trabeculae, or it may accumulate morextensively within the marrow space. Osteoblas-ic activity is increased and the combined in-rease in osteoblastic and osteoclastic activityccounts for the high rates of bone remodelingnd turnover.

The other bone disorder of high-turnover, theild lesion of 2° HPT, is characterized by onlyoderate increases in osteoclastic activity and

one formation and without evidence of peritra-ecular fibrosis (Table 4). This disorder is a lessevere manifestation of hyperparathyroid boneisease. Serum PTH levels are elevated but to aower degree than in those with osteitis fibrosa,lthough in some instances it is difficult to assesshe degree of fibrosis without a bone biopsy.etracycline-based measurements of bone forma-

ion are useful for distinguishing this subgroup
rom those with either normal or reduced rates of

bipinm

tfoclmhbc

dsifpnbrtcasaoan

GUIDELINE 2: ASSESSMENT OF BONE DISEASE ASSOCIATED WITH CKD S19

one formation. In order to carefully character-ze the different subtypes of renal osteodystro-hy according to bone formation rates (BFRs), its imperative to have tetracycline-based determi-ations of bone formation in children with nor-al renal function to be used as controls.Patients with low-turnover bone renal os-

eodystrophy may have a bone histological mani-estation of osteomalacia or adynamic/aplasticsteodystrophy. The lesion of osteomalacia isharacterized by excess osteoid, which accumu-ates in bone because of a primary defect inineralization. Osteoid seams are wide and they

ave multiple lamellae; the extent of trabecularone surfaces covered with osteoid also is in-reased. Osteoblastic activity is markedly re-

uced and bone formation often cannot be mea-ured because of the lack of tetracycline uptakento bone (Table 5). In contrast, bone biopsiesrom patients with adynamic/aplastic osteodystro-hy have normal or reduced amounts of osteoid,o tissue fibrosis, diminished numbers of osteo-lasts and osteoclasts, and low or immeasurableates of bone formation (see Table 1 in Introduc-ion). Patients with aluminum-related osteomala-ia or adynamic bone have elevated the boneluminum content. Currently, the adynamic le-ion of renal osteodystrophy that is not related toluminum, is the most common lesion of renalsteodystrophy in adult patients treated with di-lysis. In contrast, 2° HPT remains the predomi-ant lesion in children with CKD. However, a

snIia

●

●

●

●

●

●

●

eapctgntmoa

talbtpih

D

qscirtTPWDas

at

tji(vpwt“sibsticn

tddiwrshiidtamc

oBtiBobdsssiD

GUIDELINE 2: ASSESSMENT OF BONE DISEASE ASSOCIATED WITH CKDS20

ubstantial proportion of children developed ady-amic bone after intermittent calcitriol therapy.n adults, currently the most common factorsnvolved in the pathogenesis of adynamic bonere:

DiabetesOlder ageCorticosteroid therapyParathyroidectomyExcess doses of active vitamin D sterolsCalcium supplementationOral calcium saltsDialysateTreatment with peritoneal dialysis.

As measured by conventional histomorphom-try, the mineralization lag time reflects the aver-ge value for all osteoid seams, and it is oftenrolonged in adynamic renal osteodystrophy. Inontrast, the osteoid maturation time representshe average only for osteoid seams that are under-oing active mineralization, and it is usuallyormal in the adynamic lesion. The disparity inhese values between adynamic bone and osteo-alacia is due to differences in the proportion of

steoid seams undergoing active mineralizationt any given point in time.

Some patients demonstrate histological fea-ures of both osteitis fibrosa and osteomalaciand this combination is defined as the mixedesion of renal osteodystrophy. Patients may haveiochemical evidence of 2° HPT, but other fac-ors such as hypocalcemia and/or hypophos-hatemia may account for the defective mineral-zation. However, most of the described casesave been associated with aluminum toxicity.

ual-Energy X-ray Absorptiometry (DXA)

The DXA technique is widely accepted as auantitative measurement for assessing skeletaltatus in adults. The World Health Organizationriteria for the diagnosis of osteoporosis in adultss based on the comparison of a measured BMDesult with the average BMD of young adults athe time of peak bone mass (PBM), defined as a-score.31 A T-score �2.5 SD below the meanBM is used for the diagnosis of osteoporosis.hile the T-score is a standard component ofXA BMD results, it is clearly inappropriate to

ssess skeletal health in children through compari-
on with peak adult bone mass. At present, there U
re no evidence-based guidelines for classifica-ion of bone health in children.

Dual-energy X-ray absorptiometry is a projec-ional technique in which three-dimensional ob-ects are analyzed as two-dimensional, and bones presented as the total bone mineral contentBMC) within the projected bone area. It pro-ides an estimate of BMC expressed as gramser anatomical region (e.g., individual vertebrae,hole body, or hip). Dividing the BMC (g) by

he projected area of the bone (cm2) then derivesareal BMD” (g/cm2). This BMD is not a mea-ure of true volumetric density (g/cm3) becauset provides no information about the depth ofone. Furthermore, because the bone is pre-ented as the combined sum of cortical andrabecular BMC within the projected bone area,t is not possible to assess the distinct structuralharacteristics of these discrete bone compo-ents.The DXA technique has several limitations

hat are pronounced in the assessment of chil-ren. These can be broadly classified as (a)ifficulties in scan acquisition due to limitationsn the bone edge detection software in childrenith low bone mass32; (b) inadequacy of pediat-

ic reference data across varied maturationaltages, ethnic groups, and gender groups inealthy children33; and (c) difficulties in thenterpretation of DXA results in children withmpaired growth, altered body composition, orelayed maturation due to childhood illness. Al-hough varied techniques have been proposed toddress these pitfalls, the third limitation re-ains the greatest challenge in the assessment of

hildhood osteopenia.34

A significant limitation of DXA is the reliancen measurement of areal rather than volumetricMD. Bones of larger width and height also tend

o be thicker. Since bone thickness is not factorednto DXA estimates of BMD, reliance on arealMD inherently underestimates the bone densityf short people. Therefore, a child with smallerones will appear to have a mineralization disor-er (decreased areal BMD). Recent pediatrictudies have recognized the importance of shorttature in the assessment of DXA-based mea-ures of BMD in chronic childhood disease,ncluding renal disease,35 and have adjusted theXA BMD result for height and/or weight.34,35

nfortunately, this too is a misleading approach

swtscs

L

upbttttupdotvtjl

imf(etuwttdr

sbnitp

U

rob

mn2ihmdwt

dqtRpaiMtocitptroffiptcap

naaavctBrdtdimc

GUIDELINE 2: ASSESSMENT OF BONE DISEASE ASSOCIATED WITH CKD S21

ince healthy children of the same height oreight as a chronically ill child will be younger

han the ill child. Skeletal maturity and Tannertage are key determinants of bone mass, andomparison with less mature controls is a flawedolution to the influence of bone size.

imitations of DXA in Renal Osteodystrophy

Dual-energy X-ray absorptiometry has beensed extensively to evaluate renal osteodystro-hy. Clearly, since trabecular and cortical boneehave differently in response to increased para-hyroid activity (increase and decrease, respec-ively), and DXA does not allow distinction ofhe effects of renal osteodystrophy on the twoypes of bone, the technique is inherently lessseful than three-dimensional techniques such aseripheral QCT. The conflicting data on DXA-erived measures of BMD in patients with renalsteodystrophy are consistent with these limita-ions. Predictably, DXA results have been quiteariable with mean BMD values that are higherhan, the same as, or lower than control sub-ects.35-41 These studies have contributed veryittle to management of individual patients.

Quantitative computed tomography findingsn the vertebrae seem to confirm available histo-orphometric data in that trabecular BMD was

ound to be increased in high-turnover disease�1.6 SD) and decreased in low-turnover dis-ase (-1.2 SD), relative to age-matched con-rols.42 On the other hand, vertebral BMD wasnable to predict the occurrence of fractures noras there an association between BMD and the

ime on dialysis. This is not unanticipated, givenhat increased BMD in high-turnover diseaseoes not equate with improved structural integ-ity.

In summary, it is clear that integrated mea-ures of BMD—which do not allow distinctionetween cortical and trabecular bone and provideo information on bone architecture—are lim-ted in their usefulness to differentiate the spec-rum of skeletal disorders in renal osteodystro-hy.

tility of Skeletal Radiography

Bony deformities, most commonly involvingapidly growing bones of the extremities, mayccur in children with CKD and chronic meta-
olic acidosis, osteomalacia associated with vita- b
in D deficiency, or aluminum-associated ady-amic bone disease, and in children with severe° HPT. However, any bone may be affected,ncluding the skull, the chest, the spine, or theip. Atraumatic, pathological fractures are seenore commonly in patients with adynamic bone

isease, while fractures may occur in childrenith CKD with deformed bones subjected to the

rauma of normal childhood activities.The radiographic manifestations of the bone

isease associated with CKD in children areuite varied, ranging from the many manifesta-ions of severe 2° HPT to those of frank rickets.adiographic findings from plain film radiogra-hy are technique-dependent, with X-ray volt-ge, film grain quality, and processing methodsnfluencing the ability to diagnose abnormalities.

agnification techniques can increase the sensi-ivity of finding abnormalities. Cortical bone isver-represented by plain film radiography whenompared to cancellous bone. Bone scintigraphys a sensitive method for finding bone abnormali-ies in patients with CKD. However, it may beoorly discriminating, as most patients on main-enance dialysis have diffuse bony uptake of theadionuclide tracer. Accumulation at a single siter two may yield information about pathologicalractures in advance of their appearance on plainlm radiography. Overall, the technique is em-loyed sparingly. Pathological visceral calcifica-ions may be seen by routine radiography; re-ently, the use of EBCT in a population ofdolescents and young adults with CKD detectedathological coronary calcium deposition.Standards have been developed in children with

ormal kidney function to correlate chronologicalge and pubertal status with radiographic appear-nces of bones of the hand and wrist, giving rise to“bone age.” Standard deviations of bone age

ersus chronological age have been calculated forhildren with normal kidney function from birthhrough the end of growth (epiphyseal closure).one age is often retarded in children with CKD. It

emains unclear if the calculated bone age, if re-uced substantially below chronological age, isruly as low as that seen radiographically, since theisease process itself alters the radiographic imagen addition to producing a true reduction in bonyaturation. Standard deviations of bone age versus

hronologic age in children with CKD have not
een developed to date. However, the presence of

nmtc

stetbpbm

cpD

pnCtnssadtBi

l

ttamfagM

D

redr

toip

omrb

itnba

GUIDELINE 2: ASSESSMENT OF BONE DISEASE ASSOCIATED WITH CKDS22

ormal or advanced bone age is likely correct, anday guide the clinician as to the utility of using GH

o treat the failure in linear growth often seen inhildren with CKD (see Guideline 11).

RATIONALEDespite considerable advances in our under-

tanding of the pathophysiology, prevention, andreatment of osteodystrophy of CKD, an ad-quate substitute for bone biopsy in establishinghe histological type of osteodystrophy has noteen yet developed. Quantitative bone histomor-hometry with double tetracycline labeling hasecome the “gold standard” for the diagnosis ofetabolic bone disease in CKD patients.Given the extensive limitations of DXA in

hildren, and in the setting of renal osteodystro-hy, there is no current rationale for performingXA.An initial determination of bone age, and the

resence or absence of the many radiographic ab-ormalities in the bones of children presenting withKD, is useful to the clinician in planning the

herapeutic approach for the patient. Rickets mayot be appreciated clinically, and the extent ofevere hyperparathyroid bone disease can be as-essed only in the presence of the lesions, since anbsence of bony changes by plain-film radiographyoes not preclude its presence by the more sensitiveechnique of dynamic bone histomorphometry.one age is an important component of determin-

ng the utility of growth hormone therapy.

STRENGTH OF EVIDENCEThe importance of bone biopsy has been estab-

ished by many studies, and it is now accepted as t

he gold standard for the diagnosis of the variousypes of osteodystrophy in CKD if performednd interpreted using standard techniques. Nor-al bone histomorphometry should be per-

ormed and the results should be reported inccordance with the standard nomenclature sug-ested by the American Society of Bone andineral Research.43

There are no data that support the utility ofXA in children with CKD.Definitive diagnosis of AVN, SCFE, or rickets

equires skeletal radiography. Assessment of skel-tal maturation can only be accomplished byetermination of a bone age using skeletal radiog-aphy.

LIMITATIONSThere are no recent data utilizing bone biopsy

o characterize osteodystrophy in the early stagesf CKD in children. Skeletal radiography is annsensitive test when used to classify osteodystro-hy in CKD.

RESEARCH RECOMMENDATIONSConsidering the invasive nature of bone bi-

psy, there is a need to investigate whether otherarkers of bone disease could be developed to

eplace bone biopsy for the accurate diagnosis ofone disease in pediatric patients with CKD.Future studies are needed to determine if non-

nvasive imaging techniques, such as quantita-ive computed tomography and magnetic reso-ance imaging, in combination or not withiochemical determinations, are useful in thessessment of trabecular and cortical manifesta-
ions of renal osteodystrophy in children.

3

3

ctiweishabkptbc

G

mfehSttodsblti

A

GUIDELINE 3. SURGICAL MANAGEMENT OF
OSTEODYSTROPHY
pf

tsnemgtsplad

A

iittcabamHsssa

pgiiduPorgg

mgn

.1 Lower extremity angular deformity shouldbe surgically corrected if the deformity isprogressive or severe as defined by inter-ference with gait, or by the presence of amechanical axis deviation of more than10° between the femur and tibia. Controlof secondary HPT is recommended priorto surgical correction. (OPINION)

.2 Symptomatic proximal femoral slippedepiphyses (SCFE) should be surgicallystabilized if K/DOQI target values forPTH are not achieved within 3 months ofthe diagnosis of SCFE. (OPINION)

BACKGROUNDRenal osteodystrophy refers to the effects of

hronic renal failure (CRF) on the skeletal sys-em. Although the underlying defect is metabolicn nature, this section is primarily concernedith the consequences of CKD most likely to be

ncountered by the orthopedic surgeon. Thesessues are largely the result of mechanical failureuperimposed on the underlying metabolic andistological changes. They occur either acutelys seen in pathological fractures, or on a chronicasis as exemplified by severe and progressivenock-knees and bow-legs. From an orthopedicerspective, skeletal abnormalities are primarilyhe result of 2° HPT. Along with optimal meta-olic treatment of these patients is a need foroncurrent orthopedic management.

RATIONALE

eneral

Prompt treatment of musculoskeletal defor-ity prevents further deformity, restores patient

unction and mobility, and improves patient self-steem. Patients with renal osteodystrophy ex-ibit delayed acquisition of motor milestones.keletal age is also delayed, and short stature is

o be expected with children often falling belowhe 5th percentile in height.44 The role of therthopedist is to recognize these associated con-itions, refer for management of metabolic is-ues (including possible GH treatment), and treatony deformity. One of the frequently over-ooked associations is a severe myopathy. Resis-ance training in adults can result in significant
ncreases in both muscle mass and strength, and f
merican Journal of Kidney Diseases, Vol 46, No 4, Suppl 1 (Octo

hysical therapy is an essential part of treatmentor these patients.45

The treatment of musculoskeletal complica-ions must be tailored to the individual. Medicaltabilization of 2° HPT is an important compo-ent of the care of angular deformity and slippedpiphyses. When surgery is necessary, medicalanagement to achieve metabolic stability is of

reat importance. This improves surgical fixa-ion and healing by improving the biomechanicaltrength of bone while limiting the incidence ofostoperative recurrence. Elevated serum alka-ine phosphatase levels (above 500 U/L) aressociated with poor healing and continued bonyeformity despite surgery.46,47

ngular Deformities

Angular deformity of the weight-bearing boness the most common musculoskeletal abnormal-ty in children with renal osteodystrophy. Ofhese, the most common is genu valgum, al-hough genu varum, ankle valgum or varum, andoxa vara may also be seen.48,49 The cause ofngular deformity is likely multifactorial. Meta-olic abnormalities suppress physeal maturation,nd asymmetric forces placed across the physisay compound the situation according to theeuter-Volkmann principle (excessive compres-

ive forces inhibit physeal growth).50 Finally,lipping of the epiphyses (discussed below) withubsequent healing may also result in residualngulation.

Although no one parameter predicts whichatients go on to angular deformity, there iseneral consensus that it is related to metabolicnstability, and that prompt correction of thisnstability can lead to improvement of skeletaleformity.46,51-55 The age at onset of renal fail-re impacts which deformity is more common.atients with physiological knee varus at thenset of renal failure tend to develop genu va-um, while older patients with physiological val-us at disease onset tend to develop genu val-um.48

Evaluation of patients with angular defor-ity56 can be quantified with clinical photo-

raphs.56 For deformity out of the range oformal, standing lower extremity radiographs
rom hips to ankles on a 36” cassette are war-
ber), 2005: pp S23-S25 S23

rfbwmaaPdm

mtastststvrnova

S

ettglrffiwmouad

pedltpR

Ttcmamptcynefsptltdgz

A

sspGmocpcsWsficmobclmi

GUIDELINE 3: SURGICAL MANAGEMENT OF OSTEODYSTROPHYS24

anted. Deformity may be primarily at the distalemur, or proximal tibia, or variably dividedetween them. Angular deformity can improveith medical therapy alone.51 Patients withoutuch growth remaining or with severe deformity

re unlikely to satisfactorily improve, and theyre usually treated with corrective osteotomy.47,49

atients with open physes and moderate valguseformity may be treated with medial he-iepiphyseal stapling.47

Surgery is indicated when correction of theetabolic bone disease does not lead to resolu-

ion. The goal of surgery is to restore a normalnatomic axis such that a straight line passesimultaneously through the femoral head, cen-er of the knee, and center of the ankle (talarurface), with the patient in a standing posi-ion. In addition, the ankle and knee jointshould be parallel to the floor. Depending onhe relative contribution of the distal femurersus the proximal tibia, the condition mayequire osteotomies above, below, or simulta-eously above and below the knee joint inrder to achieve these goals. Occasionally aarus deformity in the distal tibia may requireseparate correction at that level.

lipped Epiphyses

In contrast to adolescent idiopathic slippedpiphyses, slipped epiphyses in the renal os-eodystrophy patient commonly occur throughhe metaphyseal—and not the physeal—re-ions of long bones. Although the most typicalocation is the proximal femur, slips have beeneported in the distal radius and ulna, distalemur, proximal humerus, and distal tibia andbula.48,57-60 They likely occur due to 2° HPT,hich leads to osteopenia and fibrosis of theetaphysis, thereby weakening it. Application

f shear forces through weight bearing ornequal muscle pull at the ends of long bonesre presumably the forces leading to gradualeformity through the area.With lower extremity slips, patients usually

resent with an abnormal waddling gait. Upperxtremity slips usually result in obvious skeletaleformity, though subtle deformity can be over-ooked because these patients have widening ofhe metaphyses of long bones, giving them are-existing abnormal appearance at any rate.
adiographs of the affected areas are diagnostic. o
he vast majority of slips stabilize with medicalreatment of the bone disease.57,58,61 Biomechani-ally, slip progression with further varus defor-ity is likely and can be prevented by medical

nd surgical stabilization of the slip. Therefore, ifedical stabilization is not achieved promptly,

inning is undertaken.57 Many children are lesshan 10 years when the hips first slip, and manyhildren do not close their physes for another 10ears since maturation is delayed. Thus, termi-ally smooth pins are usually placed with threadsngaging bone only at the lateral cortex of theemur. This allows continued growth of the phy-is along the axis of the smooth portion of thein.62 For non-hip-slipped epiphyses, observa-ion and medical therapy alone are indicated, asong as there is skeletal growth remaining andhe deformity is improving. An unacceptableeformity in a patient with little or no skeletalrowth remaining is treated with surgical stabili-ation.

vascular Necrosis

Avascular necrosis of bone occurs in theetting of CRF. The femoral head is a commonite, and symptoms are often mild when com-ared to the radiographic appearance.63 WhileH treatment may play a role in the develop-ent of AVN in these patients,64 the majority

f reports associate the incidence of AVN withhronic immunosuppression after renal trans-lantation.48,65-67 The incidence of this compli-ation appears to be dose-related, though nopecific dose-time guidelines exist.65,68,69

hile the femoral head is the most commonite, reports delineate the talus, humeral head,emoral condyles, and metatarsals as othernvolved sites. The diagnosis can be somewhatonfusing in these patients because approxi-ately 20% develop osteosclerosis, the cause

f which is poorly understood. The increasedone density seen radiographically with avas-ular necrosis before collapse can have a simi-ar appearance to osteosclerosis. The advent ofagnetic resonance imaging (MRI) has aided

n making a more secure diagnosis.

STRENGTH OF EVIDENCECase-based series of children with either SCFE

r lower-extremity angular deformities support

taTtS

pttTbl

csdremegcca

GUIDELINE 3: SURGICAL MANAGEMENT OF OSTEODYSTROPHY S25

he idea that prompt optimal metabolic control isn integral component of the orthopedic care.here are only retrospective studies regarding

he surgical treatment of angular deformity andCFE.46,47,57,62

LIMITATIONSBecause few centers treat large numbers of

atients with renal osteodystrophy, no prospec-ive studies exist regarding optimal treatment ofhe orthopedic manifestations of the disease.reatment recommendations are therefore largelyased on the opinions of those who treat the
argest number of these patients. s
RESEARCH RECOMMENDATIONSAlthough it is accepted that metabolic disease

ontrol is important if surgery is planned, futuretudies should examine the importance of controluration in the perioperative period and how thiselates to surgical outcome. Also, the musculoskel-tal manifestations of disease can improve withetabolic disease control, and a prospective study

xamining deformity improvements without sur-ery might lead to a better understanding of surgi-al indications. Studies comparing different surgi-al techniques for treatment of angular deformityre needed, as are studies exploring the optimal
urgical fixation for SCFE stabilization.

4

4

4

fr4m(sarl3attTcr

S

GUIDELINE 4. TARGET SERUM PHOSPHORUS LEVELS

rmcialictgRsdllamrbt

eldl

dcpathftplCC

.1 In CKD patients (Stages 1-4), the serumlevel of phosphorus should be maintainedat or above the age-appropriate lowerlimits (EVIDENCE) and no higher thanthe age-appropriate upper limits. (OPIN-ION)

.2 For children with kidney failure (CKDStage 5), including those treated withhemodialysis or peritoneal dialysis, theserum levels of phosphorus should bemaintained between 3.5-5.5 mg/dL (1.13-1.78 mmol/L) during adolescence and be-tween 4-6 mg/dL for children between theages of 1-12 years. (EVIDENCE)

.3 In children with renal tubular phosphatewasting, or other causes of hypophos-phatemia, hypophosphatemia should becorrected via dietary modification, en-teral supplementation, or reduction in theuse of phosphate binders. (EVIDENCE)

BACKGROUNDThere are substantial effects of age on the

asting serum concentration of phosphorus. Se-um phosphorus levels in infants range from.8-7.4 mg/dL (mean 6.2 mg/dL) in the first 3onths of life, and decrease to 4.5-5.8 mg/dL

mean 5.0 mg/dL) at age 1-2 years.70 The highererum phosphorus concentration in infants isttributed to an increased fractional phosphateeabsorption, possibly further augmented by aow GFR.70 In mid-childhood, values range from.5-5.5 mg/dL (mean 4.4 mg/dL) and decrease todult values by late adolescence.71-73 Represen-ative target ranges for serum phosphorus concen-ration in children with CKD are depicted inable 6. The normal range for serum phosphorusoncentration can vary somewhat between labo-atories.


In healthy children and in children with GFRanging from 25-50 mL/min/1.73 m2 (approxi-ately Stage 3 CKD), the serum phosphorus

oncentration decreased after breakfast to a nadirn late morning, and increased during the earlyfternoon,74 exhibiting a circadian pattern simi-ar to that observed in healthy adult subjectsngesting typical diets.75 The amplitude of theircadian variation in serum phosphorus concen-ration in healthy adolescents (3.0 mg/dL) isreater than that in healthy adults (1.2 mg/dL).76

estriction of dietary phosphorus induces sub-tantial decreases in serum phosphorus levelsuring late morning, afternoon, and evening, butittle or no change in morning fasting phosphorusevels.75 Thus, values obtained in the afternoonre more likely to be affected by diet and may beore useful in monitoring the effect of phospho-

us restriction or administration of phosphate-inding agents on serum phosphorus concentra-ions.

Hyperphosphatemia leads to 2° HPT and el-vated blood levels of PTH by: (a) lowering theevels of ionized calcium; (b) inhibiting the pro-uction of 1,25(OH)2D3; and (c) directly stimu-ating PTH secretion.77,78

These processes lead to high-turnover boneisease and other adverse consequences of ex-ess PTH, in part due to an increase in calcium-hosphate product (CaXP)79-82 and in adults, isssociated with increased morbidity83,84 and mor-ality.85-88 With respect to vascular calcification,yperphosphatemia exerts a direct calcifying ef-ect on vascular smooth muscle cells.89 Calcifica-ion of coronary arteries, cardiac valves, andulmonary tissues results in cardiac disease, theeading cause of death in patients withKD.83,90-92 In young adults who developedKD in childhood years, there is high incidence


oatr

wchdsCetdrha

CeCwvaCgoptm

dPsPlhcocribttBe

tepH

fpolaaspt

mterrIotrLmtpTcmpmm

�ittcq

pnp

ta

GUIDELINE 4: TARGET SERUM PHOSPHORUS LEVELS S27

f coronary artery calcification, associated withn elevated CaXP.80,93 It is therefore imperativeo prevent hyperphosphatemia and maintain se-um phosphorus levels within the normal range.

Children with CKD may have renal tubularasting of phosphorus. Fanconi syndrome due to

ystinosis is the most common etiology in child-ood. A variety of other genetic disorders andrug or toxin exposure may also cause Fanconiyndrome. In addition, some children developKD and hypophosphatemia due to Dent’s dis-ase. Hypophosphatemia may also be secondaryo excessive use of phosphate binders, vitamin Deficiency, inadequate dietary intake of phospho-us intake, or other tubular disorders. Chronicypophosphatemia in children results in ricketsnd poor growth.

RATIONALEAmong the factors that contribute to 2° HPT in

KD patients are phosphate retention and/orlevated levels of serum phosphorus. In adultKD patients, hyperphosphatemia is associatedith increased morbidity and mortality.79-86 Con-ersely, in adults, hypophosphatemia is associ-ted with increased mortality. In children withKD, hypophosphatemia leads to rickets androwth retardation. Therefore, the maintenancef normal serum levels of phosphorus in CKDatients is critical for the prevention of abnormali-ies in PTH metabolism, and for the reduction oforbidity and mortality.

STRENGTH OF EVIDENCEWhile available experimental data support a

irect role of phosphorus in the regulation ofTH secretion,77,78 the data in humans are lesstraightforward. One study has shown elevatedTH levels in patients with serum phosphorus

evels �6.2 mg/dL (2.0 mmol/L).83 On the otherand, other studies have failed to demonstrateonsistent changes in PTH levels across a rangef serum phosphorus levels,94 and no directorrelation between the level of serum phospho-us and PTH has been established.78 Many stud-es measuring serum PTH levels are confoundedy the use of phosphate binders and vitamin D,hus precluding the evaluation of a direct associa-ion between serum phosphorus and PTH levels.ased on available evidence and upon clinical
xperience it is the opinion of the Work Group i
hat, for adults and for children with CKD, el-vated phosphorus levels in CKD and dialysisatients contribute to the development of 2°PT.In order to eliminate the potentially con-

ounding influence of aluminum-containinghosphate binders on outcomes, only studiesf adult dialysis patients, and only those pub-ished after 1990, were included in the datanalysis. Four studies meet these criteria, andll are observational or cross-sectional in de-ign.83,85-87 These studies correlate serum phos-horus levels with multiple end-points in pa-ients treated with hemodialysis.

The four cross-sectional studies83,85-87 thatet the inclusion criteria evaluated the associa-

ion of serum phosphorus levels with extraskel-tal outcomes. Two studies evaluated the relativeisk of mortality associated with serum phospho-us levels in patients treated with hemodialysis.n one study, a reference serum phosphorus rangef 4.6-5.5 mg/dL (1.49-1.78 mmol/L) was used85;he relative risk of mortality increased with se-um phosphorus levels �6.5 mg/dL (2.10 mmol/). In the other study, a reference range of 5-7g/dL (1.61-2.26 mmol/L) was used86; the rela-

ive risk of mortality increased with serum phos-horus levels less than or greater than this range.he increase in mortality was particularly signifi-ant for levels of phosphorus �7 mg/dL (2.26mol/L) or �3 mg/dL (0.97 mmol/L). Serum

hosphorus levels �2.5 mg/dL (0.81 mmol/L)ay be associated with abnormalities in boneineralization such as osteomalacia.94

In another study, serum phosphorus levels6.2 mg/dL (2.00 mmol/L) were associated with

ncreased blood pressure, hyperkinetic circula-ion, increased cardiac work, and high arterialensile stress.83 One study failed to find an asso-iation between serum phosphorus levels anduality of life.94

In patients with tubulopathy and hypophos-hatemia, phosphate therapy is a critical compo-ent of the treatment of the bone disease, as isrovision of alkali and vitamin D.The available evidence supports an associa-

ion between serum phosphorus levels both abovend below the normal range with poor outcomes,
ncluding mortality.

hpclm1hhtpades

ttodecn

sdagigqeafaawdt

nr

GUIDELINE 4: TARGET SERUM PHOSPHORUS LEVELSS28

LIMITATIONSIn adults with CKD, cross-sectional studies

ave established a correlation between serumhosphorus levels and various extraskeletal out-omes, but this correlation does not rise to theevel of causality. Further, the studies of higherethodological quality85,86 relied on data from

990 or earlier, indicating that their results mayave been confounded by the use of aluminumydroxide and/or by less-aggressive vitamin Dherapy. To date, studies performed in dialysisatients have failed to conclusively demonstratereduction in morbidity or mortality, through

ietary intervention or the use of phosphate bind-rs to lower serum phosphorus levels to theuggested target range.

In children with CKD, there are no prospec-ive studies or retrospective analysis to establishhe effect of normalization of serum phosphorusn clinical outcome outside of rachitic boneisease.95 Even the successful treatment of rick-ts generally requires additional pharmacologi-al therapy, making the independent impact of
ormalization of serum phosphorus uncertain. a
CLINICAL APPLICATIONS

This Guideline supports intensive control oferum phosphorus in patients with CKD. Mostata indicate that �30% of dialysis patientsre able to maintain phosphorus in the sug-ested target range. The goal should be toncrease the percentage of patients in this tar-et range. Successful implementation will re-uire an increased dietitian-to-patient ratio,ducational tools to increase patient compli-nce, as well as studies to further explore theeasibility of dialytic techniques that are betterble to control serum phosphorus levels (suchs nocturnal or daily hemodialysis), and theidespread availability and affordability ofifferent phosphate binders, regardless of pa-ient insurance status.

RESEARCH RECOMMENDATIONS

Longitudinal studies of patients with CKD areeeded, evaluating the effects of controlling se-um phosphorus in the target range on morbidity
nd mortality.

5

5

5

Ceawi1ttoewciT

A

GUIDELINE 5. MANAGEMENT OF DIETARY PHOSPHORUS
INTAKE IN CHILDREN WITH CKD
ilt

iddirpawndisddtplPd1tnc

hddrsodr

.1 Dietary phosphorus should be decreasedto the Dietary Reference Intake (DRI) forage (Table 7) when the serum PTH concen-tration is above the target range for thestage of CKD and serum phosphorus iswithin the target range for age (Table 6,Guideline 4). (OPINION)

.2 Dietary phosphorus should be decreasedto 80% of the DRI for age (Table 7) whenthe serum PTH concentration is above thetarget range for the stage of CKD andserum phosphorus is above the targetrange for age (Table 6, Guideline 4).(OPINION)

.3 After initiation of phosphorus restriction,serum phosphorus concentrations shouldbe monitored at least every 3 months inpatients with CKD Stages 3-4, andmonthly in patients with CKD Stage 5.Serum phosphorus values below the tar-get range for age should be avoided.

BACKGROUNDIn children20,74,96 and adult patients97-103 with

KD, serum concentrations of PTH are increasedarly, i.e., when the GFR is only mildly to moder-tely reduced, and the values of PTH vary inverselyith those of GFR.103 When the GFR decreases

nto CKD Stage 3 and below (�60 mL/min/.73m2), serum concentrations of PTH are abovehe normal range in most children and adult pa-ients, and histological evidence of bone disease isbserved.20,104,105 At this level of GFR, how-ver, serum concentrations of phosphorus areithin the normal range or even mildly de-

reased,74,96,98,106,107 and values become clearlyncreased only when CKD Stage 4-5 is reached.hus, in CKD Stages 2 and 3, hyperphosphatemia


s rarely present and 2° HPT can be attributed, ateast in part, to the reduction in serum concentra-ions of 1,25(OH)2D.74,96,101-103,108-117

RATIONALEAlthough serum phosphorus levels are not

ncreased in the early stages of progressive CKD,ietary phosphorus is nevertheless an importanteterminant of the severity of hyperparathyroid-sm in mild and moderate, as well as severe,enal insufficiency. In both children and adultatients with mild and moderate CKD (Stages 2nd 3) in whom serum concentrations of PTHere increased and those of serum phosphorusormal, dietary phosphorus restriction induced aecrease in serum levels of PTH and an increasen levels of 1,25(OH)2D, the latter to normal orupernormal values.74,100,118 Conversely, in chil-ren with Stage 3 CKD, supplementation ofietary phosphorus to intakes approximately twicehe DRI for age induced a worsening of hyper-arathyroidism and further decrease in serumevels of 1,25(OH)2D.74 Such changes in serumTH could be attributed, at least in part, toiet-induced changes in serum levels of,25(OH)2D. Phosphorus manipulation in pa-ients with CKD Stage 2 and 3 induced little oro change in morning fasting serum phosphorusoncentrations.74,100,118

Thus, in CKD Stages 2 and 3, the severity ofyperparathyroidism can be amplified or re-uced by increases or decreases, respectively, inietary phosphorus intake. Since dietary phospho-us intakes above the DRI can contribute to theeverity of hyperparathyroidism, it is the opinionf the Work Group that phosphorus intakes beecreased to the DRI even when serum phospho-us levels are within the target range. In CKD

ber), 2005: pp S29-S31 S29

Strr

acamTiappssdccdrmssw

ereaDaprt4

tiettvdtcuad

dp

pmDtwt

epwm

apttc

stePeecw1brGtsmacadmds

pbffp

GUIDELINE 5: MANAGEMENT OF DIETARY PHOSPHORUS INTAKE IN CHILDREN WITH CKDS30

tages 4 and 5, serum phosphorus levels areypically above the target range, and phosphorusestriction to approximately 80% of the DRI isecommended.

The higher serum concentrations of calciumnd phosphorus in healthy infants and younghildren, and their physiological decrease withge, presumably reflect the increased require-ents of these minerals by the growing skeleton.his is particularly important in the newborn

nfant, as infancy is the period of most rapidccretion of bone mineral. Hence, when dietaryhosphorus is restricted to control hyperphos-hatemia and 2° HPT in children with CKD,erum phosphorus values below the target rangehould be avoided. Rickets due to phosphoruseficiency occurs in preterm infants fed insuffi-ient amounts of phosphorus, and in infants andhildren with hypophosphatemia due to inheritedisorders of renal phosphate transport.119 Severeestriction of dietary phosphorus in children withoderate and severe renal insufficiency was as-

ociated with a decrease in fasting levels oferum phosphorus and histological findings oforsening osteomalacia.118

STRENGTH OF EVIDENCEStudies in children with CKD Stages 2-3 that

xamine the relationship between serum phospho-us concentration and 2° HPT suggest that di-tary phosphorus restriction can improve 2° HPTnd maintain normal serum phosphorus levels.ata in adult patients with CKD support an

ssociation between the increase in serum phos-horus concentration and decrease in GFR, andeveal that hyperphosphatemia is observed whenhe creatinine clearance decreases to CKD Stages-5.120

The effectiveness of dietary phosphate restric-ion in controlling the hyperphosphatemia of CKDn children and adults was analyzed in 19 studiesxamining 2,476 patients. Fifteen randomized con-rolled trials121-135 and four nonrandomized con-rolled trials136-139 met the inclusion criteria. Theast majority of studies evaluated restricted proteiniets, which are usually (but not always) equivalento low phosphorus diets. In many of these studies,alcium94,140-147 and vitamin D supplements weresed,80,83,85,86,94,140-148 or phosphate binders werelso administered to the patients in addition to the
ietary intervention. Thus, the interpretation of these i
ata should be done with caution. Various end-oints were utilized:

Quality of life. One study reported that lowrotein diet did not adversely affect employ-ent,138 but the results of the Modification ofiet in Renal Disease (MDRD) study indicated

hat patients with CKD (Stages 3 and 4) treatedith very restricted protein diets were less able

o socialize.149

Mortality. Nearly all of the included studiesvaluated the role of dietary restriction of protein/hosphorus on mortality. The reported resultsere variable. When these data were analyzed byeta-analysis, no effect on mortality was found.Kidney function. Seven of nine studies in

dult patients with CKD suggest that dietaryhosphorus restriction may stabilize kidney func-ion.121,124,125,129-131,133,136,139 Conclusions inhis regard could not be drawn from studies inhildren or in adults with severe CKD.

Bone and mineral metabolism. Several smalltudies reported that dietary phosphorus restric-ion in patients with CKD had no significantffect on serum alkaline phosphatase,123,125,134,137

TH levels,125,134,136,138 serum calcium lev-ls,123,125,134,136,137 serum phosphorus lev-ls,123,132,134,136,137,150 and urinary phosphate ex-retion.127,129,132 In contrast, in a careful andell-controlled study of four patients with Stagesand 2 of CKD conducted in a metabolic ward

efore and after 8 weeks of dietary phosphateestrictions in proportion to the decrement inFR, there was a reduction in blood PTH levels

o normal without significant changes in theerum levels of phosphorus, significant decre-ents in blood levels of alkaline phosphatase

nd in urinary excretion of phosphate, and signifi-ant increments in blood levels of 1,25(OH)2D3

nd intestinal absorption of calcium.100 Also, theietary phosphate restriction was associated witharked improvement in bone resorption and

efects in bone mineralization as evidenced bytudies of bone biopsy.100

In children, the initiation of moderate dietaryhosphate restriction needs to be accompaniedy close monitoring of linear bone growth. Inour studies in children, there was no evidenceor adverse effects as a result of dietary phos-hate restriction.124,128,151,152 In addition, stud-
es in adults did not support any adverse effect on

nr

stactM3Oyrlwyte

apptpe

trustirdptswi

cnsp

tdntpitcpwrstr

aecdIcwrNsarppo1coG

dprdps

GUIDELINE 5: MANAGEMENT OF DIETARY PHOSPHORUS INTAKE IN CHILDREN WITH CKD S31

utritional status as a result of dietary phosphateestriction.123-125,127,129,131,133,134,137,139,153,154

Compliance with dietary restriction in the re-earch setting of clinical studies may not reflecthe situation in clinical practice. While compli-nce with dietary phosphorus restriction in clini-al practice is commonly believed to be poor,here is a lack of data to support this supposition.

ost studies have found compliance rates of5%-91% with low-protein diets.124,132,149,155

ne study reported 41% and 77% compliance atears 1 and 3, respectively.156 The complianceates with dietary phosphate restriction were simi-ar to compliance rates for low-protein diets. Itas not addressed whether the improvement atear 3 is related to continuous education and/orhe realization by the patient of the adverseffects of noncompliance.

Given the lack of evidence of adverse effects,nd the evidence of positive benefit of dietaryhosphate restriction, it is the consensus of theediatric (and adult) Work Group that modifica-ion of dietary phosphate intake be initiated inatients with CKD when PTH levels are el-vated.

LIMITATIONSDespite the relatively large number of prospec-

ive randomized trials evaluating dietary phospho-us restriction, most of these studies specificallytilized protein-restricted diets and therefore re-tricted phosphate intake indirectly. While pro-ein and phosphorus are closely related in foods,t is possible to restrict protein without fullyestricting phosphorus. Much of the data are alsoifficult to interpret since most of the reportsrovided analysis for “prescribed diet” ratherhan “consumed diet.” Furthermore, in manytudies, the patients had concomitant therapyith vitamin D and/or phosphate binders, mak-

ng interpretation of the results difficult.While the available data do not support the

ommon belief that dietary phosphate restrictionegatively impacts nutritional status, it must betressed that dietary phosphate restriction has the
otential of adversely impacting nutritional sta- s
us if done in a haphazard manner. The data thatemonstrate the ability to maintain good or stableutritional status during dietary phosphate restric-ion were obtained in studies in which dietitiansrovided careful instruction and regular counsel-ng and monitoring. In the research setting, pa-ients are monitored closely and have regularontact with their renal care providers. Thoseatients who have been “casually” instructed toatch their protein or phosphate intake, without

egular follow-up, may be at risk for seriouside-effects, such as malnutrition. Unfortunately,here are no data on those patients who are notegularly and closely followed.

CLINICAL APPLICATIONSIt is critical to provide consistent instruction

nd regular follow-up during prescription of di-tary phosphate restriction. In patients with CKD,ompliance with dietary phosphate restriction isifficult and requires intensive dietitian support.n CKD patients treated with dialysis (Stage 5),are must be taken to reduce phosphate intakehile maintaining adequate protein intake as

ecommended by the K/DOQI Guidelines onutrition.157 The phosphate level of the diet

hould be as low as possible while ensuring andequate protein intake. If one multiplies theecommended protein level by 10-12 mg phos-hate per gram of protein, a reasonable phos-hate level can be estimated. The average amountf phosphorus per gram of protein ranges from2-16 mg. In order to limit phosphorus signifi-antly, those protein sources with the least amountf phosphorus must be prescribed (see Table 12,uideline 7).

RECOMMENDATIONS FOR RESEARCHThere is a need for large, multicenter longitu-

inal studies evaluating the effects of dietaryhosphate restriction (as opposed to only proteinestriction) on nutritional status, growth in chil-ren, morbidity, mortality, bone disease, androgression of decline in kidney function. Thesetudies should be conducted in patients with all
tages of CKD, beginning in Stage 2.

6

6

6

6

6

6

6

S

GUIDELINE 6. USE OF PHOSPHATE BINDERS IN CKD

6

eaihlpbmatmgpcbo

hRHancatrDocbb

mrvsp

In Patients with CKD Stages 2-4:

.1 If serum phosphorus levels cannot becontrolled within the target range (seeGuideline 4), despite dietary phosphorusrestriction (see Guideline 5), phosphatebinders should be prescribed. (OPINION)

.2 Calcium-based phosphate binders are ef-fective in lowering serum phosphorus lev-els (EVIDENCE) and should be used asthe initial binder therapy. (OPINION)

In Patients with CKD Stage 5 (Dialysis):

.3 Both calcium-based phosphate bindersand the non-calcium, non-metal-contain-ing phosphate binders, such as sevelamerHCL, are effective in lowering serumphosphorus levels. (EVIDENCE) As ofthis writing, calcium-based phosphatebinders should be used as primary therapyin infants and young children. In olderchildren and adolescents, either drug maybe used. (OPINION)

.4 In dialysis patients who remain hyper-phosphatemic (above the upper targetvalue) despite the use of either calcium-based phosphate binders or other noncal-cium, non-metal-containing phosphatebinders, the dialysis prescription shouldbe modified to control hyperphos-phatemia. (OPINION)

.5 The total dose of elemental calcium pro-vided by the calcium-based phosphatebinders and dietary calcium should notexceed up to 2X DRI for calcium, basedon age (OPINION), and the total intake ofelemental calcium (including dietary cal-cium) should not exceed 2,500 mg/day.(OPINION)

.6 The dosage of calcium-based phosphatebinders should be lowered in dialysispatients with corrected serum calcium of>10.2 mg/dL (2.54 mmol/L), or with se-rum PTH levels <150 pg/mL (150 ng/L)on two consecutive measurements. (EVI-DENCE)

.7 In adolescent patients with serum phos-phorus levels >7.0 mg/dL (2.26 mmol/L),aluminum-based phosphate binders maybe used as a short-term therapy (up to 4-6
weeks), and for one course only, to be p

replaced thereafter by other phosphatebinders. (EVIDENCE)

.8 In children receiving aluminum-basedphosphate binders, concurrent use of cit-rate-based products should be avoided,due to the risk of increasing aluminumabsorption and potential toxicity.(EVIDENCE)

BACKGROUNDWhen dietary phosphate restriction is inad-

quate to control serum levels of phosphorusnd/or PTH, phosphate binders should be admin-stered. Different phosphate binder compoundsave been utilized to control serum phosphorusevels, but the search still continues for the bestossible binder. A combination of binders maye used to control serum phosphorus levels toinimize the potentially serious side-effects of

ny specific binder. The willingness of the pa-ient to adhere to the binder prescription is para-ount to control phosphorus absorption from the

astrointestinal tract and, subsequently, serumhosphorus levels. Table 8 describes the steps toalculate the initial prescription of phosphateinders, and Table 9 describes the characteristicsf various phosphate-binding agents.In children, calcium-based phosphate binders

ave been shown to be safe and effective.158-162

ecently, pediatric experience with sevelamerCl is accumulating, and it appears to be safe

nd effective as well.163a Long-term use of alumi-um-containing phosphate binders has been asso-iated with severe complications of bone diseasend encephalopathy.164-166 Thus, only a short-erm course (4-6 weeks) of aluminum can beecommended for control of hyperphosphatemia.ata demonstrate that concurrent administrationf citrate containing compounds dramatically in-reases enteral absorption of aluminum and muste avoided if aluminum-containing phosphateinders are used.167,168

RATIONALEThe goal of phosphate-binder therapy is toaintain serum phosphorus levels within the

ange as outlined in Guideline 4 without ad-ersely affecting nutritional status or causingerious side-effects. It is recommended to initiatehosphate binder therapy when: (a) serum phos-
horus levels remain elevated, despite restriction

GUIDELINE 6: USE OF PHOSPHATE BINDERS IN CKD S33

oto

hhccadcpnqeef

epwodSssppcttsiotmu

paTplwsarp

rtTwsOo2

itmhseamotlseac1nhm

ewaHtptnllv

cpepwoaac

GUIDELINE 6: USE OF PHOSPHATE BINDERS IN CKDS34

f dietary phosphate restriction; or (b) the restric-ion of phosphate intake hinders the intake ofther critical nutrients.The majority of research in the recent decade

as focused on calcium-based binders, whichave been shown to be safe and effective inhildren with CKD. Recently, other non-cal-ium, non-metal containing, binder forms arevailable, but are incompletely studied in chil-ren. With recent concern that soft-tissue calcifi-ation may be worsened by calcium-based phos-hate binders and vitamin D analogs, noncalcium,onaluminum binders are being used more fre-uently in adults with CKD. As further data onfficacy and safety in children accumulate, it isxpected that the frequency of use will increaseor children with CKD.

An increase in the frequency of dialysis cannhance phosphorus clearance in hemodialysisatients.176 Among patients treated with thrice-eekly nocturnal hemodialysis, serum levelsf phosphorus were reduced despite increasedietary intake and reduced use of binders.177

ome patients treated with nocturnal dialysisix times per week have required phosphateupplements in the dialysate to correct hy-ophosphatemia.178 Where the escalation ofhosphate-binder dose is either incapable ofontrolling serum phosphorus levels or is notolerated, modification of the dialysis prescrip-ion in both hemodialysis and peritoneal dialy-is patients should be strongly considered tomprove phosphate clearance. During the usef aluminum-based phosphate binders, pa-ients should be monitored to avoid additional

orbidity described with their prolongedse179,180 (see Guidelines 12 and 13).

