ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΤΕΛΙΚΟ ΣΤΑΔΙΟ

ΝΕΦΡΙΚΗΣ ΝΟΣΟΥ (ESRD)

ΕΥΑΓΓΕΛΙΑ ΝΤΟΥΝΟΥΣΗ,

Επίκουρη Καθηγήτρια Νεφρολογίας, Σχολή Επιστημών Υγείας, Ιατρικό Τμήμα, Πανεπιστημίου Ιωαννίνων

Yamamoto et al, Curr Opin Nephrol Hypertens. 2009

Deaths from cardiovascular disease in the general

population and CKD between 1980 and 2000

4

vol 2 Figure 5.1 Adjusted all-cause mortality by treatment modality (a) overall, dialysis, and transplant, and (b) hemodialysis and peritoneal

dialysis, for period-prevalent patients, 2001-2016

2018 Annual Data Report Volume 2 ESRD, Chapter 5

Data Source: Reference Tables H.2_adj, H.4_adj, H.8_adj, H.9_adj, and H.10_adj; and special analyses, USRDS ESRD Database. Adjusted for age, sex, race, ethnicity, primary diagnosis and vintage. Reference population: period prevalent ESRD patients, 2011. Abbreviations: ESRD, end-stage renal disease; HD, hemodialysis; PD, peritoneal dialysis.

2001 – 2016: adjusted mortality rates decreased for dialysis patients by 29%. The net reductions were 28% for HD patients and 43% for PD patients

52018 Annual Data Report Volume 2 ESRD, Chapter 5

54%

vol 2 Figure 5.4 Unadjusted percentages of deaths in 2015 by cause, excluding missing data, by modality among dialysis prevalent patients

Arrhythmia & cardiac arrest

UK Renal Registry 20th Annual Report

Cause of death in prevalent RRT patients

by cohort year (2000–2015)

33%

25%

7

vol 2 Figure 8.1 Prevalence of cardiovascular diseases in adult ESRD patients, by treatment modality, 2016

2018 Annual Data Report Volume 2 ESRD, Chapter 8

Data Source: Special analyses, USRDS ESRD Database. Point prevalent hemodialysis, peritoneal dialysis, and transplant patients aged 22 and older, who are continuously enrolled in Medicare Parts A and B, and with Medicare as primary payer from January 1, 2016 to December 31, 2016, and ESRD service date is at least 90 days prior to January 1, 2016.

Two-year survival of adult ESRD patients (age>22y) with or without CVD, adjusted for age and sex, 2015-2016

Presence of cardiovascular disease

Cardiovascular disease Survival when present (%) Survival when not present (%)

CAD 66.2 82.0

AMI 58.5 78.4

HF 66.0 83.4

VHD 63.0 78.1

CVA/TIA 65.7 78.6

PAD 66.3 81.1

AF 62.1 78.9

SCA/VA 55.3 77.2

VTE/PE 63.9 77.1

2018 Annual Data Report Volume 2 ESRD, Chapter 8

Data Source: Special analyses, USRDS ESRD Database. Point prevalent hemodialysis, peritoneal dialysis, and transplant patients aged 22 and older, who are continuously enrolled in Medicare Parts A and B, and with Medicare as primary payer from January 1, 2014 to December 31, 2014, and whose first ESRD service date is at least 90 days prior to January 1, 2014, and survived past 2014. Abbreviations: AF, atrial fibrillation; AMI, acute myocardial infarction; CAD, coronary artery disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; ESRD, end-stage renal disease; HF, heart failure; PAD, peripheral arterial disease; SCA/VA, sudden cardiac arrest and ventricular arrhythmias; VHD, valvular heart disease; VTE/PE, venous thromboembolism and pulmonary embolism.

- 15,8%

- 12,9%

- 19,9%- 17,4%

- 14,8%

- 15,1%

- 16,8%

- 21,9%

- 13,2%

As GFR ↓, NONATHEROSCLEROTIC events assume a higher proportion of the CVD events

Sarnak et al. J Am Coll Cardiol. 2019

• Coronary artery disease

• Heart failure

• Valvular heart disease

• Arrhythmias

• Sudden cardiac death

Three cardinal processes in the evolution of CVD in CKD

CARDIOVASCULAR DISEASE IN DIALYSIS

Tangri et al, Kidney Int 2015

DIALYSIS

CARDIOVASCULAR RISK FACTORS & PREDICTORS IN ESRD

Lonenecker et al, J Am Soc Nephro 2002

Many dialysis patients have more than one of these risk factors, resulting in an even higher risk of adverse outcomes

The projected 5-yr ASCVD risk based on the Framingham Risk Equation among those older than 40 yr without ASCVD was higher in CHOICE Study participants

(13%) than in the NHANES III participants (6%)

However, that the influences of some of these traditional risk factors, on CVD in the dialysis pts are less clear than in nondialysis pts

The association between under-nutrition and adverse CV outcome in dialysis patients, which stands in contrast to that seen in non-ESRD

individuals, has been referred to as “REVERSE EPIDEMIOLOGY.”