STRENGTH OF EVIDENCEStudies of the efficacy and safety of phos-

hate binders in children with CKD Stages 3-4re limited to uncontrolled case series.160,161,181

hree studies reported effective control of phos-horus with calcium carbonate160,161,181; theargest series reported treatment in 45 childrenith a follow-up period of 6-54 months.160 All

ubjects were on a phosphate-restricted dietnd 42 were also treated with vitamin D ste-ols; transient hypercalcemia occurred in 11
atients. The two smaller series161,181 also s
eported transient hypercalcemia that respondedo adjustments in vitamin D and binder doses.he required doses of calcium carbonate rangedidely, from 64-1,578 mg/kg/day in one

tudy,161 to 21-228 mg/kg/day in another.160

ne study provided data on the absolute dosef elemental calcium required to control PTH:40-6,000 mg elemental calcium per day.161

Additional case series have been publishedn children with CKD Stage 5.159,162 One ofhese suggested that episodes of hypercalce-ia were more common in children with a

istory of prior aluminum therapy.159 Anothertudy reported a comparison of calcium ac-tate with calcium carbonate in nine hemodi-lysis patients.158 Calcium carbonate was ad-inistered for 7 weeks, followed by withdrawal

f therapy; then calcium acetate was adminis-ered for an additional 7 weeks. Both agentsowered the serum phosphorus concentrationignificantly. Although significantly less el-mentary calcium was ingested with calciumcetate (mean 750 [range 375-1,500] mg cal-ium/day) than with calcium carbonate (mean,200 [range 0-3,000] mg calcium/day), theumber of episodes of hyperphosphatemia orypercalcemia did not differ between treat-ents.Studies that evaluated the efficacy and adverse

ffects of phosphate binders were analyzed. Thereere no prospective, controlled studies that evalu-

ted phosphate binders in CKD Stages 3 and 4.owever, since serum PTH levels in these pa-

ients are elevated in association with hyperphos-hatemia, it is the opinion of the Work Grouphat the use of phosphate binders may becomeecessary if the serum levels of PTH cannot beowered to the target levels (see Table 3, Guide-ine 1) by dietary phosphate restriction and/oritamin D therapy.In CKD Stage 5, there were 16 prospective,

ontrolled studies in adults that evaluated 552atients for various outcomes to quantify thefficacy of serum phosphorus control by phos-hate binders. In all these studies, the patientsere treated with dialysis and the primary focusf the analysis was on the use of calcium carbon-te and calcium acetate, although some data onluminum hydroxide, calcium gluconate, cal-ium carbonate plus magnesium carbonate, and
evelamer HCl were also available. A meta-

aporesoducspsheemHvl

E

briiceTncwpb

ddtpemscpnc(dhmp

cab

pepmhWmddFtptefP

c

fB


nalysis of these studies was performed to com-are the efficacy of the phosphate binders onutcomes, including: serum levels of phospho-us, PTH, and calcium; bone biochemical mark-rs; and extraskeletal calcification.173,182,183 Notudies evaluated the effect of phosphate bindersn patient quality of life, mortality rate, inci-ence of bone disease or fractures. Recently, these of both calcium based binders and non-alcium, non-metal containing P binders, such asevelamer HCL, have been shown to be effectivehosphate binders in children on peritoneal dialy-is and bone biopsy proven secondaryyperparathyroidism.163a Furthermore, the skel-tal lesions of high-turnover bone disease mark-dly improved with both binders and active vita-in D sterols. However, therapy with sevelamerCL allows the use of higher doses of activeitamin D without increments in serum calciumevels.163a

ffect on Phosphorus

In all studies, serum phosphorus was loweredy the phosphate binder studied. In assessing theelative efficacy of the various phosphate bindersn controlling serum phosphorus levels, 15 stud-es were evaluated: nine studies examined cal-ium carbonate and six examined calcium ac-tate. Two sets of meta-analyses were performed.he first analysis compared the relative effective-ess of various phosphate binders to that ofalcium carbonate and no significant differenceas observed. The second meta-analysis com-ared calcium acetate to a variety of phosphateinders.182,184-188 It showed that calcium acetate

Fig 5. Meta-Analysis of Size of Effect on Serum

thosphorus Levels of Calcium Acetate versus Cal-ium Carbonate

ecreased serum phosphate levels to a greateregree than the other phosphate binders, al-hough it should be emphasized that the “other”hosphate binders group was a mixture of differ-nt phosphate binders such that this comparisonay not be completely valid. A subgroup analy-

is of four studies that directly compared calciumarbonate to calcium acetate185-188 found thatost-treatment serum phosphate levels were sig-ificantly higher following treatment with cal-ium carbonate compared to calcium acetateFigure 5). One possible explanation for thisifference is that calcium acetate leads to lessypercalcemia (see below), thereby allowingore binder to be administered to control phos-

horus better.Two studies included a placebo group for

omparison against calcium acetate173 and sevel-mer,189 and both showed that efficacy of theseinders was superior compared to placebo.A single study evaluated magnesium as a

hosphate binder: it was a crossover study thatvaluated patients on calcium carbonate com-ared to a combination of calcium carbonate andagnesium carbonate.190 The magnesium arm

ad equivalent phosphorus control. However, theork Group cautions that, in this study, theagnesium concentration in the dialysate was

ecreased. This is difficult to do in most unitsue to centralized dialysate delivery systems.urthermore, there are no long-term studies on

he safety and efficacy of magnesium as a phos-hate binder, and thus the Work Group agreedhat the use of magnesium-based phosphate bind-rs may be justified only if all other compoundsail and the appropriate precautions are under-

Fig 6. Meta-Analysis of Size of Hypercalcemic Ef-ect of Calcium Carbonate versus Other Phosphateinders

aken.

E

plCpadchtprfcew(scpoacpshcatppo

O

paettbar

bbpfc

ccHvc

tfaonspasl

mbib

alMBoicsaWmipmAspofpcacit

tb


ffect on Calcium and CaXP

Ten studies evaluated the effect of differenthosphate binders on corrected serum calciumevels, ionized calcium, total calcium, oraXP.173,185-189,191-194 Five of these studies com-ared different binders to calcium carbon-te,173,186,187,190,193 but a meta-analysis failed toetect a difference in the corrected serum cal-ium levels. A placebo-controlled study foundigher total calcium levels and lower CaXP inhe calcium acetate-treated group compared tolacebo.173 Although the overall change in se-um calcium levels in 10 studies was not af-ected, meta-analysis of the data showed thatalcium carbonate led to more hypercalcemicvents compared to other phosphate binders, orhen directly compared to calcium acetate only

Figure 6).183,185-188,190,192-195 Six studies as-essed calcium-phosphorus product, one placebo-ontrolled and the others comparing differenthosphate binders. Differences were observed innly two of these studies. Calcium acetate led tolower calcium-phosphorus product than pla-

ebo,173 and calcium carbonate led to a greaterroduct than calcium ketoglutarate.194 This lattertudy found that ionized calcium levels wereigher in patients treated with calcium carbonateompared to calcium ketoglutarate.194 Thus, thevailable data do not provide guidance regardinghe choice of the appropriate calcium-based phos-hate binder. The choice is a prerogative of thehysician and depends on the patient’s tolerancef the binder.

ther Outcomes

The major side-effects observed as a result ofhosphate-binder therapy were hypercalcemia,s described above, or gastrointestinal side-ffects. A meta-analysis indicated that gastroin-estinal side-effects were lowest with patientsreated with calcium carbonate compared to otherinders, although the effect size was smallnd thus no firm conclusions could beeached.186,188,190,192,194,195

Six studies evaluated the effect of phosphateinders on nutritional outcomes,182,184,189-191,194

ut different outcome measures were utilized,recluding comparative analyses. Two studiesound that sevelamer HCl led to lower serum
holesterol levels compared to placebo or cal- p
ium acetate, primarily due to a decrease in LDLholesterol levels.184,190 In addition, sevelamerCL allows the use of higher doses of activeitamin D without inducing changes in serumalcium levels.163a

Patient compliance with prescribed binderherapy was not reported consistently, but rangedrom 30%-100%.149,156,196-202 None of the avail-ble data dealt with the effect of noncompliancen clinical outcomes. One study suggested thatoncompliance was related to gastrointestinalide-effects. While maintenance of high serumhosphorus levels could be due to noncompli-nce with phosphate binders, other factors—uch as dietary indiscretion and phosphate re-ease from the bone—must also be considered.

There are few studies that demonstrated opti-al timing for ingestion of phosphate binders,

ut the general consensus among the Work Groups that binders should be taken 10-15 minutesefore, or during, the meal.In a study comparing calcium carbonate and

luminum hydroxide, bone mineral content wasower in aluminum hydroxide-treated patients.

inor, and inconsistent, differences were found.ecause of the potential for neurotoxicity andsteomalacia associated with aluminum-contain-ng phosphate binders,179,180,203 the use of theseompounds should be reserved for patients witherum phosphorus �7.0 mg/dL (2.26 mmol/L)nd only for short-term therapy. However, theork Group acknowledges that, while there isorbidity associated with long-term aluminum

ntake, there is also increased mortality withhosphorus levels �6.5-7.0 mg/dL (2.10-2.26mol/L). Thus, the two issues must be balanced.t the present time, there is no evidence that

hort-term use of aluminum-containing phos-hate binders is associated with the developmentf aluminum bone disease or neurotoxicity. There-ore, the short-term (4 weeks) use of these com-ounds is not contraindicated. However, calciumitrate should be avoided during treatment withluminum-based compounds, since citrate in-reases the absorption of aluminum from thentestine203 and may precipitate acute aluminumoxicity.

In summary, the available evidence supportshe hypothesis that all of the current phosphateinders are effective in controlling serum phos-
horus levels. The majority of studies evaluated

cecgWersd

orbptnttiabldlupcivtHa

actcetrrtirr

ees

tphcm(iccsciwicscwAccppltbrrrtectswccptacccrLstC1


alcium-containing phosphate binders. How-ver, recent studies on the use of the non-metal-ontaining phosphate binder sevelamer HCl sug-est that it was effective,184,189,204-206 and theork Group felt that this agent has an important

merging role in the control of serum phospho-us in dialysis patients. Sevelamer HCL has beenhown to be an effective binder in children onialysis.163,163a

In CKD Stage 5, the current evidence and thepinion of the pediatric Work Group support theecommendation that the choice of calcium-ased phosphate binder should be determined byatient preference (number and size of binder,ablets or capsules), compliance, comorbid ill-esses, side-effects, cost, and the ability to con-rol serum phosphorus levels while maintaininghe desired CaXP, and limiting the total calciumntake. Additionally, the pediatric Work Grouplso recommends reducing the dosage of calcium-ased phosphate binder in dialysis patients withow PTH levels. The rationale for this recommen-ation is that these patients will usually haveow-turnover bone disease, and the bone will benable to incorporate a calcium load,207 predis-osing to extraskeletal calcification. Also, cal-ium-based phosphate binders should not be usedn patients with hypercalcemia or with severeascular calcification (see below). In such pa-ients, one should consider the use of sevelamerCL to control serum levels of phosphorus while

voiding excessive calcium intake.

LIMITATIONSThe available data do not quantify an exact

mount of calcium that can be given safely as aalcium-based phosphate binder. This is an impor-ant issue as recent studies suggest that excessivealcium intake may worsen vascular and otherxtraskeletal calcification.80,84,208 Additional datahat either did not fully meet the inclusion crite-ia, or that became available after the evidenceeport was completed, support the consensus ofhe Work Group about limitation of calciumntake from phosphate binders. These data wereeviewed by the Work Group and are summa-ized as follows.

In a cross-sectional study evaluating the pres-nce of vascular calcification as assessed bylectron-beam computed tomography (EBCT)
can in children, adolescents, and young adults, c
he CaXP, prescribed calcium intake from phos-hate binders, and duration of CKD were muchigher in the young adult patient group withalcification. In the group with calcification, theean dose of prescribed binder was 6.456 g/day

elemental calcium/day), compared to 3.325 g/dayn the group with no calcification.80 Anotherross-sectional study evaluating risks for signifi-ant vascular calcification assessed by ultra-ound found, by multivariate analysis, that thealcium load from phosphate binders was greatern those with calcification compared to thoseithout calcification.84 There was a progressive

ncrease from 1.35 � 1.10 g/day of elementalalcium in patients with no calcification by ultra-ound, to 1.50 � 0.81 g/day in those with aalcification score of 2, and 2.18 � 0.93 in thoseith a calcification score of 4 (P � 0.001 byNOVA).84 Lastly, a prospective, randomized,

ontrolled trial compared sevelamer HCl to cal-ium-based phosphate binders in 202 dialysisatients. The study compared the effect on serumhosphorus, calcium, CaXP, cholesterol and LDLevels, and aortic and coronary artery calcifica-ion evaluated by EBCT. Sevelamer and calcium-ased phosphate binders achieved control of se-um phosphorus levels similar to theecommended K/DOQI levels; calcium-phospho-us product was slightly higher in the calcium-reated group. There were more hypercalcemicpisodes and more suppression of PTH in thealcium-treated group. Blood levels of choles-erol and LDL were significantly lower in theevelamer-treated group. In the 80% of patientsith calcification at baseline, there was signifi-

ant progression in aortic and coronary arteryalcification in the calcium-treated group, but norogression in the sevelamer-treated group. Inhe calcium arm, the average dose of calciumcetate was 4.6 g/day (1,183 mg elemental cal-ium per day). The average dose of calciumarbonate was 3.9 g (1,560 mg elemental cal-ium). It should be cautioned that the observedesults could be due to calcium load or loweringDL cholesterol. However, taken together, thesetudies support the conclusion that calcium in-ake from phosphate binders should be limited inKD patients on dialysis (Stage 5) to under,500 mg/day, and possibly lower.The total calcium intake from diet, calcium-

ontaining phosphate binders, and dialysate ide-

aadcdocpilwaBWcbsTtiabddi

it

eaapi

pwaatnwd

peracpfid


lly should be equal to the recommended dailydequate intake (AI) for adults (1,000-1,500 mg/ay). Given that the daily dietary intake of cal-ium for most dialysis patients is only 500 mgue to the restricted phosphorus diet, this leavesnly 500-1,000 mg elemental calcium from cal-ium-containing phosphate binders. However, theediatric Work Group recognizes the overwhelm-ng importance of controlling serum phosphorusevels, and recognizes the difficulty of doing soith calcium-containing phosphate binders while

dhering to this limited daily calcium intake.ased on this and the above data, the pediatricork Group recommends that the amount of

alcium provided by calcium-based phosphateinders and diet should not exceed 2X the age-pecific DRI (maximum to not exceed 2.5 g/day).his recommendation is not evidence-based and

hus the clinician must individualize therapy tak-ng into account cost, other vascular risk factors,nd the patient’s tolerance of calcium-containinginders. For further discussion of the issue ofaily calcium intake in CKD patients, see theiscussion in the section “Strength of Evidence”n Guideline 6.

For those patients who are on calcium-contain-ng phosphate binders in whom the total elemen-
al calcium intake, (including dietary sources) m
xceeds the upper limit recommended, the pedi-tric Work Group recommends consideration ofdding a non-calcium, non-metal-containinghosphate binder to decrease the total calciumntake.

CLINICAL APPLICATIONSThe best phosphate binders are those that the

atient will take consistently and as prescribedhile limiting total calcium intake. The ability to

dequately control serum phosphorus rests onppropriate education, patient compliance, andhe use of tolerable phosphate binders. The lattereeds to be individualized for patients and thusill require continuous monitoring with renalietitians.

RECOMMENDATIONS FOR RESEARCHLongitudinal studies are needed to evaluate

hosphate binders and their efficacy, side-ffects, and impact on morbidity and mortality. Aecently completed study in adults demonstratedn advantage of sevelamer HCl compared toalcium-based phosphate binders in preventingrogression of aortic and coronary arteries calci-cation. Further studies in both adults and chil-ren evaluating cardiovascular morbidity and
ortality in dialysis patients are needed.

7

7

7

7

7

A

GUIDELINE 7. SERUM CALCIUM AND
CALCIUM-PHOSPHORUS PRODUCT
7

slikicat2lcrtqgchlPncp

eam90

In CKD Patients Stages 2-4:

.1 The serum levels of corrected total cal-cium should be maintained within thenormal range for the laboratory used.(EVIDENCE)

In CKD Patients with Kidney Failure (Stage 5):

.2 Serum levels of corrected total calciumshould be maintained within the normalrange for the laboratory used (8.8-9.7mg/dL [2.20-2.37 mmol/L]), and prefer-ably toward the lower end. (OPINION)

.3 In the event that the corrected total serumcalcium level exceeds 10.2 mg/dL (2.54mmol/L), therapies that increase serumcalcium should be adjusted as follows:7.3.a In patients taking calcium-based

phosphate binders, the therapyshould be discontinued and the useof non-calcium, non-metal basedphosphate binders should be consid-ered. (OPINION) See Guideline 6.

7.3.b In patients taking active vitamin Dsterols, the therapy should be discon-tinued until the serum levels of cor-rected total calcium return to thetarget range (8.8-9.5 mg/dL [2.20-2.37 mmol/L]). (OPINION) SeeGuideline 8B.

7.3.c If hypercalcemia (serum levels of cor-rected total calcium >10.2 mg/dL[2.54 mmol/L]) persists despite discon-tinuation of therapy with vitamin Dand/or modification of calcium-basedphosphate binders, dialysis usinglower dialysate calcium may be usedfor 3-4 weeks. (OPINION) See Guide-line 10.

In CKD Patients Stages 3-5:

.4 The total dose of elemental calcium pro-vided by the calcium-based phosphatebinders should not exceed up to 2X DRIfor calcium based on age, (OPINION) andthe total intake of elemental calcium (in-cluding dietary calcium) should not ex-ceed 2,500 mg/day. (OPINION)

.5 The serum CaXP should be maintained at
<55 mg2/dL2 in adolescents >12 years, s

and <65 mg2/dL2 in younger children.(OPINION) This is best achieved by con-trolling serum levels of phosphorus withinthe target range. (OPINION) See Guide-lines 4-6.

.6 Patients whose serum levels of correctedtotal calcium are below the lower limit(<8.8 mg/dL [2.20 mmol/L]) should re-ceive therapy to increase serum calciumlevels:7.6.a Therapy for hypocalcemia should

include calcium salts such as cal-cium carbonate or calcium acetateorally, or calcium gluconate or cal-cium chloride parenterally (EVI-DENCE), and/or oral vitamin D ste-rols. (EVIDENCE) See Guideline 9.

BACKGROUNDMaintenance of normal calcium balance and

erum calcium levels depends on integrated regu-ation of calcium absorption and secretion by thentestinal tract, the excretion of calcium by theidney, and calcium release from and depositionnto bone. Parathyroid hormone increases serumalcium levels by stimulating bone resorptionnd kidney distal tubular calcium reabsorption inhe kidney, and activating renal hydroxylation of5(OH)D3 to 1,25(OH)2D3. Depression in serumevels of calcium by itself stimulates, through thealcium-sensing receptor (CaR) in the parathy-oid gland, the secretion of preformed PTH fromhe parathyroid gland within seconds. Subse-uently, PTH biosynthesis by the parathyroidland increases over 24-48 hours and, if hypocal-emia persists, is followed by parathyroid glandypertrophy and hyperplasia. Vitamin D metabo-ites and serum phosphorus levels also regulateTH levels in blood. These homeostatic mecha-isms are distorted in early stages of CKD andontinue to deteriorate as loss of kidney functionrogresses.During childhood and adolescence, total skel-

tal calcium increases from approximately 25 gt birth to 900 g and 1,200 g in adult females andales, respectively. Of the total body calcium,

9% is in the skeleton, 0.6% in soft tissues, and.1% in extracellular fluid.209 Normal values for
erum total calcium concentration according to
ber), 2005: pp S39-S47 S39

aads

tmcpFta1acaetrolc

tsdahof0cfca

r

wwsemcsttritbmgdac9sllrihivp

Cdfca

we

GUIDELINE 7: SERUM CALCIUM AND CALCIUM-PHOSPHORUS PRODUCTS40

ge are summarized in Table 6, Guideline 4. Indults, variations in serum levels of calciumepending on age and gender have been ob-erved.210

Calcium in blood exists in three distinct frac-ions: protein-bound calcium (40%), free (for-erly called ionized) calcium (48%), and cal-

ium complexed with various anions such ashosphate, lactate, citrate, and bicarbonate (12%).ree calcium can be measured using ion-selec-

ive electrodes in most hospitals and values indults range between 4.65-5.28 mg/dL (1.16-.32 mmol/L).211,212 Ionized calcium should bessessed if subtle changes are expected or totalalcium measurements are not adequate. Gener-lly, measurement of ionized calcium is morexpensive than total calcium measurement. Forhis reason, and because ionized calcium is notoutinely measured, this Guideline will be basedn the levels of total calcium in the blood. Theatter does reflect the measured levels of ionizedalcium if serum levels of protein are normal.

If serum levels of albumin are low, a correc-ion of the measured serum levels of calciumhould be made. Several formulas have beeneveloped to correct total calcium for abnormallbumin or to calculate ionized calcium both inealthy subjects and patients with CKD, but allf them are encumbered with limitations. Also, aall in pH of 0.1 unit will cause approximately a.1 mEq/L rise in the concentration of ionizedalcium, since hydrogen ion displaces calciumrom albumin, whereas alkalosis decreases freealcium by enhancing the binding of calcium tolbumin.210

There are no biochemical measurements thateflect calcium nutritional status in subjects

ith normal kidney function and in patientsith kidney disease. The major indirect mea-

ures of calcium nutritional adequacy are skel-tal health assessed by risk of fractures, boneass measurements, and desirable rates of

alcium retention in bone. Based on theseurrogate markers, the Dietary Reference In-ake (DRI) Committee213 recommended theerm “adequate intakes” (AIs) of calcium. Thisepresents an approximation of the calciumntake that, in the judgment of the DRI Commit-ee, is sufficient to maintain calcium nutritureased on observed or experimentally deter-ined estimates of average calcium intake by

roups of healthy people. The recommendedietary allowance (RDA), the term used forverage daily dietary intake level that is suffi-ient to meet the nutritional requirements of7%-98% of all healthy individuals in a life-tage and gender group, could not be estab-ished. At the same time, the tolerable upperevel for calcium intake was established; thisepresents the maximal intake of calcium thats likely to pose no risks of adverse effects inealthy individuals. The examples of adequatentake and upper intake levels of calcium inarious age groups of healthy subjects areresented in Table 10.The total daily intake of elemental calcium in

KD patients should not exceed 2,500 mg peray, including both dietary sources and calciumrom phosphate binders. Table 11 provides thealcium content of various commercially avail-ble calcium-based binders.

Adequate dietary intake of calcium in patientsith different stages of CKD is more difficult to

stimate than in healthy subjects, when one takes

iptscacicmmfdtp1cct

ttmwpati

p

ilbridSchS

tcit

hpscfrittlsib

GUIDELINE 7: SERUM CALCIUM AND CALCIUM-PHOSPHORUS PRODUCT S41

nto consideration the changes in calcium, phos-horus, vitamin D, PTH, and bone metabolismhat occur in CKD. Ideal dietary calcium intakehould provide enough calcium to maintain cal-ium balance as close as possible to that of thege- and gender-matched healthy population. Cal-ium balance (intake minus the sum of all losses)n the healthy population is positive throughouthildhood and adolescence. Calcium accrual isaximal during adolescence (�200 mg to �300g/day).213 Additionally, in CKD patients, the

raction of intestinal calcium absorption in theuodenum and jejunum is reduced141 becausehis process is vitamin D-dependent,214 and CKDatients have reduced blood levels of,25(OH)2D.215 However, passive intestinal cal-ium absorption, which is gradient-dependent,an be augmented by increasing calcium in-ake.214

Patients with CKD who are treated with me-abolites of vitamin D or calcium supplementa-ion are particularly prone to develop hypercalce-

ia. This complication occurs especially in thoseith low-turnover bone disease. The clinicalresentation of hypercalcemia varies from a mild,symptomatic, biochemical abnormality de-ected during routine screening to a life-threaten-ng emergency.216,217

Hypercalcemia, together with hyperphos-
hatemia, or individually, can be responsible for h
ncreased blood CaXP. Since serum phosphorusevels in patients with CKD are usually increasedy a higher factor compared to calcium, theelative importance of serum phosphorus levelsn generating higher CaXP (expressed in mg2/L2) is greater than the serum calcium levels.till, the serum calcium levels could be criti-al218 if the serum phosphorus levels are veryigh, which is indeed the case in patients withtage 5 CKD.In the presence of high CaXP in blood, soft-

issue calcification is likely but not always asso-iated with high CaXP, since many factors arenvolved in the genesis of soft-tissue calcifica-ion (see Table 6, Guideline 4).

Adequate dietary calcium intake during child-ood is necessary for the development of optimaleak bone mass.219 Infants on breast milk ortandard formulas should meet the DRI with theonsumption of adequate volumes of breast milk/ormula. For younger children (2-8 years of age),eaching the recommended levels of adequatentake of calcium is more feasible than in the 9-o 18-year-old range due to their greater accep-ance of high-calcium foods in the diet. Theargest source of dietary calcium for most per-ons is milk and other dairy products.220 Meanntakes in the 9- to 18-year-old age group areetween 700-1,000 mg/day, with values at the
igher end of this range occurring in males.219

rSaecltbapartsc

esppcwocpcae

eaphh

fftactCpt

cmwScecbaeltk

apcraot

pt


An intake of 100% of the DRI for calcium is aeasonable starting point for children with CKDtages 1-4. The challenge is to ensure that it ischieved. Infants with CKD may not get ad-quate amounts of calcium if breast milk isontraindicated, if low-electrolyte infant formu-as are required, or if fluids are restricted. Inhese situations, calcium supplementation maye required. Since many high-phosphorus foodsre also high in calcium, restricting dietary phos-horus will inadvertently restrict dietary calciums well. Therefore, it is beneficial to avoid over-estriction of phosphorus or the premature initia-ion of a phosphorus-restricted diet in the earlytages of CKD, in order to maximize dietaryalcium intake.

If the patient’s serum phosphorus and di-tary phosphorus intake is elevated, the neces-ary dietary calcium intake can be accom-lished with the incorporation of low-hosphorus, high-calcium foods220 (Table 12),alcium-fortified foods, and supplementationith oral calcium221-223 (Table 13). However,ne should note that the food items in Table 12haracteristically do not make up a substantialart of a child’s diet and may, in fact, beontraindicated as kidney function worsensnd dietary potassium restriction becomes nec-ssary.

The bioavailability of calcium from veg-tables is generally high. An exception is spin-ch, which is high in oxalate, making the accom-anying calcium virtually unavailable. Someigh-phytate foods, such as bran cereal, also mayave poor bioavailability of calcium.224-226

Several products have been introduced that areortified with calcium.220 These products rangerom juices to breakfast foods, and it is probablehat additional products will soon become avail-ble. Limited studies of the bioavailability ofalcium when added to these products suggesthat it is at least comparable to that of milk.222

alcium-fortified products may be considered aractical approach to increasing the calcium in-ake in children/adolescents with CKD.

As noted above, supplementation should beonsidered if the dietary intake alone does noteet or exceed the DRI, which is often the caseith progression of the kidney function throughtages 2-4. Calcium supplementation, whether aombination of calcium and gluconate (9% el-mental calcium), lactate (13% elemental cal-ium), acetate (25% elemental calcium), or car-onate (40% elemental calcium), is well toleratednd is not toxic if used at dosages that do notxceed the DRI. Calcium carbonate—in particu-ar—is inexpensive, tasteless, and relatively wellolerated by children of all ages with impairedidney function.In contrast, calcium chloride should be avoided

s a supplement in uremic patients due to theossible development of metabolic acidosis. Cal-ium citrate should not be given to patientseceiving aluminum salts since citrate augmentsluminum absorption, increases the body burdenf aluminum, and increases the risk of aluminumoxicity.203

When calcium salts are prescribed for theurpose of binding phosphorus in the intestine,hey are more effective if given with meals. On

tos

ochmdctibfipeaekw

nsHttAnd

rqsechddbnt

brptt3(psAsIett


he other hand, to ensure the optimal absorptionf calcium when it is used as a supplement, ithould be taken between meals.107,141,223

It is noteworthy that the dietary calcium intakef children and adolescents on dialysis whoonsume a phosphorus-restricted diet generallyas a serious calcium deficit; typically, the esti-ated dietary calcium intake is �500 mg per

ay. Calcium-containing phosphate binders be-ome the primary source of elemental calcium inhe diet. At the same time, limiting the calciumntake from binders and dialysate solutions maye necessary in order to prevent soft-tissue calci-cations as a potential consequence of long-termositive calcium balance. One must note, how-ver, that it is impossible to accurately assess thectual absorption of calcium derived from bind-rs, which is in large part dependent upon theind and amount of food present in the stomachith the binder.

RATIONALEIt is important that patients with CKD have

ormal serum levels of corrected total calcium,ince chronic lower levels of calcium cause 2°PT, have adverse effects on bone mineraliza-

ion, and may be associated with increased mor-ality. Therefore, hypocalcemia should be treated.lso, adequate calcium intake in CKD patients iseeded to prevent negative calcium balance. Since
ietary intake of calcium in CKD patients is i
estricted, calcium supplementation may be re-uired. At the same time, high calcium intakehould be avoided since patients with CKD mayncounter difficulties in buffering increased cal-ium loads, and such difficulty may result inypercalcemia and/or soft-tissue calcification. In-eed, hypercalcemia is a frequent occurrenceuring therapy with calcium-based phosphateinders and/or active vitamin D sterols. Sponta-eous hypercalcemia also occurs in CKD pa-ients.

STRENGTH OF EVIDENCE

It is accepted that total calcium levels need toe adjusted for the level of albumin to bettereflect the ionized calcium.210 The Evidence Re-ort of these Guidelines cites two major studieshat evaluated various formulas for correction ofotal calcium for albumin in 82 hemodialysis and4 continuous ambulatory peritoneal dialysisCAPD) patients.227,228 One of these studies usedreferable statistical methods and also employedtrict control of blood drawing and handling.227

lbumin was assayed by an automated bromocre-ol green method (BCG), total calcium by arenazoII binding, and ionized calcium by ion-selectivelectrode. Therefore, the equation derived fromhis study most closely approximates correctedotal calcium in patients with CKD with an
nterclass correlation value of 0.84:

C

ecFcwiict

C

(aalrttdslhu

(tnsedCplmtfbaTtCt

rg

tfclttbanatncclpmcnldci

Rmdmmm

mmtmhais

catokaI


orrected calcium (mg/dL)� Total calcium (mg/dL) � 0.0704

� [34 � Serum albumin (g/L)]

The use of different methods for measuringither albumin or calcium may yield differentorrelations from the one derived from this study.or the routine clinical interpretation of serumalcium needed for appropriate care of patientsith kidney diseases, a simple formula for adjust-

ng total serum calcium concentration for changesn serum albumin concentration can be used bylinicians.210 This formula yields similar resultso that described above:

orrected total calcium (mg/dL)� Total calcium (mg/dL) � 0.8

� [4 � Serum albumin (g/dL)]

Patients with GFR �60 mL/min/1.73 m2

Stage 3 CKD) usually, but not invariably, showdetectable decrease in the blood levels of total

nd ionized calcium.229,230 The serum calciumevels decrease further as kidney function deterio-ates. In advanced stages of CKD, the fraction ofotal calcium bound to complexes is increased231;hus, free (ionized) calcium levels are decreasedespite normal total serum calcium levels. Acido-is, on the other hand, may increase the serumevels of free calcium. With initiation of regularemodialysis, the levels of serum total calciumsually normalize.Hypocalcemia as a risk factor for outcomes

such as increased mortality, incidence of frac-ures and bone disease, and quality of life) wasot adequately addressed in reported clinicaltudies. A few studies of adults published in thearly 1970s suggest that hypocalcemia may haveetrimental consequences for patients withKD.142,146,147,232-234 In one cohort study, 433atients beginning dialysis therapy were fol-owed prospectively for an average of 41onths.235 In 281 of the patients, the level of

otal calcium was �8.8 mg/dL. After adjustingor comorbid conditions, serum albumin andlood hemoglobin, chronic hypocalcemia wasssociated with increased mortality (P �0.006).his association was similar among patients

reated with hemodialysis or peritoneal dialysis.ovariant analysis showed that hypocalcemia in

hese patients was associated with de novo and a

ecurrent cardiac ischemic heart disease and con-estive heart failure.A positive relationship has been found be-

ween serum calcium level, mineralization sur-ace, and osteoid surface.147 A statistically signifi-ant relationship between the serum calciumevel and the percentage of metacarpal cortical/otal bone area was found by X-ray.146 However,his was not the case when the cortical area ofone in the patients was calculated as a percent-ge of cortical area of bone in subjects withormal kidney function.142 Serum levels of totallkaline phosphatase activity, used as a marker ofhe severity of 2° HPT in patients with CKD, didot correlate with the serum levels of cal-ium.142,146,147,232-234 Despite a moderate signifi-ant inverse correlation between serum calciumevels and serum PTH levels,232,233 it was notossible to calculate the relative risk for develop-ent of 2° HPT for particular levels of serum

alcium. Some of the more recent studies236 didot find a relationship between elevated serumevels of PTH observed in CKD patients withifferent levels of GFR and the levels of serumalcium, which were within the normal rangendependent of the stage of kidney disease.

Taken together, the results of the Evidenceeport for this Guideline indicate that hypocalce-ia is a risk factor for bone disease and for

evelopment of 2° HPT and/or increased risk ofortality. Thus, the detection of true hypocalce-ia and its appropriate treatment is important foranagement of patients with CKD.There are no data suggesting that transientild hypercalcemia has detrimental effects onorbidity in patients with CKD. In one study,

here was no evidence that isolated hypercalce-ia is associated with increased morbidity in the

emodialysis population.85 Hypercalcemia posesrisk for CKD patients as it increases the CaXP

n blood. Severe hypercalcemia with clinicalymptoms must be treated appropriately.

Net calcium absorption is reduced in CRF as aonsequence of both decreased calcium intakend decreased fraction of calcium absorbed byhe intestine. The fraction of intestinal absorptionf calcium is decreased early in the course ofidney disease. This is observed in Stage 3 CKDnd worsens as CKD progresses.107,141,237-239

nitiation of dialysis does not improve calcium
bsorption.107,238,239 It is common to observe

stdtea

CCtarGdtcad

fihcidvwG(at

idi

vnaCt3m(Wcmd

s4csditC(d

uaoovlttocB


ignificant variability in intestinal calcium absorp-ion within a group of patients with the sameegree of kidney dysfunction,107,141,237-239 and,herefore, population studies may not be ad-quate to address the status of intestinal calciumbsorption in individual patients.

Dietary calcium intake is low in patients withKD. Intake of calcium in adults with advancedKD ranged between 300-700 mg/day107,240; in

hose treated with hemodialysis, calcium intakeveraged 549 mg/day241; and it was 80% of theecommended daily allowance in children withFR between 20-75 mL/min/1.73 m2.242 Whenietary calcium intake was �20 mg/kg/day, pa-ients with CKD had negative net intestinal cal-ium balance, but neutral calcium balance waschievable with calcium intake around 30 mg/kg/ay.243

There are no data on calcium retention as aunction of increased long-term calcium intaken patients with CKD. In data calculated forealthy adolescents, young adults, and adult men,alcium retention reached a plateau despite anncrease in calcium intake from 1,000-2,500 mg/ay.214 Thus, we are poorly equipped to establishalues for adequate intake of calcium in patientsith kidney disease. The opinion of the Workroup is that an intake of 2X age-specific DRI

maximum 2,500 mg/day) of calcium (dietarynd supplements) is appropriate for CKD pa-ients.

While this recommendation of the Work Groups not based on evidence provided in the Evi-ence Report, there are data from different stud-es identifying the requirement of calcium for

arious components of calcium balance (intesti-al calcium absorption and calcium secretion)nd calcium losses (urinary, fecal, and sweat) inKD patients (Table 14). These data show that

he requirement of daily calcium intake in StageCKD is 1.5X to 2X age-specific DRI (maxi-um 2,500 mg/day) and in Stages 4 and 5 CKD

patients not on dialysis), it is 1.5-1.8 g/day. Theork Group’s recommendation of total daily

alcium intake of 2X age-specific DRI (maxi-um 2,500 mg/day) is in agreement with these

ata.Furthermore, in dialysis patients, calcium

upplementation of 3.0 g/day in addition to the00-500 mg in dietary calcium resulted in hyper-alcemia in up to 36% of patients.244 Othertudies show lower, but still significant, inci-ences of hypercalcemia during high calciumntake.171,245 This clearly suggests that there is aolerable upper intake level for patients withKD and, therefore, higher daily calcium intake

�2X age-specific DRI [maximum 2500 mg/ay]) should be avoided.The effectiveness of different calcium salts

sed for calcium supplementation was partiallyddressed by four studies.21,205,246,247 Only onef these studies247 directly compared the efficacyf two different calcium salts (calcium carbonateersus calcium citrate). However, this study fol-owed the patients for only 3 hours after adminis-ration of the calcium supplements, and thereforehe results represent only short-term effects. Thether three studies compared the use of calciumarbonate to placebo or no calcium supplement.ecause of the different study conditions and

pdiTcib

pafFwo

saCcdpmpcib

tst1adrsiw

acoth2wAwcica

hntrsppicarc

robqmc“cep

iefsfmdasTts1p4luSDscpnav


atient populations, and because these studiesid not directly address the question being asked,t was not useful to conduct a meta-analysis.herefore, the recommendation for the use ofalcium carbonate for calcium supplementationn this Guideline is opinion-based and endorsedy the Work Group.Similarly, the four studies cited above did not

rovide information that could be utilized toscertain whether giving the calcium salts be-ore, during, or after meals is more effective.urther, the data are not helpful in decidinghether it is better to give the calcium salts inne dose per day or divided into multiple doses.The question as to when to initiate calcium

upplementation during the course of CKD is notnswered by the available data in the literature.ertainly, in the presence of overt hypocalcemia,alcium supplementation is indicated. However,etermining when to initiate calcium therapy inatients with CKD involves a consideration ofulti-dimensional biological parameters on the

art of the clinician. It seems, however, thatalcium supplementation should be consideredn CKD patients when serum levels of PTHegin to rise.In adults, an association was observed be-

ween CaXP and the risk of death in a randomample of the U.S. population of 2,669 patientsreated for at least 1 year with hemodialysis from990-1993.85 Patients with CaXP �72 (20% ofll patients) had a 34% higher relative risk ofeath compared to patients with CaXP in theange of 42-52.85 The increased risk was ob-erved in proportion to the elevation of CaXP;ndeed, for every increase of 10 in CaXP, thereas an 11% increase in relative risk of death.The Evidence Report cites four studies that

ddress the issue of CaXP as a risk for soft-tissuealcification. One prospective, uncontrolled studyf 137 patients showed that 35 patients ages 55o 64, with poorly controlled CaXP (above 60)ad increased aortic calcification index (ACI �6.1) as compared to 20 patients of the same ageith well-controlled CaXP �60 (ACI � 17.7).79

nother prospective, controlled study using step-ise discrimination analysis showed signifi-

antly higher risk for mitral annular calcificationn hemodialysis patients with CaXP of 63 �13ompared to those with CaXP of 56 �13.248 An
dditional study showed that, in young adults on fi
emodialysis who had CaXP of 65 �10.6, coro-ary artery calcification was significantly higherhan in those with CaXP of 56 �12.7.80 Oneetrospective, controlled study in CAPD patientshowed no significant differences in CaXP in 17atients with mitral annular calcification as com-ared to 118 patients without this abnormal-ty.249 Despite the fact that these studies were notontrolled for potential confounding variablesnd are encumbered with selection bias, it seemseasonable to conclude that high levels of CaXPan pose a risk of vascular calcification.

The level of CaXP in CKD patients at whichisk for calcification is very low or unlikely toccur, has been debated over the last 40 years,ut no strong evidence is available to answer thisuestion. As discussed above, CaXP levels areost likely a risk for calcification, but assessing

alcification risk does not involve arriving atyes” or “no” answers. The theory is that calcifi-ation risk increases as CaXP increases; how-ver, evidence on this relationship is scant and isresented below.Studies in adults and children80,93,248-253 exam-

ned the calcium phosphorus product as a risk forxtraskeletal calcification. None examined riskor future calcification. All were cross-sectionaltudies. Four were retrospective249,251-253 andour prospective.80,93,248,250 They used differentethods (radiography, scintigraphy, CT, echocar-

iography) for detection of calcification and ex-mined different organs for calcification (e.g.,oft tissue, mitral and aortic valve, aorta, lung).wo studies249,252 provided enough information

o calculate risk ratios for CaXP for inducingoft-tissue calcification. One study249 included35 Stage 5 CKD predialysis patients and 76atients on CAPD, and the other252 reported on7 patients for more than 2 years on CAPD. Thisimited information suggests that CaXP may be aseful indicator of calcification in patients withtage 5 CKD, as no trend for risk was seen.249

ata on patients treated with CAPD for 2 yearshowed that the risk for mitral calcification in-reased as CaXP increased.252 In contrast, inatients treated with CAPD for 1 year, there waso relationship between the risk for calcificationnd the levels of CaXP.249 The confidence inter-als in this small study are very wide, and thus
rm conclusions cannot be reached. Neither of

tu

wptno

sCwcrt5nc

cdcemfCb

nl

oiTicicsut

cbrtcws

g


hese studies examined whether CaXP can besed as a predictor of future calcification.Two case-controlled studies indicated that there

ere significant differences in CaXP betweenatients with and without aortic valve calcifica-ion and mitral annular calcification,248,251 andormal and abnormal visceral uptake of 99Tc-PPr 99Tc-MDP.250

The incidence of visceral calcification in aelected dialysis population was high when meanaXP exceeded 68 and low when mean CaXPas 51.250 Frequent incidence of visceral calcifi-

ation248 and mitral valve calcification251 waseported when CaXP exceeded 60 and calcifica-ion was unlikely when mean CaXP was around0.250,251 It must be noted that a significantumber of patients did not develop extraskeletalalcification despite a high CaXP.80,250,251

Thus, the available evidence is limited, butonvincing, that primary outcome (increasedeath rate) and secondary outcome (extraskeletalalcification) are related to CaXP. If this valuexceeds 55, there is increased risk for develop-ent of calcification and possibly increased risk

or lower patient survival. Thus, the goal level ofaXP should be below 55 in adolescents, and
elow 65 in infants and children, due to the c
ormal higher serum phosphorus level in theatter groups.

LIMITATIONSThere are no evidence-based studies in adults

r children to define an upper limit of calciumntake to help prevent metastatic calcifications.here are no prospective studies that address

maging modalities to detect extraskeletal calcifi-ation in children. There are no prospective stud-es that address the risk factors for vascularalcifications in childhood years. There are notudies in children with vascular calcifications tonderstand how the lesions may be best treatedo promote regression.

RECOMMENDATIONS FOR RESEARCHCalcium needs of infants, children, and adoles-

ents in Stages 1-5 of CKD should be determinedy prospective, longitudinal studies. Factors thategulate the percentage of calcium absorption inhe gastrointestinal tract with the use of calcium-ontaining binders in patients of different agesith CKD and receiving either peritoneal dialy-

is or hemodialysis should be determined.Longitudinal studies of patient morbidity (e.g.,

rowth, vascular calcifications) as a function of
alcium intake should be determined.

8

8

8

S

GUIDELINE 8. PREVENTION AND TREATMENT OF VITAMIND INSUFFICIENCY AND VITAMIN D DEFICIENCY

IN CKD PATIENTS

8

1baB�Pcmv6“

In CKD Stages 2-4:

.1 If serum PTH is above the target rangefor the stage of CKD (Table 3, Guideline1) serum 25-hydroxyvitamin D should bemeasured. (EVIDENCE) Periodic assess-ment is warranted thereafter if dietary orlifestyle changes have occurred in thepatient. (OPINION)

.2 If the serum level of 25-hydroxyvitamin Dis <30 ng/mL, supplementation with vita-min D2 (ergocalciferol) should be initiated(see Table 15). (OPINION)

.3 Following initiation of vitamin D supple-mentation:8.3.a The use of ergocalciferol therapy

should be integrated with the serumcalcium and phosphorus levels (Al-gorithm 1).

8.3.b The serum levels of corrected totalcalcium and phosphorus should bemeasured after 1 month, and thenat least every 3 months. (OPINION)

8.3.c If the serum levels of corrected totalcalcium exceed 10.2 mg/dL (2.54mmol/L), discontinue ergocalciferoltherapy and all forms of vitamin Dtherapy. (OPINION)

8.3.d If the serum phosphorus exceedsthe upper limits for age, initiatedietary phosphate restriction (seeGuidelines 4 and 5) or, if hyperphos-phatemia persists but the 25(OH)Dis <30 ng/mL, initiate oral phos-phate binder therapy. If the


25(OH)D is normal, discontinue vi-tamin D therapy. (OPINION)

8.3.e Once patients are replete with vita-min D, continued supplementationwith a vitamin D-containing multivi-tamin preparation should be usedwith annual reassessment of serumlevels of 25(OH)D, as should thecontinued assessment of correctedtotal calcium and phosphorus perstage of CKD (see Table 15).(OPINION)

In CKD Stage 5:

.4 Therapy with an active vitamin D sterol(calcitriol) should be provided if the se-rum levels of PTH are >300 pg/mL.(OPINION) See Guideline 9.

BACKGROUNDSerum levels of 25(OH)D (not the levels of

,25-dihydroxyvitamin D) are the measure ofody stores of vitamin D. Recent studies indolescents with normal kidney function inoston have associated levels of 25(OH)D25 ng/mL with considerable elevations of

TH. Levels of 25(OH)D are lower in younghildren with fractures, compared to an age-atched population without fractures. In indi-

iduals with normal kidney function over age0, levels of 25-hydroxyvitamin D below thenormal” limit of 15 ng/mL, and also low to


naaowapcd

pat(tla2

GUIDELINE 8: PREVENTION AND TREATMENT OF VITAMIN D INSUFFICIENCY AND VITAMIN D DEFICIENCY S49

ormal levels of 16-32 ng/mL, are both associ-ted with increased PTH levels, reduced BMD,nd increased rates of hip fracture. Such levelsf reduced 25(OH)D are common in patientsith CKD and GFR of 20-60 mL/min/1.73 m2,

nd in CKD patients undergoing dialysis. Therevention and treatment of vitamin D insuffi-iency in patients with CKD Stages 2-4 re-

Algorithm 1. Vitamin D Sup

uces the frequency and severity of 2° HPT. In o

atients with more advanced CKD (Stage 5)nd in dialysis patients, it is not establishedhat nutritional “replacement” with vitamin Dergocalciferol or cholecalciferol) will be effec-ive since the ability to generate adequateevels of 1,25(OH)2D3 is markedly reduced orbsent. The role of reduced or absent levels of5(OH)D remains controversial in the patient

ntation in CKD (Stages 2-4)
pleme
n recovery maintenance dialysis.

f[wactaanctwmnhaoudts

Cnva24atpmoaannaptw27Ll0t2

e2UGainrlcvltttovcwdtow

dlna(olnlctiiw

lraimCbDdl

GUIDELINE 8: PREVENTION AND TREATMENT OF VITAMIN D INSUFFICIENCY AND VITAMIN D DEFICIENCYS50

RATIONALE

A reduction of serum 25(OH)D, the substrateor the kidney’s generation of calcitriol1,25(OH)2D3], produces 2° HPT in individualsith normal kidney function,254-256 and may

ggravate 2° HPT in those with CKD and de-reased kidney function.257,258 Severe manifesta-ions of vitamin D deficiency, with osteomalaciand hypocalcemia, is rare unless 25(OH)D levelsre �5 ng/mL (12 nmol/L); however, levels �30g/mL are indications of vitamin D “insuffi-iency”259 as manifested by significant eleva-ions of serum levels of PTH.259,260 Individualsith normal kidney function and with low “nor-al” 25(OH)D levels of 16-32 ng/mL (40-80

mol/L) have lower BMD256; also, patients withip fractures have lower 25(OH)D levels thange-matched patients without hip fracture.261 Thenly real disagreement in the literature is thepper range of 25(OH)D levels at which oneoes not encounter significant numbers of pa-ients with 2° HPT,259 indicating that 25(OH)Dhould be maintained at higher levels.

Studies of 25(OH)D levels in patients withKD and varying degrees of decreased kid-ey function from five reports were re-iewed.117,236,262,263 Among 63 non-nephroticdult CKD patients, the median values of5(OH)D levels in those with GFR of 60-90,0-60, and 20-40 mL/min/1.73 m2 were 12, 19,nd 18 ng/mL (30, 47, and 45 nmol/L), respec-ively.236 Obviously, a high fraction of theseatients had levels �30 ng/mL (75 nmol/L) andany were �16 ng/mL (40 nmol/L). In a report

f 76 CKD patients, 37 had CKD due to diabetesnd 39 from other causes.117 The 25(OH)D levelveraged 22.3 � 9.4 ng/mL (56 � 23 nmol/L) inondiabetics and 11.4 � 5.6 ng/mL (28 � 14mol/L) in diabetic patients; in diabetics, serumlbumin levels were lower and 76% had urinaryrotein concentrations �300 mg/dL, comparedo 23% of nondiabetics.117 For the total groupith GFR of 20-50 mL/min/1.73 m2, 47% had5(OH)D levels � 16 ng/mL (40 nmol/L) and6% had 25(OH)D levels �26ng/mL (65 nmol/). In these two studies,117,236 serum 1,25(OH)2D

evels correlated with 25(OH)D levels [r �.51236 and r � 0.47117], and P � 0.001. In thehird study of the 19 CKD patients with GFR of
0-90 mL/min/1.73 m2, 79% had 25(OH)D lev- o
ls �26 ng/mL (65 nmol/L) and 18% had5(OH)D levels �16 pg/mL (0.4 nmol/L). In a.S. study that included nine CKD patients withFR of 12-60 mL/min/1.73 m2, 25(OH)D levels

veraged 20 � 6 ng/mL (50 � 15 nmol/L)ndicating that values were �30 ng/mL (75mol/L) in the majority of patients. Over a wideange of GFR, from 11-111 mL/min/1.73 m2, aarge percentage were frankly vitamin D-defi-ient. Of those in CKD Stages 1-4, 86% hadalues �30 ng/mL. The findings that 1,25(OH)2Devels correlated with 25(OH)D levels in thehree largest series117,236 differ from observa-ions in the population with normal kidney func-ion, where 1,25(OH)2D levels are not dependentn the 25(OH)D levels, even in patients withitamin D deficiency.264 The normal, highly effi-ient production of 1,25(OH)2D by the kidneyshen the supply of 25(OH)D is markedly re-uced is altered in CKD, and the data indicatehat 1,25(OH)2D levels may be more dependentn the availability of 25(OH)D in CKD patientsith impaired kidney function.265,266

Patients with CKD or those who are dialysis-ependent are much more likely to have lowevels of 25(OH)D in comparison to those witho kidney disease for several reasons: (a) manyre inactive with reduced exposure to sunlight;b) the ingestion of foods that are natural sourcesf vitamin D (fish, cream, milk, and butter) isikely to be lower than in the population withormal kidney function; and (c) serum 25(OH)Devels may be subnormal in CKD patients be-ause the endogenous synthesis of vitamin D3 inhe skin following identical exposure to sunlights reduced in those with reduced GFR,267 inndividuals over age 60,268 and in individualsith increased melanin content of the skin.269

The ingestion of a diet low in calcium contenteads to greater conversion of 25(OH)D to calcit-iol and the need for more vitamin D intakend/or production,270 and dietary calcium intakes frequently low in CKD patients.107 Further-ore, there is increased need for vitamin D inKD patients with nephrotic-range proteinuria,ecause urinary losses of 25(OH)D and vitamin-binding protein (DBP) are high.262,271 Kidneyisease was found to be a major risk factor forow serum 25(OH)D levels in a population study
f patients hospitalized in New England (with

ps

fotvpiaaUn

lrtklaCvtdar

mcbeebDtpv48D

aalivmatSg

moptovephtDlve[epa

i�imhoaaacs8c4twceltgdvmloioi

GUIDELINE 8: PREVENTION AND TREATMENT OF VITAMIN D INSUFFICIENCY AND VITAMIN D DEFICIENCY S51

atients on dialysis excluded from the analy-is).260

In countries such as the U.S. where manyoods are supplemented with vitamin D, and inthers such as Japan and the Scandinavian coun-ries where fish intake is high, the incidence ofitamin D insufficiency is lower than in Euro-ean countries of similar latitudes but where fishntake is low and vitamin D-supplemented foodsre unavailable.259 Nonetheless, 14%-42% ofpparently healthy individuals over age 60 in the.S. had serum levels of 25(OH)D �24-25g/mL (60 or 62 nmol/L).272,273

In patients with Stage 5 CKD, there may beess need for vitamin D as a substrate for theenal 25-hydroxyvitamin D-1-� hydroxylase, ashere is little or no generation of calcitriol by theidneys. However, the data show that 25(OH)Devels below 15 ng/mL (37 nmol/L) are associ-ted with a greater severity of 2° HPT even inKD patients on dialysis.274 Nonetheless, thealue of supplementation with ergocalciferol inhese patients is less certain; although in dialysis-ependent patients, including anephric individu-ls, high doses of ergocalciferol or 25(OH)D canaise the serum levels of calcitriol.275-277

In patients with CKD and GFR of 20-60L/min/1.73 m2, nutritional vitamin D defi-

iency and insufficiency can both be preventedy supplementation with vitamin D2 (ergocalcif-rol) or vitamin D3 (cholecalciferol). If there isvidence of true vitamin D deficiency, this shoulde treated; the best available treatment is vitamin2, although the doses needed are larger than

hose needed for vitamin D insufficiency. For therevention of vitamin D deficiency, the RDA foritamin D in children and adolescents remains at00 IU, while in older individuals �60 years it is00 IU. Little is known about the DRI of vitaminfor patients of any age with CKD.There are problems with the dosage forms

vailable. In the U.S., the only forms availablere tablets of 400 IU (over the counter), andiquid forms (8,000 IU/mL) or capsules contain-ng 50,000 IU, requiring a prescription. In indi-iduals with normal kidney function, the recom-ended upper limit of vitamin D is 2,000 IU/day

ccording to the Food and Nutrition Board, Na-ional Research Council, National Academy ofciences.278,279 This dose can be achieved by
iving one capsule (50,000 IU) once a d
onth.280,281 Dosage preparations of 10,000 IUf ergocalciferol have been given daily to Frenchatients with advanced CKD for periods longerhan 1 year, with no evidence of vitamin Dverload or renal toxicity.282,283 Ergocalciferolitamin D sterol may be safer than cholecalcif-rol,284,285 although there are no controlled com-arisons of cholecalciferol and ergocalciferol inumans, and the available commercial prepara-ions employ ergocalciferol (as Calciferol™ orrisdol™). Calcitriol or another 1�-hydroxy-

ated vitamin D sterol should not be used to treatitamin D deficiency. In CKD Stages 1-4, whenvidence of severe vitamin D deficiency is found,25(OH)D levels �5 ng/mL (12 nmol/L)], rick-ts in the growing child, or osteomalacia, may beresent. Treatment with ergocalciferol may beppropriate (see Table 15).281

STRENGTH OF EVIDENCEThere is strong evidence that vitamin D

nsufficiency, defined as 25(OH)D levels27-32 ng/mL (67-80 nmol/L), is common in

ndividuals �60 years in the U.S.,272,273 andany locations in Europe.286 Such low levels

ave clinical significance based on the findingf: a) the elevated serum levels of intact PTHs evidence of 2° HPT; and b) reduced BMD256

nd higher rates of hip fracture compared toge-matched controls.287 The clinical signifi-ance of this is further demonstrated by datahowing that supplementation with vitamin D,00 IU/day, along with a modest dietary cal-ium supplement reduced hip fracture rate by3% in a double-blinded, placebo-controlledrial.286,288 There have been reports in patientsith CKD that suggest there may be adverse

linical consequences of suboptimal serum lev-ls of 25(OH)D, including the finding thatevels �15 ng/mL pose a major risk factor forhe presence of severe 2° HPT (with radio-raphic abnormalities) in CKD patients onialysis,274 although the dialysis dose pro-ided to the patients in this study was subopti-al. A substantial prevalence of suboptimal

evels of 25(OH)D in CKD patients with GFRf 20-60 mL/min/1.73 m2 has been identifiedn every study of such patients, but the numberf individuals studied has been small. Regard-ng safety, the experience with ergocalciferol
oses of 10,000 IU/day282,283 indicates a rec-

ob

att(eewttdikl“s

dr2

tmdae1arSt

GUIDELINE 8: PREVENTION AND TREATMENT OF VITAMIN D INSUFFICIENCY AND VITAMIN D DEFICIENCYS52

mmended dose of 1,000-2,000 IU/day woulde safe.

LIMITATIONSIn patients with GFR �20 mL/min/1.73 m2

nd those requiring dialysis, there is no evidencehat modest supplementation with ergocalciferolo raise serum 25(OH)D levels to 30-60 pg/mL8.25-16.5 pmol/L) will increase the serum lev-ls of 1,25(OH)2D (calcitriol) or lower the el-vated serum levels of PTH. In CKD patientsith higher GFR, there is a strong probability

hat such treatment would have benefit, althoughhere are no data to support this view. One studyemonstrated that serum 1,25(OH)2D levels werencreased in patients with CKD and moderateidney failure following the administration of aow-calcium diet, indicating that there is somereserve” for the generation of 1,25(OH)2D in
uch patients.116 i

The treatment of vitamin D insufficiency oreficiency when present in CKD patients is war-anted, since such therapy may reduce or prevent° HPT in the early stages of CKD.

RECOMMENDATIONS FOR RESEARCH

Prospective, controlled clinical trials withhe daily administration of ergocalciferol in aonthly amount equivalent to 1,000-2,000 IU/

ay are clearly warranted in patients with CKDnd those undergoing dialysis, to assess theffects on serum PTH levels, serum,25(OH)2D levels, bone histomorphometry,nd fracture rates. With the higher fractureates known to occur in adult patients withtage 5 CKD,289 studies to evaluate measures

o minimize early 2° HPT would be warranted
n patients with CKD of all ages.

G2S

9

9

9

A

GUIDELINE 9. ACTIVE VITAMIN D THERAPY
IN CKD PATIENTS
9

This Guideline encompasses two parts:uideline 9A, which is specific for CKD Stages

-4, and Guideline 9B, which refers to CKDtage 5.

GUIDELINE 9A. ACTIVE VITAMIN DTHERAPY IN PATIENTS WITH CKD

STAGES 2-4

A.1 In patients with CKD Stages 2-4, therapywith an active oral vitamin D sterol(calcitriol) should be initiated when se-rum levels of 25(OH)D are >30 ng/mL(75 nmol/L), and serum levels of PTHare above the target range for the CKDstage (see Table 3, Guideline 1). (EVI-DENCE)9A.1.a An active vitamin D sterol should

be administered only in patientswith serum levels of correctedtotal calcium <10 mg/dL (2.37mmol/L) and serum levels ofphosphorus less than age-appro-priate upper limits (Table 16).(OPINION)

A.2 After initiation of active vitamin D ste-rols, serum levels of calcium and phos-phorus should be measured at leastmonthly for the first 3 months, and atleast every 3 months thereafter. SerumPTH levels should be measured at leastevery 3 months. (OPINION)

A.3 The dosage of active vitamin D sterolsshould be adjusted as follows:9A.3.a If serum levels of PTH decrease

to values below the target rangefor the CKD stage (Table 3,Guideline 1), active vitamin Dsterol therapy should be helduntil serum levels of PTH in-


crease to above the target range;treatment should then be re-sumed at half the previous doseof active vitamin D sterols. If thedosage is below a 0.25 �g cap-sule or 0.05 �g dose as liquid,alternate-day dosing should beused. (OPINION)

9A.3.b If serum levels of corrected totalcalcium exceed 10.2 mg/dL (2.37mmol/L), active vitamin D steroltherapy should be held until se-rum calcium decreases to <9.8mg/dL (2.37 mmol/L); treatmentshould then be resumed at halfthe previous dose. If the lowestdaily dose of the active vitamin Dsterol is being given, alternate-daydosing should be used. If the dos-age is below a 0.25 �g capsule or0.05 �g dose as liquid, alternate-day dosing should be used. (OPIN-ION) See algorithm 2.

9A.3.c The dosage of active vitamin Dsterols should be adjusted down-ward as follows: If serum levelsof phosphorus increase to greaterthan age-appropriate upper lim-its, active vitamin D therapyshould be held; the dose of phos-phate binders should be in-creased or initiated until the lev-els of serum phosphorus decreaseto age-appropriate levels; then,treatment at half the prior doseof active vitamin D sterol shouldbe resumed. (OPINION)

A.4 The dosage of active vitamin D sterolsshould be adjusted upward as follows:

ber), 2005: pp S53-S63 S53

t2asgh

GUIDELINE 9: ACTIVE VITAMIN D THERAPY IN CKD PATIENTSS54

If serum levels of PTH fail to decreaseby at least 30% after the initial 3months of therapy, and the serumlevels of calcium and phosphorus arewithin the target ranges based onCKD stage, the dose of active vitaminD sterols should be increased by 50%.Serum levels of PTH, calcium, andphosphorus must be measured monthly

Algorithm 2. Management of CKD Patie

for 3 months thereafter. e

BACKGROUND

In patients with CKD, 2° HPT occurs whenhe GFR declines to �75 mL/min/1.73 m2 (Stages-3). The administration of small doses of thective vitamin D sterol, calcitriol, can reduce theerum levels of PTH and may improve linearrowth. With the use of low dosages of calcitriol,yperparathyroidism can be suppressed without

tages 2-4) with Active Vitamin D Sterols
nts (S
vidence of worsening of kidney function; how-

ec

1ibpe1rermftsps

3�ocptBpt1bawwnsadwtgSnnsostC

sgCifiamsbiliceagcwSlmgmC

uptd0ttCtmdccaegtais

C

GUIDELINE 9: ACTIVE VITAMIN D THERAPY IN CKD PATIENTS S55

ver, careful monitoring of serum levels of cal-ium, phosphorus, and PTH is essential.

RATIONALEIn adult CKD patients with GFR �60 mL/min/

.73 m2 (Stage 3), serum levels of PTH arencreased.103,116,290,291 In such patients, boneiopsies show histomorphometric features of hy-erparathyroid bone disease despite only modestlevations of PTH.10,292-294 Serum levels of,25(OH)2D3 are either normal or in the lowerange of normal,103,116,290,291 despite the el-vated PTH levels and serum levels of phospho-us that are often in the low range of nor-al.74,100,230 Normal 1,25(OH)2D3 levels in the

ace of high levels of PTH are inappropriate andhus contribute to defective feedback suppres-ion by 1,25(OH)2D3 of prePTH synthesis in thearathyroid glands, with a resultant increasedecretion of PTH.295

In controlled trials in adult patients with StageCKD, the administration of oral calcitriol, 0.25g/day and occasionally up to 0.5 �g/daily,292,296

r of alfacalcidol, 0.25-0.5 �g daily10 were asso-iated with lowering of PTH levels,294,296 im-rovement of histological features of hyperpara-hyroid bone disease,292-294,297 or an increase ofMD.296 Preliminary evidence also suggests thatatients who had calcitriol therapy initiated whenhe creatinine clearance exceeded 30 mL/min/.73 m2 (0.50 nmol/L/min/1.73 m2) had normalone histology when they reached Stage 5 CKDnd received a kidney transplant, while thosehose treatment was started when kidney failureas more advanced were less likely to haveormal bone histology when they reached end-tage kidney disease.298 Calcitriol deficiency maylso contribute to growth retardation and boneisease in children with CKD. Indeed, treatmentith daily doses of calcitriol (1,25-dihydroxyvi-

amin D3), has been reported to improve linearrowth in small numbers of children with CKDtages 2-4.299 Such findings provide the ratio-ale for the routine administration of calcitriol toearly all children with CKD. However, in othertudies, enhanced growth velocity was not dem-nstrated on long-term follow-up and furthertudies have not shown that calcitriol consis-ently improves linear growth in children with
KD Stages 2-4.300 A more recent study demon- m
trated a direct relationship between changes inrowth velocity and PTH levels in children withKD Stages 2-3 treated with either daily or

ntermittent calcitriol therapy,301 similar to thendings reported in children with CKD Stage 5nd treated with peritoneal dialysis.302 Further-ore, more severe growth retardation was ob-

erved in those patients that developed adynamicone after treatment with calcitriol was givenntermittently, either orally or intraperitoneal-y.302 These results suggest that large doses ofntermittent calcitriol therapy in conjunction withalcium-containing binders adversely affectpiphyseal growth plate chondrocytes activity,nd thereby contribute to reduction in linearrowth. On the other hand, others have describedatch-up growth associated with PTH levelsithin the normal range in children with CKDtages 2-3 treated with calcium supplements and

ow doses of 1-�-calcidol.303 Although the opti-al PTH levels that are required to maximize

rowth remain to be defined, it may be prudent toaintain serum PTH according to the stage ofKD.There has been concern about the safety of the

se of vitamin D metabolites with regard to aossible adverse effect on kidney function. Withhe use of calcitriol in doses �0.25 �g/day andoses of alfacalcidol that were generally below.5 �g/day, the progressive loss of kidney func-ion did not differ from observations in placebo-reated or control patients.10,292,294,297,304 In allKD patients receiving vitamin D therapy, con-

inued surveillance is needed, and hypercalcemiaust be avoided. When calcitriol was given in

oses of �0.5 �g/day, reductions of creatininelearance were observed,305,306 although it is notertain that true GFR (inulin clearance) wasffected.306,307 In CKD patients with serum lev-ls of phosphorus greater than upper limits sug-ested by Guideline 4, dietary phosphorus restric-ion and/or phosphate binders should be employednd the serum phosphorus normalized beforenitiation of treatment with an active vitamin Dterol.

STRENGTH OF EVIDENCEEach of the placebo-controlled trials of adult

KD patients with GFR of 20-60 mL/min/1.73
2,10,292,297 and two studies without a placebo-

chtatpeotpitttmvabSashoo

wmpkedvwdsitfaa

fntaco

ht

utatarcth2

iaalncvmwtPcbplevowtaaPbpwbpr


ontrol group293,294 have shown evidence ofyperparathyroid bone disease in a high frac-ion of baseline “control” bone biopsies. Thesebnormalities were common in the CKD pa-ients recruited only on the basis of their im-aired kidney function (reduced GFR or el-vated serum creatinine levels) with the degreef elevation of pretreatment levels of PTHotally unknown.10,292,296,297 In each of thelacebo-controlled trials, there was either nomprovement or worsening10,292,297 of the fea-ures of hyperparathyroid bone disease in pa-ients assigned to placebo therapy. Followingreatment for 8, 12, or 24 months, an improve-ent of bone biopsy features was noted in the

itamin D-treated patients.10,292,293,297 Meta-nalysis could not be done for these studiesecause one reported their data as mean �D,293 one reported medians and ranges,10 andnother reported the fractions of patients whohowed improvement or worsening of variousistological features on bone biopsy.10 An-ther study was excluded because the numberf subjects was too small (n �10).297

The safety of calcitriol or alfacalcidol in CKDith moderately reduced kidney function is aatter of concern; however, the data from the

lacebo-controlled studies show no reduction ofidney function compared to placebo in patientsntered into these trials and using relatively lowoses.10,292,293,296,297 Should hypercalcemia de-elop during vitamin D treatment, particularlyith higher doses, transient or even long-lastingeterioration of kidney function has been ob-erved.308-310 With regard to the risk of produc-ng “adynamic bone,” the placebo-controlled trialhat included the largest number of bone biopsiesailed to show any increase in the appearance ofdynamic bone disease following treatment withlfacalcidol.10

LIMITATIONS

The available evidence in adults is obtainedrom short-term studies and on a relatively smallumber of patients. Also, no data are available onhe effect of the new vitamin D analogs, whichre noted to be less hypercalcemic. Data inhildren with CKD Stages 2-4 are not available
r very limited with respect to PTH and bone f
istology, or the effects of vitamin D sterolherapies.

CLINICAL APPLICATION

It appears that the active vitamin D sterols areseful in the treatment of 2° HPT and high-urnover bone disease in early stages of CKD indults. This provides a good therapeutic tool forhe prevention and management of these twobnormalities in CKD patients, before these de-angements advance and their treatment be-omes more difficult. Attention should be paid tohe beneficial effect on linear growth in reducingyperparathyroid bone disease in CKD Stages-4 as well.

RECOMMENDATIONS FOR RESEARCH

In children with CKD Stages 2-4, random-zed, placebo-controlled trials of the extentnd therapy of hyperparathyroid bone diseasere warranted. In adults, further trials withonger-term treatment (�24 months) in largerumbers of patients are needed to satisfy theoncern about the safety of the therapy withitamin D sterols. Trials with the newer vita-in D sterols, which may be less calcemic,ill be of great interest. An ideal goal of such

reatment would be to reduce serum levels ofTH with little or no change in serum levels ofalcium. Studies should evaluate the effect onone, in particular to ascertain whether im-rovement in bone mineral content or in histo-ogical features of hyperparathyroid bone dis-ase could be achieved. Comparisons of neweritamin D sterols with calcitriol, alfacalcidol,r even ergocalciferol, at 50,000 IU monthly,ould be ideal. It is apparent that the ideal

arget for serum levels of PTH that should bechieved are not established, and biopsy evalu-tions in such trials with correlations betweenTH or iPTH levels and skeletal findings woulde ideal. Also, in the trials that have beenublished,10,294 it would be useful if the dataere reanalyzed to evaluate the relationshipetween serum levels of PTH and the degree ofarathyroid bone disease found on biopsy inelation to the degree of impairment of kidney
unction.

9

9

9

9

9

9

rt(piHrrmpa


GUIDELINE 9B. ACTIVE VITAMIN DTHERAPY IN PATIENTS ON DIALYSIS

(CKD STAGE 5)

B.1 In patients with CKD Stage 5 and serumPTH levels >300 pg/mL, an active vita-min D sterol (calcitriol; see Table 17)should be administered to reduce theserum levels of PTH to a target range of200-300 pg/mL. (EVIDENCE)

B.2 The intermittent administration of calcit-riol by intravenous or oral routes ismore effective than daily oral calcitriolin lowering serum PTH levels. (EVI-DENCE)

B.3 When therapy with vitamin D sterols isinitiated or the dose is increased, serumlevels of calcium and phosphorus shouldbe measured at least every 2 weeks for 1month and then monthly thereafter. Theserum PTH level should be measuredmonthly for at least 3 months and thenat least every 3 months once target levelsof PTH are achieved. (OPINION)

B.4 For patients treated with peritoneal di-alysis, initial oral doses of calcitriol (0.5-1.0 �g) can be given three times weekly.Alternatively, an equivalent lower doseof calcitriol (0.25 �g) can be adminis-tered daily. (OPINION)

B.5 The dosage of active vitamin D sterolsshould be adjusted upward as follows: If

serum levels of PTH fail to decrease byat least 30% after the initial 3 months oftherapy, and the serum levels of calciumand phosphorus are within the targetranges based on CKD stage, increase thedose of active vitamin D sterols by 50%.Serum levels of PTH, calcium, and phos-phorus must be measured monthly for 3months thereafter.

B.6 Treatment with active vitamin D sterolsshould be integrated with the changes inserum calcium, phosphorus, and PTH.A separate algorithm is shown for eachof these three variables with suggestedinterventions based on the values ob-tained. (OPINION)

BACKGROUND

Patients with CKD who undergo dialysis haveeduced serum levels of 1,25(OH)2D3. This leadso reduced intestinal absorption of calciumthereby contributing to hypocalcemia) and im-aired suppression of the parathyroid gene thatnitiates the synthesis of PTH. The result is 2°PT that often progresses. Treatment with calcit-

iol or another active vitamin D sterol botheduces PTH secretion with resultant improve-ent of hyperparathyroid bone disease, and im-

roves musculoskeletal symptoms, when thesere present.

ipaassbFpmag

Snedbsmdtastmt

rcrtwetrvhs

tefsww

dstsaHn

ltmltsoclCwiPtdbatp

bttpaI

vclH�shobbP5ou(


A major side-effect of vitamin D treatment isncreased intestinal absorption of calcium andhosphorus; this can produce hypercalcemia andggravate hyperphosphatemia. Treatment withctive vitamin D sterols can also markedly lowererum levels of PTH and reduce bone formationtrikingly; this can produce a condition with lowone turnover, termed adynamic bone disease.or these reasons, serum levels of calcium, phos-horus, and PTH must be monitored during vita-in D therapy, and vitamin D therapy adjusted

ccordingly (Algorithm 3, Algorithm 4, and Al-orithm 5).

RATIONALETreatment of 2° HPT in patients with CKD

tage 5 by oral or intravenous calcitriol, intrave-ous paricalcitol, oral or intravenous doxercalcif-rol, or oral or intravenous alfacalcidol can re-uce the elevated levels of PTH,313-323 and maye useful to treat various clinical features ofymptomatic 2° HPT.313,315,318 With such treat-ent, improved features of hyperparathyroid bone

isease have been reported.314,315,324,325 Reduc-ions of both serum total alkaline phosphatasend/or bone-specific alkaline phosphatase, con-istent with a reduction of the elevated boneurnover state, have been shown during treat-ent with several of these vitamin D prepara-

ions.314-316,318,321,324,326

STRENGTH OF EVIDENCEAlthough daily calcitriol therapy has been

ecommended for more than two decades tohildren with chronic renal disease, 2° HPTemains the predominant bone lesion in childrenreated with dialysis.22,23 Indeed, when patientsith bone biopsy-proven high-turnover bone dis-

ase were followed for 1 year with calcitriolherapy given daily, bone lesions of hyperparathy-oid bone disease persisted or progressed in theast majority of the patients.311 Dosage regimensave generally ranged from 0.25-1.0 �g/day inuch patients undergoing peritoneal dialysis.311

Over the last decade, the 1st PTH-IMA provedo be a reasonably reliable predictor of the differ-nt subtypes of renal osteodystrophy and it per-ormed well in assessing the therapeutic re-ponse to active vitamin D sterols in patientsith renal failure.22,23,327 In dialyzed children
ho are either untreated or are receiving small s
aily oral doses of calcitriol, PTH levels (mea-ured by 1st PTH-IMA) of approximately threeimes the upper limit of normal generally corre-pond to normal BFRs. Levels �250-300 pg/mLre associated with bone biopsy evidence of 2°PT, while values �150 pg/mL indicate an ady-amic bone lesion.22

Similar values may not be applicable in dia-yzed children receiving intermittent calcitriolherapy, since suppression of bone formationay develop despite persistently elevated PTH

evels (measured by 1st PTH-IMA) in these pa-ients.312 In patients treated with peritoneal dialy-is, high-dose intermittent calcitriol therapy (bothral and intraperitoneal) results in marked de-line in BFRs and development of the adynamicesion in a substantial proportion of patients.312,328

orresponding reductions in serum PTH levelsere observed only in patients who received

ntraperitoneal doses of calcitriol, while serumTH levels remained persistently elevated in

hose given intermittent oral doses of calcitriol,espite significant reductions in BFRs on repeatiopsy.312 Thus, the relationship between PTHnd bone formation is disrupted during intermit-ent calcitriol therapy in children undergoingeritoneal dialysis.The disparity between the histological and

iochemical findings highlights the potential limi-ation of single PTH determinations to predicthe skeletal manifestations of renal osteodystro-hy, direct effects of calcitriol on osteoblasticctivity and/or limitations of the current 1st PTH-MA among the main potential factors.

In dialysis patients who have not receiveditamin D, or those who have received daily oralalcitriol in doses lower than 0.5 �g/day, serumevels of PTH correlate with the degree of 2°PT25,26,329; moreover, patients with PTH levels400 pg/mL (44.0 pmol/L) and normal (or low)

erum levels of calcium usually have only mildyperparathyroidism.26,329 In these patients, theptimal control of serum phosphorus levels, com-ined with the use of calcium-based phosphateinders, may result in no further rise of serumTH levels. When serum levels of PTH exceed00-600 pg/mL (55.0 to 66.0 pmol/L), moderater even severe hyperparathyroid bone disease issual. When PTH levels exceed 1,000 pg/mL110.0 pmol/L), larger doses of the vitamin D
terols are generally required.322,330-333 During

tdwtcpshlwsrt

tm

Dscpvettt


reatment with intravenous calcitriol330 or oraloxercalciferol322 in prospective trials, thereas evidence that larger doses are required for

he treatment of patients with severe 2° HPTompared to patients with less severe hyper-arathyroidism. Moreover, the suppression oferum levels of PTH in patients with severeyperparathyroidism may require treatment foronger periods of time, e.g., more than 12-24eeks.322,330-332 The reason for the delayed re-

ponse of some patients is unclear; it might beelated to upregulation of vitamin D receptors

Algorithm 3. Managing Vitamin D

hat are often reduced in the large nodular para- c

hyroid glands in CKD Stage 5 patients withore severe 2° HPT.334

It is recommended that the dosage of a vitaminsterol be adjusted in accordance with the

everity of 2° HPT. The evidence that PTH levelsorrelate with the severity of bone disease inatients who have not received pulse-dose intra-enous or oral calcitriol is quite good.25,26 How-ver, the optimal doses of vitamin D sterols andhe optimal serum levels of PTH that should behe target in patients who have received suchherapy for longer than 6-12 months is less

s Based on Serum Calcium Levels
Sterol
ertain.

tmcpiimdwmmrcntfTc

cwtmbispt(tnht1Iij

erols B


Several trials that were not placebo-con-rolled have shown the effectiveness of inter-ittent intravenous and intermittent oral cal-

itriol to suppress serum levels of PTH inatients undergoing hemodialysis,335,336 includ-ng some patients with severe hyperparathyroid-sm336-339; moreover, these results appeared

ore favorable than earlier experiences withaily oral dosing when reductions of dosageere commonly needed.340,341 However, theeta-analysis of four trials that compared inter-ittent intravenous calcitriol with oral calcit-

iol in randomized, controlled studies342,343 orrossover trials344,345 indicated that intrave-ous therapy was more effective than oralreatment (either daily or “pulse” treatment)or the suppression of PTH levels (Figure 7).here are certain qualifications about the trials

Algorithm 4. Managing Vitamin D St

ombined for this meta-analysis: Two trials n

ompared daily oral treatment with thriceeekly intravenous treatment343,345; in the trial

hat studied patients with the highest pretreat-ent PTH levels, the oral “group” was a com-

ination of one group randomly assigned tontermittent treatment and a second group as-igned to daily therapy.346 The degree of hyper-arathyroidism was very mild in two trials, ashe entry PTH levels averaged �400 pg/mL44.0 pmol/L).343,344 In two trials that prospec-ively compared intermittent oral and intrave-ous calcitriol in patients with more severeyperparathyroidism,347,348 the numbers of pa-ients completing the study was too small (n �0) to meet the criteria for the meta-analysis.n patients with more severe hyperparathyroid-sm (trials with intravenous calcitriol that ad-usted the dosage upward if PTH levels were

ased on Serum Phosphorus Levels

ot suppressed), the use of calcitriol doses

blMw

cd


elow 0.75-1.0 �g per treatment were ofteness effective in lowering PTH levels.330,349

oreover, the earlier placebo-controlled trials

Algorithm 5. Managing Vitamin D Sterols Based on

ith daily oral calcitriol found that patients w

ould rarely tolerate daily doses of 0.5 �g peray without developing hypercalcemia.340,341

The results of oral trials with calcitriol that

evels in Children Not Receiving Growth Hormones
PTH L
ere not placebo-controlled lead to the conclu-

sbtrosdhiPDsmwsPwcpv

sipehDpssaSammtmrS

ecttasdtdra

fwtdeTtee

wootrpmn�ahacliacwwaetP(tSw

C


ion that pulse or intermittent therapy yieldedetter results than were reported with dailyherapy; meta-analysis of the results of threeandomized, controlled trials that compared dailyral with intermittent oral calcitriol failed tohow any superiority of intermittent therapy overaily therapy.317,346,350 Two of these studies317,350

ad patients with only mild hyperparathyroid-sm, and few patients entered into treatment withTH levels above 600 pg/mL (66.0 pmol/L).espite randomization of treatment in one

tudy,350 each of the five patients having pretreat-ent PTH levels �600 pg/mL (66.0 pmol/L)ere assigned to intermittent therapy. In another

tudy,346 the trial with the highest pretreatmentTH levels, the serum calcium levels were higherith daily than with intermittent therapy. Thus,

onclusions about there being no difference de-ending on the frequency of dosing must beiewed with caution.The major side-effects of active vitamin D

terols, including calcitriol and alfacalcidol, arencreases in the serum levels of calcium andhosphorus, leading to hypercalcemia and wors-ning of hyperphosphatemia. These concernsave led to efforts to develop analogs of vitamin

which might have less calcemic and/or phos-hatemic effects, while retaining efficacy for theuppression of high levels of PTH.351,352 Severaluch analogs are now in clinical use. Paricalcitolnd doxercalciferol are available in the Unitedtates, and maxicalcitol and falecalcitol are avail-ble in Asia.321,323,353,354 Extensive data in ani-als with normal kidney function and in experi-ental animals with uremia have demonstrated

hat maxicalcitol and paricalcitol are less calce-ic and phosphatemic than calcitriol and yet

etain effectiveness in suppressing PTH.355-357

Fig 7. Meta-Analysis of Oral versus Intravenousalcitriol on PTH Suppression

tudies in vitamin D-deficient animals with dox- h

rcalciferol have demonstrated no difference inalcium or phosphorus absorption from the intes-ine and in changes in serum calcium comparedo alfacalcidol, but doxercalciferol was associ-ted with a decreased mortality in toxicologytudies.358,359 Additional studies have shown thatoxercalciferol is associated with less calciuriahan alfacalcidol.360,361 Definitive quantitativeata comparing these vitamin D sterols to calcit-iol or to each other in controlled clinical trialsre not available at the present time.

In placebo-controlled trials with calcitriol, al-acalcidol, paricalcitol, and doxercalciferol, thereere increments of serum phosphorus during

reatment,321,322,362-365 and analysis indicated noifference between the sterols regarding theirffects on raising serum levels of phosphorus.reatment with vitamin D should not be under-

aken or continued if serum phosphorus levelsxceed 6.5 mg/dL, because of this risk of furtherlevating serum phosphorus levels.

Another side-effect of intermittent treatmentith an active vitamin D sterol is the appearancef subnormal bone formation, with “adynamic”r “aplastic” bone.328,366 In CKD Stage 5 pa-ients who had not received pulse doses of calcit-iol and had PTH levels �150 pg/mL (16.5mol/L), there was a high incidence of subnor-al bone formation on bone biopsy, with ady-

amic or aplastic bone.26 When PTH levels are65 pg/mL (7.15 pmol/L), the occurrence of

dynamic bone is nearly universal.17,26 Mildyperparathyroid bone disease may be prefer-ble to adynamic bone because of the loss of theapacity of bone buffering for the added extracel-ular calcium207; this likely accounts for thencreased risk of hypercalcemia in patients withdynamic bone.327,366 Also, there may be in-reased risk of vascular calcification in patientsith biochemical features that are consistentith adynamic bone.84 In adolescents and young

dults with CKD Stage 5, adynamic bone328 andven reduced linear growth occurred in associa-ion with intermittent calcitriol therapy when theTH levels were reduced below 400-450 pg/mL44.0-49.5 pmol/L).302 Reported observations ofhe development of adynamic bone in adult CKDtage 5 patients in association with pulse therapyith calcitriol are limited to a small number367;
owever, there is little reason to believe that the

bs

woss

aptvtts“t2se3

mPcsDflAbc

irtt

or

pasashel

ispbsdiMfvamoaacatrtt


one of adults would not show the effects ob-erved in pediatric-age patients.

When one elects to observe dialysis patientsith PTH levels �600 pg/mL (66.0 pmol/L) with-ut initiating vitamin D therapy, serial PTH levelshould be monitored. If the levels show a progres-ive rise, treatment should be initiated.

LIMITATIONSMany of the studies cited above with calcitriol

nd alfacalcidol that originated before 1980 lackedarallel control groups,313-316,318,324,325,368-370 andhe assays for PTH were variable and some in-olved PTH fragments313-316,318 that are cleared byhe kidney; thus, comparison with the current trialshat utilize so-called “1st PTH-IMA” is not pos-ible. Also, many patients in the early trials hadsevere” and symptomatic bone disease, findingshat have become more rare with better control of° HPT. With studies of the “newer” vitamin Dterols, such as falecalcitriol, paricalcitol, and dox-rcalciferol, there were often parallel controls.320-

22,354 However, the severity of 2° HPT was mild tooderate, based on pretreatment serum levels ofTH, in most patients entered into trials with fale-alcitriol320,354 or paricalcitol.321 For these rea-ons, comparison of data with the different vitamin

sterols must be regarded as tentative, particularlyor patients with severe 2° HPT, defined as serumevels of PTH �1,200 pg/mL (132.0 pmol/L).lso, it is almost certain that such patients woulde considered inappropriate for a long-term, pla-ebo-controlled trial.

The conclusions that pulse intravenous therapys better then pulse oral treatment must also beegarded as tentative; similarly, the conclusionshat daily oral therapy is as effective as pulse oral
herapy given two or three times a week may t
nly apply to patients with mild 2° HPT for theeasons noted above.

CLINICAL APPLICATIONSSecondary hyperparathyroidism and hyper-

arathyroid high-turnover bone disease in CKDre treatable abnormalities with active vitamin Dterols. There are many of these sterols availablend others are being developed. Since one of theide-effects of the therapy with these sterols isypercalcemia, one would want to use a sterolffective in treatment of the bone disorder withittle or no hypercalcemic effects.

RECOMMENDATIONS FOR RESEARCHTrials that compare different vitamin D sterols

n CKD Stage 5 patients are needed. Also, pro-pective trials are needed to evaluate the effect ofulse-dose calcitriol or other vitamin D sterol onone, with study of the relationship betweenerum levels of PTH and bone turnover usingouble tetracycline labeling, to assess a possiblymportant side-effect of vitamin D treatment.

oreover, little is known about the ideal targetor serum levels of PTH during treatment withitamin D. It is possible that the incidence ofdynamic bone will increase substantially if vita-in D sterols are employed in patients who have

nly modest elevations of PTH levels. Studiesre needed to examine the value of bone markersnd to assess the relationship between the so-alled “whole PTH molecule,” “1st PTH-IMA,”nd bone histomorphometry during vitamin Dreatment. Large studies that evaluate fractureates should include data on previous vitamin Dherapy in an effort to identify whether vitamin Dreatment can modify the high incidence of frac-
ures noted in CKD Stage 5 patients.

1

1

mbbppelccueo

icbeoCsmcmasqacpdPocstHch

S

GUIDELINE 10. DIALYSATE CALCIUM CONCENTRATIONS

tdmccvchbsPncmahtctEssdad

vactucatpacwctc

trapp

0.1 In patients receiving calcium-based phos-phate binders, the dialysate calcium con-centration should be targeted to 2.5mEq/L (1.25 mM). (OPINION)

0.2 In patients not receiving calcium-contain-ing phosphate binders, the dialysate cal-cium should be targeted to 2.5-3.0 mEq/L(1.25-3 mM) based on serum calciumlevels and the need for therapy withactive vitamin D sterols. (OPINION)

BACKGROUNDIn patients receiving dialysis, the normal ho-eostatic mechanisms for regulating calcium

alance are impaired. Calcium absorption cannote adjusted, due to the kidney’s inability toroduce 1,25(OH)2D. Further, the level of theeripheral tissue VDR may be reduced. Calciumxcretion, usually regulated through urinaryosses, is severely impaired or absent. Dialysatealcium, activated vitamin D sterols, and dietaryalcium intake—itself highly influenced by these of oral, calcium-containing phosphate bind-rs—are the physician-prescribed determinantsf calcium balance in patients receiving dialysis.Because bone mass increases dramatically dur-

ng childhood and adolescence, there is signifi-ant net body accretion of calcium, where, onalance, absorption must exceed losses. Inad-quate calcium absorption is an important causef 2° HPT and osteodystrophy in the setting ofKD. Historically, dialysate calcium levels were

et at a physiological level of 2.5 mEq/L, approxi-ately equivalent to the serum ionized calcium

oncentration. However, it became clear thatany patients were in a negative calcium bal-

nce in the era when oral aluminum-containingalts were the principal phosphate binder. Conse-uently, in both hemodialysis and peritoneal di-lysis, a supraphysiological dialysate calciumoncentration (3.0-3.5 mEq/L) became standard,ermitting transfer of calcium to the patienturing dialysis. This was effective in reducingTH levels.371 With the current widespread usef activated vitamin D sterols and oral, calcium-ontaining phosphate binders, calcium balance ishifted upward dramatically, so that a return tohe use of 2.5 mEq/L calcium dialysate is safe.owever, the use of calcium- and other metal-

ontaining phosphate binders may require a
igher dialysate calcium. c

RATIONALE

There are three major clinical concerns relatedo excess calcium balance: bone, growth, andevelopment of vascular calcifications. Patientsay develop frank hypercalcemia, which most

ommonly occurs in patients receiving both oralalcium-containing phosphate binders, and acti-ated vitamin D sterols. This may limit the use ofalcium-containing phosphate binders to controlyperphosphatemia and 2° HPT. Excess calciumalance, resulting in hypercalcemia and therebyuppressing the parathyroid gland secretion ofTH, may contribute to the development of ady-amic bone disease, which has become an in-reasing problem in both adults and children onaintenance dialysis.24,327,328,372 Patients with

dynamic bone disease have an increased risk ofypercalcemia due to the limited capacity ofheir bone to incorporate calcium.207 There isoncern that excessive calcium balance may con-ribute to systemic calcification, as reflected byBCT evidence of enhanced coronary calciumcores, present in young adults who started dialy-is as children.80,84 In addition, adynamic boneisease was associated with a greater degree ofrterial calcification in patients on maintenanceialysis.373

The dialysate calcium concentration and theolume of ultrafiltrate determine calcium bal-nce during dialysis. A higher dialysate calciumoncentration increases diffusion of calcium intohe patient. In contrast, the calcium present in theltrafiltrate is a potentially important source ofalcium loss from the patient. The calcium bal-nce during peritoneal dialysis is usually nega-ive with use of 2.5 mEq/L calcium dialysate andositive with 3.0-3.5 mEq/L calcium dialysate,lthough high volumes of dialysate ultrafiltratean produce a negative calcium balance evenith 3.5 mEq/L calcium dialysate.374-378 Cal-

ium balance during hemodialysis may be neu-ral or negative with the use of a 2.5 mEq/Lalcium dialysate.379,380 (See Guideline 14).

The use of dialysate with a calcium concentra-ion of 2.5 mEq/L is an effective strategy foreducing calcium intake, and thereby reducing bal-nce, if patients are treated with calcium-basedhosphate binders. Studies in adults using thisreparation have shown fewer episodes of hypercal-
emia and patient tolerance of increased doses of

cdtsuaedtTsh

ccapvtgpstsPaticcpceac

cpaisappctbbi

s

madrnd

ddtfimcvapgslCurt

upmCdac2ocofimt

odceos

GUIDELINE 10: DIALYSATE CALCIUM CONCENTRATIONS S65

alcium-containing phosphate binders without theevelopment of hypercalcemia.381-384 Hyperpara-hyroidism may worsen after decreasing the dialy-ate calcium, but this often responds to increasedse of calcium-containing phosphate binders and/orctive vitamin D sterols.385,386 Patients with anlevated PTH prior to switching to a low-calciumialysate are at greater risk for worsening hyperpara-hyroidism and may not tolerate the change.387

here are, however, biochemical data in patientsuggesting that a 2.5 mEq/L calcium dialysate mayave a positive effect on adynamic bone disease.388

Along with the reduction of dialysate calciumoncentration, other strategies designed to de-rease the intake of calcium have focused onctive vitamin D sterols and calcium-containinghosphate binders. While reduction of the activeitamin D sterol dose is an alternative therapeu-ic option, the trade-off is decreased parathyroidland suppression and possible worsening orroduction of 2° HPT. This has led to approachesuch as intermittent active vitamin D sterolherapy, and the development of active vitamin Dterols that produce equivalent suppression ofTH but with less effective intestinal calciumbsorption. Strategies to minimize calcium in-ake from calcium-containing phosphate bindersnclude decreasing their use through improvedontrol of dietary phosphorous intake, an in-rease in the dialysis prescription to improvehosphate clearance, and the use of calcium-ontaining phosphate binders that producequivalent phosphate binding but less calciumbsorption than calcium carbonate, such as cal-ium acetate.

Another approach to the excess dietary cal-ium intake is the substitution of a calcium-freehosphate binder.184,389-391 However, when onlyresin is used, concern over appropriate calcium

ntake should be taken into consideration. Food-tuffs in younger children that provide calciumre often limited, since they represent sources ofhosphorus too, and are therefore restricted. Suchatients may benefit from a higher dialysatealcium concentration and/or calcium supplemen-ation with a calcium-containing phosphateinder.204 No calcium and metal-free phosphateinder is currently approved by the FDA for usen children.

Finally, there is evidence in adult hemodialy-
is patients that a 2.5 mEq/L calcium dialysate p
ay predispose patients to arrhythmias392,393

lthough a higher dialysate calcium during hemo-ialysis may impair cardiac relaxation and arte-ial compliance.394,395 Similar experiences haveot been reported in children, but cardiovascularisease is the leading cause of death in children.

STRENGTH OF EVIDENCEThere are no longitudinal studies evaluating

ifferent dialysate calcium concentrations in pe-iatric dialysis patients. There are few prospec-ive adult studies addressing this issue. In theseew adult-based studies, comparison of the datas difficult due to major differences in outcomeeasures, study design, and concurrent use of

alcium-containing phosphate binders and activeitamin D sterols. In addition, the adult studiesre characteristically in patients receiving eithereritoneal dialysis or hemodialysis and theseroups may not be comparable. Moreover, adulttudies only include patients receiving CAPD or,ess commonly, a mixture of patients receivingAPD or CCPD, the latter being the most widelytilized form of dialysis in pediatric patients. Theelevance of findings derived from CAPD pa-ients to patients receiving CCPD is unknown.