Kalantar-Zadeh et al, Kidney International 2003

Moradi et al, Am J Nephrol 2013

Involvement of UREMIC TOXINS in the major domains of CVD

Moradi et al, Am J Nephrol 2013

Mechanisms by which UREMIC TOXINS cause cardiovascular damage

• Endothelial dysfunction,

a pro-atherogenic alteration, is

pervasive in CKD

• Accumulation of the

endogenous inhibitor of NO

synthase, asymmetric

dimethylarginine (ADMA),

appears to be of primary

importance for the CVD outcome

Zoccali C et al, Lancet 2001, Zoccali C, Kidney int. 2006

Relationship between ADMA and CV events in the CREED study

Among several biomarkers,

IL-6 is the only biomarker

that consistently and

independently can classify

the presence of clinical

overt CVD at baseline and

predict subsequent

mortality over 60 months.

- A post hoc analysis of data from a longitudinal study on malnutrition, inflammation, and CVD in 543 incident dialysis patients.- Markers: albumin, ferritin, hsCRP, IGF-1, IL-6, orosomucoid, troponin T, TNF, sICAM, sVCAM-1, and PLT and WBC counts

Sun et al, Clin J Am Soc Nephrol. 2016

Figure 1.

Open in a separate window

The optimal predictive cutoff value for each biomarker was defined using receiver operating characteristics

curves. In the example shown here, age appeared as a stronger predictor of outcomes than IL-6 and high-

sensitivity CRP, a finding which was confirmed by the subsequent analyses. Areas under the curves (AUCs) of

receiver operating characteristics in 543 patients with stage 5 CKD for patient age, IL-6, and high–sensitivity C–reactive

protein (CRP) in relation to (A) presence of clinically overt cardiovascular disease (CVD) and (B) 60 months all-cause

mortality censored for transplantation. (A) The AUC of age, IL-6, and high-sensitivity CRP for CVD in patients with

stage 5 CKD (n=543). (B) The AUC of age, IL-6, and high-sensitivity CRP for all-cause mortality in patients with stage 5

CKD (n=543).

Clin J Am Soc Nephrol. 2016 Jul 7; 11(7): 1163–1172.

Published online 2016 Jun 8.

doi: 10.2215/CJN.10441015: 10.2215/CJN.10441015

PMCID: PMC4934843

PMID: 27281698

Biomarkers of Cardiovascular Disease and Mortality Risk in Patients

with Advanced CKD

Jia Sun, Jonas Axelsson, Anna Machowska, Olof Heimbürger, Peter Bárány, Bengt Lindholm,

Karin Lindström, Peter Stenvinkel, and Abdul Rashid Qureshi

Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology and

Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm,

Sweden

Corresponding author.

J.S. and J.A. contributed equally to this work.

Correspondence: Dr. Abdul Rashid Qureshi, M-99, Karolinska University Hospital at Huddinge, 141 86

Stockholm, Sweden. Email: tony.qureshi@ki.se

Received 2015 Oct 2; Accepted 2016 Mar 12.

Copyright © 2016 by the American Society of Nephrology

Abstract

Background and objectives

The high risk of cardiovascular disease (CVD) and premature death in patients with CKD associates with a

plethora of elevated circulating biomarkers that may reflect distinct signaling pathways or simply, are

epiphenomena of CKD. We compared the predictive strength of 12 biomarkers analyzed concomitantly in

patients with stage 5 CKD.

Design, setting, participants, & measurements

From 1994 to 2014, 543 patients with stage 5 CKD (median age =56 years old; 63% men; 199 patients had

CVD) took part in our study on malnutrition, inflammation, and CVD in incident dialysis patients.

Circulating levels of albumin, ferritin, high–sensitivity C–reactive protein (hsCRP), IGF-1, IL-6,

orosomucoid, troponin T (TnT), TNF, soluble intracellular adhesion molecule, soluble vascular cellular

adhesion molecule 1 (sVCAM-1), and platelet and white blood cell (WBC) counts were analyzed as

predictors of the presence of clinically overt CVD at baseline, protein-energy wasting (PEW), and

subsequent all–cause mortality. During follow-up for a median of 28 months, there were 149 deaths, 81 of

which were caused by CVD.