A variety of outcome measures have beensed in the adult studies. One study analyzedatient mortality, comparing a 3.5 mEq/L and 2.0Eq/L calcium dialysate in patients receivingAPD.396 There was no statistically significantifference, although both groups had a highttrition rate, making a meaningful analysis diffi-ult. In the same study, the group that received.0 mEq/L calcium dialysate had fewer episodesf hypercalcemia and were able to receive morealcium carbonate.396 In contrast, another studyf patients receiving either CCPD or CAPDound no statistically significant difference in thencidence of hypercalcemia when comparing 3.5Eq/L and 2.0 mEq/L calcium dialysate, al-

hough the sample size was small.397

A number of studies have analyzed the riskf infection in patients receiving peritonealialysis with either a high or low dialysatealcium concentration, but none has shown anffect of the dialysate calcium concentrationn the frequency of either peritonitis or exit-ite infections.396,398,399

Three studies have compared BMD in adult
atients randomized to high- or low-calcium

dats

desaaccsbtoBcltwsw2

ccmpn2testgeasDmmth

tttuao

hs4sv

hdmcscatniralsDdamcccwmis

onbGm(sv

chmdnth

GUIDELINE 10: DIALYSATE CALCIUM CONCENTRATIONSS66

ialysate. None of these studies demonstratedny effect of dialysate calcium on BMD, al-hough all of these studies also had a smallample size.396,400,401

Four studies have analyzed the effect ofialysate calcium on biochemical bone mark-rs. Among the three studies that evaluatederum alkaline phosphatase levels, one showed

greater increase in alkaline phosphatasemong the patients on 2.0 mEq/L dialysatealcium versus those on 3.5 mEq/L dialysatealcium.396 The other two studies showed noignificant difference, but both had small num-ers of patients.400,402 Two studies evaluatedhe effect of dialysate calcium concentrationn bone gla protein (BGP, or osteocalcin).oth studies reporting BGP data found signifi-antly higher levels of BGP in patients onow-calcium dialysate after about 6 months ofreatment; however, at 12 months, the effectas not statistically significant in the smaller

tudy403 in contrast to the larger study396,400 inhich the effect was statistically significant at4 months.Three studies reported PTH levels as an out-

ome measure after 6 months follow-up whenomparing 3.5 mEq/L calcium dialysate to 2.5Eq/L calcium dialysate. In a study of CAPD

atients, significantly higher PTH levels wereoted at 6 months in patients who received the.5 mEq/L calcium dialysate.403 The remainingwo studies showed no statistically significantffect of dialysate calcium on PTH, but thesetudies had small sample sizes with a clear trendowards higher PTH values in the low-calciumroups.397,400 Another study followed PTH lev-ls in 10 dialysis patients with biopsy-provendynamic bone disease after lowering the dialy-ate calcium from 3.25 mEq/L to 2.0 mEq/L.366

uring the initial 9 months of follow-up, theean PTH level increased from 37 to 106 pg/L; there was no increase in the PTH level over

he last 3 months of the study. In addition,ypercalcemia resolved.Finally, there are studies that have evaluated

he risk of hyperparathyroidism and the impor-ance of calcium supplementation in patientsreated with low-calcium dialysate but withoutse of calcium-containing phosphate binders. Indults receiving CAPD, it was shown that the use
f 2.5 mEq/L calcium dialysate and aluminum m
ydroxide as a phosphate binder resulted in aignificant increase in the PTH level (from 259 to05 pg/mL; P � 0.0001). The limitation of thistudy was that no patient received an activeitamin D sterol.404

CLINICAL APPLICATIONSThe use of 2.5 mEq/L calcium dialysate may

elp to prevent hypercalcemia, adynamic boneisease, and systemic calcification. This is recom-ended for children who are receiving calcium-

ontaining phosphate binders. Alternate dialy-ate calcium concentrations may be required ifalcium- and other metal-free phosphate bindersre used. When the dialysate calcium concentra-ion is decreased, careful monitoring of PTH isecessary to avoid the development of worsen-ng 2° HPT and high-turnover bone disease. Theisk is further increased if the PTH level islready elevated when the dialysate calcium isowered. Patients on a 2.5 mEq/L calcium dialy-ate may require adjustment in activated vitamin

sterol dosing, or even a return to a higherialysate calcium concentration. In the child withn inappropriately low PTH level (�150 pg/L), even further reduction of the dialysate

alcium concentration may be necessary in selectircumstances. A reduction in the dialysate cal-ium concentration is also indicated in the childith symptomatic hypercalcemia, or hypercalce-ia that does not respond to adjustments in the

ntake of oral calcium and/or active vitamin Dterol dosing.

Patients with hypocalcemia may require a 3.0r 3.5 mEq/L calcium dialysate. This may also beecessary transiently in the setting of hungryone syndrome following parathyroidectomy (seeuideline 15). A 3.0 mEq/L calcium dialysateay be necessary if persistent hypocalcemia

�8.5 mg/dL, corrected for serum albumin) per-ists despite adequate treatment with an activeitamin D sterol and there is refractory 2° HPT.Children who are not receiving a calcium-

ontaining phosphate binder probably do notave a positive calcium balance when they are onaintenance dialysis. They usually require a

ialysate calcium concentration that allows foret absorption of calcium (�3.0 mEq/L) and/orhe use of a dietary calcium supplement, unlessypercalcemia is present. Such children must be
onitored for adequate calcium intake and the

dnbco

dtbicsltstatc

acat

dscmapcbpcccc

GUIDELINE 10: DIALYSATE CALCIUM CONCENTRATIONS S67

evelopment of 2° HPT. It may be that the use ofon-calcium, non-metal containing phosphateinder, combined with a low dialysate calciumoncentration, may allow the use of higher dosesf active vitamin D sterols.

LIMITATIONSThere are no pediatric studies that have ad-

ressed the topic of dialysate calcium concentra-ion with specific attention to the correlationetween calcium balance and growth. Adult stud-es have focused on hypercalcemia, 2° HPT, andontrol of serum phosphorus as outcome mea-ures. Another limitation is the fact that there isess information available for hemodialysis pa-ients than peritoneal dialysis patients, and notudies address the dialysate calcium concentra-ion in patients receiving CCPD. Finally, studiesre difficult to compare because of wide varia-ions in the use of active vitamin D sterols and
alcium-containing phosphate binders, and there t
re limited data on the effect of the dialysatealcium concentration on long-term issues suchs adynamic bone disease and systemic calcifica-ions.

RECOMMENDATIONS FOR RESEARCHCalcium balance studies are necessary in chil-

ren receiving hemodialysis or peritoneal dialy-is to determine the effect of different dialysatealcium concentrations. Research needs to deter-ine the relative roles of dialysate calcium,

ctive vitamin D sterols, and calcium-containinghosphate binders in the development of hyper-alcemia, systemic calcifications, and adynamicone disease. Calcium- and aluminum-free phos-hate binders should be evaluated for use inhildren. Studies in patients not receiving cal-ium-containing phosphate binders should in-lude an evaluation of higher dialysate calciumoncentrations and/or oral calcium supplementa-
ion.

1

1

1

1

1

1

S

GUIDELINE 11. RECOMMENDATIONS FOR THE USE OF
GROWTH HORMONE FOR CHILDREN WITH CKD
1

wattGlswnsnetla

eeroiWddo

itasIm

gTeae

1.1 Children should have hip X-rays and awrist bone age performed prior to initia-tion of GH therapy. Children with activerickets or a slipped capital femoralepiphysis should not begin GH therapyuntil these problems have been resolved.(EVIDENCE)

1.2 Growth hormone therapy should not beinitiated until the PTH level is no greaterthan 2X the target upper limit for CKDStages 2-4 or 1.5X (450 pg/mL) the targetupper limit in CKD Stage 5 (dialysis)(see Guideline 1). (OPINION)

1.3 Growth hormone therapy should not beinitiated until the phosphorus is nogreater than 1.5X the upper limit for age(see Guideline 4). (OPINION)

1.4 Children receiving GH therapy in Stages2-4 CKD should have calcium, phospho-rus, PTH, and alkaline phosphatasemonitored at least every 3 months dur-ing the first year of therapy. Childrenreceiving GH therapy in CKD Stage 5should have calcium, phosphorus, PTH,and alkaline phosphatase monitored atleast every month during the first 6months of therapy. Thereafter, intervalmeasurements should be made accord-ing to stage of CKD (see Guideline 1).(OPINION)

1.5 Children receiving GH therapy shouldhave a wrist bone age performed yearly.Hip X-rays should be performed whenclinically indicated.

1.6 Growth hormone therapy should bestopped temporarily:11.6.a CKD Stages 2-4: If the patient

has a PTH level >400 pg/mL; GHshould not be restarted until thePTH level is <200 pg/mL (EVI-DENCE AND OPINION)

11.6.b CKD Stage 5: If the patient has aPTH level >900 pg/mL; GHshould not be restarted until thePTH level is <450 pg/mL (EVI-DENCE AND OPINION)

11.6.c In all stages of CKD, if the patientdevelops a slipped capital femoral
epiphysis or symptomatic high- t

turnover renal osteodystrophy(EVIDENCE)

1.7 Growth hormone therapy should bestopped permanently when the epiphy-ses are closed.

BACKGROUNDGrowth retardation is common in children

ith CKD, and frequently leads to decreaseddult height. Metabolic acidosis, inadequate nu-ritional intake, and osteodystrophy may all con-ribute to this complication. In healthy children,H acts by stimulating the production of insulin-

ike growth factor I (IGF-I), which is the primarytimulus for linear growth. In contrast, childrenith CKD have an inadequate response despiteormal or elevated levels of GH, reflecting atate of apparent GH resistance. Possible mecha-isms include: reduced GH-receptor expressionspecially in the liver, which decreases produc-ion of IGF-I; increased IGF-I-binding proteinevels, which reduces the levels of free IGF-I;nd decreased IGF-I receptor signaling.

Pharmacological doses of rhGH improve lin-ar growth in children with CKD, although thefficacy appears to be less in children who areeceiving dialysis.405,406 The recommended dosef rhGH, which is given as a daily subcutaneousnjection, is 0.05 mg/kg/day or 30 IU/m2/week.

hile the response to rhGH therapy tends toecrease after the first year of treatment, thereoes appear to be a positive effect of the therapyn final adult height.405-407

For some children with CKD, an improvementn growth will occur with optimization of nutri-ional management and correction of metaboliccidosis.408 Malnutrition and metabolic acidosishould be corrected prior to initiating rhGH.nadequate nutrition and metabolic acidosis di-inish the effectiveness of rhGH therapy.157

RATIONALEThere are complex interactions between

rowth, growth hormone, and bone metabolism.he use of rhGH is regularly associated withnhanced height velocity in children with CKDnd poor growth, but may lead to complications,specially without careful attention to bone me-
abolism.

ihsicatppshi

eangeicastfivrtapnitti

g

vcitp

cdcrccw

iiccrint

dr

GTGpm

GUIDELINE 11: RECOMMENDATIONS FOR THE USE OF GROWTH HORMONE FOR CHILDREN WITH CKD S69

The skeletal complications of CKD in childrennclude rickets, avascular necrosis of the femoralead,54,63 and slipped capital femoral epiphy-is.49,58,409 Recombinant growth hormone therapyn children without CKD may cause slippedapital femoral epiphysis, perhaps due to ancceleration of growth.410 In children with CKD,he inherent predisposition to these skeletal com-lications makes it necessary to screen for com-lications such as slipped capital femoral epiphy-is,405 avascular necrosis of the femoralead,63,411,412 and active rickets, prior to thenitiation of rhGH therapy.

Recombinant human GH may have beneficialffects on the BMD of children with CKD,lthough the long-term clinical consequences areot known.413-415 However, clinical reports sug-est that rhGH therapy can have deleteriousffects on bone metabolism through the worsen-ng of 2° HPT.416-418 Hence, 2° HPT should beontrolled prior to the initiation of rhGH therapy,nd monitoring for this complication is neces-ary throughout the course of therapy. The risk ofhis complication is likely greatest during therst 6-12 months of rhGH therapy, and moreigilant monitoring is indicated during this pe-iod of time. Control of 2° HPT after the initia-ion of rhGH may require increased use of anctive vitamin D sterol417 in addition to therevention of hyperphosphatemia. Therapy mayeed to be stopped until 2° HPT resolves. Anncreased alkaline phosphatase level secondaryo new bone formation is expected with rhGHherapy, although a continued increase may bendicative of worsening 2° HPT.

STRENGTH OF EVIDENCEThe effectiveness of rhGH in improving linear

rowth in children with CKD and impaired height a

elocity has been demonstrated in a placebo-ontrolled study.405 The clinical evidence for annteraction between rhGH therapy and bone me-abolism has not been extensively studied in arospective manner in CKD patients.

LIMITATIONSIn children with CKD, there is insufficient

linical research on rhGH therapy and boneisease. Guidelines for monitoring PTH, cal-ium, phosphorus, alkaline phosphatase, and X-ays are based on expert opinion, not firm clini-al evidence. There is also an absence of firmlinical data supporting the levels of PTH uponhich cessation and reinitiation of GH are based.

CLINICAL APPLICATIONSThese guidelines recommend close monitor-

ng of mineral metabolism during rhGH therapyn children with CKD. A patient who has poorlyontrolled 2° HPT, active rickets, or a slippedapital femoral epiphysis may be at increasedisk for more severe bone disease if rhGH therapys continued. Given this potential, it is prudentot to use rhGH in children with poorly con-rolled osteodystrophy.

Along with appropriate monitoring of boneisease, optimal response to rhGH requires cor-ection of malnutrition and metabolic acidosis.

RECOMMENDATIONS FOR RESEARCHThe mechanism for the variable response to

H in some children with CKD is unknown.here is little information on optimal dosing ofH in children with CKD, especially duringuberty or while receiving dialysis. More infor-ation is needed on the relationship between GH

nd clinical outcomes beyond linear growth.

1

1

1

S

GUIDELINE 12. ALUMINUM OVERLOAD AND TOXICITY
IN CKD
1

1

moabnroaddttstbpttfaub

2.1 To prevent aluminum toxicity, the regu-lar administration of aluminum shouldbe avoided and the dialysate concentra-tion of aluminum should be main-tained at <10 �g/L. (EVIDENCE)12.1.a CKD patients ingesting aluminum

should not receive citrate salts simul-taneously. (EVIDENCE)

2.2 In CKD Stage 5, to assess aluminumexposure and the risk of aluminum toxic-ity, serum aluminum levels should bemeasured at least yearly and every 3months in those receiving aluminum-containing medications. (OPINION)12.2.a In children with CKD prior to

Stage 5, serum levels of alumi-num should be measured yearly ifchildren have been exposed toaluminum for 3 months or morein the prior year. (OPINION)

12.2.b Baseline levels of serum alumi-num should be <20 �g/L. (OPIN-ION)

12.2.c If levels of serum aluminum arebetween 20-60 �g/L, a search forand elimination of all sources ofaluminum should be performed.(OPINION)

2.3 A deferoxamine (DFO) test should beperformed if there are elevated serumaluminum levels (60-200 �g/L) or clini-cal signs and symptoms of aluminumtoxicity (Table 18), or prior to parathy-roidectomy if the patient has had alumi-num exposure for at least 4 months ormore. (OPINION) (See Algorithm 6 andAlgorithm 7.)12.3.a The test is performed by infusing

5 mg/kg of DFO during the lasthour of the dialysis session with aserum aluminum measured bothbefore DFO infusion and 2 dayslater, before the next dialysis ses-sion. (OPINION)

12.3.b The test is considered positive ifthe increment of serum alumi-num is >50 �g/L. (OPINION)

12.3.c A DFO test should not be per-
formed if the serum levels of d

aluminum are >200 �g/L toavoid DFO-induced neurotoxic-ity. (OPINION)

2.4 The presence of aluminum bone diseasecan be predicted by a rise in serumaluminum of >50 �g/L following DFOchallenge combined with serum PTHlevels of <150 pg/mL (150 ng/L). (OPIN-ION) However, the gold standard for thediagnosis of aluminum bone disease is abone biopsy showing increased alumi-num staining of the bone surface (>15%-25%) using an aluminum-specific stain,and often the presence of adynamic boneor osteomalacia. (EVIDENCE)

2.5 Asymptomatic patients receiving mainte-nance hemodialysis, with elevated levelsof serum aluminum between 60-200�g/L, should be treated with removal ofaluminum based gels and intensive dialy-sis. Treatment with DFO is optionalunless desired serum aluminum levelsare not achieved. (OPINION)

BACKGROUNDAluminum is widely present in nature, butost aluminum salts are quite insoluble. More-

ver, only a tiny fraction of ingested aluminum isbsorbed; this small amount is normally excretedy the kidney so that the body burden of alumi-um does not increase. When there is a markedlyeduced or absent kidney function, there is littler no ability to excrete aluminum and it canccumulate slowly. When aluminum is present inialysate, it enters the body directly across theialysis membrane, and the type of syndromehat develops depends on the rapidity and magni-ude of aluminum accumulation. The variousyndromes of aluminum toxicity were first iden-ified in dialysis patients, but they can occur inoth CKD Stage 4 patients and CKD Stage 5atients not yet treated with dialysis. Because ofheir devastating nature and the difficulties inheir management, it is essential that the clinicaleatures of aluminum toxicity are recognized inddition to the specific biochemical methodssed for their recognition. These problems haveecome substantially less common with the re-
uced use of aluminum gels as phosphate bind-

GUIDELINE 12: ALUMINUM OVERLOAD AND TOXICITY IN CKD S71

eactii

o(afndlm

bfabStilem“raAtw

n of A

GUIDELINE 12: ALUMINUM OVERLOAD AND TOXICITY IN CKDS72

rs and proper purification of dialysate; however,luminum toxicity still occurs. It is necessary toonsider the means for proper monitoring andhe appropriate diagnostic procedures needed todentify the various syndromes of aluminum tox-city.

RATIONALEAluminum toxicity occurs in dialysis patients

r CKD patients with GFR �30 mL/min/1.73 m2

CKD Stages 4 and 5) because aluminum that isbsorbed from the gut or that enters the bodyrom dialysate or another parenteral route419 isot excreted, or is inadequately excreted by theiseased kidneys.420,421 When aluminum accumu-ates in dialysis patients, it is only slowly re-

Algorithm 6. Evaluatio

oved by dialysis because 90% of aluminum is a

ound to serum proteins (primarily trans-errin422,423). The aluminum entering the bodyccumulates in various tissues, including bone,rain, parathyroid glands, and other organs.424,425

uch accumulation of aluminum can produceoxicity with several distinct syndromes, depend-ng on the rate and magnitude of aluminumoading. The first to be described was dialysisncephalopathy (or dialysis dementia).426,427 Alu-inum was then recognized as the cause of both

fracturing dialysis osteomalacia” (aluminum-elated bone disease)427-429 and a microcyticnemia developing without iron deficiency.430-432

fulminant variant of dialysis encephalopathy,ermed “acute aluminum neurotoxicity,” occursith the sudden, marked elevation of serum

luminum Neurotoxicity

luminum levels and is commonly fatal.433,434

Tdmi

tpc

T


hese disorders are briefly described below. Theevelopment and availability of a method toeasure trace quantities of aluminum accurately

Algorithm 7. Evaluation of Aluminum-Related Disoreatment

n biological fluids and tissues435 permits detec- r

ion of these disorders, and this methodologyrovides a means to identify patients with in-reased body burden of aluminum (see Algo-

Considerations for DFO Test and Subsequent DFO
rders:
ithm 7).

bsaspscscd�mstociattmiaaasgssd

dpossmiiaatcszdtwue

ibnclst

sUaottcwddgcLwnqgamo

oeoagwfcppttdlor

beuw


Acute aluminum neurotoxicity is diagnosedased on clinical features and the elevation oferum aluminum levels to 400-1,000 �g/L. Itrises from aluminum contamination of dialy-ate, often to levels of 150-1,000 �g/L. As a rule,atients may become ill simultaneously in theame dialysis center. They develop agitation,onfusion, myoclonic jerks, and major motoreizures; these symptoms are often followed byoma and death.433,434 The syndrome can alsoevelop in patients with CKD Stages 3-4 (GFR30 mL/min/1.73 m2) when they are given alu-inum gels (to control hyperphosphatemia) plus

odium citrate (Bicitra™ or Shohl’s solution) forhe correction of metabolic acidosis.436,437 Vari-us citrate salts, including citric acid, sodiumitrate, or calcium citrate, markedly enhancentestinal absorption of aluminum.203,438,439 Acuteluminum neurotoxicity can also appear in pa-ients with large aluminum body load soon afterhe start of treatment with DFO in doses of 20-40g/kg.440,441 When acute aluminum neurotoxic-

ty developed due to: a) very high dialysateluminum levels; or b) the ingestion of bothluminum gels and citrate salts, most symptom-tic patients had died.433,434,436,437 When theyndrome appeared in aluminum-loaded patientsiven DFO, some patients died; however, othersurvived when DFO treatment was stopped foreveral weeks and restarted later using a lowerose.440,441

Dialysis encephalopathy is an insidious disor-er with symptoms generally appearing afteratients have undergone dialysis for 12-24 monthsr even longer.426,427 Initial symptoms includeubtle personality changes and a progressivepeech disorder, characterized by stuttering, stam-ering, and hesitant speech, or even total inabil-

ty to talk.442 Motor disturbances include twitch-ng, myoclonic jerks, and motor apraxia. Auditorynd visual hallucinations, spatial disorientation,nd paranoid behavior are common. These fea-ures can fluctuate widely and are characteristi-ally worse shortly after dialysis. With time, theymptoms become persistent and worsen, sei-ures appear, and most untreated patients haveied within 6-12 months after the onset of symp-oms.426 The only distinctive laboratory findingsere substantial elevations of serum aluminum,sually 150-350 �g/L. Findings from an electro-
ncephalogram (EEG) differ from the general- e
zed slowing noted with other causes of meta-olic encephalopathy. The diagnosis of theseeurological disorders rests on clinical suspi-ion, the finding of elevated serum aluminumevels, and the EEG features. New cases of thisyndrome disappeared after the initiation of wa-er purification using reverse osmosis.

Aluminum-related bone disease was first de-cribed in certain specific geographic areas of the.K. and the U.S.428,443; there was a suspicion of

luminum toxicity because many patients devel-ped clinical features of dialysis encephalopa-hy.428,443 Epidemiological studies showed thathis disorder—which presented with bone pain, aharacteristic “waddling” gait, proximal muscleeakness, and fractures430—was associated withialysate aluminum levels �100 �g/L.429 Theisorder was limited to certain geographical re-ions, and aluminum-contaminated dialysate wasonsidered the only source of aluminum loading.ater, sporadic cases appeared in dialysis centershere elevated dialysate aluminum levels wereever found,444,445 and it was shown that smalluantities of aluminum are absorbed from in-ested aluminum gels.446 Such sporadic cases ofluminum bone disease have become less com-on since the use of aluminum gels was stopped

r their dosage reduced substantially.327,447

Patients with aluminum-related bone diseaseften exhibit hypercalcemia,448,449 and PTH lev-ls which are variably elevated, particularly withlder C-terminal or mid-region 1st PTH-IMAssays.449,450 Some of these patients had radio-raphic features of subperiosteal erosions and,hen parathyroidectomy was done, the clinical

eatures worsened. Bone biopsies revealed typi-al aluminum-related bone disease, and the termseudohyperparathyroidism was applied to suchatients.450 Other observations have documentedhe appearance or worsening of skeletal symp-oms when patients with aluminum-related boneisease or aluminum loading had their PTHevels reduced by either parathyroid surgery451

r by treatment with an active vitamin D ste-ol.367,452

Indirect methods to identify aluminum-relatedone disease were sought. Serum aluminum lev-ls were elevated in afflicted patients, with val-es usually �100 �g/L; however, similar levelsere found in many patients lacking bone biopsy

vidence of aluminum-related bone disease.327,453

T2wibwtatoea

napidwwklrn

IlDmaaAud

tldPae

cnlpc

SM

masbnqp(arstssdisesmafstanLsefwg2tcumaa�h“s1ca


he DFO infusion test, using DFO in doses of0-40 mg/kg, was introduced to identify thoseith aluminum bone disease.454,455 The results

ndicated that the rise in aluminum correlatedetter with the total bone aluminum content thanith surface staining of aluminum.456,457 Fur-

her, the presence of bone surface staining forluminum of �15%-25% showed a close associa-ion with clinical symptoms and with bone bi-psy features of reduced bone formation andven osteomalacia, the histological features ofluminum bone disease.458-460

Population studies suggested that the combi-ation of the increment of serum aluminumfter DFO combined with PTH levels �150g/mL (16.5 pmol/L) provided better sensitiv-ty and specificity to predict aluminum boneisease than the DFO test alone.455,461 Also, itas found that the sensitivity of the DFO testas reduced substantially in patients with nonown exposure to aluminum for 6 months oronger.461 Most information indicates that se-um aluminum levels only reflect recent alumi-um intake.462

Problems arose with use of the DFO test.solated reports documented permanent visualoss from ophthalmological damage after oneFO test with a dose of 40 mg/kg.463,464 Further-ore, the use of DFO, 20-40 mg/kg, was associ-

ted with fulminant and fatal mucormycosis inn unacceptable number of dialysis patients.465

s a consequence, there has been reluctance tose a DFO test dose of 40 mg/kg, and smalleroses have been evaluated.466-468

Prevention of aluminum toxicity is preferableo use of toxic methods for treatment, particu-arly with the mortality of the neurological disor-ers and high morbidity of the bone disease.eriodic monitoring of serum aluminum levelsnd assessment of aluminum in dialysate aressential for its prevention.


The evidence for the devastating neurologi-al and skeletal disorders produced by contami-ation of dialysate with aluminum is compel-ing. However, these reports are notrospective, randomized trials, and such trials
an never be done. m
erum Aluminum Levels and Frequency ofonitoring

Early studies of serum aluminum measure-ents in dialysis patients indicated that serum

luminum levels reflect relatively recent expo-ure to aluminum.424,469 The population studiesased on a single measurement of serum alumi-um provide no information on the optimal fre-uency to monitor serum aluminum levels. Theurpose of monitoring serum aluminum levels is:a) to identify excessive aluminum intake orbsorption in individual patients; or (b) to aid inecognition of accidental contamination of dialy-ate with aluminum. The recent reported acciden-al events with aluminum contamination of dialy-ate were often detected because neurologicalymptoms appeared in dialysis patients434,470,471;eaths often occurred before the source wasdentified or corrected. Under these circum-tances, dialysate aluminum levels were mark-dly elevated (�200 �g/L). Although the dialy-ate aluminum levels were high, dialysateonitoring may not be frequent enough to detectproblem, as water aluminum levels can vary

rom day to day. Twice-yearly monitoring oferum aluminum would be capable of detectinghe slow accumulation of aluminum from oralbsorption or from “modest” dialysate contami-ation (dialysate aluminum levels of 20-40 �g/). Indirect evidence can be derived from studieshowing the increment of serum aluminum lev-ls during the ingestion of aluminum gels orrom studies of serum aluminum levels after theithdrawal of aluminum gels. These studies sug-est that serum levels change very slightly over-3 weeks of ingesting aluminum gels (whenhere is no intake of citrate). A prospective,ontrolled study in children and young adultsndergoing peritoneal dialysis166 with measure-ents of aluminum levels every 2 months showedslow increase of basal (or unstimulated) serum

luminum from 22.4 � 30 �g/L to 57.8 � 13g/L after 12 months with intake of aluminumydroxide, 30 mg/kg BW, a dose consideredsafe” in children with CKD165; this contrasts toerum aluminum decreasing from 21.6 � 2.3 to3.2 � 1.3 �g/L in the group given only calciumarbonate.166 In the aluminum-gel group, serumluminum levels had increased significantly by 4
onths (P � 0.05), and the levels differed from

t0“vpbmada

dots�gm“ielr6s

IT

taind1nbstarbitOp0crb

bAninawgspwa9�maniygfdgitbhdcSwp

Mo

n1tcw�svwnnso


he group not ingesting aluminum gels (P �.05). These studies showed that “safe” andlow” aluminum hydroxide doses failed to pre-ent significant rises in serum PTH and alkalinehosphatase, and worsening of hyperparathyroidone disease on repeat bone biopsy after 13onths. Such data suggest that measuring serum

luminum every 4 months would be capable ofetecting increased aluminum burden from oralluminum gels.

The changes in serum aluminum after with-rawal of aluminum gels provides informationn how rapidly serum aluminum levels fall afterhey were known to be elevated. In 32 hemodialy-is patients, serum aluminum fell from 105 � 21g/L to 34 � 11 �g/L, 8 months after aluminumels were stopped; the fall was slow with theagnitude of reduction being –67.3 � 5.1% of

baseline” after 8 months.244 In another study ofndividual serum aluminum values measured ev-ry 6 months in 13 patients,472 serum aluminumevels—ranging up to 66 �g/L while the patientseceived aluminum gels—fell below 20 �g/L at

months in all except one patient who “con-umed large doses of Al(OH)3.”

ngestion of Aluminum Gels and Aluminumoxicity

Is there a dose of aluminum gels that is effec-ive and yet safe for long-term use? The safety ofluminum gels cannot be evaluated unless theres confidence that the dialysate contains no alumi-um. The prevalence of aluminum-related boneisease has decreased markedly over the last0-15 years in association with increased use ofonaluminum phosphate-binding agents in com-ination with purification of water used for dialy-ate.327,447 A large population study of 289 pa-ients reported that the cumulative dose ofluminum is a continuous variable predicting theisk of aluminum bone disease compared to otherone pathology, based on a difference of totalntake of 1 kg of aluminum hydroxide (equal towo Alucap™ capsules thrice daily for 1 year).473

ne study of 17 patients with bone evaluatedostmortem showed a close correlation (r �.80) between bone aluminum content and theumulative intake of aluminum gels.474 Anothereport of 92 dialysis patients undergoing bone
iopsy also showed a close relationship between g
one aluminum content and total intake ofl(OH)3 (r � 0.83)475; moreover, bone alumi-um levels were trivially elevated above normaln the dialysis patients who never ingested alumi-um gels. In these reports,474,475 the finding ofluminum bone disease was limited to patientsith the greatest cumulative dose of aluminumels; the latter is related to the duration of dialy-is treatment. Among 253 Italian hemodialysisatients ingesting aluminum hydroxide, thereas a relatively close association between serum

luminum levels and bone aluminum content;3% of patients with serum aluminum levels60 �g/L had bone aluminum content �60g/kg BW.476 A study in children and young

dults on CAPD166 showed evidence of alumi-um accumulation based on the result of a DFOnfusion test (using 40 mg/kg BW), after only 1ear of consuming a “low dose” of aluminumels; thus, the increment of serum aluminum roserom 58 � 65 �g/L to 206 � 153 �g/L. Theseata point to the risk of ingestion of aluminumels for any length of time. If aluminum gels arengested, care must be taken to avoid the concomi-ant intake of any compound containing citrateecause of the profound effect of citrate to en-ance aluminum absorption.438 Such intake isifficult to monitor since several over-the-ounter preparations contain citrate (e.g., Alka-eltzer™ or Citracal™); they can be consumedithout any knowledge of those treating theatient.477

onitoring Serum Aluminum and Recognitionf Aluminum Toxicity

One study reported monitoring serum alumi-um twice yearly over a 4-year period, 1984-987.472 There were 1,193 Belgian dialysis pa-ients in dialysis units with “negligible aluminumontamination of dialysate”; from 1986 onward,ater aluminum concentrations were constantly3 �g/L. Data analysis involved individual mea-

urements of serum aluminum rather than meanalues for each patient. In a subset of 77 patientsith bone biopsies, 31% demonstrated alumi-um bone disease. With a cut-off serum alumi-um of 60 �g/L, there was a sensitivity andpecificity for detecting aluminum bone diseasef 82% and 86%, respectively. Among the total
roup of patients, six were diagnosed with dialy-

sampttsw

DA

udoctgbwiassotccwtlboUnisdm

bbwapdhdwa

iaaro0o

atotilpmmpoimpt

apaei

csytapt

awawtlow


is encephalopathy, based on clinical featuresnd EEG abnormalities. The median serum alu-inum was 121 �g/L (range, 15-462 �g/L) in

atients with dialysis encephalopathy comparedo 42 �g/L (range 4-140 �g/L) in matched con-rols. Most patients had undergone dialysis forome time before these aluminum measurementsere initiated.

FO Infusion Test as a Predictor ofluminum Bone Disease

Because of side-effects with the DFO testsing doses of 20-40 mg/kg BW,463,464,478 suchoses have been abandoned in favor of lowernes.466-468 In a study of patients from Europeanountries, North Africa, and South America, DFOests, both 10 mg/kg BW and 5 mg/kg BW, wereiven to 77 hemodialysis patients with boneiopsies. Both doses were given to 71 patients,ith alternate order of giving the two doses. The

ndications for bone biopsy included a serumluminum level above 60 �g/L or in those witherum aluminum below 60 �g/L, the presence ofymptoms of osteodystrophy, radiological signsf osteodystrophy, or the need for calcitriolherapy or parathyroidectomy based on biochemi-al parameters. Based on a chemical aluminumontent of bone �15 �g/g wet weight combinedith positive aluminum staining (�0%), 57 pa-

ients were classified as having aluminum over-oad; 15 others were classified with aluminumone disease based on aluminum staining �15 %f bone surface and BFR reduced below normal.sing the DFO dose of 5 mg/kg BW, the combi-ation of iPTH �150 pg/mL (150 ng/L) and anncrement of serum aluminum �50 �g/L had aensitivity of 87% and a specificity of 95% foretecting aluminum bone disease. Use of the 10g/kg DFO dose provided no additional benefit.Several studies evaluated low doses of DFO

ut did not compare the results to findings onone biopsy. The increment of serum aluminumas evaluated after two DFO tests, 30 mg/kg,

nd a total dose of 500 mg, in 22 hemodialysisatients; the lower dose was as efficacious inetecting evidence of aluminum overload as theigher dose.479 Other reports utilized still loweroses of DFO: doses of 0.5, 2.5, and 5.0 mg/kgere each given to five patients with serum

luminum levels above 40 �g/L and the change t

n total and ultrafilterable aluminum measuredfter 44 hours.467 The total and ultrafilterableluminum rose with each dose, suggesting aeliable test value of even the lowest dose. An-ther study described repeated use of doses of.5 mg/kg, demonstrating significant chelationf aluminum with this so-called minidose.468

LIMITATIONSThe evidence that aluminum is absorbed from

luminum hydroxide and other aluminum-con-aining compounds is indirect; however, the meth-dology for measuring true aluminum absorp-ion using a stable isotope and mass spectroscopys very expensive, has limited availability, and isikely to be done in very small numbers ofatients. The close relationship between the cu-ulative aluminum intake and the skeletal accu-ulation of aluminum, along with the reduced

revalence of aluminum bone disease as the usef aluminum gels has decreased, provides onlyndirect—but convincing—evidence to recom-end that aluminum gels not be used as phos-

hate binders, except for a very short periods ofime.

The substantial reduction in prevalence ofluminum bone disease, and the apparent disap-earance of this problem in dialysis units whereluminum gels are not used as phosphate bind-rs, makes this a problem that may be disappear-ng.

Prospective comparison of aluminum gels andalcium-based phosphate binders was done in amall numbers of patients and was limited to aear of therapy.166 Also, the studies that showedhe close correlation between the quantity ofluminum ingested and that present in bone atostmortem474 or on biopsy476 were not prospec-ive studies.

CLINICAL APPLICATIONSAwareness of the various manifestations of

luminum toxicity by all health-care providersill allow early recognition of aluminum loading

nd aluminum toxicity in CKD patients. Thisill permit the earlier diagnosis and treatment of

he syndromes of aluminum toxicity, therebyeading to reduced morbidity and disability. Usef the recommended low dose for the DFO testill minimize any risk of side-effects from the

est. Such better safety should lead clinicians to

ucTltlo

ovqssplnb

otSnp

upmsspggdct


se the DFO test with more confidence in clinicalonditions when it may be useful or necessary.hrough proper monitoring of serum aluminum

evels and the interpretation of these values,here will be earlier recognition of aluminumoading, with a greater ability to prevent theccurrence of aluminum toxicity.

RECOMMENDATIONS FOR RESEARCHLongitudinal studies with the measurement

f serum aluminum at every 6 months from theery outset of dialysis, combined with a subse-uent DFO test and bone biopsy in randomlyelected patients and others chosen becauseerum aluminum levels rise �40 �g/L, couldrovide information on the “peak” aluminumevels at which there may be a risk of alumi-um loading or the development of aluminum
one disease. c
Limited long-term trials with very low dosesf aluminum gels, which remain the most “po-ent” of phosphate binders, would be useful.uch doses, however, almost certainly wouldeed to be combined with another type of phos-hate-binding agent.Large, prospective, long-term trials with the

se of “low doses” of aluminum gels as phos-hate binders would be useful. Those who re-ain convinced that low doses of aluminum are

afe (and there remain some with this viewpoint)hould seem compelled to design such trials torove the point. Whether low doses of aluminumels might be effective and safe when they areiven in combination with continued “mini-oses” of DFO treatment468 would be useful toonsider for a prospective trial, particularly withhe growing concern about potential risks of
alcium-based phosphate binders.

1

1

1

rpmccwhlfieiacmswnahsbppts

A

GUIDELINE 13. TREATMENT OF ALUMINUM TOXICITY

au

BAo

fbcpmspI1wmwdonltgwa

S

tnm

P

sftms

Fr

cg

3.1 In all patients with baseline serum alumi-num levels between 20-60 �g/L, a posi-tive DFO test, or clinical symptoms con-sistent with aluminum toxicity (Guideline12, Table 18) the source of aluminumshould be identified and eliminated.(OPINION)

3.2 In symptomatic patients with serum alu-minum levels >60 �g/L but <200 �g/Lor increase in aluminum after DFO >50�g/L, DFO should be given to treat thealuminum overload. (See Algorithm 8and Algorithm 9.) (OPINION)

3.3 To avoid DFO-induced neurotoxicity inpatients with serum aluminum >200�g/L, DFO should not be given until thepredialysis serum aluminum level hasbeen reduced to <200 �g/L, which canbe achieved by intensive dialysis withhigh-flux dialysis membrane and a dialy-sate aluminum level of <5 �g/L.(OPINION)

BACKGROUNDWhen dialysis encephalopathy and dialysis-

elated bone disease were first recognized, mostatients had progressive disease with profoundorbidity and very high mortality. The early

ases arose, in large part, due to aluminum-ontaminated dialysate. However, most patientsere also receiving aluminum gels to controlyperphosphatemia, as it was then believed thatittle or none of the aluminum was absorbed. Therst successful reversal of symptoms of dialysisncephalopathy were observed with DFO givenn doses of 20-40 mg/kg for treating patients withluminum-related bone disease. There was clini-al and histological improvement; however, im-ediate side-effects affecting vision and mental

tatus appeared in isolated patients, and thereas concern about the use of DFO. More omi-ous was the appearance of rapidly progressivend fatal mucormycosis in dialysis patients whoad been receiving DFO treatment. At about theame time, there was the introduction of calcium-ased phosphate binders as well as widespreadurification of water used for dialysate, so therevalence of severe aluminum toxicity seemedo diminish. However, some aluminum toxicity
till occurs and there remains a question of when s

nd how chelation therapy with DFO should besed.

RATIONALE

eneficial Effect of DFO Treatment onluminum Bone Disease and Other Featuresf Aluminum Toxicity

Long-term DFO treatment reduces the sur-ace-stainable aluminum on trabecularone.460,480-483 This is associated with an in-rease of BFR,460,480-482 and symptoms ofroximal muscle weakness and bone pain com-only improve.480,484,485 Isolated reports have

hown improved neurological symptoms inatients with dialysis encephalopathy.486-490

n these reports, DFO doses have varied from-6 g460,484 or, expressed in relation to bodyeight, 30-40 mg/kg BW per treat-ent.481,482,491 The treatment was given onceeekly in some trials,460,485 and with eachialysis (thrice weekly) in others.481,482,491 Inne study,460 the reduction of stainable alumi-um and improved BFRs were substantiallyess in patients with an earlier parathyroidec-omy than in those with intact parathyroidlands. Treatment with DFO was associatedith improvement of anemia in some, but not

ll, patients.483,491,492

ide-Effects of DFO Treatment

Two serious problems associated with DFOherapy are: (a) the precipitation of acute alumi-um neurotoxicity; and (b) the development ofucormycosis, which is commonly fatal.

recipitation of acute aluminum neurotoxicity

When DFO is given to patients with very higherum aluminum levels (�200 �g/L), acute andatal aluminum neurotoxicity has been precipi-ated440,441; this presumably occurs because alu-inum is rapidly mobilized from various tissue

tores.

atal mucormycosis in dialysis patientseceiving DFO

In experimental infections with Mucor spe-ies, DFO administration markedly augments therowth and pathogenicity of the mucormyco-
is.493,494 When DFO is given, it chelates iron to
ber), 2005: pp S79-S86 S79

fwatiatirttob

et

M

nemn

sa

GUIDELINE 13: TREATMENT OF ALUMINUM TOXICITYS80

orm feroxamine; the latter has a moleculareight of 714 Da and several dialysis treatments

re needed to clear it from the circulation. Cer-ain species of Mucor, with very low pathogenic-ty, exist widely in nature and are found on skinnd mucous membranes; feroxamine enhancesheir growth and pathogenicity, thereby promot-ng the development of fatal disseminated orhinocerebral mucormycosis in hemodialysis pa-ients given DFO.465,495,496 Most afflicted pa-ients had received DFO, 20-40 mg/kg BW, oncer thrice weekly, with standard dialysis mem-

Algorithm 8. DFO Treatment

ranes (usually cuprophane) employed. The short- b

st reported duration of treatment before infec-ion appeared was 3 weeks.465

ethods to avoid serious side-effects

In patients exposed to high dialysate alumi-um levels or with high serum aluminum lev-ls (�60 �g/L), the following scheme is recom-ended to reduce the risk of acute

eurotoxicity:The very first dose of DFO is withheld until

erum aluminum levels are substantially reducedfter total withdrawal of aluminum exposure—

Al Rise between 50-300 �g/L
After P
oth from dialysate and from ingesting aluminum-

c�unDwrqn

bntamhl

GUIDELINE 13: TREATMENT OF ALUMINUM TOXICITY S81

ontaining drugs. With serum aluminum levels200 �g/L, daily hemodialysis should be done

sing high-flux membranes and dialysate alumi-um concentration �5 �g/L. The first “low dose”FO test (5 mg/kg) should be done only after 4-6eeks of such treatment, with increment of se-

um aluminum determining the timing of subse-uent DFO treatments. If the increment of alumi-

Algorithm 9. Subsequent DFO

um is high (�300 �g/L), DFO treatments should fi

e given via a peripheral vein, 5 hours before theext dialysis that uses a high-flux membrane;his allows for rapid removal of the DFO-luminum complexes from the circulation andinimizes the duration of patient exposure to

igh concentrations of the DFO-aluminum che-ate (aluminoxamine).

If the increment of serum aluminum after the

ment after PAl Rise >300 �g/L
Treat
rst DFO test is �300 �g/L and no neurological

oct4mmflmcIbi

Ms

llthmalu(tbocarrbterdtt

B

tiottrf

bosienm

DchmsAodahosoghwsmaglgcw

mmtsthsstfna�w1hw


r ophthalmological symptoms appear, the DFOan be given over the last hour of dialysis, withhe next dialysis done using a high-flux dialyzer,4 hours later. The dose of DFO should be 5g/kg, with an expanded interval between treat-ents of 3-4 dialysis procedures using a high-ux hemodialysis membrane; this allows forore complete clearance of feroxamine from the

irculation, reducing the risk of mucormycosis.ntravenous iron should be avoided while DFO iseing given to limit the formation of feroxam-ne.465, 493

anagement of aluminum overload withoutymptoms

The proper management of aluminum over-oad in the absence of symptoms is not estab-ished. There have been “consensus” viewpointshat aluminum overload be treated with DFO497;owever, there are no data to support this recom-endation. When CKD Stage 5 patients with

luminum overload and high serum aluminumevels have aluminum gels withdrawn and theyndergo dialysis with aluminum-free dialysate�5 �g/L), serum aluminum levels fall substan-ially and progressively.166,244,472 Small num-ers of patients with histomorphometric featuresf aluminum bone disease but without any mus-uloskeletal symptoms were treated as above;fter 1 year, repeat bone biopsies showed aeduction of surface stainable aluminum and aise in BFR consistent with reversal of aluminumone disease.498,499 The exception was two pa-ients who had previously undergone parathyroid-ctomy; in these patients, there was a modesteduction of surface-stainable aluminum but BFRid not improve to normal.499 These data suggesthat DFO therapy may not be needed for thereatment of such patients.


eneficial Effects of DFO Therapy

Several trials with DFO therapy showed a reduc-ion of surface aluminum staining,460,481-484 and anncrease in BFR,460,481,482,484 after treatment peri-ds of 8-12 months. Meta-analysis of four trialshat provided data on aluminum staining and threerials with BFR are shown in Figure 8 and Figure 9,espectively. The doses used were variable, ranging
rom 20-40 mg/kg; there are no data to indicate a fl
enefit of thrice-weekly treatment compared tonce-weekly.All these trials utilized standard dialy-is membranes (probably cuprophane). The data onmprovement of neurological features of dialysisncephalopathy involve many reports of smallumbers of patients who received such treat-ent.486-490,500-502

Data on the most efficient means to clearFO-bound aluminum from the circulation in-

lude dialysis using a high-flux membrane503 oremoperfusion with a charcoal filter504; theseethods remove aluminum more rapidly than

tandard dialysis using cuprophane membranes.crossover study compared: a) the combination

f charcoal perfusion combined with standardialysis; b) dialysis using a high-flux membrane;nd c) standard dialysis. The hemoperfusion/emodialysis combination had a small advantagever the high-flux dialyzer,505 and standard dialy-is was inferior to both. In this study, the removalf feroxamine (the DFO-iron complex) was farreater with either the high-flux dialyzer or theemoperfusion/hemodialysis combination thanith the standard cuprophane dialyzer. Other

tudies showed that either intraperitoneal or intra-uscular administration of DFO was effective in

ugmenting aluminum removal in patients under-oing peritoneal dialysis.506,507 The intramuscu-ar administration of DFO, as it is sometimesiven in hematological disorders, may provide aonvenient method 4-5 hours before dialysishen an intravenous route is not available.507

Experience with the “safe” long-term treat-ent with DFO is derived from an outbreak ofarked aluminum loading due to aluminum con-

amination of water used to prepare the dialysateolution. A 6-month course of “low-dose” DFOreatment was used in 42 patients exposed toigh dialysate aluminum.508 After neurologicalymptoms first appeared, but before the diagno-is of aluminum intoxication was made, 11 pa-ients had died. Forty-two other patients wereollowed. All aluminum gels were stopped, aew reverse-osmosis system was installed, andn alternate water source was used (dialysate Al2 �g/L). The initial basal aluminum levelsere 506 � 253 �g/L [mean � SD; range,04-1,257 �g/L]; hemodialysis was done for 4ours, 6 days per week; charcoal hemoperfusionas combined with the dialysis weekly. (High-
ux dialysis membranes, which had similar clear-

affw

hf�wi

1ccctshtw�

s for th

S


nce of DFO-stimulated aluminum as hemoper-usion, were not available.) After 4 weeks, therequency of dialysis was reduced to thriceeekly with hemoperfusion once weekly.After 6 weeks of such “intensive hemodialysis/

emoperfusion,” the basal serum aluminum fellrom 506 � 253 �g/L to 121 � 46 �g/L (mean

SD). The first DFO infusion test (5 mg/kg)as given during the last hour of dialysis; the

ncrement of serum aluminum was 300 �g/L in

Fig 8. Individual Study and Summary Effect Size

Fig 9. Individual Study and Summary Effect Sizes for thetain

1 patients, seven of whom developed neurologi-al symptoms (headache, hallucinations, or myo-lonic jerks) and two developed ophthalmologi-al symptoms (transiently blurred vision) afterhe DFO test; 30 patients had increments oferum aluminum �300 �g/L, only three of whomad developed neurological symptoms. Thesehree symptomatic patients and the 11 patientsith a post-DFO aluminum increment �300g/L received DFO treatment given via a periph-

e Effect of DFO Therapy on Bone Formation Rate

Effect of DFO Therapy on Bone Surface Aluminum

ehpdsTp4p��Galaccs5

naawvs

M

nmwwpim7i9cdamappBcoiD

kdanfar

iaaOuaftmccgict

lrDdfambatfdapsgdWicpiIh


ral vein 5 hours before starting a hemodialysis/emoperfusion session (Group 1). The other 27atients (Group 2) received DFO (5 mg/kg)uring the last hour of dialysis with a hemodialy-is/hemoperfusion session done 44 hours later.he DFO treatments were given weekly in allatients. After 4 months, DFO was stopped for a-week “washout,” and the DFO test was re-eated. If the basal serum aluminum was �60g/L and the increment after DFO was �50g/L, the DFO treatment was stopped (2/14 ofroup I and 8/27 of Group 2). If the basal serum

luminum level or the increment exceeded theseimits, DFO treatment was continued weekly forn additional 2 months. There have been noomparisons of different doses of DFO, althoughross-over studies with single infusions and smallhort-term studies suggest that doses lower thanmg/kg may be useful.Throughout this 6 months of DFO treatment,

o neurological or ophthalmological symptomsppeared and the baseline serum aluminum gradu-lly fell, as did the increment after DFO. Thereere significant increments in the mean cellolume (MCV) of RBCs and a modest rise inerum PTH levels in both groups.509

ucormycosis and DFO Treatment

Numerous case reports have described fulmi-ant, fatal cases of systemic or rhinocerebralucormycosis in dialysis patients being treatedith DFO for aluminum toxicity,465,495,496,510,511

hile reports of mucormycosis among dialysisatients not receiving DFO are unusual.420 Annternational registry collected 59 cases of mucor-

ycosis among dialysis patients465; among these,8% had been treated with DFO for aluminum orron overload. In this report, the mortality was1%, the disorder was the disseminated or rhino-erebral variety in 75% of the cases, and aiagnosis of mucormycosis was made only atutopsy in 61%. Experimental infections withucormycosis in animals demonstrated that DFO,

nd in particular feroxamine, augmented theathogenicity of certain species of Mucor andrevented effective treatment with amphotericin.493,494,512 Increased susceptibility to mucormy-osis was found to occur because of persistencef significant concentrations of feroxamine, theron chelate with DFO, in CKD patients given
FO. Such feroxamine is rapidly excreted by the p
idneys of hematology patients treated with therug, and mucormycosis has been very raremong DFO-treated hematology patients withormal kidney function.420 The clearance oferoxamine by a standard dialyzer is quite low,nd three to four dialysis treatments may beequired to clear this substance from the blood.505

With proper water purification and reductionn the intake of aluminum gels, the incidence ofluminum bone disease and other features ofluminum toxicity has decreased substantially.ver the same period, there have been trialstilizing much lower doses of DFO to treatluminum toxicity. Also, there appeared to beewer cases of mucormycosis in 1986-1989 ashe DFO usage decreased. For a recent review ofucormycosis, an attempt was made to locate

ases that had occurred over the last 10 years; inommunications with various individuals in Bel-ium, Spain, Portugal, and the U.S. with interestn aluminum toxicity and use of DFO, no recentases of mucormycosis associated with DFOherapy could be identified.513

Attention has been given to methods that uti-ize DFO in a manner that reduces its risk. Byeducing the time between the administration ofFO and the next dialysis, and by doing theialysis with a highly permeable membrane, botheroxamine and the aluminum chelate, aluminox-mine, are removed more effectively.503 He-operfusion with a sorbent cartridge has also

een very effective505; however, such cartridgesre not presently available in the U.S. In addi-ion, there has been a reduction of the DFO doserom 20-40 mg/kg to 5-10 mg/kg, with the DFOose given 4-6 hours before the next dialysis,long with the use of a high-flux or highlyermeable dialysis membrane and/or the use of aorbent system.508 Also, DFO should only beiven every 7-10 days,508 with three to fourialysis procedures between each dose of DFO.508

ith attention to prevention of aluminum toxic-ty by curtailing the administration of aluminum-ontaining drugs and attention to proper waterurification, the incidence of aluminum toxicitys now much lower than it was 10-15 years ago.t has not been possible to identify patients whoave developed mucormycosis when these newer
rotocols have been followed.

taaw2papnaaffetitiwn(fsmardd

Dtmmbwmds

“ctcdld1d

ritfhDmefDn

masltpamtaucpouoeao

mipcbrttnledo


LIMITATIONS

The trials showing beneficial effects of DFOreatment on bone biopsies and symptoms ofluminum bone disease were done several yearsgo when symptomatic aluminum bone diseaseas common, and most used DFO in doses of0-40 mg/kg BW. Despite this, the numbers ofatients in prospective trials were relatively small;lso, because of the severity of the disorder andoor prognosis in untreated patients, there wereo controlled trials. In a small trial of asymptom-tic patients found to have biopsy evidence ofluminum bone disease, there was reduced sur-ace staining of aluminum and increased boneormation when all exposure to aluminum wasliminated.499 There is evidence in one trial thathe use of DFO in a dose of 5 mg/kg is effectiven lowering basal serum aluminum. The largestrial represented acute marked aluminum load-ng, and neurological rather than skeletal diseaseas the major risk. Fourteen patients who wereot treated died, and there was only one deathdue to hyperkalemia) among 42 patients whoollowed the recommended protocol.434 Smalltudies suggest that doses of DFO as low as 1g/kg and 0.5 mg/kg can raise the ultrafilterable

luminum in serum, so such aluminum can beemoved by dialysis, but there are no long-termata documenting the effectiveness of such lowoses.With regard to the safety of using low doses of

FO, the reduced frequency of its administrationo once weekly, and use of high-flux dialyzers toinimize the increased susceptibility to mucor-ycosis, the evidence is only indirect. It has not

een possible to find any cases of mucormycosisith this schema. If no new cases of fatal mucor-ycosis appear, this will be presumptive evi-

ence of the effectiveness of the preventive mea-ures.

The management of dialysis patients withasymptomatic aluminum loading” has not beenarefully evaluated, and the recommendation ofreating such patients with DFO497 has not beenritically evaluated. There was a small number ofialysis patients with elevated serum aluminumevels and histological features of aluminum boneisease, who had repeat biopsies approximately2 months after all aluminum was with-
rawn.498,499 The close association between the t
eduction of surface stainable aluminum and themprovement of bone formation and mineraliza-ion rate499 is consistent with a “cause and ef-ect” relationship. Whether such patients wouldave had greater improvement after receivingFO treatment is uncertain. The lack of improve-ent of bone formation in the patients with

arlier parathyroidectomy499 is consistent withailure of bone histomorphometry to improve inFO-treated patients with symptomatic alumi-um bone disease.460

CLINICAL APPLICATIONSThe proper and early identification and treat-ent of aluminum toxicity, even that occurring

ccidentally via unusual contamination of dialy-ate or water, is now possible and safe using theow doses of DFO that are recommended. Al-hough prevention of aluminum toxicity is greatlyreferred, the early recognition and initiation ofggressive treatment might reduce the very highortality associated with acute aluminum neuro-

oxicity when patients are seen in the early phasesnd treated with daily, high-efficiency dialysisntil it is safe to begin DFO treatment. A clini-ian’s fear of using DFO, based entirely onroblems that occurred with use of DFO in dosesf 20-40 mg/kg, should give way to the timelyse of DFO when it is needed using a “safe” dosef 5 mg/kg, followed by dialysis using a high-fficiency dialysis membrane. These precautionsre designed to minimize any risk of side-effectsf the DFO treatment.

RECOMMENDATIONS FOR RESEARCHWith the great reduction of incidences of alu-inum toxicity, large clinical trials to evaluate

ts treatment are not likely to occur or to beossible. Some nephrologists still believe thatertain “low doses” of aluminum gels are indeedoth safe and effective to control serum phospho-us levels. It would be well to establish long-erm, prospective trials in such patients to assesshe safety of the treatment in comparison to otheronaluminum-based phosphate binders. There isittle doubt that aluminum-based phosphate bind-rs are more potent and effective in bindingietary phosphate, in comparison to similar dosesf other phosphate-binding agents.174

Very small and uncontrolled trials indicate
hat it is possible to give aluminum-based

bDpaemtdngcndn

isdwwe

psnwm


inders combined with very small doses ofFO (�1 mg/kg), and the investigators re-orted a slow, gradual reduction of serumluminum levels during such treatment.468 Oth-rs have shown that DFO in doses of 0.5-1.0g/kg increases the ultrafilterable (and hence

he dialyzable) level of serum aluminum inialysis patients with elevated serum alumi-um levels.467 These data provide the back-round for a potential prospective trial thatould test the safety and effectiveness of alumi-um gels combined with repeated, very lowoses of DFO in comparison to other nonalumi-
um-based phosphate binders. n
Investigators with interest in aluminum toxic-ty and its treatment need to collect additionaleries and cases where the DFO is given in “low”oses of 5 mg/kg BW or even less. Recognizinghether cases of mucormycosis will be seenith such doses and use of high-efficiency dialyz-

rs is also needed.In a population with substantial numbers of

atients with aluminum overload and minimalymptoms, controlled trials comparing total alumi-um withdrawal with DFO treatment would beorthwhile to prove the advantage of DFO treat-ent over total withdrawal of exposure to alumi-

um.

bcw11

1

1

chwtPdt

hr

A

GUIDELINE 14. TREATMENT OF BONE DISEASE IN CKD

cysuvTfd

8cotbt

btpoPgCitcvi

1

1

1

The treatment of bone disease in CKD isased on its specific type. This Guideline en-ompasses three parts: Guideline 14A dealsith high-turnover bone disease; Guideline4B with rickets/osteomalacia; and Guideline4C with adynamic bone disease.

GUIDELINE 14A.HYPERPARATHYROID

(HIGH-TURNOVER) BONE DISEASE

4A.1 In CKD patients who have serum PTHlevels >70 pg/mL (Stages 2-3) or >110pg/mL (Stage 4), dietary phosphateintake should be modified according toGuidelines 5 and 6, and dietary cal-cium should be modified according toGuideline 7. Nutritional vitamin D in-sufficiency or deficiency should be cor-rected according to Guideline 8. If arepeat 1st PTH-IMA after 3 months ofdietary intervention shows that PTHlevels remain elevated, then patientsshould be treated with calcitriol or1-�-vitamin D2 (EVIDENCE), to pre-vent or ameliorate high-turnover bonedisease.

4A.2 In CKD Stage 5 patients who haveelevated serum PTH levels (>300 pg/mL) despite modification of dietaryphosphate intake according to Guide-lines 5 and 6, calcitriol or 1-�-vitaminD2 (EVIDENCE) should be used toreverse the bone features of hyperpara-thyroidism (i.e., high-turnover bonedisease).

BACKGROUNDIn the untreated patient, studies in adults and

hildren with CKD Stage 5 have shown thatigh-turnover bone disease is often associatedith serum levels of PTH �300 pg/mL. High-

urnover bone disease may also be seen at similarTH values despite treatment with daily low-ose calcitriol or intermittent high-dose calcitriolherapy in CKD Stage 5.

RATIONALEThe understanding of bone disease in CKD

as evolved dramatically over the years. The
ecognition that hyperparathyroidism is a compli-

ation of kidney failure may predate by manyears the initiation of dialysis treatment. Earlytudies of osteodystrophy focused largely onnderstanding the pathophysiology and the pre-ention of severe hyperparathyroid bone disease.he development of more specific 1st PTH-IMA

acilitated more accurate classification of theifferent forms of renal osteodystrophy.

LIMITATIONSSee the corresponding section in Guidelines

A and 8B. There are no published data on theorrelation between PTH levels and bone histol-gy in children with CKD Stages 2-4. At thisime, there are no data to support the use ofisphosphonates in children with renal osteodys-rophy (see Guideline 16).

RECOMMENDATIONS FOR RESEARCHStudies are needed to evaluate the changes in

one histology, iPTH, and PTH fragments withhe available vitamin D analogs and other thera-eutic approaches for the treatment of renalsteodystrophy. The relationship among iPTH,TH fragments, vitamin D therapies, and linearrowth needs to be established in children withKD. The influence of GH in osteodystrophy is

ncompletely known at this time and needs fur-her study. Randomized clinical trials should beonducted in order to determine the effects ofitamin D therapies on bone histology and growthn children on maintenance dialysis.

GUIDELINE 14B.RICKETS/OSTEOMALACIA

4B.1 Rickets and osteomalacia due to alu-minum toxicity should be preventedin dialysis patients by maintainingaluminum concentration in dialysatefluid at <10 �g/L and by avoiding theuse of aluminum-containing com-pounds. (OPINION)

4B.2 Rickets and osteomalacia due to vita-min D deficiency should be treatedaccording to Guideline 7. (EVIDENCE)

4B.3 Rickets and osteomalacia due to hy-pophosphatemia should be treated withneutral sodium phosphate salts. Con-comitant active vitamin D therapyshould be considered. See Guidelines 7
and 8. (EVIDENCE)
ber), 2005: pp S87-S90 S87

iottHpbaeodrtoiD

rCcphdmdmmlDnRCTncaotcdao

a

oc

lmi

csncbnlmib

mcflblSo

1

GUIDELINE 14: TREATMENT OF BONE DISEASE IN CKDS88

BACKGROUNDAs aluminum accumulates on bone surfaces, it

mpairs bone formation, leading to either rickets,steomalacia, or adynamic bone disease. Sincehis was recognized and aluminum exposure cur-ailed, osteomalacia has largely disappeared.owever, patients may still be seen with thisroblem and its diagnosis and treatment need toe understood. If osteomalacia is found in thebsence of aluminum, it is often related to pre-xisting tubular defects of phosphate depletion,r vitamin D2 or D3 deficiency. While the inci-ence of aluminum bone disease has been greatlyeduced it still may occur and its diagnosis andreatment should be addressed. Osteomalacia mayccur in the absence of aluminum exposure ands often related to hypophosphatemia or vitamin

deficiency.

RATIONALEIn the late 1970s, it was documented that

ickets or osteomalacia occurred in patients withKD secondary to aluminum intoxication. Thelinical manifestations in children include boneain, bone deformities, deranged mineral ionomeostasis, and reduced linear growth. In chil-ren, aluminum toxicity may cause neurologicalanifestations, including seizures, microcephaly,

evelopment delays, and encephalopathy. Whenarked aluminum loading occurs, brain abnor-alities develop which, if untreated, are usually

ethal. Treatment with a chelating agent, such asFO, may improve patients’ bone disease andeurological abnormalities in children with CKD.ickets and osteomalacia occur in children withKD in the absence of aluminum intoxication.he avoidance of aluminum has largely elimi-ated aluminum-related osteomalacia as a clini-al problem in the dialysis population. Occasion-lly, dialysis patients may present withsteomalacia not associated with aluminum in-oxication. This may be due to vitamin D defi-iency, hypophosphatemia or metabolic acidosis,rugs (inducers of cytochrome P450 pathways),lcohol, calcium and/or phosphate deficiency, orther toxins.

STRENGTH OF EVIDENCEThere is compelling evidence of the role of

luminum in the development of rickets and

steomalacia. For detailed discussion, see theorresponding sections in Guidelines 11 and 12.

LIMITATIONSDue to the severe clinical outcome of osteoma-

acia and other complications resulting from alu-inum toxicity, no placebo-controlled studies of

ts treatment are possible.

CLINICAL APPLICATIONADFO challenge test (see Guidelines 12 and 13)

an often identify aluminum overload, but is notpecific for the presence of bone lesions. The diag-osis of bone aluminum accumulation and its asso-iated histological derangements requires a boneiopsy (see Guideline 12). Treatment approaches toonaluminum-related osteomalacia need to be tai-ored according to the underlying mechanism. Treat-

ent should be continued until clinical laboratoryndicators of osteomalacia and the associated meta-olic acidosis have disappeared.

RECOMMENDATIONS FOR RESEARCHAluminum accumulation in bone has becomeuch less frequent as the use of aluminum-

ontaining phosphate binders has declined. Un-ortunately, the calcium-based binders which haveargely replaced aluminum-containing phosphateinders may be associated with calcium over-oad, hypercalcemia, and vascular calcification.tudies need to evaluate the safety and efficacyf non-metal-containing phosphate binders.

GUIDELINE 14C. ADYNAMIC BONEDISEASE

4C.1 In CKD Stage 5, adynamic bone dis-ease not related to aluminum (as deter-mined either by bone biopsy or sug-gested by PTH <150 pg/mL) should betreated by allowing serum levels ofPTH to rise in order to increase boneturnover. (OPINION)14C.1.a The increase in PTH levels can

be accomplished by discontinu-ing treatment with activated vi-tamin D analogs, decreasing oreliminating the use of calcium-based phosphate binders, reduc-
ing the dialysate calcium concen-

iaAcoafia

pshsTlCatp

sdhcmtlthtrAtitdspewT

abbpebotctfbrol

Cediboistaatsbom

t5bcssofiemndot

GUIDELINE 14: TREATMENT OF BONE DISEASE IN CKD S89

tration (see Guideline 8)(EVIDENCE), and/or using ametal-free phosphate binder.(OPINION)

BACKGROUNDThe prevalence of adynamic bone disease has

ncreased with more frequent use of vitamin Dnalogs and calcium-based phosphate binders.dynamic bone disease has been reported in

hildren and adolescents receiving hemodialysisr peritoneal dialysis. The clinical sequelae ofdynamic bone disease are the risk of boneractures, impairment of linear growth, and thenability of adynamic bone to contribute to over-ll mineral ion homeostasis.

RATIONALEWith the use of high-dose calcium salts for

hosphate binding, and more frequent and aggres-ive vitamin D treatment, adynamic bone lesionsave become increasingly common as demon-trated by bone histomorphometric studies.514

he disease has been ascribed to insufficientevels of PTH (�150 pg/mL in patients withKD Stage 5) due to the use of active vitamin Dnalogs, chronic positive calcium in excess ofhat needed for growth, or following subtotalarathyroidectomy.22,327,515

Although blood levels of PTH (�150 pg/mL)trongly suggest the presence of adynamic boneisease, adynamic bone disease may occur atigher levels of PTH often associated with hyper-alcemia or hyperphosphatemia. Bone biopsyay therefore be required to establish or rule out

he diagnosis of adynamic bone disease. Accumu-ating data in adults with CKD Stage 5 suggesthat evidence for adynamic bone disease byistology is not benign. In this dialysis popula-ion, there is a four-fold increase in hip fractureisk compared to the general population.516,517

ge, duration of dialysis, female sex, and diabe-es appear to confer an increased risk for fracturen such patients. In children with CKD Stage 5,he clinical manifestations of adynamic boneisease are not well characterized. The singletudy in children that included bone histomor-hology demonstrated that adynamic bone dis-ase in the setting of high-dose calcitriol therapyas associated with impaired linear growth.518

he relatively inert, adynamic bone does not a

llow an appropriate deposition of calcium intoone and thus leads to impaired regulation oflood calcium. Because of the inability to de-osit calcium into bone, calcium loading (forxample, by oral calcium-containing phosphateinders or by loading through dialysate calcium)ften leads to marked hypercalcemia. In addi-ion, with the failure of the bone to accruealcium, other tissues such as the vascular sys-em become vulnerable to its accumulation in theorm of metastatic calcification. Indeed, it haseen demonstrated that a greater degree of arte-ial calcification in those patients with adynamicsteodystrophy is also evident in patients withow bone turnover.373

STRENGTH OF EVIDENCECalcium kinetic studies clearly show that adult

KD Stage 5 patients with adynamic bone dis-ase have decreased calcium accretion in bone,espite the fact that intestinal calcium absorptions similar in these patients and those with highone turnover.207 There are no controlled studiesn treatment of adynamic bone disease, thoughts consequences are troublesome. Indeed, moreevere growth retardation has been described inhose children that developed adynamic bonefter treatment with calcium-containing bindersnd intermittent calcitriol therapy. Recommenda-ions for therapy should be of the current under-tanding of the pathogenetic mechanisms of theone abnormalities as well as the abnormalitiesf the growth plate described in experimentalodels of adynamic bone.Bone densitometry and its relationship to frac-

ure is incompletely defined in adult CKD Stagepatients, though data continue to suggest that

one density is reduced and fracture rates in-reased. In the healthy population, there is atrong association between decreased bone den-ity and fractures. While adult patients withsteoporosis and normal renal function benefitrom treatment with intermittent PTH injections,t is not clear whether this approach would beffective in the context of CKD Stage 5. Further-ore, treatment with daily PTH injections should

ot be pursued in pediatric patients with CKDue to the risk of osteosarcoma, which wasbserved in rats treated intermittently with ex-remely high doses of synthetic PTH (see pack-
ge insert, Forteo™, Lilly Laboratories).

rbdfapbibtdcc

icbuddca

tusatncdil

cbusotfccsab

GUIDELINE 14: TREATMENT OF BONE DISEASE IN CKDS90

LIMITATIONSMuch of the data described above suggest a

elationship between relatively low PTH levels,one mass, and low bone turnover in the adultialysis population, leading to an increased riskor fractures. In addition, a greater degree ofrterial calcifications has been described in adultatients treated with hemodialysis and adynamicone. However, there are no published data ofncreased fracture rate in children, but adynamicone disease appears to be associated with fur-her impairment in longitudinal growth in chil-ren with CKD Stage 5 after treatment withalcium-containing binders and intermittent cal-itriol therapy.312

CLINICAL APPLICATIONAdynamic bone should be treated by increas-

ng bone turnover by allowing the serum PTHoncentration to rise to 200-300 pg/mL. This canest be accomplished by discontinuation of these of active vitamin D analogs and loweringoses of calcium-based phosphate binders asescribed in Guideline 8. The lowering of bathalcium (1.0-2.0 mEq/L) has also been suggested
s a possible approach. One published study of a
his therapy in a small number of adult patientsndergoing peritoneal dialysis did lead to a sub-tantial increase in PTH levels366; however, thispproach must be considered experimental athis point. Furthermore, the use of non-calcium,on-metal containg phosphate binders should beonsidered in those patients especially with evi-ence of vascular calcifications, in order to dimin-sh the potential role of the exogenous calciumoad in its progression.

RECOMMENDATIONS FOR RESEARCHThe long-term safety of lower dialysate cal-

ium concentration for treatment of adynamicone disease needs to be carefully studied. These of new phosphate binders should be carefullytudied in pediatric patients with CKD. More-ver, agents with a potential to increase boneurnover such as rhGH or PTH need to be studiedor the treatment of adynamic bone disease inhildren with CKD Stage 5. Manipulation of thealcium receptor with either calcilytics (whichtimulate PTH release and are not yet FDApproved) or calcimimetics (which suppress PTH,ut may lead to intermittent PTH release) may
lso become an important therapeutic approach.

1

1

1

A

GUIDELINE 15. PARATHYROIDECTOMY IN PATIENTS
WITH CKD
1

tattdptotapcrmahau

5.1 Parathyroidectomy should be consid-ered in patients with severe hyperpara-thyroidism (persistent serum levels ofPTH >1,000 pg/mL [1,000 ng/L]), anddisabling bone deformities associatedwith hypercalcemia and/or hyperphos-phatemia that are refractory to medicaltherapy. (OPINION)

5.2 Effective surgical therapy of severe hy-perparathyroidism can be accomplishedby subtotal parathyroidectomy or totalparathyroidectomy with parathyroid tis-sue autotransplantation. (EVIDENCE)15.2a Total parathyroidectomy prob-

ably is not the procedure ofchoice in patients who may sub-sequently receive a kidney trans-plant, since the subsequent con-trol of serum calcium levels maybe problematic.

5.3 In patients who undergo parathyroidec-tomy the following should be done:15.3.a In the 72 hours prior to parathy-

roidectomy, consideration shouldbe given to administration of cal-citriol or other active vitamin Dsterols, to lessen postoperative hy-pocalcemia.

15.3.b The blood level of ionized calciumshould be measured every 4-6hours for the first 24 hours aftersurgery, and then less frequentlyuntil less stable. (OPINION)

15.3.c If the level of ionized calcium fallsbelow normal (<1 mM or <4mg/dL, corresponding to cor-rected total calcium of 7.2 mg/dL[1.80 mmol/L]), a calcium glu-conate infusion should be initi-ated at a rate of 1-2 mg elementalcalcium per kilogram body weightper hour and adjusted to main-tain an ionized calcium in thenormal range (1.15-1.36 mM or4.6-5.4 mg/dL). (OPINION) A10-mL ampule of 10% calciumgluconate contains 90 mg of el-
emental calcium. t

15.3.d The calcium infusion should begradually reduced when the levelof ionized calcium attains the nor-mal range and remains stable.(OPINION)

15.3.e When oral intake is possible, thepatient should receive elementalcalcium 1-2 g, three times a day,as well as calcitriol 1-2 �g/day,and these therapies should be ad-justed as necessary to maintainthe level of ionized calcium in thenormal range. (OPINION)

15.3.f If the patient was receiving phos-phate binders prior to surgery,this therapy may need to be dis-continued or reduced as dictatedby the levels of serum phospho-rus. (OPINION)

5.4 Imaging of parathyroid glands with 99Tc-Sestamibi scan, ultrasound, CT scan, orMagnetic Resonance Imaging (MRI)should be done prior to re-explorationparathyroid surgery. (OPINION)

BACKGROUNDHyperparathyroidism is a common complica-

ion of CKD that results in significant morbiditynd warrants monitoring and therapy throughouthe course of kidney disease. The cornerstones ofhe treatment of hyperparathyroidism includeietary phosphate restriction, the use of phos-hate binders, correction of hypocalcemia, andhe use of vitamin D sterols. While the majorityf patients can be controlled in this way, medicalherapy is not always successful in achievingdequate control of 2° HPT. Accordingly, someatients require surgical parathyroidectomy toorrect the problem. Hyperparathyroidism is cur-ently most often assessed using PTH measure-ents from 1st PTH-IMA. Newer assays which

re more specific for the PTH 1-84 moleculeave been developed, and are becoming avail-ble, but warrant further study of their clinicaltility.

RATIONALEWhile medical therapy is often effective for

he control of hyperparathyroidism, surgical

ber), 2005: pp S91-S93 S91

tsspathmpda(sgcdfoeapIaoss

ptermnocire(pfftbptmubqr

utib

tswwcsptrtpnt

vtobiptwcc

fbiti

rwiute

tpo

GUIDELINE 15: PARATHYROIDECTOMY IN PATIENTS WITH CKDS92

herapy can provide effective reductions in theerum levels of PTH. In general, it is felt thaturgical parathyroidectomy is indicated in theresence of severe hyperparathyroidism associ-ted with hypercalcemia, which precludes fur-her approaches with medical therapy, and/oryperphosphatemia which also may precludeedical therapy with vitamin D sterols. The

resence and magnitude of the disabling boneeformities should be an additional consider-tion in the decision for parathyroidectomy.See Table 1 in Introduction.) In these circum-tances, surgical ablation of the parathyroidlands can provide effective therapy. The effi-acy of surgical parathyroidectomy is wellocumented.519-525 An additional indicationor surgical parathyroidectomy is the presencef calciphylaxis with PTH levels that are el-vated (�500 pg/mL [55.0 pmol/L]), as therere several reports of clinical improvement inatients with calciphylaxis after such therapy.t is important to emphasize, however, that notll patients with calciphylaxis have high levelsf PTH, and parathyroidectomy—in the ab-ence of documented hyperparathyroidism—hould not be undertaken.

There are many variations on the procedureerformed to accomplish surgical parathyroidec-omy, which include subtotal or total parathyroid-ctomy, with or without implantation of parathy-oid tissue (usually in the forearm). All of theseethods can result in satisfactory outcomes, and

o one technique appears to provide superiorutcomes.519-525 Accordingly, the choice of pro-edure may be at the discretion of the surgeonsnvolved. It is important to emphasize that, ifeimplantation of parathyroid tissue is consid-red, a portion of the smallest parathyroid glandi.e., one less likely to have severe nodular hyper-lasia) should be reimplanted. It would be help-ul if noninvasive assessments of parathyroidunction or of parathyroid mass were availablehat could predict whether medical therapy woulde helpful. There is insufficient evidence at theresent time to support this approach, althoughhere are some preliminary suggestions that thisight be helpful.526 Parathyroid imaging is not

sually required, preoperatively, although it maye helpful in cases where re-exploration is re-uired, such as persistent hypercalcemia or recur-
ent hyperparathyroidism.527-529 Of the methods i
sed, 99Tc-sestamibi with or without subtractionechniques appears to have the highest sensitiv-ty, although MRI, CT, and ultrasound have alsoeen regarded to be useful.526-528,530-538

STRENGTH OF EVIDENCEThe indications for surgical parathyroidec-

omy are not well defined and there are notudies to define absolute biochemical criteriahich would predict whether medical therapyill not be effective and surgery is required to

ontrol the hyperparathyroidism. There has beenome suggestion that those patients with largearathyroid mass might fail attempts at medicalherapy and, therefore, assessments of parathy-oid mass with ultrasonographic or radionuclideechniques could conceivably be useful as aredictor of efficacy of medical therapy. Unfortu-ately, there is insufficient evidence to supporthis at the present time.

The type of surgery performed has beenariable and, while subtotal parathyroidec-omy or total parathyroidectomy with or with-ut autotransplantation have all been shown toe successful, there are no comparative stud-es. Efficacy and recurrence rates are all com-arable. There is some concern that total para-hyroidectomy may not be suitable for patientsho will receive a kidney transplant since the

ontrol of serum calcium levels may be diffi-ult following kidney transplantation.

While some advocate parathyroid imagingor re-exploration surgery and have shown it toe useful in some cases, others do not feel thatt is necessary. There are no studies comparinghe results with and without preoperativemaging.

An alternative to surgical removal of parathy-oid glands has recently been introduced inhich parathyroid tissue is ablated by direct

njection of alcohol into the parathyroid glandnder ultrasound guidance. Additional long-erm studies with this technique are needed tovaluate its role in long-term therapy.539

LIMITATIONSIn the absence of firm criteria for surgery,

he use of different operations, the use ofarathyroidectomy in limited, selected groupsf patients, limited follow-up, and heterogene-
ty of the patients studied, it is difficult to

pc

capttbtctS

ritnnaaatabsa

GUIDELINE 15: PARATHYROIDECTOMY IN PATIENTS WITH CKD S93

rovide conclusive guidelines to address thisomplication of CKD.


Clearly, hyperparathyroidism is a frequentomplication of CKD which requires monitoringnd therapy. Many cases can be managed withhosphate control, calcium supplementation, andhe use of vitamin D sterols. Some, however, failhese measures and therefore, surgical ablationecomes an option which can effectively controlhe overactivity of the parathyroid, although re-urrence rates are high. There are no data abouthe use of calcimimetics in children with CKD
tage 5. i
RECOMMENDATIONS FOR RESEARCHThe monitoring and control of hyperparathy-

oidism remains a difficult problem and furthernformation is needed in several areas. Correla-ions of PTH values with bone histology areecessary in the current era. New PTH assayseed to be evaluated for their clinical utility. Theppropriate target values for PTH that arechieved by medical therapy need to be definednd related to bone histology. The appropriatearget values for PTH during the course of CKDt various stages of kidney dysfunction need toe defined. Comparative studies of medical andurgical therapy would be of interest. Novelpproaches to the control of hyperparathyroid-
sm will be forthcoming with calcimimetic agents.

1

1

ddgSgtotmpmtnory

nC

S

GUIDELINE 16. METABOLIC ACIDOSIS

sbmoe

tsCteeiaCirCcgatebcasldmcd

pwfbrsv

6.1 In CKD Stages 1-5, the serum level oftotal CO2 should be measured.16.1.a The frequency of these measure-

ments should be based on thestage of CKD as shown in Table19. (OPINION)

6.2 In patients >2 years of age, serum levelsof total CO2 should be maintained at>22 mEq/L (22 mmol/L); in neonatesand young infants below age two, serumlevels of total CO2 should be maintainedat >20 mEq/L (20 mmol/L). (EVI-DENCE) If necessary, supplemental al-kali salts should be given to achieve thisgoal. Elevation of the bicarbonate con-centration in the hemodialysis bath is anadditional or alternative strategy.(OPINION)

BACKGROUNDAcidosis is a common component of many

iseases of the kidney that affect the proximal oristal tubules, and is often present even whenlomerular function is relatively intact (CKDtages 1-2). Such diseases include inherited andenetic tubulopathies or acquired dysfunction ofhe tubules through, for example, the presence ofbstructive uropathies or recurrent pyelonephri-is. As glomerular function declines, acidosisay become more common and is uniformly

resent in CKD Stages 4-5. There is a develop-ental regulation of serum bicarbonate, such

hat values of �20 mEq/L (20 mmol/L) areormal for neonates and infants below two yearsf age, and values of 22 mEq/L (22 mmol/L)epresent the lower limit of normal after age 2ears.Chronic metabolic acidosis is a major compo-

ent of the linear growth failure associated withKD in infants and children with relatively pre-


erved GFR. The mechanisms whereby acidosislunts linear growth involve its effects on boneineral on the growth hormone-IGF-I axis, and

n renal synthesis of 1,25-(OH)2D, among oth-rs.

Classical studies in humans demonstratedhe powerful effect of chronic metabolic acido-is, induced experimentally or resulting fromKD, on the loss of bone mineral. Experimen-

al studies performed largely in animals fedxcess mineral acid, or bone organ culturesxposed to varying pH environments, havenvestigated mechanisms whereby chronic met-bolic acidosis alters bone composition.hronic metabolic acidosis produces a change

n the ionic composition of bone, with neteductions in apatite, sodium, and potassium.ellular functions within bone are changed byhronic metabolic acidosis, such that matrixene expression associated with osteoblasticctivity is inhibited, while osteoclastic activi-ies are increased. Additionally, the trophicffects of the growth hormone-IGF-I axis onone growth and structure are blunted withhronic metabolic acidosis. Chronic metaboliccidosis reduces the kidney proximal tubuleynthesis of 1,25(OH)2D, and may therebyimit the supply of calcium absorbed from theiet. Chronic metabolic acidosis alters the ho-eostatic relationships between blood ionized

alcium, PTH, and 1,25(OH)2D such that boneissolution is exaggerated.Chronic metabolic acidosis contributes, in

art, to the renal osteodystrophy in patientsith CKD. Rickets is the most common mani-

estation of chronic metabolic acidosis in theone of children with CKD Stages 1-3. Theickets may be cured by provision of alkalialts in some cases, but require supplementalitamin D or its analogs in others. In adults,


bfrrbhtaLmr

kitoaainlabaoelw

bptotCM(tiTeaba

cpvaetitt

GUIDELINE 16: METABOLIC ACIDOSIS S95

one fractures are a relatively common mani-estation of chronic metabolic acidosis. Moreecent studies in adults have demonstrated aeduction in bone mineral density, and in BFRs,y dynamic histomorphometry.540 Additionalistomorphometric analyses of bone in pa-ients with forms of chronic metabolic acidosisre quite limited, and remain controversial.inear growth in children is reduced by chronicetabolic acidosis and successful treatment

estores linear growth potential.541

RATIONALEThere is scant evidence per se, in patients with

idney failure (adult or pediatric) and undergo-ng maintenance dialysis, that either ameliora-ion or improvement of renal osteodystrophyccurs through elimination of chronic metaboliccidosis. However, a cross-sectional study of 76dult patients studied with percutaneous, trans-liac bone biopsy demonstrated that those with aormal biopsy result had a serum bicarbonateevel �23 mM while those with either mild ordvanced mixed osteodystrophy had serum bicar-onate levels �20 mM.542 It appears that thebsence of acidosis renders therapy of renalsteodystrophy with a vitamin D metabolite moreffective. Correction of metabolic acidosis al-ows normalization of linear growth in children
ith isolated renal tubular acidosis.541 b
CLINICAL APPLICATIONSMeasurement and monitoring of the serum

icarbonate level is warranted in patients withroximal or distal tubulopathies or acquiredubulo-interstitial renal disease (such as frombstructive uropathies or recurrent pyleonephri-is) regardless of glomerular filtration rates, inKD Stages 1-5, and with maintenance dialysis.easures to keep the bicarbonate level �22 mM

20 mM for the neonate and young infant belowwo years of age) are warranted for improvementn bone histology, and to improve linear growth.he clinician is reminded that the use of exog-nous alkali salts containing citrate increases thebsorption of aluminum in patients, and shoulde avoided as GFR declines into CKD Stage 3nd below (see Guideline 12).

RECOMMENDATIONS FOR RESEARCHAreas for future research into the effects of

hronic metabolic acidosis and renal osteodystro-hy include a fuller understanding of the calcium-itamin D-PTH and the growth hormone-IGF-Ixes in humans with CKD at the level of bone,specially at the growth plate. The role of newerherapeutic agents for treatment of osteoporosisn adults, such as bisphosphonates, selective es-rogen-receptor modulators, or isoflavones in pa-ients with CKD, with or without chronic meta-
olic acidosis, remains unknown.

1

1

1

1

obhrhlpmCtp

S

GUIDELINE 17. BONE DISEASE IN THE PEDIATRIC KIDNEY
TRANSPLANT RECIPIENT
H

cihdd(dttiitppaliw

C

bemtbddmothcbraa

7.1 Serum levels of calcium, phosphorus,total CO2 and PTH should be monitoredfollowing kidney transplantation. (OPIN-ION)17.1.a The frequency of these measure-

ments should be at least as oftenas shown in Table 20. (OPINION)

17.1.b Six months after transplantation,the frequency of measurementsshould follow the recommenda-tions of Table 2, Guideline 1,depending on the stage of CKD.

7.2 The care of osteodystrophy in kidneytransplant patients reaching CKD Stage2 and below should follow the guidelinesestablished for native CKD. (OPINION)

7.3 Kidney transplant recipients who de-velop persistent hypophosphatemia (be-low the age-appropriate lower limits)should be treated with phosphate supple-mentation. (OPINION)

7.4 To minimize bone mass loss and osteone-crosis, the lowest effective dose of glu-cocorticoids should be used. (OPINION)

BACKGROUND

Successful renal transplantation corrects manyf the underlying abnormalities contributing toone disease in children with CKD. However,ypophosphatemia, pre-existing hyperparathy-oidism, and glucocorticoid therapy may impairealing of renal bone disease and lead to boneoss. In addition, progressive damage to the trans-lanted kidney will result in CKD and bone andineral disorders comparable to the effects ofKD in the native kidney. Therefore, the kidney

ransplant recipient is at risk for multifactorial,rogressive bone disease.


ypophosphatemia

Hypophosphatemia is a frequent, early compli-ation of renal transplantation. The primary causes increased urinary phosphate loss and persistentyperparathyroidism.543 A recent series in adultsemonstrated that as many as 93% of patientsevelop moderate to severe hypophosphatemiaserum phosphate concentration 0.9-2.25 mg/L), an average of 5 weeks following transplan-ation.544 In the setting of good allograft func-ion, gradual decreases in serum PTH andmprovements in allograft tubular function resultn normalization of serum phosphate concentra-ions within months. Hypophosphatemia mayersist as a late complication in patients withrolonged hyperparathyroidism.188 Numerousdult studies have demonstrated incomplete reso-ution of hyperparathyroidism and persistentlyncreased bone turnover in long-term recipientsith good renal function.545,546

orticosteroid-Induced Osteopenia

The pathogenesis of corticosteroid-inducedone loss is multifactorial and has been reviewedxtensively in the adult literature.547 The pri-ary mechanism of glucocorticoid-induced os-

eopenia is decreased bone formation by osteo-lasts due to a decreased work rate and aecreased active life span of osteoblasts. Animalata from a rat model suggest that cyclosporineay induce a high-turnover osteopenia with loss

f trabecular bone,548 potentially compoundinghe bone toxicities of glucocorticoid therapy andyperparathyroidism. It is well-recognized thatorticosteroids result in rapid loss of trabecularone in adults; however, the effects of corticoste-oids, cyclosporin A and tacrolimus on trabecularnd cortical bone mineral accretion during growthre not known.


H

lrmsIrtolpppeP

C

ssripCnbioecgnHamrcC

H

iwc1fc

vt5

IT

fcaftpsmitrdsccattdtpifinspsro

isiastzcsdq

GUIDELINE 17: BONE DISEASE IN THE PEDIATRIC KIDNEY TRANSPLANT RECIPIENT S97

RATIONALE

ypophosphatemia

Severe hypophosphatemia may result in hemo-ytic anemia, impaired cardiac contractility andespiratory insufficiency. Therefore, it is com-on practice to supplement with oral phosphate

alts in patients with severe hypophosphatemia.n adults, a preliminary study assessed phosphateeplacement for moderate hypophosphatemia inhe early post-transplant period, and the impactn serum calcium, PTH, and acid/base metabo-ism. Oral supplementation with neutral sodiumhosphate (Na2HPO4) effectively corrected hy-ophosphatemia, increased muscular ATP andhosphodiester content, and improved renal acidxcretion without any adverse effect on serumTH levels.

KD in the Transplanted Kidney

There are no available data on the clinicalequelae of bone disease in children with progres-ive CKD due to allograft failure in the setting ofenal transplantation. However, progressive CKDn the allograft will likely set in motion the sameathophysiological abnormalities observed withKD in the native kidney. In addition, the combi-ation of glucocorticoid-induced suppression ofone formation and hyperparathyroid-inducedncreases in bone resorption result in uncouplingf bone. This likely has particularly devastatingffects on bone modeling and bone mineral ac-rual during growth. Glucocorticoids may impairastrointestinal calcium absorption, resulting inegative calcium balance and exacerbating 2°PT. Therefore, the child with progressive CKD

nd a kidney transplant requires ongoing assess-ent and treatment of serum calcium, phospho-

us, PTH, serum bicarbonate and 25(OH)D con-entrations, consistent with the guidelines forKD in the native kidney.


ypophosphatemia

We are unaware of any investigations examin-ng the incidence of hypophosphatemia in theeeks immediately following transplantation in

hildren. One study recently described a series of6 children evaluated at 3, 6, and 12 monthsollowing transplantation. Serum phosphate con-
entrations were not decreased at these inter- w
als.549 The median serum phosphate concentra-ion at 3 months was 3.99 mg/dL, range 3.16-.54 mg/dL.

mpaired Bone Mineralization Followingransplantation in Children

While there are numerous DXA studies of boneollowing transplantation in children, only one in-luded bone histomorphometry.372 This study evalu-ted 47 children and adolescents with stable renalunction an average of 3.2 years after transplanta-ion.372 Eleven of 47 children had PTH values �65g/mL and four exceeded 100 pg/mL. Bone biop-ies revealed that 31 transplant recipients had nor-al bone formation, 11 had mild hyperparathyroid-

sm, and five had adynamic skeletal lesions. Neitherhe interval since transplantation, serum PTH, se-um creatinine, nor the cumulative prednisone dosesiffered according to histological subgroups. De-pite normal bone formation rates (BFRs) in manyhildren, all three subgroups demonstrated in-reased eroded bone perimeter, increased osteoidrea, and increased osteoid perimeter. Hyperpara-hyroidism improved or resolved after transplanta-ion in all 14 subjects with high-turnover boneisease prior to transplantation; however, one pa-ient developed an adynamic lesion following trans-lantation. Bone histology did not change follow-ng transplantation among those with normal boneormation prior to transplantation. Bone formationmproved in two of the three children with ady-amic bone disease prior to transplantation. Inummary, most—but not all—skeletal lesions im-rove substantially in pediatric patients undergoinguccessful transplantation; however, concern isaised over residual hyperparathyroidism or devel-pment of adynamic bone disease in a few.

Studies of bone using DXA in children follow-ng transplantation have yielded conflicting re-ults, largely related to the difficulties in interpret-ng DXA results in children with delayed growthnd development.35,372,549-551 One study first de-cribed bone loss in children following renalransplantation.552 Bone mineral content (BMC)-scores were less than -2.0 in 11 of 18 (62%)hildren. Children receiving daily steroid demon-trated significantly greater bone loss than chil-ren on alternate-day steroid treatment. A subse-uent longitudinal study of DXA measures of
hole body BMC following renal transplanta-

tf-dSrOomevhBccAz(wgattcl

C

ifdstainvrtr

art1shps

ma

B

enCeg

cctdttppptot

ctf

●

●

●

●

●

●

GUIDELINE 17: BONE DISEASE IN THE PEDIATRIC KIDNEY TRANSPLANT RECIPIENTS98

ion in 16 children showed that BMC decreasedrom the initial z-score of 0.98 to a z-score of0.55 three months after transplant.549 A furtherecrease was noted at the end of month 6 (-1.34D) and month 12 (-1.32 SD). These studieselated bone mineralization to chronologic age.thers have investigated the possible influencef height and weight retardation on the measure-ent of BMD in pediatric transplantation recipi-

nts.35 Only one patient had low values forertebral BMD when the data were corrected foreight or weight. The authors concluded thatMD among pediatric renal transplantation re-ipients is not diminished when the data areorrected for height or weight, rather than age.nother study reported similar results372: BMD

-scores for age were significantly decreased-0.67 � 1.2); however, BMD z-scores for heightere above normal in all three histological sub-roups (0.68 � 1.0). This may be a misleadingpproach since shorter controls will be less ma-ure than the patients with CKD. With the excep-ion of a case series of fractures in children withystinosis,553 there are no data on fractures fol-owing transplantation in children.

orticosteroid-Induced Osteopenia

There are currently no data available address-ng the impact of different corticosteroid doses orormulations on bone mineral accretion in chil-ren with a kidney transplant. None of the DXAtudies reviewed above demonstrated a consis-ent relationship between glucocorticoid therapynd bone mass. However, glucocorticoid therapys a major factor in the development of osteope-ia in adult transplantation recipients, as re-iewed in the adult guidelines. Therefore, it isecommended that clinicians use the lowest effec-ive dose of corticosteroids necessary to preserveenal function.

Prior studies have suggested that calcium andctive vitamin D therapy may lessen corticoste-oid-induced bone loss in non-transplant pa-ients.554,555 A recent randomized clinical trial in11 adult renal transplant recipients demon-trated that low-dose (0.25 �g/day) 1-�-ydroxyvitamin D plus calcium (1,000 mg/day)artially prevented the bone loss at the lumbar
pine and proximal femur during the first six
onths following renal transplantation.556 Therere no data in children.

isphosphonate Therapy

The effects of bisphosphonate therapy on skel-tal modeling and bone mineral accretion haveot been adequately addressed in children withKD. There are no data assessing the safety andfficacy of these drugs in children with CKD orlucocorticoid-induced osteoporosis.

LIMITATIONS

As outlined above, DXA studies of bone inhildren following transplantation have yieldedonflicting results, largely related to the difficul-ies in interpreting DXA results in children withelayed growth and development. Furthermore,here are no data assessing the prevalence andiming of hypophosphatemia in the immediateost-transplant interval, risk factors for hypophos-hatemia in children, or the efficacy of phos-hate supplementation. Finally, there are no con-rolled studies, either clinical trials or controlledbservational studies, examining bone disease inhe pediatric renal transplant recipient.

RESEARCH RECOMMENDATIONS

Bone disease may not regress completely inhildren following successful kidney transplanta-ion. Future research is needed to address theollowing issues:

Do children with renal osteodystrophy recovercortical bone dimensions and trabecular archi-tecture following transplantation with a func-tioning allograft?What is the impact of transplantation duringchildhood and adolescence on peak bone mass?Does supplementation with calcium and vita-min D following transplantation decrease pro-gressive bone loss?Are the bisphosphonates safe and effective inchildren following transplantation? What arethe effects of bisphosphonates on bone model-ing and growth in children?Does GH following transplantation affect bonemineral accretion?What is the best method to evaluate bonemineralization in children? Do DXA results
predict fracture risk?

lnbhwtWarbj

ItmcOaa

itiorsrbaC

rec

A

AFTERWORD

itd

dcfst

vtbotwIthl

gfimcpkwbP

Since the time of our last committee meetings,ong and frequent telecommunications, and late-ight E-mail communiqués, additional drugs haveecome available for the treatment of secondaryyperparathyroidism and hyperphosphatemia thatill have an impact in the field of renal osteodys-

rophy in children with chronic kidney disease.e would like to highlight such developments

nd suggest that the next group of experts whoeviews the care of pediatric osteodystrophy wille forthcoming with guidelines about these sub-ects.

VITAMIN D ANALOGUESA) Doxercalciferol (Hectorol ®, Bone Care

nternational R, Madison, WI) was approved byhe Food and Drug Administration for the treat-ent of osteodystrophy in adult patients with

hronic kidney disease stages 2-5, in April 2004.ral soft gelatin formulations (2.5 mcg; 0.5 mcg)

nd a parenteral formulation (2 mcg/mL) arevailable. Its structure is shown below:

Doxercalciferol acts as a pro-hormone, need-ng 25-hydroxylation in the liver for bioactiva-ion into 1�, 25-hydroxyvitamin D2. Pivotal stud-es in adults on dialysis have demonstrated controlf secondary hyperparathyroidism that is supe-ior to placebo therapy, without undue suppres-ion of 1st IMA-PTH � 300 pg/mL, or occur-ences of hypercalcemia. Doxercalciferol haseen shown to be effective in controlling second-ry hyperparathyroidism of adult patients withKD stages 3-4.Use in children is not yet FDA approved, but

ecent data demonstrated that oral doxercalcif-rol given thrice-weekly is as effective as
alcitriol in reducing PTH levels and improv- b

ng the skeletal lesions of secondary hyperpara-hyroidism in children treated with peritonealialysis. 163a

B) Paricalcitol ( Zemplar ®, or 19-nor-1�,25-ihydroxvitamin D3, Abbot Laboratories, Chi-ago, IL) has been available as a parenteralormulation for some time for patients with CKDtage 5, and is now available as 1-4 micrograms.ablets Its structure is shown below.