Results

Most biomarkers were elevated compared with reference values and–—except for albumin, ferritin, and

IGF-1—higher in patients with CVD. In receiver operating characteristic analysis, age, IL-6, TnT, hsCRP,

and IGF-1 were classifiers of baseline CVD and predictors of all-cause mortality. In addition to age,

diabetes mellitus, smoking (for CVD), and PEW, only IL-6, relative risk (RR) 1.10 and 95% confidence

interval ([95% CI], 1.02 to 1.19), sVCAM-1 RR 1.09 (95% CI, 1.01 to 1.17), and serum albumin RR 0.89

(95% CI, 0.83 to 0.95) associated with baseline CVD, and only WBC, hazard ratio (HR) 1.94 (95% CI,

1.34 to 2.82), IL-6 HR 1.79 (95% CI, 1.20 to 2.67), and TNF HR 0.65 (95% CI, 0.44 to 0.97) predicted all-

cause mortality.

* † * * * *

* * *

*

†

Dounousi et al, Oxid Med Cell Longev. 2017

Uremia & Renal

replacement therapies

Aortic valve with massive macroscopically

detectable calcification, explanted due to calcific

aortic stenosis, from a dialysis patient.

Transversal, sagittal and

lateral views of arterial

calcifications from a

dialysis patient.

Tissue & Vascular calcification in ESRD:the smoke or the fire in arterial disease

• Significant medial calcification of coronary arteries versus intimal calcification.

• Pathohistological processes differ according to histological location in the vessel or anatomical location in the arterial tree.

• Current clinical tools used to quantify VC likely detect different pathological processes and are unable to distinguish one from the other (CACS)

Vervloet et al, Kidney Int 2016

Vascular calcification

is not a single entity

TH Marwick et al.: a KDIGO conference report, Kidney Int. 2019

VALVULAR HEART DISEASE in ESRD: conclusions from a KDIGO Controversies Conference - 2019

• 2-year survival of pts with VHD and ESKD was 30% lower compared with persons without these conditions.

• Even in the absence of significant valvular dysfunction, the EchoCardiac identification of valvular calcification in 45%-54% ESKD pts was independently associated with adverse CV outcomes

The prevalence of VHD in the US is 14% in hemodialysis and 12% in peritoneal dialysisAortic stenosis is the most prevalent (change in AV area of –0.19 cm2/year)

1-year all-cause

mortality is:

➢ 57% both aortic +

mitral valves

➢ 40% with either

valve calcified

➢ 15% if neither was

valve calcified.

Among long-term dialysis pts, the number of calcified valves is associated with all-cause and CV mortality

Wang et al, J Am Soc Nephrol. 2003

Molecular, cellular, and biomechanical mechanisms of calcified aortic valve disease

TH Marwick et al.: a KDIGO conference report, Kidney Int. 2019

HEART FAILURE IN ESRD Cumulative probability & two years survival

Herzog C et al, Am J Kidney Dis. 2008, USRDS 2018

An estimated 44% of hemodialysis patients have HF• 10% with HFpEF• 13% with HFrEF• 21% with unspecified HF

Heart failure (HF)

Two-year survival of adult ESRD patients (age>22y) with or without HF, adjusted for age and sex, 2015-2016

- 17,4%

Sudden cardiac death in dialysis patients: different causes and management strategies

❖ Extradialysis SCD vs intradialysis SCA in ESKD patientsdifferent clinical situations

❖ Intradialysis SCAmodifiable risk factors: low concentration of potassium and calcium in the dialysateadvantages: presence of automated external defibrillators in dialysis units

❖ Extradialysis SCD• More complex • More frequently bradyarrhythmias than tachyarrhythmias• Unknown mechanism ???

Ischaemic heart disease and/or heart failureLVHElectrolyte imbalancesOther risk factors due to cardiac comorbidities and uraemia per se

Genovesi S et al, European Dialysis Working Group of ERA-EDTA, NDT Sept 2019

Screening & evaluation for CVD-CHD in ESRD

❖All pts at initiation/change in clinical symptoms or hemodynamic stability

❖History, physical examination, screen for risk factors

❖Baseline ECG: for comparison (LVH – absence of sinus rhythm)

❖Transthoracic Echocardiogram (pt at dry weight)

EF<40% without known CHD → further evaluation for CHD

❖Noninvasive stress imaging

o Dobutamine, adenosine, dipyridamole stress echocardiography

o Nuclear scintigraphy

o Electron beam computed tomography (EBCT)

o Noninvasive coronary CT angiography (CCTA)

❖Coronary angiography (Gold standard - residual kidney function !!)