Paricalcitol is a synthetic, biologically activeitamin D analog of calcitriol with modificationo the side chain (D2) and the A (19-nor) ring. Itsiological actions are mediated through bindingf the vitamin D receptor, which results in selec-ive activation of vitamin D-responsive path-ays. Paricalcitol has been shown to reduce 1st

MA-PTH by inhibiting PTH synthesis and secre-ion in adult patients undergoing maintenanceemodialysis.321 Use in children remains unpub-ished.

CALCIMIMETIC AGENTSCinacalcet hydrochloride (Sensipar®, Am-

en, Thousand Oaks, CA) ) is a calcimimetic, therst of a new class of pharmacologic agents thatodulate the actions of the membrane-anchored

alcium-sensing receptor (CaSR) located on thearathyroid cells. The CaSR is also located in theidney tubules, as well as many other cellsithin the body. Activation of the CaSR, whethery calcium or by a calcimimetic agent, reducesTH secretion. The reduction in PTH diminishes
one resorption and is thus associated with a
ber), 2005: pp S99-S100 S99

cp

fiacydresc

I(Laahpr

llmft

nptpl

AFTERWORDS100

oncomitant decrease in serum calcium and phos-horus levels.Its structure is shown below.

Cinacalcet hydrochloride has been approvedor the treatment of secondary hyperparathyroid-sm of stage 5 CKD (maintenance dialysis) indults. Its pharmacokinetics are being studied inhildren on maintenance dialysis, but no data areet available. At present, there is no recommen-ation regarding the use of cinacalcet hydrochlo-ide in children with CKD. As the eCaSR) isxpressed at the level of the growth plate, theafety of cinacalcet hydrochloride in growing
hildren remains to be demonstrated. h
PHOSPHATE BINDER

Lanthanum carbonate (Fosrenol ®, Shire USnc., Wayne, PA) contains lanthanum carbonate2:3) hydrate with a molecular formula ofa2(CO3)3 xH2O (on average, x�4-5) and servess a dietary phosphate binder. Lanthanum carbon-te inhibits absorption of phosphate by formingighly insoluble lanthanum-phosphate com-lexes and thereby reduces both serum phospho-us and the Ca � P product in patients with CKD.

In 105 adults with kidney failure treated withanthanum carbonate for up to 4-5 years, risingevels of lanthanum were noted over time. Esti-ates of elimination half-life from bone ranged

rom 2-3.6 years. Steady-state bone concentra-ions were not reached during the period studied.

There are no studies in children on mainte-ance dialysis. Further, the current FDA-ap-roved label for lanthanum carbonate indicateshat lanthanum can be found in the growthlate.557 Therefore, we do not recommend use ofanthanum carbonate for the chronic treatment of
yperphosphatemia in children.

CCKcKCcaopfntprtJfHBCntPPcSEUohtCmciNtH

CSUraahth

A

BIOGRAPHICAL SKETCHES OF WORK GROUP MEMBERS

swdlvibNoct

aPsioea“TTtWtWfJosOMW

fBicdBssipTlho

raig B. Langman, MD (Work Groupo-Chair), is the Isaac A. Abt MD Professor ofidney Disease at the Feinberg School of Medi-

ine at Northwestern University and Head ofidney Diseases and Director of Dialysis athildren’s Memorial Medical Center in Chi-ago. Dr Langman’s research has focused on thenatomical, biochemical and clinical expressionf inherited or acquired disorders of calcium,hosphorus and vitamin D metabolism in in-ants, children, and adolescents. He has pio-eered the use of noninvasive testing in childreno assess bone cell function. Dr Langman hasublished more than 160 articles, chapters, andeviews in his discipline and currently serves ashe Senior Associate Editor for the Americanournal of Nephrology and on the Editorial Boardor the Journal for Bone and Mineral Research.e previously served on the Editorial Advisoryoard of Pediatric Nephrology, Advances inhronic Kidney Disease and Pediatric Endocri-ology. Dr Langman has served as President ofhe American Board of Pediatrics sub board ofediatric Nephrology, the American Society ofediatric Nephrology, and the Council of Ameri-an Kidney Societies. He has served on thecientific Advisory Board, Public Policy, and thexecutive Committee of the Council of Pediatricrology and Nephrology Committees, amongthers, of the National Kidney Foundation. Heas also served on the Growth Advisory Board ofhe North American Pediatric Renal Transplantooperative Study. He serves as a consultant forany pharmaceutical laboratories, health care

ompanies, and health care related Foundations,ncluding Merck USA, Roche Pharmaceuticals,ovartis, Genentech, Amgen, Bone Care Interna-

ional, Abbott Laboratories, and the Oxalosis andyperoxaluria Foundation.Isidro B. Salusky, MD, FAAP (Work Group

o-Chair), is Professor of Pediatrics at UCLAchool of Medicine, Program Director of theCLA General Clinic Research Center, and Di-

ector of the Pediatric Dialysis Program. He haslong-standing interest in the fields of growth

nd nutrition in children with renal failure thatas ranged from experimental models to patientsreated with maintenance dialysis. Dr Salusky
as done extensive work to characterize the P

yndromes of renal osteodystrophy in childrenith chronic renal failure undergoing regularialysis and postrenal transplantation. Dr Sa-usky has published more than 150 papers and isery active in many professional societies. Dur-ng the course of these studies, Dr Salusky haseen successful in obtaining funding from theational Institutes of Health, as well as fromther profit and nonprofit organizations. He is aonsultant for Genzyme, Inc, Bone Care Interna-ional, and Abbott Laboratories.

Larry Greenbaum, MD, PhD, is the Associ-te Professor of Pediatrics and Vice Chair of theediatric IRB at the Medical College of Wiscon-in in Milwaukee, WI. He has been a principalnvestigator for multicenter studies in the areasf pediatric dialysis and transplantation. He co-dited the textbook Practical Strategies in Pedi-tric Diagnosis and Therapy and has written thePathophysiology of Body Fluids and Fluidherapy” section for the next edition of Nelsonextbook of Pediatrics. His research on nutri-ional rickets has led to policy changes in the

isconsin WIC program. He has received mul-iple teaching awards at the Medical College of

isconsin and UCLA. He has been a revieweror numerous journals, including the Americanournal of Kidney Disease, Pediatric Nephrol-gy and Peritoneal Dialysis International. Heerves on the Medical Advisory Board of thexalosis and Hyperoxaluria Foundation and theedical Advisory Committee of the NKF ofisconsin.Harald Jueppner, MD, is the Associate Pro-

essor of Pediatrics at Harvard Medical School inoston, Massachusetts. A researcher interested

n areas such as bone and mineral homeostasis,artilage and bone development and uremic boneisease, Dr Jueppner also serves as Associateiologist and Associate Pediatrician at the Mas-

achusetts General Hospital in Boston. He haserved as an invited guest speaker in numerousnternational symposiums including the Euro-ean Renal Association– European Dialysis andransplantation Association in Geneva, Switzer-

and and the International Bone Forum in Yoko-ama, Japan. Dr Jueppner is the author of numer-us scientific papers in his field and is the
resident of Advance in Mineral Metabolism.
ber), 2005: pp S101-S102 S101

sdSoUssiorohRcStNoN

DSaspgrnpnpSAon

rosp

iapctaenhtAP

oaoKcddDed(ripdtablDoaAanC

WORK GROUP BIOGRAPHIESS102

Mary Leonard, MD, is the Assistant Profes-or of Pediatrics and Epidemiology at The Chil-ren’s Hospital of Philadelphia. She is also aenior Scholar at Center for Clinical Epidemiol-gy and Biostatistics (CCEB) and serves on thenited States Renal Data System Scientific Advi-

ory Committee. Dr Leonard has special re-earch interest in the assessment of bone liberal-zation in children, glucocorticoid-inducedsteoporosis in children, structural effects ofenal osteodystrophy during growth, and dialysisutcomes in children. She has received grants forer research in areas such as Structural Effects ofenal Osteodystrophy During Growth and Glu-ocorticoid-Induced Osteoporosis in Children.he is also an active member several organiza-

ions including the American Society of Pediatricephrology, the International Pediatric Nephrol-gy Association and the American Society ofephrology.Pauline Nelson, RD, is the Pediatric Renal

ietitian at the UCLA Center for the Healthciences, working with children in the inpatientnd outpatient settings on all modalities of end-tage renal disease (ESRD) care. She has partici-ated in many clinical research studies related torowth and nutrition, especially in the areas ofecombinant human growth hormone and perito-eal dialysis. Ms Nelson has written numerousrofessional and lay papers on various aspects ofutrition in ESRD, with a particular emphasis onractical approaches to the delivery of nutrients.he has been active in the American Dieteticssociation and the Council on Renal Nutritionf the National Kidney Foundation on local andational levels.Anthony Portale, MD, is Professor of Pediat-

ics, Chief of Pediatric Nephrology, and Directorf the Pediatric Dialysis Program at the Univer-ity of California San Francisco Children’s Hos-
ital. Dr Portale’s clinical and research focus is B
nherited and acquired disorders of phosphorusnd vitamin D metabolism, renal osteodystro-hy, and metabolic bone disease in infants andhildren. He has done extensive work to charac-erize the physiologic regulation of phosphorusnd vitamin D metabolism in individuals and inxperimental models. Dr Portale has publishedumerous scientific papers and book chapters inis field, and serves on the editorial boards forhe Journal of Bone and Mineral Research, themerican Journal of Nephrology, and Clinicalediatric Endocrinology.Bradley A. Warady, MD, is Chief of Nephrol-

gy and Director of Dialysis and Transplantationt The Children’s Mercy Hospital, and Professorf Pediatrics at the University of Missouri-ansas City School of Medicine. Dr Warady’s

linical and research focus is end-stage renalisease with particular emphasis on peritonealialysis. He established the Pediatric Peritonealialysis Study Consortium, and he is on the

xecutive committee of the North American Pe-iatric Renal Transplant Cooperative StudyNAPRTCS). He currently directs or co-directsesearch projects on a number of topics includ-ng: growth hormone usage in pediatric dialysisatients; peritoneal dialysis adequacy in chil-ren; intravenous iron therapy in pediatric pa-ients receiving hemodialysis, and anemia man-gement in children on dialysis. He co-edited theook CAPD/CCPD in Children and has pub-ished more than 180 articles and book chapters.r Warady serves on the executive committeesf the American Society of Pediatric Nephrologynd the Nephrology section of the Americancademy of Pediatrics. Dr Warady also serves as

n Associate Editor for Peritoneal Dialysis Inter-ational, an Assistant Editor for Advances inhronic Kidney Disease, and sits on the Editorial
oard for Pediatric Nephrology.

c2

IhmP

2rv

oV

BsS

tCS

gk

aI

u2

JFb3

d4

sph

Hm1

Jho1

Bht2

A

REFERENCES

Rgs2

PbA

wsA

AVcp

Ar

isf

SoC

Syt

Arc

Morl

Ghp2

PS

ZmM

p1

1. Bachrach LK: Acquisition of optimal bone mass inhildhood and adolescence. Trends Endocrinol Metab 12:22-8, 20012. Klaus G, Jux C, Leiber K, Hugel U, Mehls O:

nteraction between insulin-like growth factor I, growthormone, parathyroid hormone, 1 alpha,25-dihydroxyvita-in D3 and steroids on epiphyseal chondrocytes. Actaaediatr Suppl 417:69-71, 19963. Langman CB, Mazur AT, Baron R, Norman ME:

5-hydroxyvitamin D3 (calcifediol) therapy of juvenileenal osteodystrophy: beneficial effect on linear growthelocity. J Pediatr 100:815-820, 19824. Krempien B, Mehls O, Ritz E: Morphological studies

n pathogenesis of epiphyseal slipping in uremic children.irchows Arch A Pathol Anat Histol 362:129-143, 19745. Schober HC, Han ZH, Foldes AJ, Shih MS, Rao DS,

alena R, Parfitt AM: Mineralized bone loss at differentites in dialysis patients: implications for prevention. J Amoc Nephrol 9:1225-1233, 19986. National Kidney Foundation. K/DOQI Clinical Prac-

ice Guidelines for Chronic Kidney Disease: Evaluation,lassification and Stratification. Am J Kidney Dis 39:S1-000, 2002 (suppl 1)7. Manjunath G, Sarnak MJ, Levey AS: Estimating the

lomerular filtration rate. Dos and don’ts for assessingidney function. Postgrad Med. Dec;110:55-62, 20018. Malluche HH, Faugere MC: Effects of 1,25(OH)2D3

dministration on bone in patients with renal failure. Kidneynt Suppl 29:S48-S53, 1990

9. Malluche H, Faugere MC: Renal bone disease 1990: annmet challenge for the nephrologist. Kidney Int 38:193-11, 199010. Hamdy NA, Kanis JA, Beneton MN, Brown CB,

uttmann JR, Jordans JG, Josse S, Meyrier A, Lins RL,airey IT: Effect of alfacalcidol on natural course of renalone disease in mild to moderate renal failure. BMJ10:358-363, 199511. Goodman WG, Coburn JW: The use of 1,25-

ihydroxyvitamin D3 in early renal failure. Annu Rev Med3:227-237, 199212. de Caestecker MP, Bottomley M, Telfer BA, Hutchin-

on IV, Vose BM, Ballardie FW: Detection of abnormaleripheral blood mononuclear cell cytokine networks inuman IgA nephropathy. Kidney Int 44:1298-1308, 199313. Feldman HI, Held PJ, Hutchinson JT, Stoiber E,

artigan MF, Berlin JA: Hemodialysis vascular accessorbidity in the United States. Kidney Int 43:1091-1096,

99314. Hutchison AJ, Whitehouse RW, Boulton HF, Adams

E, Mawer EB, Freemont TJ, Gokal R: Correlation of boneistology with parathyroid hormone, vitamin D3, and radiol-gy in end-stage renal disease. Kidney Int 44:1071-1077,99315. Gerakis A, Hutchison AJ, Apostolou T, Freemont AJ,

illis A: Biochemical markers for non-invasive diagnosis ofyperparathyroid bone disease and adynamic bone in pa-ients on haemodialysis. Nephrol Dial Transplant 11:2430-
438, 1996 a

16. Quigg RJ, Brathwaite M, Gardner DF, Gretch DR,uddy S: Successful cyclophosphamide treatment of cryo-lobulinemic membranoproliferative glomerulonephritis as-ociated with hepatitis C virus infection. Am J Kidney Dis5:798-800, 199517. Qi Q, Monier-Faugere MC, Geng Z, Malluche HH:

redictive value of serum parathyroid hormone levels forone turnover in patients on chronic maintenance dialysis.m J Kidney Dis 26:622-631, 199518. Block GA, Port FK: Re-evaluation of risks associated

ith hyperphosphatemia and hyperparathyroidism in dialy-is patients: recommendations for a change in management.m J Kidney Dis 35:1226-1237, 200019. Urena P, Ferreira A, Kung VT, Morieux C, Simon P,

ng KS, Souberbielle JC, Segre GV, Drueke TB, Deernejoul MC: Serum pyridinoline as a specific marker ofollagen breakdown and bone metabolism in hemodialysisatients. J Bone Miner Res 10:932-939, 199520. Norman ME, Mazur AT, Borden S 4th, Gruskin A,

nast C, Baron R, Rasmussen H: Early diagnosis of juvenileenal osteodystrophy. J Pediatr 97:226-232, 1980

21. Martinez I, Saracho R, Montenegro J, Llach F: Themportance of dietary calcium and phosphorous in theecondary hyperparathyroidism of patients with early renalailure. Am J Kidney Dis 29:496-502, 1997

22. Salusky IB, Ramirez JA, Oppenheim W, Gales B,egre GV, Goodman WG: Biochemical markers of renalsteodystrophy in pediatric patients undergoing CAPD/CPD. Kidney Int 45:253-258, 199423. Mathias R, Salusky I, Harman W, Paredes A, Emans J,

egre G, Goodman W: Renal bone disease in pediatric andoung adult patients on hemodialysis in a children’s hospi-al. J Am Soc Nephrol 3:1938-1946, 1993

24. Ziolkowska H, Paniczyk-Tomaszewska M, Debinski, Polowiec Z, Sawicki A, Sieniawska M: Bone biopsy

esults and serum bone turnover parameters in uremichildren. Acta Paediatr 89:666-671, 2000

25. Solal ME, Sebert JL, Boudailliez B, Marie A,oriniere P, Gueris J, Bouillon R, Fournier A: Comparison

f intact, midregion, and carboxy terminal assays of parathy-oid hormone for the diagnosis of bone disease in hemodia-yzed patients. J Clin Endocrinol Metab 73:516-524, 1991

26. Wang M, Hercz G, Sherrard DJ, Maloney NA, SegreV, Pei Y: Relationship between intact 1-84 parathyroidormone and bone histomorphometric parameters in dialysisatients without aluminum toxicity. Am J Kidney Dis6:836-844, 199527. Huraib S, Souqqiyeh MZ, Aswad S, al-Swailem AR:

attern of renal osteodystrophy in haemodialysis patients inaudi Arabia. Nephrol Dial Transplant 8:603-608, 199328. DeVita MV, Rasenas LL, Bansal M, Gleim GW,

abetakis PM, Gardenswartz MH, Michelis MF: Assess-ent of renal osteodystrophy in hemodialysis patients.edicine (Baltimore) 71:284-290, 199229. Eastwood JB: Quantitative bone histology in 38

atients with advanced renal failure. J Clin Pathol 35:125-34, 198230. Hasselblad V, Hedges LV: Meta-analysis of screening

nd diagnostic tests. Psychol Bull 117:167-178, 1995

ber), 2005: pp S103-S121 S103

oJ2

Bsc

FsJ

Mh1

MdN

Et

Ht1

Csr1

Cts

Btc

HMb

stp

Fh2

f

KMlA9

do

cr

p9

c1

CB

rJ

hvS

or

Ft

Rop

t5

ed

EA

fnO

t

fp

ne1

Sc

REFERENCESS104

31. World Health Organization diagnostic criteria forsteoporosis and trends in Europe and USA. Nippon Rinsho.apanese Journal of Clinical Medicine Feb;62:235-239,004 (Suppl 2)32. Leonard MB, Feldman HI, Zemel BS, Berlin JA,

arden EM, Stallings VA: Evaluation of low density spineoftware for the assessment of bone mineral density inhildren. J Bone Miner Res 13:1687-1690, 1998

33. Leonard MB, Propert KJ, Zemel BS, Stallings VA,eldman HI: Discrepancies in pediatric bone mineral den-ity reference data: potential for misdiagnosis of osteopenia.Pediatr 135:182-188, 199934. Molgaard C, Thomsen BL, Prentice A, Cole TJ,ichaelsen KF: Whole body bone mineral content in

ealthy children and adolescents. Arch Dis Child 76:9-15,99735. Klaus G, Paschen C, Wuster C, Kovacs GT, Barden J,ehls O, Scharer K: Weight-/height-related bone mineral

ensity is not reduced after renal transplantation. Pediatrephrol 12:343-348, 199836. Kim MS, Kim YS, Lim SK, Kim SI, Moon JI, Park K:

ffect of deflazacort on bone mineral density in renalransplant recipients. Transplant Proc 30:3041-3042, 1998

37. Hurst G, Alloway R, Hathaway D, Somerville T,ughes T, Gaber A: Stabilization of bone mass after renal

ransplant with preemptive care. Transplant Proc 30:1327-328, 199838. Aroldi A, Tarantino A, Montagnino G, Cesana B,

ocucci C, Ponticelli C: Effects of three immunosuppres-ive regimens on vertebral bone density in renal transplantecipients: a prospective study. Transplantation 63:380-386,99739. Pichette V, Bonnardeaux A, Prudhomme L, Gagne M,

ardinal J, Ouimet D: Long-term bone loss in kidneyransplant recipients: a cross-sectional and longitudinaltudy. Am J Kidney Dis 28:105-114, 1996

40. Setterberg L, Sandberg J, Elinder CG, Nordenstrom J:one demineralization after renal transplantation: contribu-

ion of secondary hyperparathyroidism manifested by hyper-alcaemia. Nephrol Dial Transplant 11:1825-1828, 1996

41. Yazawa K, Ishikawa T, Ichikawa Y, Shin J, Usui Y,anafusa T, Fukunishi T, Sakai R, Nagano S, Fujita N,izuno K: Positive effects of kidney transplantation on

one mass. Transplant Proc 30:3031-3033, 199842. Torres A, Lorenzo V, Gonzalez-Posada JM: Compari-

on of histomorphometry and computerized tomography ofhe spine in quantitating trabecular bone in renal osteodystro-hy. Nephron 44:282-287, 198643. Glorieux FH, Travers R, Taylor A, Bowen JR, Rauch

, Norman M, Parfitt AM: Normative data for iliac boneistomorphometry in growing children. Bone 26:103-109,00044. Mehls O, Ritz E, Gilli G, Kreusser W: Growth in renal

ailure. Nephron 21:237-247, 197845. Castaneda C, Gordon PL, Uhlin KL, Levey AS,

ehayias JJ, Dwyer JT, Fielding RA, Roubenoff R, SinghF: Resistance training to counteract the catabolism of a

ow-protein diet in patients with chronic renal insufficiency.randomized, controlled trial. Ann Intern Med 135:965-

76, 2001 h

46. Davids JR, Fisher R, Lum G, Von Glinski S: Angulareformity of the lower extremity in children with renalsteodystrophy. J Pediatr Orthop 12:291-299, 199247. Oppenheim WL, Fischer SR, Salusky IB: Surgical

orrection of angular deformity of the knee in children withenal osteodystrophy. J Pediatr Orthop 17:41-49, 1997

48. Apel DM, Millar EA, Moel DI: Skeletal disorders in aediatric renal transplant population. J Pediatr Orthop:505-511, 198949. Barrett IR, Papadimitriou DG: Skeletal disorders in

hildren with renal failure. J Pediatr Orthop 16:264-272,99650. Beskin JL, Burke SW, Johnston CE 2nd, Roberts JM:

linical basis for a mechanical etiology in adolescentlount’s disease. Orthopedics 9:365-370, 198651. Blockey NJ, Murphy AV, Mocan H: Management of

achitic deformities in children with chronic renal failure.Bone Joint Surg Br 68:791-794, 198652. Evans GA, Arulanantham K, Gage JR: Primary

ypophosphatemic rickets. Effect of oral phosphate anditamin D on growth and surgical treatment. J Bone Jointurg Am 62:1130-1138, 198053. Fine RN, Isaacson AS, Payne V, Grushkin CM: Renal

steodystrophy in children: the effect of hemodialysis andenal homotransplantation. J Pediatr 80:243-249, 1972

54. Mehls O, Ritz E, Oppermann HC, Guignard JP:emoral head necrosis in uremic children without steroid

reatment or transplantation. J Pediatr 99:926-929, 198155. Rubinovitch M, Said SE, Glorieux FH, Cruess RL,

ogala E: Principles and results of corrective lower limbsteotomies for patients with vitamin D-resistant hypophos-hatemic rickets. Clin Orthop:264-270, 198856. Salenius P, Vankka E: The development of the

ibiofemoral angle in children. J Bone Joint Surg Am7:259-261, 197557. Loder RT, Hensinger RN: Slipped capital femoral

piphysis associated with renal failure osteodystrophy. J Pe-iatr Orthop 17:205-211, 199758. Mehls O, Ritz E, Krempien B, Gilli G, Link K, Willich

, Scharer K: Slipped epiphyses in renal osteodystrophy.rch Dis Child 50:545-554, 197559. Swierstra BA, Diepstraten AF, vd Heyden BJ: Distal

emoral physiolysis in renal osteodystrophy. Successfulonoperative treatment of 3 cases followed for 5 years. Actarthop Scand 64:382-384, 199360. Tebor GB, Ehrlich MG, Herrin J: Slippage of the distal

ibial epiphysis. J Pediatr Orthop 3:211-215, 198361. Hartjen CA, Koman LA: Treatment of slipped capital

emoral epiphysis resulting from juvenile renal osteodystro-hy. J Pediatr Orthop 10:551-554, 199062. Oppenheim WL, Bowen RE, McDonough PW, Fu-

ahashi TT, Salusky IB: Outcome of slipped capital femoralpiphysis in renal osteodystrophy. J Pediatr Orthop 23:169-74, 200363. Boechat MI, Winters WD, Hogg RJ, Fine RN, Watkins

L: Avascular necrosis of the femoral head in children withhronic renal disease. Radiology 218:411-413, 2001

64. Watkins SL: Bone disease in patients receiving growth
ormone. Kidney Int Suppl 53:S126-S127, 1996

AJ

niM

t

OC

t

m1

Bf6

Aa4

rdp

E1hJ

ocp1

MP

PfD

Dpr9

Ya7

BEyi

Rmd

Cic

Adp

Ar

Apa

paf

Gc9

Ppr1

MvE

Rc

pfet1

cbA

Qcc

bm1

F

REFERENCES S105

65. Harrington KD, Murray WR, Kountz SL, Belzer FO:vascular necrosis of bone after renal transplantation.Bone Joint Surg Am 53:203-215, 197166. Ibels LS, Alfrey AC, Huffer WE, Weil R 3rd: Aseptic

ecrosis of bone following renal transplantation: experiencen 194 transplant recipients and review of the literature.

edicine (Baltimore) 57:25-45, 197867. Stern PJ, Watts HG: Osteonecrosis after renal transplan-

ation in children. J Bone Joint Surg Am 61:851-856, 197968. Davidson JK, Tsakiris D, Briggs JD, Junor BJ:

steonecrosis and fractures following renal transplantation.lin Radiol 36:27-35, 198569. Murray WR: Hip problems associated with organ

ransplants. Clin Orthop 90:57-69, 197370. Brodehl J, Gellissen K, Weber HP: Postnatal develop-ent of tubular phosphate reabsorption. Clin Nephrol 17:163-

71, 198271. Burritt MF, Slockbower JM, Forsman RW, Offord KP,

ergstralh EJ, Smithson WA: Pediatric reference intervalsor 19 biologic variables in healthy children. Mayo Clin Proc5:329-336, 199072. Arnaud SB, Goldsmith RS, Stickler GB, McCall JT,

rnaud CD: Serum parathyroid hormone and blood miner-ls: interrelationships in normal children. Pediatr Res 7:485-93, 197373. Greenberg BG, Winters RW, Graham JB: The normal

ange of serum inorganic phosphorus and its utility as aiscriminant in the diagnosis of congenital hypophos-hatemia. J Clin Endocrinol Metab 20:364-379, 196074. Portale AA, Booth BE, Halloran BP, Morris RC Jr:

ffect of dietary phosphorus on circulating concentrations of,25-dihydroxyvitamin D and immunoreactive parathyroidormone in children with moderate renal insufficiency.Clin Invest 73:1580-1589, 198475. Portale AA, Halloran BP, Morris RC Jr: Dietary intake

f phosphorus modulates the circadian rhythm in serumoncentration of phosphorus. Implications for the renalroduction of 1,25-dihydroxyvitamin D. J Clin Invest 80:147-1154, 1987

76. Markowitz ME, Rosen JF, Laxminarayan S, Mizruchi: Circadian rhythms of blood minerals during adolescence.

ediatr Res 18:456-462, 198477. Naveh-Many T, Rahamimov R, Livni N, Silver J:

arathyroid cell proliferation in normal and chronic renalailure rats. The effects of calcium, phosphate, and vitamin. J Clin Invest 96:1786-1793, 199578. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong M,

usso A, MacDonald PN, Brown AJ: Phosphorus restrictionrevents parathyroid gland growth. High phosphorus di-ectly stimulates PTH secretion in vitro. J Clin Invest7:2534-2540, 199679. Kimura K, Saika Y, Otani H, Fujii R, Mune M,

ukawa S: Factors associated with calcification of thebdominal aorta in hemodialysis patients. Kidney Int Suppl1:S238-S241, 199980. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales

, Sider D, Wang Y, Chung J, Emerick A, Greaser L,lashoff RM, Salusky IB: Coronary-artery calcification inoung adults with end-stage renal disease who are undergo-
ng dialysis. N Engl J Med 342:1478-1483, 2000 2
81. Mazhar AR, Johnson RJ, Gillen D, Stivelman JC,yan MJ, Davis CL, Stehman-Breen CO: Risk factors andortality associated with calciphylaxis in end-stage renal

isease. Kidney Int 60:324-332, 200182. Ahmed S, O’Neill KD, Hood AF, Evan AP, Moe SM:

alciphylaxis is associated with hyperphosphatemia andncreased osteopontin expression by vascular smooth muscleells. Am J Kidney Dis 37:1267-1276, 2001

83. Marchais SJ, Metivier F, Guerin AP, London GM:ssociation of hyperphosphataemia with haemodynamicisturbances in end-stage renal disease. Nephrol Dial Trans-lant 14:2178-2183, 199984. Guerin AP, London GM, Marchais SJ, Metivier F:

rterial stiffening and vascular calcifications in end-stageenal disease. Nephrol Dial Transplant 15:1014-1021, 2000

85. Block GA, Hulbert-Shearon TE, Levin NW, Port FK:ssociation of serum phosphorus and calcium x phosphateroduct with mortality risk in chronic hemodialysis patients:national study. Am J Kidney Dis 31:607-617, 199886. Lowrie EG, Lew NL: Death risk in hemodialysis

atients: the predictive value of commonly measured vari-bles and an evaluation of death rate differences betweenacilities. Am J Kidney Dis 15:458-482, 1990

87. Blacher J, Guerin AP, Pannier B, Marchais SJ, LondonM: Arterial calcifications, arterial stiffness, and cardiovas-

ular risk in end-stage renal disease. Hypertension 38:938-42, 200188. Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T,

ort FK: Association of elevated serum PO(4), Ca x PO(4)roduct, and parathyroid hormone with cardiac mortalityisk in chronic hemodialysis patients. J Am Soc Nephrol2:2131-2138, 200189. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y,ori K, Morii H, Giachelli CM: Phosphate regulation of

ascular smooth muscle cell calcification. Circ Res 87:E10-17, 200090. Rostand SG, Sanders C, Kirk KA, Rutsky EA, Fraser

G: Myocardial calcification and cardiac dysfunction inhronic renal failure. Am J Med 85:651-657, 1988

91. Katz AI, Hampers CL, Merrill JP: Secondary hyper-arathyroidism and renal osteodystrophy in chronic renalailure. Analysis of 195 patients, with observations on theffects of chronic dialysis, kidney transplantation and subto-al parathyroidectomy. Medicine (Baltimore) 48:333-374,96992. Raggi P, Reinmuller R, Chertow GM: Cardiac calcifi-

ation is prevalent and severe in ESRD patients as measuredy electron beam CT scanning. J Am Soc Nephrol Abstract0405:75A, 200093. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P,

uerfeld U, Mehls O, Schaefer F: Advanced coronary andarotid arteriopathy in young adults with childhood-onsethronic renal failure. Circulation 106:100-105, 2002

94. Greene SV, Falciglia G, Rademacher R: Relationshipetween serum phosphorus levels and various outcomeeasures in adult hemodialysis patients. J Ren Nutr 8:77-82,

99895. Greenbaum LA: Pathophysiology of Body Fluids and

luid Therapy, 17th ed. Philadelphia, PA, Elsevier Science,
004

Ri2

JruA

JrcM

Ka

hE

Ao

Csi1

Gds1

Hi1

Sc

ss1

Sr

2jh1

Dt

Vo

D

s2

Bt(

MM

Cs2

Wtc

Rr1

EMdl1

Hdb

T2

srcS

dK

Ha

RpSF

pt3

CpN

J

REFERENCESS106

96. Portale AA, Booth BE, Tsai HC, Morris RC, Jr.:educed plasma concentration of 1,25-dihydroxyvitamin D

n children with moderate renal insufficiency. Kidney Int1:627-632, 198297. Massry SG, Coburn JW, Popovtzer MM, Shinaberger

H, Maxwell MH, Kleeman CR: Secondary hyperparathy-oidism in chronic renal failure. The clinical spectrum inremia, during hemodialysis, and after renal transplantation.rch Intern Med 124:431-441, 196998. Llach F, Massry SG, Singer FR, Kurokawa K, Kaye

H, Coburn JW: Skeletal resistance to endogenous parathy-oid hormone in patients with early renal failure. A possibleause for secondary hyperparathyroidism. J Clin Endocrinoletab 41:339-345, 197599. von Lilienfeld-Toal H, Gerlach I, Klehr HU, Issa S,

eck E: Immunoreactive parathyroid hormone in early anddvanced renal failure. Nephron 31:116-122, 1982

100. Llach F, Massry SG: On the mechanism of secondaryyperparathyroidism in moderate renal insufficiency. J Clinndocrinol Metab 61:601-606, 1985101. Wilson L, Felsenfeld A, Drezner MK, Llach F:

ltered divalent ion metabolism in early renal failure: rolef 1,25(OH)2D. Kidney Int 27:565-573, 1985102. Tessitore N, Venturi A, Adami S, Roncari C, Rugiu

, Corgnati A, Bonucci E, Maschio G: Relationship betweenerum vitamin D metabolites and dietary intake of phosphaten patients with early renal failure. Miner Electrolyte Metab3:38-44, 1987103. Pitts TO, Piraino BH, Mitro R, Chen TC, Segre GV,

reenberg A, Puschett JB: Hyperparathyroidism and 1,25-ihydroxyvitamin D deficiency in mild, moderate, andevere renal failure. J Clin Endocrinol Metab 67:876-881,988104. Malluche HH, Ritz E, Lange HP, Kutschera L,

odgson M, Seiffert U, Schoeppe W: Bone histology inncipient and advanced renal failure. Kidney Int 9:355-362,976105. Hodson EM, Evans RA, Dunstan CR, Hills EE,

haw PF: Quantitative bone histology in children withhronic renal failure. Kidney Int 21:833-839, 1982

106. Friis T, Hahnemann S, Weeke E: Serum calcium anderum phosphorus in uraemia during administration ofodium phytate and aluminium hydroxide. Acta Med Scand83:497-505, 1968107. Coburn JW, Koppel MH, Brickman AS, Massry SG:

tudy of intestinal absorption of calcium in patients withenal failure. Kidney Int 3:264-272, 1973

108. Taylor A, Norman ME: Interrelationship of serum5-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D inuvenile renal osteodystrophy after therapy with 25-ydroxyvitamin D3. Metab Bone Dis Relat Res 4:255-261,982109. Chesney RW, Hamstra AJ, Mazess RB, Rose P,

eLuca HF: Circulating vitamin D metabolite concentra-ions in childhood renal diseases. Kidney Int 21:65-69, 1982

110. Mason RS, Lissner D, Wilkinson M, Posen S:itamin D metabolites and their relationship to azotaemicsteodystrophy. Clin Endocrinol (Oxf) 13:375-385, 1980111. Christiansen C, Christensen MS, Melsen F, Rodbro P,

eLuca HF: Mineral metabolism in chronic renal failure with o

pecial reference to serum concentrations of 1.25(OH)2D and4.25(OH)2D. Clin Nephrol 15:18-22, 1981

112. Juttmann JR, Visser TJ, Buurman C, de Kam E,irkenhager JC: Seasonal fluctuations in serum concentra-

ions of vitamin D metabolites in normal subjects. Br Med JClin Res Ed) 282:1349-1352, 1981

113. Tessitore N, Lund B, Bonucci E, Sorensen OH,aschio G: Vitamin D metabolites in early renal failure.inerva Nefrol 28:293-297, 1981114. Cheung AK, Manolagas SC, Catherwood BD, Mosely

A Jr, Mitas JA 2nd, Blantz RC, Deftos LJ: Determinants oferum 1,25(OH)2D levels in renal disease. Kidney Int4:104-109, 1983115. Lucas PA, Brown RC, Bloodworth L, Jones CR,oodhead JS: Effects of chronic renal failure, renal transplan-

ation and unilateral nephrectomy on 1,25-dihydroxychole-alciferol. Berlin, Walter de Gruyter, 1985

116. Prince RL, Hutchison BG, Kent JC, Kent GN,etallack RW: Calcitriol deficiency with retained synthetic

eserve in chronic renal failure. Kidney Int 33:722-728,988117. Ishimura E, Nishizawa Y, Inaba M, Matsumoto N,

moto M, Kawagishi T, Shoji S, Okuno S, Kim M, Miki T,orii H: Serum levels of 1,25-dihydroxyvitamin D, 24,25-

ihydroxyvitamin D, and 25-hydroxyvitamin D in nondia-yzed patients with chronic renal failure. Kidney Int 55:1019-027, 1999118. Turner C, Compston J, Mak RH, Vedi S, Mellish RW,

aycock GB, Chantler C: Bone turnover and 1,25-ihydroxycholecalciferol during treatment with phosphateinders. Kidney Int 33:989-995, 1988119. Tenenhouse HS, Murer H: Disorders of Renal

ubular Phosphate Transport. J Am Soc Nephrol 14:240-47, 2003121. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hun-

icker L, Kusek JW, Striker G: The effects of dietary proteinestriction and blood-pressure control on the progression ofhronic renal disease. Modification of Diet in Renal Diseasetudy Group. N Engl J Med 330:877-884, 1994122. The Modification of Diet in Renal Disease Study:

esign, methods, and results from the feasibility study. Am Jidney Dis 20:18-33, 1992123. Malvy D, Maingourd C, Pengloan J, Bagros P, Nivet

: Effects of severe protein restriction with ketoanalogues indvanced renal failure. J Am Coll Nutr 18:481-486, 1999

124. Wingen AM, Fabian-Bach C, Schaefer F, Mehls O:andomised multicentre study of a low-protein diet on therogression of chronic renal failure in children. Europeantudy Group of Nutritional Treatment of Chronic Renalailure in Childhood. Lancet 349:1117-1123, 1997125. Herselman MG, Albertse EC, Lombard CJ, Swane-

oel CR, Hough FS: Supplemented low-protein diets–arehey superior in chronic renal failure? S Afr Med J 85:361-65, 1995126. D’Amico G, Gentile MG, Fellin G, Manna G,

ofano F: Effect of dietary protein restriction on therogression of renal failure: a prospective randomized trial.ephrol Dial Transplant 9:1590-1594, 1994127. Dullaart RP, Beusekamp BJ, Meijer S, van Doormaal

J, Sluiter WJ: Long-term effects of protein-restricted diet
n albuminuria and renal function in IDDM patients without

c4

JAc

Ftt1

RccS

ssd

CcC

Kp1

EmO

FatM

GEgi1

ab2

KfI

Pr

pfi

fcC

ct

Mwp1

e

Mi3

BN

cmc

CS

TLdR

MDh1

Tor

hwPC

GLpD

lmtK

Ano1

N

REFERENCES S107

linical nephropathy and hypertension. Diabetes Care 16:483-92, 1993128. Kist-van Holthe tot Echten JE, Nauta J, Hop WC, de

ong MC, Reitsma-Bierens WC, Ploos van Amstel SL, vancker KJ, Noordzij CM, Wolff ED: Protein restriction in

hronic renal failure. Arch Dis Child 68:371-375, 1993129. Williams PS, Stevens ME, Fass G, Irons L, Bone JM:

ailure of dietary protein and phosphate restriction to retardhe rate of progression of chronic renal failure: a prospec-ive, randomized, controlled trial. Q J Med 81:837-855,991130. Locatelli F, Alberti D, Graziani G, Buccianti G,

edaelli B, Giangrande A: Prospective, randomised, multi-entre trial of effect of protein restriction on progression ofhronic renal insufficiency. Northern Italian Cooperativetudy Group. Lancet 337:1299-1304, 1991131. Zeller K, Whittaker E, Sullivan L, Raskin P, Jacob-

on HR: Effect of restricting dietary protein on the progres-ion of renal failure in patients with insulin-dependentiabetes mellitus. N Engl J Med 324:78-84, 1991132. Forget D, Caranhac G, Quillot MJ, Besnier MO:

ompliance with very low protein diet and ketoanalogues inhronic renal failure. The French Multicentric Trial IRCCA.ontrib Nephrol 81:79-86, 1990133. Ihle BU, Becker GJ, Whitworth JA, Charlwood RA,

incaid-Smith PS: The effect of protein restriction on therogression of renal insufficiency. N Engl J Med 321:1773-777, 1989134. Mahmoud MD, Bouche V, Collin P, Girault A:

ffects of keto-analogues on phosphocalcic and aminoacidetabolism in dialysed patients: a crossover study. Int J Artifrgans 12:692-696, 1989135. Ando A, Orita Y, Nakata K, Fukuhara Y, Mikami H,

ujii M, Nakajima Y, Ueda N, Abe H: The effect of essentialmino acid supplementation therapy on prognosis of pa-ients with chronic renal failure estimated on the basis of the

arkov process. Med J Osaka Univ 32:31-37, 1981136. Barsotti G, Lazzeri M, Polloni A, Morelli E,

iovannetti E, Lupetti S, Cupisti A, Dani L, Giovannetti S:ffects of the impairment of renal function and of the pH ofastric secretion on the efficacy of Al(OH)3 to reduce serumnorganic phosphorus. Adv Exp Med Biol 208:493-499,986137. Meisinger E, Strauch M: Controlled trial of two keto

cid supplements on renal function, nutritional status, andone metabolism in uremic patients. Kidney Int Suppl2:S170-S173, 1987138. Schmicker R, Vetter K, Lindenau K, Frohling PT,

okot F: Conservative long-term treatment of chronic renalailure with keto acid and amino acid supplementation.nfusionsther Klin Ernahr 14:34-38, 1987 (suppl 5)

139. Gentile MG, Manna GM, Ferrario L, D’Amico G:reliminary experience on dietary management of chronicenal failure. Contrib Nephrol 53:102-108, 1986

140. Drueke TB: Primary and secondary uraemic hyper-arathyroidism: from initial clinical observations to recentndings. Nephrol Dial Transplant 13:1384-1387, 1998141. Recker RR, Saville PD: Calcium absorption in renal

ailure: its relationship to blood urea nitrogen, dietaryalcium intake, time on dialysis, and other variables. J Lab
lin Med 78:380-388, 1971 c
142. Hosking DJ, Chamberlain MJ: Calcium balance inhronic renal failure. A study using in vivo neutron activa-ion analysis. Q J Med 42:467-479, 1973

143. Popovtzer MM, Massry SG, Makoff DL, MaxwellH, Kleeman CR: Renal handling of phosphate in patientsith chronic renal failure. The role of variations in serumhosphorus and parathyroid activity. Isr J Med Sci 5:1018-023, 1969144. Suzuki M, Hirasawa Y: Renal osteodystrophy in

arly chronic renal failure. Contrib Nephrol 22:28-38, 1980145. Better OS, Kleeman CR, Gonick HC, Varrady PD,axwell MH: Renal handling of calcium, magnesium and

norganic phosphate in chronic renal failure. Isr J Med Sci:60-79, 1967146. Cochran M, Bulusu L, Horsman A, Stasiak L, Nordin

E: Hypocalcaemia and bone disease in renal failure.ephron 10:113-140, 1973147. Duursma SA, Visser WJ, Mees EJ, Njio L: Serum

alcium, phosphate and alkaline phosphatase and morpho-etric bone examinations in 30 patients with renal insuffi-

iency. Calcif Tissue Res 16:129-138, 1974148. London GM, Pannier B, Marchais SJ, Guerin AP:

alcification of the aortic valve in the dialyzed patient. J Amoc Nephrol 11:778-783, 2000149. Milas NC, Nowalk MP, Akpele L, Castaldo L, Coyne

, Doroshenko L, Kigawa L, Korzec-Ramirez D, ScherchK, Snetselaar L: Factors associated with adherence to theietary protein intervention in the Modification of Diet inenal Disease Study. J Am Diet Assoc 95:1295-1300, 1995150. Foret M, Renversez JC, Meftahi H, Kuentz F,ilongo R, Hachache T, Vallin J, Dechelette E, Cordonnier: How far can plasmatic levels of beta-2-microglobulin inemodialysis be relied upon? Contrib Nephrol 62:54-59,988151. Jureidini KF, Hogg RJ, van Renen MJ, Southwood

R, Henning PH, Cobiac L, Daniels L, Harris S: Evaluationf long-term aggressive dietary management of chronicenal failure in children. Pediatr Nephrol 4:1-10, 1990

152. Uauy RD, Hogg RJ, Brewer ED, Reisch JS, Cunning-am C, Holliday MA: Dietary protein and growth in infantsith chronic renal insufficiency: a report from the Southwestediatric Nephrology Study Group and the University ofalifornia, San Francisco. Pediatr Nephrol 8:45-50, 1994153. Kopple JD, Levey AS, Greene T, Chumlea WC,

assman JJ, Hollinger DL, Maroni BJ, Merrill D, ScherchK, Schulman G, Wang SR, Zimmer GS: Effect of dietaryrotein restriction on nutritional status in the Modification ofiet in Renal Disease Study. Kidney Int 52:778-791, 1997154. Coggins CH, Dwyer JT, Greene T, Petot G, Snetse-

aar LG, Van Lente F: Serum lipid changes associated withodified protein diets: results from the feasibility phase of

he Modification of Diet in Renal Disease Study. Am Jidney Dis 23:514-523, 1994155. Combe C, Deforges-Lasseur C, Caix J, Pommereau

, Marot D, Aparicio M: Compliance and effects ofutritional treatment on progression and metabolic disordersf chronic renal failure. Nephrol Dial Transplant 8:412-418,993156. Cianciaruso B, Capuano A, D’Amaro E, Ferrara N,

astasi A, Conte G, Bellizzi V, Andreucci VE: Dietary
ompliance to a low protein and phosphate diet in patients

w1

rK

Bpp

Jpp2

Khd

cc

Epdr

Rp1

PcccJ

Aa

Af

Ahc

Gc3

Ht

Sp3

Fa1

Kpu

Pa

SsD

Npi

WnoT

GhJ

is

Rpa

3

iiJ

Oc1

vamD

Eb1

LSbtA

Wa

REFERENCESS108

ith chronic renal failure. Kidney Int Suppl 27:S173-176,989157. Clinical practice guidelines for nutrition in chronic

enal failure. K/DOQI, National Kidney Foundation. Am Jidney Dis 35:S1-S140, 2000158. Wallot M, Bonzel KE, Winter A, Georger B, Lettgen

, Bald M: Calcium acetate versus calcium carbonate as oralhosphate binder in pediatric and adolescent hemodialysisatients. Pediatr Nephrol 10:625-630, 1996159. Sieniawska M, Roszkowska-Blaim M, Weglarska J,

ablczynska A, Welc-Dobies J: Calcium carbonate as ahosphate binder in children on continuous ambulatoryeritoneal dialysis and hemodialysis. Mater Med Pol 23:203-08, 1991160. Tamanaha K, Mak RH, Rigden SP, Turner C, Start

M, Haycock GB, Chantler C: Long-term suppression ofyperparathyroidism by phosphate binders in uremic chil-ren. Pediatr Nephrol 1:145-149, 1987161. Andreoli SP, Dunson JW, Bergstein JM: Calcium

arbonate is an effective phosphorus binder in children withhronic renal failure. Am J Kidney Dis 9:206-210, 1987

162. Salusky IB, Coburn JW, Foley J, Nelson P, Fine RN:ffects of oral calcium carbonate on control of serumhosphorus and changes in plasma aluminum levels afteriscontinuation of aluminum-containing gels in childreneceiving dialysis. J Pediatr 108:767-770, 1986

163. Mahdavi H, Kuizon BD, Gales B, Wang HJ, ElashoffM, Salusky IB: Sevelamer hydrochloride: an effectivehosphate binder in dialyzed children. Pediatr Nephrol8:1260-1264, 2003163a. Salusky IB, Goodman WG, Sahney S, Gales B,

erilloux A, Wang HJ, Elashoff RM, Juppner H: Sevelamerontrols parathyroid hormone-induced bone disease as effi-iently as calcium carbonate without increasing serumalcium levels during therapy with active vitamin D sterols.Am Soc Nephrol 16:2501-2508, 2005164. Sedman AB, Wilkening GN, Warady BA, Lum GM,

lfrey AC: Encephalopathy in childhood secondary toluminum toxicity. J Pediatr 105:836-838, 1984

165. Sedman AB, Miller NL, Warady BA, Lum GM,lfrey AC: Aluminum loading in children with chronic renal

ailure. Kidney Int 26:201-204, 1984166. Salusky IB, Foley J, Nelson P, Goodman WG:

luminum accumulation during treatment with aluminumydroxide and dialysis in children and young adults withhronic renal disease. N Engl J Med 324:527-531, 1991

167. Lefebvre A, de Vernejoul MC, Gueris J, Goldfarb B,raulet AM, Morieux C: Optimal correction of acidosis

hanges progression of dialysis osteodystrophy. Kidney Int6:1112-1118, 1989168. Mauro LS, Kuhl DA, Kirchhoff JR, Mauro VF,

amilton RW: Impact of oral bases on aluminum absorp-ion. Am J Ther 8:21-25, 2001

169. Mai ML, Emmett M, Sheikh MS, Santa Ana CA,chiller L, Fordtran JS: Calcium acetate, an effectivehosphorus binder in patients with renal failure. Kidney Int6:690-695, 1989170. Schiller LR, Santa Ana CA, Sheikh MS, Emmett M,

ordtran JS: Effect of the time of administration of calciumcetate on phosphorus binding. N Engl J Med 320:1110-
113, 1989 N
171. Slatopolsky E, Weerts C, Lopez-Hilker S, Norwood, Zink M, Windus D, Delmez J: Calcium carbonate as ahosphate binder in patients with chronic renal failurendergoing dialysis. N Engl J Med 315:157-161, 1986172. Balasa RW, Murray RL, Kondelis NP, Bischel MD:

hosphate-binding properties and electrolyte content ofluminum hydroxide antacids. Nephron 45:16-21, 1987

173. Emmett M, Sirmon MD, Kirkpatrick WG, Nolan CR,chmitt GW, Cleveland MB: Calcium acetate control oferum phosphorus in hemodialysis patients. Am J Kidneyis 17:544-550, 1991174. Sheikh MS, Maguire JA, Emmett M, Santa Ana CA,

icar MJ, Schiller LR, Fordtran JS: Reduction of dietaryhosphorus absorption by phosphorus binders. A theoretical,n vitro, and in vivo study. J Clin Invest 83:66-73, 1989

175. Rosenbaum DP, Holmes-Farley SR, MandevilleH, Pitruzzello M, Goldberg DI: Effect of RenaGel, a

on-absorbable, cross-linked, polymeric phosphate binder,n urinary phosphorus excretion in rats. Nephrol Dialransplant 12:961-964, 1997176. Tom A, McCauley L, Bell L, Rodd C, Espinosa P, Yu

, Yu J, Girardin C, Sharma A: Growth during maintenanceemodialysis: impact of enhanced nutrition and clearance.Pediatr 134:464-471, 1999177. Raj DS, Charra B, Pierratos A, Work J: In search of

deal hemodialysis: is prolonged frequent dialysis the an-wer? Am J Kidney Dis 34:597-610, 1999

178. Mucsi I, Hercz G, Uldall R, Ouwendyk M, Francoeur, Pierratos A: Control of serum phosphate without anyhosphate binders in patients treated with nocturnal hemodi-lysis. Kidney Int 53:1399-1404, 1998

179. Alfrey AC: Aluminum intoxication. N Engl J Med10:1113-1115, 1984180. Andreoli SP, Bergstein JM, Sherrard DJ: Aluminum

ntoxication from aluminum-containing phosphate bindersn children with azotemia not undergoing dialysis. N EnglMed 310:1079-1084, 1984181. Alon U, Davidai G, Bentur L, Berant M, Better OS:

ral calcium carbonate as phosphate-binder in infants andhildren with chronic renal failure. Miner Electrolyte Metab2:320-325, 1986182. Birck R, Zimmermann E, Wassmer S, Nowack R,

an der Woude FJ: Calcium ketoglutarate versus calciumcetate for treatment of hyperphosphataemia in patients onaintenance haemodialysis: a cross-over study. Nephrolial Transplant 14:1475-1479, 1999183. Lerner A, Kramer M, Goldstein S, Caruana R,

pstein S, Raja R: Calcium carbonate. A better phosphateinder than aluminum hydroxide. ASAIO Trans 32:315-318,986184. Bleyer AJ, Burke SK, Dillon M, Garrett B, Kant KS,

ynch D, Rahman SN, Schoenfeld P, Teitelbaum I, Zeig S,latopolsky E: A comparison of the calcium-free phosphateinder sevelamer hydrochloride with calcium acetate in thereatment of hyperphosphatemia in hemodialysis patients.m J Kidney Dis 33:694-701, 1999185. Janssen MJ, van der Kuy A, ter Wee PM, van BovenP: Aluminum hydroxide, calcium carbonate and calcium

cetate in chronic intermittent hemodialysis patients. Clin
ephrol 45:111-119, 1996

CbT

Sch8

Jpt2

WPpc

SbI

Kth

CPr5

Hpem

Fivs

ACa8D

hc

PiD

Mr5

Wm

bi1

Pm2

d

It7

ASrSp2

St1

Ss

Rmd

at

PN

sDp

C22

lCd

cW

cMl

REFERENCES S109

186. Pflanz S, Henderson IS, McElduff N, Jones MC:alcium acetate versus calcium carbonate as phosphate-inding agents in chronic haemodialysis. Nephrol Dialransplant 9:1121-1124, 1994187. Ring T, Nielsen C, Andersen SP, Behrens JK,

odemann B, Kornerup HJ: Calcium acetate versus calciumarbonate as phosphorus binders in patients on chronicaemodialysis: a controlled study. Nephrol Dial Transplant:341-346, 1993188. Caravaca F, Fernandez MA, Ruiz-Calero R, Cubero

, Aparicio A, Jimenez F, Garcia MC: Effects of oralhosphorus supplementation on mineral metabolism of renalransplant recipients. Nephrol Dial Transplant 13:2605-611, 1998189. Chertow GM, Burke SK, Lazarus JM, Stenzel KH,ombolt D, Goldberg D, Bonventre JV, Slatopolsky E:

oly[allylamine hydrochloride] (RenaGel): a noncalcemichosphate binder for the treatment of hyperphosphatemia inhronic renal failure. Am J Kidney Dis 29:66-71, 1997

190. Delmez JA, Kelber J, Norword KY, Giles KS,latopolsky E: Magnesium carbonate as a phosphorusinder: a prospective, controlled, crossover study. Kidneynt 49:163-167, 1996

191. van den Bergh JP, Gelens MA, Klaassen HA,aufmann BG, Bottger WM, Verstappen VM: Efficacy and

olerance of three different calcium acetate formulations inemodialysis patients. Neth J Med 55:222-228, 1999192. Tan SY, Irish A, Winearls CG, Brown EA, Gower PE,

lutterbuck EJ, Madhoo S, Lavender JP, Pepys MB, HawkinsN: Long term effect of renal transplantation on dialysis-elated amyloid deposits and symptomatology. Kidney Int0:282-289, 1996193. Ittel TH, Schafer C, Schmitt H, Gladziwa U, Sieberth

G: Calcium carbonate as a phosphate binder in dialysisatients: evaluation of an enteric-coated preparation andffect of additional aluminium hydroxide on hyperaluminae-ia. Klin Wochenschr 69:59-67, 1991194. Bro S, Rasmussen RA, Handberg J, Olgaard K,

eldt-Rasmussen B: Randomized crossover study compar-ng the phosphate-binding efficacy of calcium ketoglutarateersus calcium carbonate in patients on chronic hemodialy-is. Am J Kidney Dis 31:257-262, 1998

195. Jespersen B, Jensen JD, Nielsen HK, Lauridsen IN,ndersen MJ, Poulsen JH, Gammelgaard B, Pedersen EB:omparison of calcium carbonate and aluminium hydroxides phosphate binders on biochemical bone markers, PTH(1-4), and bone mineral content in dialysis patients. Nephrolial Transplant 6:98-104, 1991196. Bame SI, Petersen N, Wray NP: Variation in

emodialysis patient compliance according to demographicharacteristics. Soc Sci Med 37:1035-1043, 1993

197. Coyne T, Olson M, Bradham K, Garcon M, Gregory, Scherch L: Dietary satisfaction correlated with adherencen the Modification of Diet in Renal Disease Study. J Amiet Assoc 95:1301-1306, 1995198. Cleary DJ, Matzke GR, Alexander AC, Joy MS:edication knowledge and compliance among patients

eceiving long-term dialysis. Am J Health Syst Pharm
2:1895-1900, 1995 W
199. Morduchowicz G, Sulkes J, Aizic S, Gabbay U,inkler J, Boner G: Compliance in hemodialysis patients: aultivariate regression analysis. Nephron 64:365-368, 1993200. Weed-Collins M, Hogan R: Knowledge and health

eliefs regarding phosphate-binding medication in predict-ng compliance. Anna J 16:278-282, 285; discussion 286,989201. Cummings KM, Becker MH, Kirscht JP, Levin NW:

sychosocial factors affecting adherence to medical regi-ents in a group of hemodialysis patients. Med Care

0:567-580, 1982202. Blackburn SL: Dietary compliance of chronic hemo-

ialysis patients. J Am Diet Assoc 70:31-37, 1977203. Coburn JW, Mischel MG, Goodman WG, Salusky

B: Calcium citrate markedly enhances aluminum absorp-ion from aluminum hydroxide. Am J Kidney Dis 17:708-11, 1991204. Chertow GM, Dillon M, Burke SK, Steg M, Bleyer

J, Garrett BN, Domoto DT, Wilkes BM, Wombolt DG,latopolsky E: A randomized trial of sevelamer hydrochlo-ide (RenaGel) with and without supplemental calcium.trategies for the control of hyperphosphatemia and hyper-arathyroidism in hemodialysis patients. Clin Nephrol 51:18-6, 1999205. Chertow GM, Dillon MA, Amin N, Burke SK:

evelamer with and without calcium and vitamin D: observa-ions from a long-term open-label clinical trial. J Ren Nutr0:125-132, 2000206. Slatopolsky E, Finch J, Clay P, Martin D, Sicard G,

inger G, Gao P, Cantor T, Dusso A: A novel mechanism forkeletal resistance in uremia. Kidney Int 58:753-761, 2000

207. Kurz P, Monier-Faugere MC, Bognar B, Werner E,oth P, Vlachojannis J, Malluche HH: Evidence for abnor-al calcium homeostasis in patients with adynamic bone

isease. Kidney Int 46:855-861, 1994208. Chertow GM, Burke SK, Raggi P: Sevelamer

ttenuates the progression of coronary and aortic calcifica-ion in hemodialysis patients. Kidney Int 62:245-252, 2002

209. Nordin BEC: Nutritional consideration, in Calcium,hosphate and Magnesium Metabolism, Nordin BEC (ed).ew York, Churchill Livingston, 1976, pp 3-35210. Portale AA: Blood calcium, phosphorus, and magne-

ium, in Primer on the Metabolic Bone Diseases andisorders of Mineral Metabolism, Favus MJ (ed). Philadel-hia, Lippincott, Williams & Wilkins, 1999, pp 115-118211. Elin RJ: Laboratory reference intervals and values, in

ecil Textbook of Medicine, Goldman L, Bennett JC (eds),1st ed. Philadelphia, W. B. Saunders Co., 2000, pp299-2308212. Enders DB, Rude RK: Mineral and bone metabo-

ism, in Tietz Fundamentals of Clinical Chemistry, BurtisA, Ashwood ER (eds), 5th ed. Philadelphia, W. B. Saun-ers Co., 2001, pp 795-821213. Institute of Medicine. Dietary references intakes:

alcium, phosphorus, magnesium, vitamin D3, and fluoride.ashington, DC, National Academy Press, 2000214. Lemann J, Favus MJ: The intestinal absorption of

alcium, magnesium, and phosphate, in Primer on theetabolic Bone Diseases and Disorders of Mineral Metabo-

ism, Favus MJ (ed). Philadelphia, Lippincott, Williams &
ilkins, 1999, pp 63-67

1r

mPMc

MSW

ms9

JPo1

UR1

p2

Cw3

v

t

aA

e1

Ah1

p2

Oof

Cd1

ioJ

hM

Mph

gR

Oa1

CtD

aa1

ai

Vrt

ps

Rtw1

Hbbo(

Wp1

CcE

Jafm3

ce

REFERENCESS110

215. Brickman AS, Coburn JW, Massry SG, Norman AW:,25 Dihydroxy-vitamin D3 in normal man and patients withenal failure. Ann Intern Med 80:161-168, 1974

216. Shane E: Hypercalcemia; pathogenesis, clinicalanifestation, differential diagnosis and management, inrimer on the Metabolic Bone Diseases and Disorders ofineral Metabolism, Favus MJ (ed). Philadelphia, Lippin-

ott, Williams & Wilkins, 1999, pp 183-187217. Massry SG, Smogorzewski M: Dyscalcemias, inassry and Glassock’s Textbook of Nephrology, Massry

G, Glassock RJ (eds), Philadelphia, Lippincott, Williams &ilkins, 2001, pp 326-340218. Fernandez E, Montoliu J: Successful treatment ofassive uraemic tumoral calcinosis with daily haemodialy-

is and very low calcium dialysate. Nephrol Dial Transplant:1207-1209, 1994219. Baker SS, Cochran WJ, Flores CA, Georgieff MK,

acobson MS, Jaksic T, Krebs NF: American Academy ofediatrics. Committee on Nutrition. Calcium requirementsf infants, children, and adolescents. Pediatrics 104:1152-157, 1999

220. Raper NR, Zissa C, Rourke J: Nutrient Content of theS Food Supply, 1909-1988, in Home Economics Researcheport No. 50. Washington, DC, US Dept of Agriculture,992221. Hsu CH: Are we mismanaging calcium and phos-

hate metabolism in renal failure? Am J Kidney Dis9:641-649, 1997222. Andon MB, Peacock M, Kanerva RL, De Castro JA:

alcium absorption from apple and orange juice fortifiedith calcium citrate malate (CCM). J Am Coll Nutr 15:313-16, 1996223. Gonzalez E, Martin K: Calcium, phosphorus and

itamin D. Philadelphia, PA, Lippincott-Raven, 1998224. Weaver CM: Calcium bioavailability and its relation

o osteoporosis. Proc Soc Exp Biol Med 200:157-160, 1992225. Weaver CM, Proulx WR, Heaney R: Choices for

chieving adequate dietary calcium with a vegetarian diet.m J Clin Nutr 70:543S-548S, 1999226. Weaver CM, Plawecki KL: Dietary calcium: ad-

quacy of a vegetarian diet. Am J Clin Nutr 59:1238S-241S, 1994227. Clase CM, Norman GL, Beecroft ML, Churchill DN:

lbumin-corrected calcium and ionized calcium in stableaemodialysis patients. Nephrol Dial Transplant 15:1841-846, 2000228. Morton AR, Hercz G: Hypercalcemia in dialysis

atients: comparison of diagnostic methods. Dial Transplant0:661-667, 1991229. Rix M, Andreassen H, Eskildsen P, Langdahl B,

lgaard K: Bone mineral density and biochemical markersf bone turnover in patients with predialysis chronic renalailure. Kidney Int 56:1084-1093, 1999

230. Coburn JW, Popovtzer MM, Massry SG, KleemanR: The physicochemical state and renal handling ofivalent ions in chronic renal failure. Arch Intern Med24:302-311, 1969231. Wasler M: The separate effects of hyperparathyroid-

sm, hypercalcemia of malignancy, renal failure and acidosisn the state of calcium phosphate and other ions in plasma.
Clin Invest 41:1454-1464, 1962 c
232. Campos C, Arata RO, Mautalen CA: Parathyroidormone and vertebral osteosclerosis in uremic patients.etabolism 25:495-501, 1976233. Fuss M, De Backer M, Brauman J, Nijs-Dewolf N,anderlier T, Brauman H, Corvilain J: Parathyroid hormone

lasma level in untreated chronic renal failure and inemodialyzed patients. Nephron 17:144-154, 1976234. Malhotra KK, Gadekar NG, Umashankar P, Bhar-

ava S: Bone disease in chronic renal failure. Indian J Medes 56:1687-1695, 1968235. Foley RN, Parfrey PS, Harnett JD, Kent GM, Hu L,

’Dea R, Murray DC, Barre PE: Hypocalcemia, morbidity,nd mortality in end-stage renal disease. Am J Nephrol6:386-393, 1996236. Reichel H, Deibert B, Schmidt-Gayk H, Ritz E:

alcium metabolism in early chronic renal failure: implica-ions for the pathogenesis of hyperparathyroidism. Nephrolial Transplant 6:162-169, 1991237. Malluche HH, Werner E, Ritz E: Intestinal calcium

bsorption and whole-body calcium retention incipient anddvanced renal failure. Miner Electrolyte Metab 1:263-270,978238. Wiegmann TB, Kaye M: Malabsorption of calcium

nd phosphate in chronic renal failure: 32P and 45Ca studiesn dialysis patients. Clin Nephrol 34:35-41, 1990

239. Mountokalakis TH, Singhellakis PN, Alevizaki CC,irvidakis K, Ikkos DG: Relationship between degree of

enal failure and impairment of intestinal calcium absorp-ion. Nephron 16:20-30, 1976

240. Kopple JD, Coburn JW: Metabolic studies of lowrotein diets in uremia. II. Calcium, phosphorus and magne-ium. Medicine (Baltimore) 52:597-607, 1973

241. Popovtzer MM, Michael UF, Johnson-Dial KS,onstadt C, Nelson D, Ogden DA: Dietary calcium depriva-

ion and secondary hyperparathyroidism in patients treatedith chronic dialysis. Miner Electrolyte Metab 12:298-302,986242. Trachtman H, Chan JC, Boyle R, Farina D, Baluarte

J, Chinchilli VM, Dresner IG, Feld LG: The relationshipetween calcium, phosphorus, and sodium intake, race, andlood pressure in children with renal insufficiency: a reportf the Growth Failure in Children with Renal DiseasesGFRD) Study. J Am Soc Nephrol 6:126-131, 1995

243. Clarkson EM, Eastwood JB, Koutsaimanis KG, deardener HE: Net intestinal absorption of calcium in

atients with chronic renal failure. Kidney Int 3:258-263,973244. Hercz G, Kraut JA, Andress DA, Howard N, Roberts

, Shinaberger JH, Sherrard DJ, Coburn JW: Use of calciumarbonate as a phosphate binder in dialysis patients. Minerlectrolyte Metab 12:314-319, 1986245. Moriniere P, Fournier A, Leflon A, Herve M, Sebert

L, Gregoire I, Bataille P, Gueris J: Comparison of 1lpha-OH-vitamin D3 and high doses of calcium carbonateor the control of hyperparathyroidism and hyperalumine-ia in patients on maintenance dialysis. Nephron 39:309-

15, 1985246. Petersen LJ, Rudnicki M, Hojsted J: Long-term oral

alcium supplementation reduces diastolic blood pressure innd stage renal disease. A randomized, double-blind, pla-
ebo controlled study. Int J Artif Organs 17:37-40, 1994

Pcc

Je

SGpap

HGB

AFo1

Cat

Bs

WdA

Bsb

pt

Po5

Vf

aF6

ARt

Wp2

C

m4

Ppp

Omc

PC2

3

D

Is

Pi7

p1

KcwN

es2i

Jd(a5

Tem

EK

Sr7

cAP

REFERENCES S111

247. Saha H, Pietila K, Mustonen J, Pasternack A, Morsky, Seppala E, Reinikainen P: Acute effects of calciumarbonate and citrate on secondary hyperparathyroidism inhronic renal failure. Am J Nephrol 11:465-469, 1991

248. Maher ER, Young G, Smyth-Walsh B, Pugh S, CurtisR: Aortic and mitral valve calcification in patients withnd-stage renal disease. Lancet 2:875-877, 1987

249. Fernandez-Reyes MJ, Auxiliadora Bajo M, Robles P,elgas R, Oliver J, Del Peso G, Garcia G, Jimenez C,arcia-Gallego F: Mitral annular calcification in CAPDatients with a low degree of hyperparathyroidism. Annalysis of other possible risk factors. Nephrol Dial Trans-lant 10:2090-2095, 1995250. Valentzas C, Meindok H, Oreopoulos DG, Meema

K, Rabinovich S, Jones M, Sutton D, Rapaport A, deVeberA: Visceral calcification and Ca - P product. Adv Exp Mediol 103:187-193, 1978251. Ribeiro S, Ramos A, Brandao A, Rebelo JR, Guerra

, Resina C, Vila-Lobos A, Carvalho F, Remedio F, Ribeiro: Cardiac valve calcification in haemodialysis patients: rolef calcium-phosphate metabolism. Nephrol Dial Transplant3:2037-2040, 1998252. Cassidy MJ, Owen JP, Ellis HA, Dewar J, Robinson

J, Wilkinson R, Ward MK, Kerr DN: Renal osteodystrophynd metastatic calcification in long-term continuous ambula-ory peritoneal dialysis. Q J Med 54:29-48, 1985

253. Milliner DS, Zinsmeister AR, Lieberman E, Landing: Soft tissue calcification in pediatric patients with end-

tage renal disease. Kidney Int 38:931-936, 1990254. Bouillon RA, Auwerx JH, Lissens WD, PelemansK: Vitamin D status in the elderly: seasonal substrate

eficiency causes 1,25-dihydroxycholecalciferol deficiency.m J Clin Nutr 45:755-763, 1987255. Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ,

outer LM, Lips P: Prevention of bone loss by vitamin Dupplementation in elderly women: a randomized double-lind trial. J Clin Endocrinol Metab 80:1052-1058, 1995256. Khaw KT, Sneyd MJ, Compston J: Bone density,

arathyroid hormone and 25-hydroxyvitamin D concentra-ions in middle aged women. Br Med J 305:373-376, 1992

257. Eastwood JB, Stamp TC, De Wardener HE, BordierJ, Arnaud CD: The effect of 25-hydroxy vitamin D3 in thesteomalacia of chronic renal failure. Clin Sci Mol Med2:499-508, 1977258. Eastwood JB, Stamp TC, Harris E, de Wardener HE:

itamin-D deficiency in the osteomalacia of chronic renalailure. Lancet 2:1209-1211, 1976

259. Chapuy MC, Meunier PJ: Vitamin D insufficiency indults and the elderly, in Vitamin D, Feldman D, GlorieuxH, Pike JW (eds). San Diego, Academic Press, 1997, pp79-693260. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw

C, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, PrinceL, Finkelstein JS: Hypovitaminosis D in medical inpa-

ients. N Engl J Med 338:777-783, 1998261. LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J,right J, Glowacki J: Occult vitamin D deficiency in

ostmenopausal US women with acute hip fracture. JAMA81:1505-1511, 1999262. Koenig KG, Lindberg JS, Zerwekh JE, Padalino PK,

ushner HM, Copley JB: Free and total 1,25-dihydroxyvita- c

in D levels in subjects with renal disease. Kidney Int1:161-165, 1992263. Messa P, Vallone C, Mioni G, Geatti O, Turrin D,

assoni N, Cruciatti A: Direct in vivo assessment ofarathyroid hormone-calcium relationship curve in renalatients. Kidney Int 46:1713-1720, 1994264. Papapoulos SE, Clemens TL, Fraher LJ, Gleed J,

’Riordan JL: Metabolites of vitamin D in human vita-in-D deficiency: effect of vitamin D3 or 1,25-dihydroxy-

holecalciferol. Lancet 2:612-615, 1980265. National Kidney Foundation. K/DOQI Clinical

ractice Guidelines for Bone Metabolism and Disease inhronic Kidney Disease. Am J Kidney Dis 42:S1-S202,003 (suppl 3)267. Holick MF: Vitamin D and the kidney. Kidney Int

2:912-929, 1987268. Holick MF, Matsuoka LY, Wortsman J: Age, vitamin

, and solar ultraviolet. Lancet 2:1104-1105, 1989269. Clemens TL, Adams JS, Henderson SL, Holick MF:

ncreased skin pigment reduces the capacity of skin toynthesise vitamin D3. Lancet 1:74-76, 1982

270. Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan, Hercberg S, Meunier PJ: Prevalence of vitamin Dnsufficiency in an adult normal population. Osteoporos Int:439-443, 1997271. Saha H: Calcium and vitamin D homeostasis in

atients with heavy proteinuria. Clin Nephrol 41:290-296,994272. Kinyamu HK, Gallagher JC, Balhorn KE, Petranick

M, Rafferty KA: Serum vitamin D metabolites and cal-ium absorption in normal young and elderly free-livingomen and in women living in nursing homes. Am J Clinutr 65:790-797, 1997273. Webb AR, Pilbeam C, Hanafin N, Holick MF: An

valuation of the relative contributions of exposure tounlight and of diet to the circulating concentrations of5-hydroxyvitamin D in an elderly nursing home populationn Boston. Am J Clin Nutr 51:1075-1081, 1990

274. Ghazali A, Fardellone P, Pruna A, Atik A, AchardM, Oprisiu R, Brazier M, Remond A, Moriniere P, Garabe-ian M, Eastwood J, Fournier A: Is low plasma 25-OH)vitamin D a major risk factor for hyperparathyroidismnd Looser’s zones independent of calcitriol? Kidney Int5:2169-2177, 1999275. Lambert PW, Stern PH, Avioli RC, Brackett NC,

urner RT, Greene A, Fu IY, Bell NH: Evidence forxtrarenal production of 1 alpha ,25-dihydroxyvitamin D inan. J Clin Invest 69:722-725, 1982276. Dusso A, Lopez-Hilker S, Rapp N, Slatopolsky E:

xtra-renal production of calcitriol in chronic renal failure.idney Int 34:368-375, 1988277. Dusso AS, Finch J, Brown A, Ritter C, Delmez J,

chreiner G, Slatopolsky E: Extrarenal production of calcit-iol in normal and uremic humans. J Clin Endocrinol Metab2:157-164, 1991278. Food and Nutrition Board. National Research Coun-

il. National Academy of Sciences. Recommended Dailyllowances. 10 ed. Washington, DC, National Academyress, 1989279. Food and Nutrition Board. National Research Coun-

il. National Academy of Sciences. Dietary Reference

Ia1

tJ

c7

rK

Ki1

KvT

scA

GvL

dss

BcN

BIr

tmEd

dtr

pJ

MCr1E

V

cD

PpJ

dop

SmK

Acd

Mop

BSfeyI

Mi4

NdC

Rh1

FTpd8

ae

nr

SD1

HT

REFERENCESS112

ntakes for Calcium, Phosphorus, Magnesium, Vitamin D,nd Fluoride. Washington, DC, National Academy Press,997280. Shah BR, Finberg L: Single-day therapy for nutri-

ional vitamin D-deficiency rickets: a preferred method.Pediatr 125:487-490, 1994281. Kruse K: Pathophysiology of calcium metabolism in

hildren with vitamin D-deficiency rickets. J Pediatr 126:736-41, 1995282. Combe C, Aparicio M: Phosphorus and protein

estriction and parathyroid function in chronic renal failure.idney Int 46:1381-1386, 1994283. Lafage MH, Combe C, Fournier A, Aparicio M:

etodiet, physiological calcium intake and native vitamin Dmprove renal osteodystrophy. Kidney Int 42:1217-1225,992284. Coburn JW, Tan AU Jr, Levine BS, Mazess RB,

yllo DM, Knutson JC, Bishop CW: 1 alpha-Hydroxy-itamin D2: a new look at an ‘old’ compound. Nephrol Dialransplant 11:153-157, 1996 (suppl 3)285. Harrington DD, Page EH: Acute vitamin D3 toxico-

is in horses: case reports and experimental studies of theomparative toxicity of vitamins D2 and D3. J Am Vet Medssoc 182:1358-1369, 1983286. van der Wielen RP, Lowik MR, van den Berg H, de

root LC, Haller J, Moreiras O, van Staveren WA: Serumitamin D concentrations among elderly people in Europe.ancet 346:207-210, 1995287. Lips P, van Ginkel FC, Jongen MJ, Rubertus F, van

er Vijgh WJ, Netelenbos JC: Determinants of vitamin Dtatus in patients with hip fracture and in elderly controlubjects. Am J Clin Nutr 46:1005-1010, 1987

288. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet, Arnaud S, Delmas PD, Meunier PJ: Vitamin D3 andalcium to prevent hip fractures in the elderly women.

Engl J Med 327:1637-1642, 1992289. Alem AM, Sherrard DJ, Gillen DL, Weiss NS,

eresford SA, Heckbert SR, Wong C, Stehman-Breen C:ncreased risk of hip fracture among patients with end-stageenal disease. Kidney Int 58:396-399, 2000

290. Rickers H, Christiansen C, Christensen P, Chris-ensen M, Rodbro P: Serum concentrations of vitamin Detabolites in different degrees of impaired renal function.stimation of renal and extrarenal secretion rate of 24,25-ihydroxyvitamin D. Nephron 39:267-271, 1985291. Martinez I, Saracho R, Montenegro J, Llach F: A

eficit of calcitriol synthesis may not be the initial factor inhe pathogenesis of secondary hyperparathyroidism. Neph-ol Dial Transplant 11:22-28, 1996 (suppl 3)

292. Nordal KP, Dahl E: Low dose calcitriol versuslacebo in patients with predialysis chronic renal failure.Clin Endocrinol Metab 67:929-936, 1988293. Coen G, Mazzaferro S, Bonucci E, Ballanti P,assimetti C, Donato G, Landi A, Smacchi A, Della Rocca, Cinotti GA, et al: Treatment of secondary hyperparathy-

oidism of predialysis chronic renal failure with low doses of,25(OH)2D3: humoral and histomorphometric results. Minerlectrolyte Metab 12:375-382, 1986294. Bianchi ML, Colantonio G, Campanini F, Rossi R,

alenti G, Ortolani S, Buccianti G: Calcitriol and calcium d

arbonate therapy in early chronic renal failure. Nephrolial Transplant 9:1595-1599, 1994295. Silver J, Naveh-Many T, Mayer H, Schmelzer HJ,

opovtzer MM: Regulation by vitamin D metabolites ofarathyroid hormone gene transcription in vivo in the rat.Clin Invest 78:1296-1301, 1986296. Przedlacki J, Manelius J, Huttunen K: Bone mineral

ensity evaluated by dual-energy X-ray absorptiometry afterne-year treatment with calcitriol started in the predialysishase of chronic renal failure. Nephron 69:433-437, 1995297. Baker LR, Abrams L, Roe CJ, Faugere MC, Fanti P,

ubayti Y, Malluche HH: 1,25(OH)2D3 administration inoderate renal failure: a prospective double-blind trial.idney Int 35:661-669, 1989298. Nordal KP, Dahl E, Halse J, Attramadal A, Flatmark

: Long-term low-dose calcitriol treatment in predialysishronic renal failure: can it prevent hyperparathyroid boneisease? Nephrol Dial Transplant 10:203-206, 1995299. Chesney RW, Moorthy AV, Eisman JA, Jax DK,azess RB, DeLuca HF: Increased growth after long-term

ral 1alpha,25-vitamin D3 in childhood renal osteodystro-hy. N Engl J Med 298:238-242, 1978300. Chan JC, McEnery PT, Chinchilli VM, Abitbol CL,

oineau FG, Friedman AL, Lum GM, Roy S, 3rd, Ruley EJ,trife CF: A prospective, double-blind study of growthailure in children with chronic renal insufficiency and theffectiveness of treatment with calcitriol versus dihydrotach-sterol. The Growth Failure in Children with Renal Diseasesnvestigators. J Pediatr 124:520-528, 1994

301. Schmitt CP, Ardissino G, Testa S, Claris-Appiani A,ehls O: Growth in children with chronic renal failure on

ntermittent versus daily calcitriol. Pediatr Nephrol 18:440-44, 2003302. Kuizon BD, Goodman WG, Juppner H, Boechat I,

elson P, Gales B, Salusky IB: Diminished linear growthuring intermittent calcitriol therapy in children undergoingCPD. Kidney Int 53:205-211, 1998303. Waller S, Ledermann S, Trompeter R, van’t Hoff W,

idout D, Rees L: Catch-up growth with normal parathyroidormone levels in chronic renal failure. Pediatr Nephrol8:1236-1241, 2003304. Coen G, Mazzaferro S, Manni M, Napoletano I,

ondi G, Sardella D, Perruzza I, Pasquali M, Taggi F:reatment with small doses of 1,25-dihydroxyvitamin D inredialysis chronic renal failure may lower the rate ofecline of renal function. Ital J Miner Electrolyte Metab:117-121, 1994305. Jensen GF, Christiansen C, Transbol I: 1,25(OH)2D3

nd renal function. A controlled clinical study in normallderly women. Acta Med Scand 211:51-54, 1982

306. Bertoli M, Luisetto G, Ruffatti A, Urso M, Romag-oli G: Renal function during calcitriol therapy in chronicenal failure. Clin Nephrol 33:98-102, 1990

307. Perez A, Raab R, Chen TC, Turner A, Holick MF:afety and efficacy of oral calcitriol (1,25-dihydroxyvitamin3) for the treatment of psoriasis. Br J Dermatol 134:1070-078, 1996308. Kanis JA, Cundy T, Earnshaw M, Henderson RG,

eynen G, Naik R, Russell RG, Smith R, Woods CG:reatment of renal bone disease with 1 alpha-hydroxylated
erivatives of vitamin D3. Clinical, biochemical, radio-

g1

Jf

Hnbr

hr

Gtb5

NtC

Wam

Cdd

Bfc

GHct1

FGf

BPh1c

MNfsM

Amla

AKMJDK

KJCCimr5

Md9

(p1

Btvs1

wse

Gbi1

rpE

ll5

Eohn

hdC

dh

REFERENCES S113

raphic and histological responses. Q J Med 48:289-322,979309. Naik RB, Cundy T, Robinson BH, Russell RG, Kanis

A: Effects of vitamin D metabolites and analogues on renalunction. Nephron 28:17-25, 1981

310. Nielsen HE, Romer FK, Melsen F, Christensen MS,ansen HE: 1 alpha-hydroxy vitamin D3 treatment ofon-dialyzed patients with chronic renal failure. Effects onone, mineral metabolism and kidney function. Clin Neph-ol 13:103-108, 1980

311. Goodman WG, Salusky IB: Evolution of secondaryyperparathyroidism during oral calcitriol therapy in pediat-ic renal osteodystrophy. Contrib Nephrol 90:189-195, 1991

312. Salusky IB, Kuizon BD, Belin TR, Ramirez JA,ales B, Segre GV, Goodman WG: Intermittent calcitriol

herapy in secondary hyperparathyroidism: a comparisonetween oral and intraperitoneal administration. Kidney Int4:907-914, 1998313. Brickman AS, Coburn JW, Sherrard DJ, Wong EG,

orman AW, Singer FR: Clinical effects of 1,25-dihydroxyvi-amin D3 in uremic patients with overt osteodystrophy.ontrib Nephrol 18:29-41, 1980314. Kanis JA, Russell RG, Cundy T, Earnshaw M,oods CG, Smith R, Heynen G: An evaluation of 1

lpha-hydroxy- and 1,25-dihydroxyvitamin D3 in the treat-ent of renal bone disease. Contrib Nephrol 18:12-28, 1980315. Berl T, Berns AS, Huffer WE, Alfrey AC, Arnaud

D, Schrier RR: Controlled trial of the effects of 1,25-ihydroxycholecalciferol in patients treated with regularialysis. Contrib Nephrol 18:72-81, 1980316. Peacock M, Aaron JE, Walker GS, Davison AM:

one disease and hyperparathyroidism in chronic renalailure: the effect of 1alpha-hydroxyvitamin D3. Clin Endo-rinol (Oxf) 7 Suppl:73s-81s, 1977

317. Herrmann P, Ritz E, Schmidt-Gayk H, Schafer I,eyer J, Nonnast-Daniel B, Koch KM, Weber U, Horl W,aas-Worle A, et al.: Comparison of intermittent and

ontinuous oral administration of calcitriol in dialysis pa-ients: a randomized prospective trial. Nephron 67:48-53,994318. Papapoulos SE, Brownjohn AM, Junor BJ, Marsh

P, Goodwin FJ, Hately W, Lewin IG, Tomlinson S, HendyN, O’Riordan JL: Hyperparathyroidism in chronic renal

ailure. Clin Endocrinol (Oxf) 7 Suppl:59s-65s, 1977319. Moriniere P, Esper NE, Viron B, Judith D, Bourgeon

, Farquet C, Gheerbrandt JD, Chapuy MC, Orshoven AV,amphile R, Fournier A: Improvement of severe secondaryyperparathyroidism in dialysis patients by intravenous-alpha(OH) vitamin D3, oral CaCo3 and low dialysatealcium. Kidney Int 43:S121-S124, 1993 (suppl 41)

320. Morii H, Ogura Y, Koshikawa S, Mimura N, Suzuki, Kurokawa K, Marumo F, Kawaguchi Y, Maeda K,ishizawa Y, Inoue S, Fujimi S: Efficacy and safety of oral

alecalcitriol in reducing parathyroid hormone in hemodialy-is patients withh secondary hyperparathyroidism. J Boneiner Metab 16, 1988321. Martin KJ, Gonzalez EA, Gellens M, Hamm LL,

bboud H, Lindberg J: 19-Nor-1-alpha-25-dihydroxyvita-in D2 (Paricalcitol) safely and effectively reduces the

evels of intact parathyroid hormone in patients on hemodi-
lysis. J Am Soc Nephrol 9:1427-1432, 1998 K
322. Frazao JM, Elangovan L, Maung HM, Chesney RW,cchiardo SR, Bower JD, Kelley BJ, Rodriguez HJ, NorrisC, Robertson JA, Levine BS, Goodman WG, Gentile D,azess RB, Kyllo DM, Douglass LL, Bishop CW, Coburn

W: Intermittent doxercalciferol (1alpha-hydroxyvitamin(2)) therapy for secondary hyperparathyroidism. Am Jidney Dis 36:550-561, 2000323. Maung HM, Elangovan L, Frazao JM, Bower JD,

elley BJ, Acchiardo SR, Rodriguez HJ, Norris KC, SigalaF, Rutkowski M, Robertson JA, Goodman WG, Levine BS,hesney RW, Mazess RB, Kyllo DM, Douglass LL, BishopW, Coburn JW: Efficacy and side effects of intermittent

ntravenous and oral doxercalciferol (1alpha-hydroxyvita-in D(2)) in dialysis patients with secondary hyperparathy-

oidism: a sequential comparison. Am J Kidney Dis 37:532-43, 2001324. Sherrard DJ, Coburn JW, Brickman AS, Singer FR,aloney N: Skeletal response to treatment with 1,25-

ihydroxyvitamin D in renal failure. Contrib Nephrol 18:92-7, 1980325. Krempien B, Ritz E, Tschope W: The effect of 1,25

OH)2D3 on bone mineralization: ultrastructural studies inatients with renal osteodystrophy. Contrib Nephrol 18:122-34, 1980326. Tan AU Jr, Levine BS, Mazess RB, Kyllo DM,

ishop CW, Knutson JC, Kleinman KS, Coburn JW: Effec-ive suppression of parathyroid hormone by 1 alpha-hydroxy-itamin D2 in hemodialysis patients with moderate to severeecondary hyperparathyroidism. Kidney Int 51:317-323,997327. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Green-

ood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: Thepectrum of bone disease in end-stage renal failure–anvolving disorder. Kidney Int 43:436-442, 1993

328. Goodman WG, Ramirez JA, Belin TR, Chon Y,ales B, Segre GV, Salusky IB: Development of adynamicone in patients with secondary hyperparathyroidism afterntermittent calcitriol therapy. Kidney Int 46:1160-1166,994329. Quarles LD, Lobaugh B, Murphy G: Intact parathy-

oid hormone overestimates the presence and severity ofarathyroid-mediated osseous abnormalities in uremia. J Clinndocrinol Metab 75:145-150, 1992330. Sprague SM, Moe SM: Safety and efficacy of

ong-term treatment of secondary hyperparathyroidism byow-dose intravenous calcitriol. Am J Kidney Dis 19:532-39, 1992331. Cannella G, Bonucci E, Rolla D, Ballanti P, Moriero

, De Grandi R, Augeri C, Claudiani F, Di Maio G: Evidencef healing of secondary hyperparathyroidism in chronicallyemodialyzed uremic patients treated with long-term intrave-ous calcitriol. Kidney Int 46:1124-1132, 1994332. Dressler R, Laut J, Lynn RI, Ginsberg N: Long-term

igh dose intravenous calcitriol therapy in end-stage renalisease patients with severe secondary hyperparathyroidism.lin Nephrol 43:324-331, 1995333. Llach F, Hervas J, Cerezo S: The importance of

osing intravenous calcitriol in dialysis patients with severeyperparathyroidism. Am J Kidney Dis 26:845-851, 1995334. Fukuda N, Tanaka H, Tominaga Y, Fukagawa M,

urokawa K, Seino Y: Decreased 1,25-dihydroxyvitamin

DpI

Htc2

mrld

OKcN

YThr

Kit

GSp

CR1hm

Fct

msK

os1

Msp

Atcp

Mo

h1

op

BLhf1

NaN

p3

v

ErN

Ctpa1

ic

s1cK

Jmpr

ah

ah1

Dhp1

1tm

REFERENCESS114

3 receptor density is associated with a more severe form ofarathyroid hyperplasia in chronic uremic patients. J Clinnvest 92:1436-1443, 1993

335. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter, Martin KJ: Marked suppression of secondary hyperpara-

hyroidism by intravenous administration of 1,25-dihydroxy-holecalciferol in uremic patients. J Clin Invest 74:2136-143, 1984336. Fukagawa M, Kitaoka M, Yi H, Fukuda N, Matsu-oto T, Ogata E, Kurokawa K: Serial evaluation of parathy-

oid size by ultrasonography is another useful marker for theong-term prognosis of calcitriol pulse therapy in chronicialysis patients. Nephron 68:221-228, 1994337. Fukagawa M, Okazaki R, Takano K, Kaname S,

gata E, Kitaoka M, Harada S, Sekine N, Matsumoto T,urokawa K: Regression of parathyroid hyperplasia by

alcitriol-pulse therapy in patients on long-term dialysis.Engl J Med 323:421-422, 1990338. Tsukamoto Y, Nomura M, Takahashi Y, Takagi Y,

oshida A, Nagaoka T, Togashi K, Kikawada R, Marumo F:he ‘oral 1,25-dihydroxyvitamin D3 pulse therapy’ inemodialysis patients with severe secondary hyperparathy-oidism. Nephron 57:23-28, 1991

339. Muramoto H, Haruki K, Yoshimura A, Mimo N, Oda, Tofuku Y: Treatment of refractory hyperparathyroidism

n patients on hemodialysis by intermittent oral administra-ion of 1,25(OH)2vitamin D3. Nephron 58:288-294, 1991

340. Baker LR, Muir JW, Sharman VL, Abrams SM,reenwood RN, Cattell WR, Goodwin FJ, Marsh FP, Adami, Hately W: Controlled trial of calcitriol in hemodialysisatients. Clin Nephrol 26:185-191, 1986341. Memmos DE, Eastwood JB, Talner LB, Gower PE,

urtis JR, Phillips ME, Carter GD, Alaghband-Zadeh J,oberts AP, de Wardener HE: Double-blind trial of oral,25-dihydroxy vitamin D3 versus placebo in asymptomaticyperparathyroidism in patients receiving maintenance hae-odialysis. Br Med J (Clin Res Ed) 282:1919-1924, 1981342. Bacchini G, Fabrizi F, Pontoriero G, Marcelli D, Di

ilippo S, Locatelli F: ‘Pulse oral’ versus intravenousalcitriol therapy in chronic hemodialysis patients. A prospec-ive and randomized study. Nephron 77:267-272, 1997

343. Indridason OS, Quarles LD: Comparison of treat-ents for mild secondary hyperparathyroidism in hemodialy-

is patients. Durham Renal Osteodystrophy Study Group.idney Int 57:282-292, 2000344. Fischer ER, Harris DC: Comparison of intermittent

ral and intravenous calcitriol in hemodialysis patients withecondary hyperparathyroidism. Clin Nephrol 40:216-220,993345. Liou HH, Chiang SS, Huang TP, Shieh SD, Akmal: Comparative effect of oral or intravenous calcitriol on

econdary hyperparathyroidism in chronic hemodialysisatients. Miner Electrolyte Metab 20:97-102, 1994346. Caravaca F, Cubero JJ, Jimenez F, Lopez JM,

paricio A, Cid MC, Pizarro JL, Liso J, Santos I: Effect ofhe mode of calcitriol administration on PTH-ionized cal-ium relationship in uraemic patients with secondary hyper-arathyroidism. Nephrol Dial Transplant 10:665-670, 1995347. Quarles LD, Yohay DA, Carroll BA, Spritzer CE,inda SA, Bartholomay D, Lobaugh BA: Prospective trial

f pulse oral versus intravenous calcitriol treatment of M

yperparathyroidism in ESRD. Kidney Int 45:1710-1721,994348. Levine BS, Song M: Pharmacokinetics and efficacy

f pulse oral versus intravenous calcitriol in hemodialysisatients. J Am Soc Nephrol 7:488-496, 1996349. Gallieni M, Brancaccio D, Padovese P, Rolla D,

edani P, Colantonio G, Bronzieri C, Bagni B, Tarolo G:ow-dose intravenous calcitriol treatment of secondaryyperparathyroidism in hemodialysis patients. Italian Groupor the Study of Intravenous Calcitriol. Kidney Int 42:1191-198, 1992

350. Moe SM, Kraus MA, Gassensmith CM, FinebergS, Gannon FH, Peacock M: Safety and efficacy of pulse

nd daily calcitriol in patients on CAPD: a randomized trial.ephrol Dial Transplant 13:1234-1241, 1998351. Brown AJ, Slatopolsky E: Vitamin D analogs:

erspectives for treatment. Miner Electrolyte Metab 25:337-41, 1999352. Slatopolsky E, Dusso A, Brown A: New analogs of

itamin D3. Kidney Int Suppl 73:S46-S51, 1999353. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata

, Slatopolsky E: Effect of 22-oxacalcitriol on hyperparathy-oidism of dialysis patients: results of a preliminary study.ephrol Dial Transplant 11:121-124, 1996 (suppl 3)354. Akiba T, Marumo F, Owada A, Kurihara S, Inoue A,

hida Y, Ando R, Shinoda T, Ishida Y, Ohashi Y: Controlledrial of falecalcitriol versus alfacalcidol in suppression ofarathyroid hormone in hemodialysis patients with second-ry hyperparathyroidism. Am J Kidney Dis 32:238-246,998355. Taga T: The signal transducer gp130 is shared by

nterleukin-6 family of haematopoietic and neurotrophicytokines. Ann Med 29:63-72, 1997

356. Slatopolsky E, Finch J, Ritter C, Denda M, Morris-ey J, Brown A, DeLuca H: A new analog of calcitriol,9-nor-1,25-(OH)2D2, suppresses parathyroid hormone se-retion in uremic rats in the absence of hypercalcemia. Am Jidney Dis 26:852-860, 1995357. Nishii Y, Abe J, Mori T, Brown AJ, Dusso AS, Finch

, Lopez-Hilker S, Morrissey J, Slatopolsky E: The noncalce-ic analogue of vitamin D, 22-oxacalcitriol, suppresses

arathyroid hormone synthesis and secretion. Contrib Neph-ol 91:123-128, 1991

358. Sjoden G, Lindgren JU, DeLuca HF: Antirachiticctivity of 1 alpha-hydroxyergocalciferol and 1 alpha-ydroxycholecalciferol in rats. J Nutr 114:2043-2046, 1984359. Sjoden G, Smith C, Lindgren U, DeLuca HF: 1

lpha-Hydroxyvitamin D2 is less toxic than 1 alpha-ydroxyvitamin D3 in the rat. Proc Soc Exp Biol Med78:432-436, 1985360. Gallagher JC, Bishop CW, Knutson JC, Mazess RB,

eLuca HF: Effects of increasing doses of 1 alpha-ydroxyvitamin D2 on calcium homeostasis in postmeno-ausal osteopenic women. J Bone Miner Res 9:607-614,994361. Weber K, Goldberg M, Stangassinger M, Erben RG:

alpha-hydroxyvitamin D2 is less toxic but not bone selec-ive relative to 1alpha-hydroxyvitamin D3 in ovariecto-ized rats. J Bone Miner Res 16:639-651, 2001362. Vlassopoulos D, Noussias C, Revenas K, Hadjilouka-
antaka A, Arvanitis D, Tzortzis G, Hadjiconstantinou V:

LsR

Sut4

Tb4

Oah

Gop

ErJ

Rtd

6d

H(sN

Ksb

Gcp

MbS

PdN

tA

NncS

hoI

m11

Lca

clS

hc8

(sp1

LCmr

hicN

aps

KcLc2

EsmI

KSib

Lcp

REFERENCES S115

ong-term effects of small doses of calcitriol in hemodialy-is patients with moderate secondary hyperparathyroidism.en Fail 21:199-207, 1999363. Martinez ME, Selgas R, Miguel JL, Balaguer G,

anchez-Cabezudo MJ, Llach F: Osteocalcin levels inremic patients: influence of calcitriol treatment throughwo different routes and type of dialysis. Nephron 59:429-33, 1991364. Morita A, Tabata T, Inoue T, Nishizawa Y, Morii H:

he effect of oral 1 alpha-hydroxycalciferol treatment onone mineral density in hemodialysis patients. Clin Nephrol6:389-393, 1996365. Shimamatsu K, Maeda T, Harada A, Nishitani H,

noyama K, Fujimi S, Omae T: 1-year controlled trial of 1lpha-hydroxycholecalciferol in patients on maintenanceemodialysis. Nephron 28:70-75, 1981366. Hercz G, Pei Y, Greenwood C, Manuel A, Saiphoo C,

oodman WG, Segre GV, Fenton S, Sherrard DJ: Aplasticsteodystrophy without aluminum: the role of “suppressed”arathyroid function. Kidney Int 44:860-866, 1993367. Andress DL, Norris KC, Coburn JW, Slatopolsky

A, Sherrard DJ: Intravenous calcitriol in the treatment ofefractory osteitis fibrosa of chronic renal failure. N EnglMed 321:274-279, 1989368. Kanis JA, Russell RG, Naik RB, Earnshaw M, Smith

, Heynen G, Woods CG: Factors influencing the responseo 1alpha-hydroxyvitamin D3 in patients with renal boneisease. Clin Endocrinol (Oxf) 7 Suppl:51s-57s, 1977369. Malluche HH, Goldstein DA, Massry SG: Effects ofmonths therapy with 1,25 (OH)2D3 on bone disease of

ialysis patients. Contrib Nephrol 18:98-104, 1980370. Delling G, Luhmann H, Bulla M, Fuchs C, Henning

V, Jansen JL, Kohnle W, Schulz W: The action of 1,25OH)2D3 on turnover kinetic, remodelling surfaces andtructure of trabecular bone in chronic renal failure. Contribephrol 18:105-121, 1980371. Johnson WJ, Goldsmith RS, Beabout JW, Jowsey J,

elly PJ, Arnaud CD: Prevention and reversal of progres-ive secondary hyperparathyroidism in patients maintainedy hemodialysis. Am J Med 56:827-832, 1974372. Sanchez CP, Salusky IB, Kuizon BD, Ramirez JA,

ales B, Ettenger RB, Goodman WG: Bone disease inhildren and adolescents undergoing successful renal trans-lantation. Kidney Int 53:1358-1364, 1998373. London GM, Marty C, Marchais SJ, Guerin AP,etivier F, de Vernejoul MC: Arterial calcifications and

one histomorphometry in end-stage renal disease. J Amoc Nephrol 15:1943-1951, 2004374. Piraino B, Bernardini J, Holley J, Johnston JR,

erlmutter JA, Martis L: Calcium mass transfer in peritonealialysis patients using 2.5 mEq/l calcium dialysate. Clinephrol 37:48-51, 1992375. Malberti F, Corradi B, Imbasciati E: Calcium mass

ransfer and kinetics in CAPD using calcium-free solutions.dv Perit Dial 9:274-279, 1993376. Weinreich T, Colombi A, Echterhoff HH, Mielke G,

ebel M, Ziegelmayer C, Passlick-Deetjen J: Transperito-eal calcium mass transfer using dialysate with a lowalcium concentration (1.0 mM). Perit Dial Int 13:S467-
470, 1993 (suppl 2) P
377. Sieniawska M, Roszkowska-Blaim M, Wojciec-owska B: The influence of dialysate calcium concentrationn the PTH level in children undergoing CAPD. Perit Dialnt 16:S567-S569, 1996 (suppl 1)

378. Banalagay EE, Bernardini J, Piraino B: Calciumass transfer with 10-hour dwell time using 1.25 versus

.75 mmol/L calcium dialysate. Adv Perit Dial 9:271-273,993379. Fabrizi F, Bacchini G, Di Filippo S, Pontoriero G,

ocatelli F: Intradialytic calcium balances with differentalcium dialysate levels. Effects on cardiovascular stabilitynd parathyroid function. Nephron 72:530-535, 1996

380. Fernandez E, Borras M, Pais B, Montoliu J: Low-alcium dialysate stimulates parathormone secretion and itsong-term use worsens secondary hyperparathyroidism. J Amoc Nephrol 6:132-135, 1995381. Honkanen E, Kala AR, Gronhagen-Riska C, Ika-

eimo R: CAPD with low calcium dialysate and calciumarbonate: results of a 24-week study. Adv Perit Dial:356-361, 1992382. Bro S, Brandi L, Olgaard K: High-normal calcium

1.35 mmol/l) dialysate in patients on CAPD: efficient andafe long-term control of plasma calcium, phosphate, andarathyroid hormone. Nephrol Dial Transplant 11:1586-591, 1996383. Hutchison AJ, Freemont AJ, Boulton HF, Gokal R:

ow-calcium dialysis fluid and oral calcium carbonate inAPD. A method of controlling hyperphosphataemia whilstinimizing aluminium exposure and hypercalcaemia. Neph-

ol Dial Transplant 7:1219-1225, 1992384. Sawyer N, Noonan K, Altmann P, Marsh F, Cunning-

am J: High-dose calcium carbonate with stepwise reductionn dialysate calcium concentration: effective phosphateontrol and aluminium avoidance in haemodialysis patients.ephrol Dial Transplant 4:105-109, 1989385. Carozzi S, Nasini MG, Santoni O, Pietrucci A: Low-

nd high-turnover bone disease in continuous ambulatoryeritoneal dialysis: effects of low-Ca2� peritoneal dialysisolution. Perit Dial Int 13:S473-S475, 1993 (suppl 2)

386. Brandi L, Nielsen PK, Bro S, Daugaard H, Olgaard: Long-term effects of intermittent oral alphacalcidol,

alcium carbonate and low-calcium dialysis (1.25 mmol-1) on secondary hyperparathyroidism in patients onontinuous ambulatory peritoneal dialysis. J Intern Med44:121-131, 1998387. Buijsen CG, Struijk DG, Huijgen HJ, Boeschoten

W, Wilmink JM: Can low-calcium peritoneal dialysisolution safely replace the standard calcium solution in theajority of chronic peritoneal dialysis patients? Perit Dial

nt 16:497-504, 1996388. Shigematsu T, Kawaguchi Y, Kubo H, Nakayama M,

ato N, Yamamoto H, Osaka N, Hayakawa H, Ogawa A,akai O: Low calcium (1.25 mmol/L) dialysate can normal-

ze relative hypoparathyroidism in CAPD patients with lowone turnover. Adv Perit Dial 12:250-256, 1996389. Chertow GM, Burke SK, Dillon MA, Slatopolsky E:

ong-term effects of sevelamer hydrochloride on the cal-ium x phosphate product and lipid profile of haemodialysisatients. Nephrol Dial Transplant 14:2907-2914, 1999390. Slatopolsky E, Weerts C, Norwood K, Giles K, Fryer

, Finch J, Windus D, Delmez J: Long-term effects of

cm

GEfit

Mh

Ps2

Pi

aMp2

srD4

ci1

rD

deM

DdN

Bv1

Jfhh

Fcp

Rl

a

crt

tcGC

MhGF

tf

odl

Atp1

Lch

nwE3

EmJ

JHde2

Dmpm

tGE

ob8

t

REFERENCESS116

alcium carbonate and 2.5 mEq/liter calcium dialysate onineral metabolism. Kidney Int 36:897-903, 1989391. Goldberg DI, Dillon MA, Slatopolsky EA, Garrett B,

ray JR, Marbury T, Weinberg M, Wombolt D, Burke SK:ffect of RenaGel, a non-absorbed, calcium- and aluminium-

ree phosphate binder, on serum phosphorus, calcium, andntact parathyroid hormone in end-stage renal disease pa-ients. Nephrol Dial Transplant 13:2303-2310, 1998

392. Morrison G, Michelson EL, Brown S, Morganroth J:echanism and prevention of cardiac arrhythmias in chronic

emodialysis patients. Kidney Int 17:811-819, 1980393. Nappi SE, Virtanen VK, Saha HH, Mustonen JT,

asternack AI: QTc dispersion increases during hemodialy-is with low-calcium dialysate. Kidney Int 57:2117-2122,000394. Nappi SE, Saha HH, Virtanen VK, Mustonen JT,

asternack AI: Hemodialysis with high-calcium dialysatempairs cardiac relaxation. Kidney Int 55:1091-1096, 1999

395. Kyriazis J, Stamatiadis D, Mamouna A: Intradialyticnd interdialytic effects of treatment with 1.25 and 1.75mol/L of calcium dialysate on arterial compliance in

atients on hemodialysis. Am J Kidney Dis 35:1096-1103,000396. Weinreich T, Passlick-Deetjen J, Ritz E: Low dialy-

ate calcium in continuous ambulatory peritoneal dialysis: aandomized controlled multicenter trial. The Peritonealialysis Multicenter Study Group. Am J Kidney Dis 25:452-60, 1995397. Wadhwa NK, Howell N, Suh H, Cabralda T: Low

alcium (2.5 mEq/l) and high calcium (3.5 mEq/l) dialysaten peritoneal dialysis patients. Adv Perit Dial 8:385-388,992398. Stein A, Baker F, Moorhouse J, Walls J: Peritonitis

ate: traditional versus low calcium dialysate. Am J Kidneyis 26:632-633, 1995399. Weinreich T, Ritz E, Passlick-Deetjen J: Long-term

ialysis with low-calcium solution (1.0 mmol/L) in CAPD:ffects on bone mineral metabolism. Collaborators of theulticenter Study Group. Perit Dial Int 16:260-268, 1996400. Van der Niepen P, Sennesael J, Louis O, Verbeelen

: Effect of treatment with 1.25 and 1.75 mmol/l calciumialysate on bone mineral density in haemodialysis patients.ephrol Dial Transplant 10:2253-2258, 1995401. Hamdy NA, Boletis J, Charlesworth D, Kanis JA,

rown CB: Low calcium dialysate increases the tolerance toitamin D in peritoneal dialysis. Contrib Nephrol 89:190-98, 1991402. Holgado R, Haire H, Ross D, Sprague S, Pahl M,

ara A, Martin-Malo A, Rodriguez M, Almaden Y, Felsen-eld AJ: Effect of a low calcium dialysate on parathyroidormone secretion in diabetic patients on maintenanceemodialysis. J Bone Miner Res 15:927-935, 2000403. Johnson DW, Rigby RJ, McIntyre HD, Brown A,

reeman J: A randomized trial comparing 1.25 mmol/lalcium dialysate to 1.75 mmol/l calcium dialysate in CAPDatients. Nephrol Dial Transplant 11:88-93, 1996404. Armstrong A, Beer J, Noonan K, Cunningham J:

educed calcium dialysate in CAPD patients: efficacy andimitations. Nephrol Dial Transplant 12:1223-1228, 1997

405. Fine RN, Kohaut EC, Brown D, Perlman AJ: Growth
fter recombinant human growth hormone treatment in I
hildren with chronic renal failure: report of a multicenterandomized double-blind placebo-controlled study. Genen-ech Cooperative Study Group. J Pediatr 124:374-382, 1994

406. Schaefer F, Wuhl E, Haffner D, Mehls O: Stimula-ion of growth by recombinant human growth hormone inhildren undergoing peritoneal or hemodialysis treatment.erman Study Group for Growth Hormone Treatment inhronic Renal Failure. Adv Perit Dial 10:321-326, 1994407. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B,ehls O: Effect of growth hormone treatment on the adult

eight of children with chronic renal failure. German Studyroup for Growth Hormone Treatment in Chronic Renalailure. N Engl J Med 343:923-930, 2000408. Van Dyck M, Bilem N, Proesmans W: Conservative

reatment for chronic renal failure from birth: a 3-yearollow-up study. Pediatr Nephrol 13:865-869, 1999

409. Nixon JV, Narahara KA, Smitherman TC: Estimationf myocardial involvement in patients with acute myocar-ial infarction by two-dimensional echocardiography. Circu-ation 62:1248-1255, 1980

410. Prasad V, Greig F, Bastian W, Castells S, Juan C,vRuskin TW: Slipped capital femoral epiphysis during

reatment with recombinant growth hormone for isolated,artial growth hormone deficiency. J Pediatr 116:397-399,990411. Fine RN, Kohaut E, Brown D, Kuntze J, Attie KM:

ong-term treatment of growth retarded children withhronic renal insufficiency, with recombinant human growthormone. Kidney Int 49:781-785, 1996412. Mehls O, Broyer M: Growth response to recombi-

ant human growth hormone in short prepubertal childrenith chronic renal failure with or without dialysis. Theuropean/Australian Study Group. Acta Paediatr Suppl99:81-87, 1994413. Van Dyck M, Gyssels A, Proesmans W, Nijs J,

eckels R: Growth hormone treatment enhances boneineralisation in children with chronic renal failure. EurPediatr 160:359-363, 2001414. van der Sluis IM, Boot AM, Nauta J, Hop WC, de

ong MC, Lilien MR, Groothoff JW, van Wijk AE, Pols HA,okken-Koelega AC, de Muinck Keizer-Schrama SM: Boneensity and body composition in chronic renal failure:ffects of growth hormone treatment. Pediatr Nephrol 15:221-28, 2000415. Lanes R, Gunczler P, Orta N, Bosquez M, Scovino R,

ominguez L, Esaa S, Weisinger JR: Changes in boneineral density, growth velocity and renal function of

repubertal uremic children during growth hormone treat-ent. Horm Res 46:263-268, 1996416. Fujisawa Y, Kida K: Effect of growth hormone (GH)

herapy on parathyroid hormone metabolism in a girl withH deficient short stature and chronic renal failure. J Pediatrndocrinol Metab 9:555-558, 1996417. Sieniawska M, Panczyk-Tomaszewska M, Zi-

lkowska H: The influence of growth hormone treatment onone metabolism in dialysis patients. Br J Clin Pract Suppl5:61-63, 1996418. Kaufman DB: Growth hormone and renal osteodys-

rophy: a case report. Pediatr Nephrol 12:157-159, 1998419. Milliner DS, Shinaberger JH, Shuman P, Coburn JW:

nadvertent aluminum administration during plasma ex-

cr

MM

S

WK

L

t

t3

eN

PA“1

Dw1

Ke4

lt3

a

iN

eC(p

npD

aa5

Aa1

ti

Wo9

ca

dr

er

Ras1

R8

LVl9

Bat

ai

o2(

H3

MDn“6

tt1

Et1

Gr

REFERENCES S117

hange due to aluminum contamination of albumin-eplacement solutions. N Engl J Med 312:165-167, 1985

420. Daly AL, Velazquez LA, Bradley SF, Kauffman CA:ucormycosis: association with deferoxamine therapy. Am Jed 87:468-471, 1989421. Alfrey AC: The toxicity of the aluminum burden.

emin Nephrol 3:329-334, 1983422. Graf H, Stummvoll HK, Meisinger V, Kovarik J,olf A, Pinggera WF: Aluminum removal by hemodialysis.idney Int 19:587-592, 1981423. Trapp GA: Plasma aluminum is bound to transferrin.

ife Sci 33:311-316, 1983424. Alfrey AC: Aluminum metabolism in uremia. Neuro-

oxicol 1:43-53, 1980425. Alfrey AC, Hegg A, Craswell P: Metabolism and

oxicity of aluminum in renal failure. Am J Clin Nutr3:1509-1516, 1980426. Alfrey AC, LeGendre GR, Kaehny WD: The dialysis

ncephalopathy syndrome. Possible aluminum intoxication.Engl J Med 294:184-188, 1976427. Kerr DN, Ward MK, Arze RS, Ramos JM, Grekas D,

arkinson IS, Ellis HA, Owen JP, Simpson W, Dewar J, et al:luminum-induced dialysis osteodystrophy: the demise of

Newcastle bone disease”? Kidney Int Suppl 18:S58-S64,986428. Ward MK, Feest TG, Ellis HA, Parkinson IS, Kerr

N: Osteomalacic dialysis osteodystrophy: Evidence for aater-borne aetiological agent, probably aluminium. Lancet:841-845, 1978429. Parkinson IS, Ward MK, Feest TG, Fawcett RW,

err DN: Fracturing dialysis osteodystrophy and dialysisncephalopathy. An epidemiological survey. Lancet 1:406-09, 1979430. Parkinson IS, Ward MK, Kerr DN: Dialysis encepha-

opathy, bone disease and anaemia: the aluminum intoxica-ion syndrome during regular haemodialysis. J Clin Pathol4:1285-1294, 1981431. McGonigle RJ, Parsons V: Aluminium-induced

naemia in haemodialysis patients. Nephron 39:1-9, 1985432. O’Hare JA, Murnaghan DJ: Reversal of aluminum-

nduced hemodialysis anemia by a low-aluminum dialysate.Engl J Med 306:654-656, 1982433. Berkseth RO, Shapiro FL: An epidemic of dialysis

ncephalopathy and exposure to high aluminum dialysate, inontroversies in Nephrology, Schreiner GE, Winchester JF

eds), Washington, DC, Georgetown University Press, 1980,p 42-51434. Simoes J, Barata JD, D’Haese PC, De Broe ME: Cela

’arrive qu’aux autres (aluminium intoxication only hap-ens in the other nephrologist’s dialysis centre). Nephrolial Transplant 9:67-68, 1994435. LeGendre GR, Alfrey AC: Measuring picogram

mounts of aluminum in biological tissue by flamelesstomic absorption analysis of a chelate. Clin Chem 22:53-6, 1976436. Bakir AA, Hryhorczuk DO, Berman E, Dunea G:

cute fatal hyperaluminemic encephalopathy in undialyzednd recently dialyzed uremic patients. ASAIO Trans 32:171-
76, 1986 8
437. Kirschbaum BB, Schoolwerth AC: Acute aluminumoxicity associated with oral citrate and aluminum-contain-ng antacids. Am J Med Sci 297:9-11, 1989

438. Molitoris BA, Froment DH, Mackenzie TA, HufferH, Alfrey AC: Citrate: a major factor in the toxicity of

rally administered aluminum compounds. Kidney Int 36:49-953, 1989439. Nolan CR, Califano JR, Butzin CA: Influence of

alcium acetate or calcium citrate on intestinal aluminumbsorption. Kidney Int 38:937-941, 1990

440. Sherrard DJ, Walker JV, Boykin JL: Precipitation ofialysis dementia by deferoxamine treatment of aluminum-elated bone disease. Am J Kidney Dis 12:126-130, 1988

441. McCauley J, Sorkin MI: Exacerbation of aluminiumncephalopathy after treatment with desferrioxamine. Neph-ol Dial Transplant 4:110-114, 1989

442. Alfrey AC, Mishell JM, Burks J, Contiguglia SR,udolph H, Lewin E, Holmes JH: Syndrome of dyspraxiand multifocal seizures associated with chronic hemodialy-is. Trans Am Soc Artif Intern Organs 18:257-261, 266-257,972443. Dunea G, Mahurkar SD, Mamdani B, Smith EC:

ole of aluminum in dialysis dementia. Ann Intern Med8:502-504, 1978444. Hodsman AB, Sherrard DJ, Wong EG, Brickman AS,

ee DB, Alfrey AC, Singer FR, Norman AW, Coburn JW:itamin-D-resistant osteomalacia in hemodialysis patients

acking secondary hyperparathyroidism. Ann Intern Med4:629-637, 1981445. Hodsman AB, Sherrard DJ, Alfrey AC, Ott S,

rickman AS, Miller NL, Maloney NA, Coburn JW: Boneluminum and histomorphometric features of renal osteodys-rophy. J Clin Endocrinol Metab 54:539-546, 1982

446. Kaehny WD, Hegg AP, Alfrey AC: Gastrointestinalbsorption of aluminum from aluminum-containing antac-ds. N Engl J Med 296:1389-1390, 1977

447. Monier-Faugere MC, Malluche HH: Trends in renalsteodystrophy: a survey from 1983 to 1995 in a total of248 patients. Nephrol Dial Transplant 11:111-120, 1996suppl 3)

448. Puschett JB, Piraino B, Greenberg A, Rault R:ypercalcemia in a dialysis patient. Am J Nephrol 6:388-95, 1986449. Norris KC, Crooks PW, Nebeker HG, Hercz G,illiner DS, Gerszi K, Slatopolsky E, Andress DL, SherrardJ, Coburn JW: Clinical and laboratory features of alumi-um-related bone disease: differences between sporadic andepidemic” forms of the syndrome. Am J Kidney Dis:342-347, 1985450. Sherrard DJ, Ott SM, Andress DL: Pseudohyperpara-

hyroidism. Syndrome associated with aluminum intoxica-ion in patients with renal failure. Am J Med 79:127-130,985451. Andress DL, Ott SM, Maloney NA, Sherrard DJ:

ffect of parathyroidectomy on bone aluminum accumula-ion in chronic renal failure. N Engl J Med 312:468-473,985452. Recker R, Schoenfeld P, Letteri J, Slatopolsky E,

oldsmith R, Brickman A: The efficacy of calcifediol inenal osteodystrophy. Arch Intern Med 138 Spec No:857-
63, 1978

Eid

Soa7

AIdt

uaJ

MDnnA

Sic

Sa6

Ahb

Map

1

oa

Hd2

ti

oLawaT

G

aD

Add

Rnp

e1

RhK

Lst

So1

nac

aT

ZbS

N

Mni

dh

MhS

op1

Cbr

Mg

REFERENCESS118

453. Kausz AT, Antonsen JE, Hercz G, Pei Y, Weiss NS,merson S, Sherrard DJ: Screening plasma aluminum levels

n relation to aluminum bone disease among asymptomaticialysis patients. Am J Kidney Dis 34:688-693, 1999454. Milliner DS, Nebeker HG, Ott SM, Andress DL,

herrard DJ, Alfrey AC, Slatopolsky EA, Coburn JW: Usef the deferoxamine infusion test in the diagnosis ofluminum-related osteodystrophy. Ann Intern Med 101:775-79, 1984455. Nebeker HG, Andress DL, Milliner DS, Ott SM,

lfrey AC, Slatopolsky EA, Sherrard DJ, Coburn JW:ndirect methods for the diagnosis of aluminum boneisease: plasma aluminum, the desferrioxamine infusionest, and serum iPTH. Kidney Int Suppl 18:S96-S99, 1986

456. Malluche HH, Smith AJ, Abreo K, Faugere MC: These of deferoxamine in the management of aluminiumccumulation in bone in patients with renal failure. N EnglMed 311:140-144, 1984457. Fournier A, Fohrer P, Leflon P, Moriniere P, Tolani, Lambrey G, Demontis R, Sebert JL, Van Devyver F,ebroe M: The desferrioxamine test predicts bone alumi-ium burden induced by A1(OH)3 in uraemic patients butot mild histological osteomalacia. Proc Eur Dial Transplantssoc Eur Ren Assoc 21:371-376, 1985458. Ott SM, Maloney NA, Coburn JW, Alfrey AC,

herrard DJ: The prevalence of bone aluminum depositionn renal osteodystrophy and its relation to the response toalcitriol therapy. N Engl J Med 307:709-713, 1982

459. Andress DL, Maloney NA, Coburn JW, Endres DB,herrard DJ: Osteomalacia and aplastic bone disease inluminum-related osteodystrophy. J Clin Endocrinol Metab5:11-16, 1987460. Andress DL, Nebeker HG, Ott SM, Endres DB,

lfrey AC, Slatopolsky EA, Coburn JW, Sherrard DJ: Boneistologic response to deferoxamine in aluminum-relatedone disease. Kidney Int 31:1344-1350, 1987461. Pei Y, Hercz G, Greenwood C, Sherrard D, Segre G,anuel A, Saiphoo C, Fenton S: Non-invasive prediction of

luminum bone disease in hemo- and peritoneal dialysisatients. Kidney Int 41:1374-1382, 1992462. Alfrey AC: Aluminum metabolism. Kidney Int Suppl

8:S8-S11, 1986463. Bene C, Manzler A, Bene D, Kranias G: Irreversible

cular toxicity from single “challenge” dose of deferox-mine. Clin Nephrol 31:45-48, 1989

464. Pengloan J, Dantal J, Rossazza C, Abazza M, Nivet: Ocular toxicity after a single intravenous dose ofesferrioxamine in 2 hemodialyzed patients. Nephron 46:211-12, 1987465. Boelaert JR, Fenves AZ, Coburn JW: Deferoxamine

herapy and mucormycosis in dialysis patients: report of annternational registry. Am J Kidney Dis 18:660-667, 1991

466. D’Haese PC, Couttenye MM, Goodman WG, Lem-niatou E, Digenis P, Sotornik I, Fagalde A, Barsoum RS,amberts LV, De Broe ME: Use of the low-dose desferriox-mine test to diagnose and differentiate between patientsith aluminium-related bone disease, increased risk for

luminium toxicity, or aluminium overload. Nephrol Dialransplant 10:1874-1884, 1995467. Canteros A, Diaz-Corte C, Fernandez-Martin JL,

ago E, Fernandez-Merayo C, Cannata J: Ultrafiltrable K

luminium after very low doses of desferrioxamine. Nephrolial Transplant 13:1538-1542, 1998468. Jorge C, Gil C, Possante M, Catarino MC, Cruz A,

ndrade R, Teixeira R, Santos N, Ferreira A: Use of aesferrioxamine “microdose” to chelate aluminum in hemo-ialysis patients. Clin Nephrol 52:335-336, 1999469. Salusky IB, Coburn JW, Paunier L, Sherrard DJ, Fine

N: Role of aluminum hydroxide in raising serum alumi-um levels in children undergoing continuous ambulatoryeritoneal dialysis. J Pediatr 105:717-720, 1984470. Rozas VV, Port FK, Rutt WM: Progressive dialysis

ncephalopathy from dialysate aluminum. Arch Intern Med38:1375-1377, 1978471. Burwen DR, Olsen SM, Bland LA, Arduino MJ,

eid MH, Jarvis WR: Epidemic aluminum intoxication inemodialysis patients traced to use of an aluminum pump.idney Int 48:469-474, 1995472. D’Haese PC, Clement JP, Elseviers MM, Lamberts

V, Van de Vyver FL, Visser WJ, De Broe ME: Value oferum aluminium monitoring in dialysis patients: a multicen-re study. Nephrol Dial Transplant 5:45-53, 1990

473. Pei Y, Hercz G, Greenwood C, Segre G, Manuel A,aiphoo C, Fenton S, Sherrard D: Risk factors for renalsteodystrophy: a multivariant analysis. J Bone Miner Res0:149-156, 1995474. Heaf JG, Podenphant J, Andersen JR: Bone alumi-

um deposition in maintenance dialysis patients treated withluminium-free dialysate: role of aluminium hydroxideonsumption. Nephron 42:210-216, 1986

475. Channon SM, Arfeen S, Ward MK: Long-termccumulation of aluminum in patients with renal failure.race Elements Med 5:147-157, 1988476. Costantini S, Giordano R, Vernillo I, Piccioni A,

apponi GA: Predictive value of serum aluminium levels forone accumulation in haemodialyzed patients. Ann Ist Superanita 25:457-461, 1989477. Sherrard DJ: Aluminum–much ado about something.Engl J Med 324:558-559, 1991478. Cases A, Kelly J, Sabater J, Campistol JM, Torras A,ontoliu J, Lopez I, Revert L: Acute visual and auditory

eurotoxicity in patients with end-stage renal disease receiv-ng desferrioxamine. Clin Nephrol 29:176-178, 1988

479. Janssen MJ, van Boven WP: Efficacy of low-doseesferrioxamine for the estimation of aluminium overload inaemodialysis patients. Pharm World Sci 18:187-191, 1996480. Ott SM, Andress DL, Nebeker HG, Milliner DS,aloney NA, Coburn JW, Sherrard DJ: Changes in bone

istology after treatment with desferrioxamine. Kidney Intuppl 18:S108-S113, 1986481. Faugere MC, Arnala IO, Ritz E, Malluche HH: Loss

f bone resulting from accumulation of aluminum in bone ofatients undergoing dialysis. J Lab Clin Med 107:481-487,986482. Charhon SA, Chavassieux P, Boivin G, Parisien M,

hapuy MC, Traeger J, Meunier PJ: Deferoxamine-inducedone changes in haemodialysis patients: a histomorphomet-ic study. Clin Sci (Lond) 73:227-234, 1987

483. Bia MJ, Cooper K, Schnall S, Duffy T, Hendler E,alluche H, Solomon L: Aluminum induced anemia: patho-

enesis and treatment in patients on chronic hemodialysis.
idney Int 36:852-858, 1989

Lw1

ea

rl

CdiN

ld

Tsa1

iS

Afa

hoN

fm

CYes

Ro

c7

Ci8

Sbn

Sfc1

Gp

Md

Ta

Ra1

Sld

oah

Jv1

Klt

Sisr

So1

cA

Ap

Ypt

pL

t1

n3

O

REFERENCES S119

484. Felsenfeld AJ, Rodriguez M, Coleman M, Ross D,lach F: Desferrioxamine therapy in hemodialysis patientsith aluminum-associated bone disease. Kidney Int 35:1371-378, 1989485. McCarthy JT, Milliner DS, Johnson WJ: Clinical

xperience with desferrioxamine in dialysis patients withluminium toxicity. Q J Med 74:257-276, 1990

486. Ackrill P, Ralston AJ, Day JP, Hodge KC: Successfulemoval of aluminium from patient with dialysis encepha-opathy. Lancet 2:692-693, 1980

487. Hood SA, Clark WF, Hodsman AB, Bolton CF,ordy PE, Anderson C, Leung F: Successful treatment ofialysis osteomalacia and dementia, using desferrioxaminenfusions and oral 1-alpha hydroxycholecalciferol. Am Jephrol 4:369-374, 1984488. Milne FJ, Sharf B, Bell P, Meyers AM: The effect of

ow aluminum water and desferrioxamine on the outcome ofialysis encephalopathy. Clin Nephrol 20:202-207, 1983489. Sprague SM, Corwin HL, Wilson RS, Mayor GH,

anner CM: Encephalopathy in chronic renal failure respon-ive to deferoxamine therapy. Another manifestation ofluminum neurotoxicity. Arch Intern Med 146:2063-2064,986490. Ackrill P, Ralston AJ, Day JP: Role of desferrioxam-

ne in the treatment of dialysis encephalopathy. Kidney Intuppl 18:S104-S107, 1986491. Altmann P, Plowman D, Marsh F, Cunningham J:

luminium chelation therapy in dialysis patients: evidenceor inhibition of haemoglobin synthesis by low levels ofluminium. Lancet 1:1012-1015, 1988

492. von Bonsdorff M, Sipila R, Pitkanen E: Correction ofaemodialysis-associated anaemia by deferoxamine. Effectsn serum aluminum and iron overload. Scand J Urolephrol Suppl 131:49-54, 1990493. Van Cutsem J, Boelaert JR: Effects of deferoxamine,

eroxamine and iron on experimental mucormycosis (zygo-ycosis). Kidney Int 36:1061-1068, 1989494. Boelaert JR, de Locht M, Van Cutsem J, Kerrels V,

antinieaux B, Verdonck A, Van Landuyt HW, SchneiderJ: Mucormycosis during deferoxamine therapy is a sid-

rophore-mediated infection. In vitro and in vivo animaltudies. J Clin Invest 91:1979-1986, 1993

495. Windus DW, Stokes TJ, Julian BA, Fenves AZ: Fatalhizopus infections in hemodialysis patients receiving defer-xamine. Ann Intern Med 107:678-680, 1987496. Boelaert JR, Vergauwe PL, Vandepitte JM: Mucormy-

osis infection in dialysis patients. Ann Intern Med 107:782-83, 1987497. De Broe ME, Drueke TB, Ritz E: Consensus

onference: Diagnosis and treatment of aluminum overloadn end-stage renal failure patients. Nephrol Dial Transplant:1-4, 1993 (suppl 1)498. Hercz G, Andress DL, Nebeker HG, Shinaberger JH,

herrard DJ, Coburn JW: Reversal of aluminum-relatedone disease after substituting calcium carbonate for alumi-um hydroxide. Am J Kidney Dis 11:70-75, 1988499. Hercz G, Andress DL, Norris KC, Shinaberger JH,

latopolsky EA, Sherrard DJ, Coburn JW: Improved boneormation in dialysis patients after substitution of calciumarbonate for aluminum gels. Trans Assoc Am Physicians
00:139-146, 1987 r
500. Adhemar JP, Laederich J, Jaudon MC, Masselot JP,alli A, Kleinknecht D: Removal of aluminium fromatients with dialysis encephalopathy. Lancet 2:1311, 1980501. Arze RS, Parkinson IS, Cartlidge NE, Britton P, WardK: Reversal of aluminium dialysis encephalopathy after

esferrioxamine treatment. Lancet 2:1116, 1981502. Pogglitsch H, Petek W, Wawschinek O, Holzer W:

reatment of early stages of dialysis encephalopathy byluminium depletion. Lancet 2:1344-1345, 1981

503. Molitoris BA, Alfrey AC, Alfrey PS, Miller NL:apid removal of DFO-chelated aluminum during hemodi-lysis using polysulfone dialyzers. Kidney Int 34:98-101,988504. Delmez J, Weerts C, Lewis-Finch J, Windus D,

latopolsky E: Accelerated removal of deferoxamine mesy-ate-chelated aluminum by charcoal hemoperfusion in hemo-ialysis patients. Am J Kidney Dis 13:308-311, 1989505. Vasilakakis DM, D’Haese PC, Lamberts LV, Lem-

niatou E, Digenis PN, De Broe ME: Removal of aluminox-mine and ferrioxamine by charcoal hemoperfusion andemodialysis. Kidney Int 41:1400-1407, 1992506. Hercz G, Salusky IB, Norris KC, Fine RN, Coburn

W: Aluminum removal by peritoneal dialysis: intravenouss. intraperitoneal deferoxamine. Kidney Int 30:944-948,986507. Molitoris BA, Alfrey PS, Miller NL, Hasbargen JA,

aehney WD, Alfrey AC, Smith BJ: Efficacy of intramuscu-ar and intraperitoneal deferoxamine for aluminum chela-ion. Kidney Int 31:986-991, 1987

508. Barata JD, D’Haese PC, Pires C, Lamberts LV,imoes J, De Broe ME: Low-dose (5 mg/kg) desferrioxam-

ne treatment in acutely aluminium-intoxicated haemodialy-is patients using two drug administration schedules. Neph-ol Dial Transplant 11:125-132, 1996

509. Widmer B, Gerhardt RE, Harrington JT, Cohen JJ:erum electrolyte and acid base composition. The influencef graded degrees of chronic renal failure. Arch Intern Med39:1099-1102, 1979510. Eiser AR, Slifkin RF, Neff MS: Intestinal mucormy-

osis in hemodialysis patients following deferoxamine.m J Kidney Dis 10:71-73, 1987511. Veis JH, Contiguglia R, Klein M, Mishell J, Alfrey

C, Shapiro JI: Mucormycosis in deferoxamine-treatedatients on dialysis. Ann Intern Med 107:258, 1987512. Boelaert JR, Van Cutsem J, de Locht M, Schneider

J, Crichton RR: Deferoxamine augments growth andathogenicity of Rhizopus, while hydroxypyridinone chela-ors have no effect. Kidney Int 45:667-671, 1994

513. Coburn JW, Maung HM: Mucormycosis in dialysisatients, in Sweny P, Rubin RH, Tolkoff-Rubin N (eds),ondon, Oxford University Press, 2002514. Salusky IB, Goodman WG: Adynamic renal osteodys-

rophy: is there a problem? J Am Soc Nephrol 12:1978-985, 2001515. Malluche HH, Monier-Faugere MC: Risk of ady-

amic bone disease in dialyzed patients. Kidney Int Suppl8:S62-S67, 1992516. Atsumi K, Kushida K, Yamazaki K, Shimizu S,

hmura A, Inoue T: Risk factors for vertebral fractures in
enal osteodystrophy. Am J Kidney Dis 33:287-293, 1999

fh

ei

Af1

Gtf

DpC

Dr

Aeip

Mti

tr

ADsd1

CtpM

Hp9nJ

Ns(

BAtt3

Ha7

PDtt

Itp1

Fts1

SgA

pc

Pc4

Mhp

KttP2

Wmat

nc6

Spf1

paoE

REFERENCESS120

517. Coco M, Rush H: Increased incidence of hipractures in dialysis patients with low serum parathyroidormone. Am J Kidney Dis 36:1115-1121, 2000518. D’Amour P, Huet PM: Ca2� concentration influ-

nces the hepatic extraction of bioactive human PTH-(1-34)n rats. Am J Physiol 256:E87-E92, 1989

519. Chou FF, Chan HM, Huang TJ, Lee CH, Hsu KT:utotransplantation of parathyroid glands into subcutaneous

orearm tissue for renal hyperparathyroidism. Surgery 124:-5, 1998520. Kostakis A, Vaiopoulos G, Kostantopoulos K, Zavos

, Bocos I, Sgouromalis S: Parathyroidectomy in thereatment of secondary hyperparathyroidism in chronic renalailure. Int Surg 82:85-86, 1997

521. Gasparri G, Camandona M, Jeantet A, Nano M,esimone M, Bronda M, Deipoli M: Results after 223arathyroidectomies for secondary hyperparathyroidism.Actahir Austriaca 28:32-34, 1996 (suppl 124)522. Neonakis E, Wheeler MH, Krishnan H, Coles GA,

avies F, Woodhead JS: Results of surgical treatment ofenal hyperparathyroidism. Arch Surg 130:643-648, 1995

523. Gagne ER, Urena P, Leite-Silva S, Zingraff J, Chevalier, Sarfati E, Dubost C, Drueke TB: Short- and long-term

fficacy of total parathyroidectomy with immediate autograft-ng compared with subtotal parathyroidectomy in hemodialysisatients. J Am Soc Nephrol 3:1008-1017, 1992

524. Takagi H, Tominaga Y, Uchida K, Yamada N, Kawai, Kano T, Morimoto T: Subtotal versus total parathyroidec-

omy with forearm autograft for secondary hyperparathyroid-sm in chronic renal failure. Ann Surg 200:18-23, 1984

525. Esselstyn CB Jr, Popowniak KL: Parathyroid surgery inhe treatment of renal osteodystrophy and tertiary hyperparathy-oidism. Surg Clin North Am 51:1211-1217, 1971

526. Olaizola I, Zingraff J, Heuguerot C, Fajardo L, Leger, Lopez J, Acuna G, Petraglia A, Alvarez A, Caorsi H,rueke T, Ambrosoni P: [(99m)Tc]-sestamibi parathyroid

cintigraphy in chronic haemodialysis patients: static andynamic explorations. Nephrol Dial Transplant 15:1201-206, 2000527. Neumann DR, Esselstyn CB, Jr., Madera A, Wong

O, Lieber M: Parathyroid detection in secondary hyperpara-hyroidism with 123I/99mTc-sestamibi subtraction singlehoton emission computed tomography. J Clin Endocrinoletab 83:3867-3871, 1998528. Blocklet D, Martin P, Schoutens A, Verhas M,

ooghe L, Kinnaert P: Presurgical localization of abnormalarathyroid glands using a single injection of technetium-9m methoxyisobutylisonitrile: comparison of different tech-iques including factor analysis of dynamic structures. EurNucl Med 24:46-51, 1997529. Tanaka Y, Tominaga Y, Funahashi H, Sato K,

umano M, Takagi H: Preoperative localization studies inecondary hyperplasia. Acta Chir Austriaca 28:14-16, 1996suppl 124)

530. Hindie E, Urena P, Jeanguillaume C, Melliere D,erthelot JM, Menoyo-Calonge V, Chiappini-Briffa D, Janin, Galle P: Preoperative imaging of parathyroid glands with

echnetium-99m-labelled sestamibi and iodine-123 subtrac-ion scanning in secondary hyperparathyroidism. Lancet
53:2200-2204, 1999 B
531. Ishibashi M, Nishida H, Okuda S, Suekane S,ayabuchi N: Localization of parathyroid glands in hemodi-

lysis patients using Tc-99m sestamibi imaging. Nephron8:48-53, 1998532. Jeanguillaume C, Urena P, Hindie E, Prieur P,

etrover M, Menoyo-Calonge V, Janin A, Chiappini-Briffa, Melliere D, Boulahdour H, Galle P: Secondary hyperpara-

hyroidism: detection with I-123-Tc-99m-Sestamibi subtrac-ion scintigraphy versus US. Radiology 207:207-213, 1998

533. Chesser AM, Carroll MC, Lightowler C, MacdougallC, Britton KE, Baker LR: Technetium-99m methoxy isobu-yl isonitrile (MIBI) imaging of the parathyroid glands inatients with renal failure. Nephrol Dial Transplant 12:97-00, 1997534. Pons F, Torregrosa JV, Vidal-Sicart S, Sabater L,

uster D, Fernandez-Cruz L, Herranz R: Preoperative para-hyroid gland localization with technetium-99m sestamibi inecondary hyperparathyroidism. Eur J Nucl Med 24:1494-498, 1997535. Takebayashi S, Matsui K, Onohara Y, Hidai H:

onography for early diagnosis of enlarged parathyroidlands in patients with secondary hyperparathyroidism. AJRm J Roentgenol 148:911-914, 1987536. Fabretti F, Calabrese V, Fornasari V, Poletti I: Subtotal

arathyroidectomy for secondary hyperparathyroidism inhronic renal failure. J Laryngol Otol 105:562-567, 1991

537. Tomic Brzac H, Pavlovic D, Halbauer M, Pasini J:arathyroid sonography in secondary hyperparathyroidism:orrelation with clinical findings. Nephrol Dial Transplant:45-50, 1989538. Takagi H, Tominaga Y, Uchida K, Yamada N, Ishii T,orimoto T, Yasue M: Preoperative diagnosis of secondary

yperparathyroidism using computed tomography. J Com-ut Assist Tomogr 6:527-528, 1982539. Fukagawa M, Kitaoka M, Tominaga Y, Akizawa T,

urokawa K: Selective percutaneous ethanol injectionherapy (PEIT) of the parathyroid in chronic dialysis patients–he Japanese strategy. Japanese Working Group on PEIT ofarathyroid, Tokyo, Japan. Nephrol Dial Transplant 14:2574-577, 1999540. Domrongkitchaiporn S, Pongsakul C, Stitchantrakul, Sirikulchayanonta V, Ongphiphadhanakul B, Radinaha-ed P, Karnsombut P, Kunkitti N, Ruang-raksa C, Rajatan-

vin R: Bone mineral density and histology in distal renalubular acidosis. Kidney Int 59:1086-1093, 2001

541. McSherry E, Morris RC Jr: Attainment and mainte-ance of normal stature with alkali therapy in infants andhildren with classic renal tubular acidosis. J Clin Invest1:509-527, 1978542. Coen G, Mazzaferro S, Ballanti P, Sardella D, Chicca

, Manni M, Bonucci E, Taggi F: Renal bone disease in 76atients with varying degrees of predialysis chronic renalailure: a cross-sectional study. Nephrol Dial Transplant1:813-819, 1996

543. Parfitt AM, Kleerekoper M, Cruz C: Reducedhosphate reabsorption unrelated to parathyroid hormonefter renal transplantation: implications for the pathogenesisf hyperparathyroidism in chronic renal failure. Minerlectrolyte Metab 12:356-362, 1986544. Ambuhl PM, Meier D, Wolf B, Dydak U, Boesiger P,

inswanger U: Metabolic aspects of phosphate replacement

tpa

LSat

GFdt

gN

1ph4

cK

i1

Sl4

dt

fP

Noc

PWpf

JaN

c

REFERENCES S121

herapy for hypophosphatemia after renal transplantation: im-act on muscular phosphate content, mineral metabolism, andcid/base homeostasis. Am J Kidney Dis 34:875-83, 1999

545. Giannini S, D’Angelo A, Carraro G, Antonello A, Diandro D, Marchini F, Plebani M, Zaninotto M, Rigotti P,artori L, Crepaldi G: Persistently increased bone turnovernd low bone density in long-term survivors to kidneyransplantation. Clin Nephrol 56:353-363, 2001

546. Cayco AV, Wysolmerski J, Simpson C, Mitnick MA,undberg C, Kliger A, Lorber M, Silver D, Basadonna G,riedman A, Insogna K, Cruz D, Bia M: Posttransplant boneisease: evidence for a high bone resorption state. Transplan-ation 70:1722-1728, 2000

547. Lane NE, Lukert B: The science and therapy oflucocorticoid-induced bone loss. Endocrinol Metab Clinorth Am 27:465-483, 1998548. Erben RG, Bante U, Birner H, Stangassinger M:

alpha-hydroxyvitamin D2 partially dissociates betweenreservation of cancellous bone mass and effects on calciumomeostasis in ovariectomized rats. Calcif Tissue Int 60:449-56, 1997549. Feber J, Braillon P, David L, Cochat P: Body

omposition in children after renal transplantation. Am Jidney Dis 38:366-370, 2001550. Feber J, Cochat P, Braillon P: Bone mineral density

n children after renal transplantation. Pediatr Nephrol
4:654-657, 2000 P
551. Ellis EN, Floyd-Gimon DM, Berry PL, Wells TG,eibert J, Belsha C: Risk factors for bone mineral density

oss in pediatric renal transplant patients. Pediatr Transplant:146-150, 2000552. Chesney RW, Rose PG, Mazess RB: Persistence of

iminished bone mineral content following renal transplan-ation in childhood. Pediatrics 73:459-466, 1984

553. Zimakas PJ, Sharma AK, Rodd CJ: Osteopenia andractures in cystinotic children post renal transplantation.ediatr Nephrol 18:384-390, 2003554. Sambrook P, Birmingham J, Kelly P, Kempler S,

guyen T, Pocock N, Eisman J: Prevention of corticosteroidsteoporosis. A comparison of calcium, calcitriol, andalcitonin. N Engl J Med 328:1747-1752, 1993

555. Adachi JD, Bensen WG, Bianchi F, Cividino A,illersdorf S, Sebaldt RJ, Tugwell P, Gordon M, Steele M,ebber C, Goldsmith CH: Vitamin D and calcium in the

revention of corticosteroid induced osteoporosis: a 3 yearollowup. J Rheumatol 23:995-1000, 1996

556. De Sevaux RG, Hoitsma AJ, Corstens FH, WetzelsF: Treatment with vitamin D and calcium reduces bone lossfter renal transplantation: a randomized study. J Am Socephrol 13:1608-1614, 2002557. Harris AF, Cotty VF: The effect of lanthanum

hloride and related compounds on calcification. Arch Int
harmacodyn Ther 186:269-278, 1970

Documents

Bone Children NKFguideline