Accuracy in ESRD?

Less studied

Accuracy of dobutamine stress echocardiography vs myocardial perfusion scintigraphy for diagnosing CAD in renal transplant

candidates

Among dialysis pts dobutamine echocardio

graphy rather than other noninvasive tests,

appears to be more sensitive

Gautam R. Shroff, and Charles A.

Herzog JASN 2016;27:3521-3529

A comparison of accuracy of various non-invasive imaging techniques to detect CAD in renal Tx candidates

Gautam R. Shroff, and Charles A. Herzog JASN 2016;27:3521-3529©2016 by American Society of Nephrology

138 pts CKD 5+5D

Evidence of benefit with Cardiovascular Risk Factor Modification in Dialysis Patients

• Risk-factor modification for all dialysis patients is recommend

given that CKD is a coronary heart disease risk equivalent

• Most interventions have not been rigorously examined

• Few interventions have been examined in large randomized trials

• Even fewer interventions have shown to be effective

Cardiovascular Risk Factor Modification in Dialysis Patients

• Individualization of BP targets (24h ABPM, SBP<130mmHg)

• Na restriction / Smoking cessation / Regular exercise

• Statins??? (4-D, AURORA, SHARP + 3 Meta-analyses)

Do not stop / Do not start unless ↑↑ Tchol-LDL or diabetic

• Aspirin ? (Palmer et al, Cochrane meta-analysis 2013)

Low-dose (81 mg/day) is probably safe / the avoidance is reasonable

• Anemia: Hb values recommended 10-11 g/dL

• No clear benefit over CVD outcomes in ESRD from Rx for CKD-MBD,

lower homocysteine levels /oxidative stress ??

ISCHEMIA-CKD trial - ongoing The benefit of revascularization vs medical therapy in ESRD is not clear

• Aim: determine the best management strategy for pts with stable ischemic heart disease (SIHD) and advanced CKD (eGFR <30 ml/min/1.73 m² or on dialysis)

• A multicenter randomized controlled trial of 777 pts

• 2 GROUPS

• Routine invasive strategy (INV) with cardiac catheterization (cath) followed by revascularization (if suitable) plus optimal medical therapy (OMT) OR

• Conservative strategy (CON) of OMT, with cath and revascularization reserved for those who fail OMT

• Main outcome: reduction in the incidence of death or nonfatal MI

Dialysis modality & better survival

➢Peritoneal dialysis VS Hemodialysis (HD)

33

vol 2 Figure 5.1 Adjusted ALL-CAUSE MORTALITY by treatment modality hemodialysis and peritoneal dialysis, for period-prevalent patients,

2001-2016

2018 Annual Data Report Volume 2 ESRD, Chapter 5

Data Source: Reference Tables H.2_adj, H.4_adj, H.8_adj, H.9_adj, and H.10_adj; and special analyses, USRDS ESRD Database. Adjusted for age, sex, race, ethnicity, primary diagnosis and vintage. Reference population: period prevalent ESRD patients, 2011. Abbreviations: ESRD, end-stage renal disease; HD, hemodialysis; PD, peritoneal dialysis.

…for most patients, survival on HD and PD is similar, with perhaps a slight advantage favoring PD…

Lozier et al, Perit Dial Int 2019

Peritoneal dialysis is a non-inferior, suitable and cost-effective

alternative to HD for ESRD patients at risk of CVD

5 cohort studies, 47,062 patients

Dialysis modality & better survival

➢Peritoneal dialysis VS Hemodialysis (HD)

➢High flux VS low flux HD

➢Hemodiafiltration (HDF)

➢Nocturnal HD

➢HOME HD

➢Expanded HD?

Optimization of dialysis prescription

➢Optimizing volume status (BCM, Cardiac & Lung US)

➢Optimizing the duration or frequency of dialysis

➢Avoid intradialytic hypotension (myocardial stunning)

Cardiovascular risk reduction in ESRD

=RENAL TRANSPLANTATION / PRE-EMPTIVE

EBCT – CCTA: Drawbacks in Dialysis• KDOQI: further study is required prior to recommending the use of

these modalities to screen for CHD in dialysis • Drawbacks include the following:• Tests are difficult to perform and interpret in ESRD patients,

particularly those who have been on dialysis for an extended period of time or are older. Older patients or those with greater dialysis vintage often have extensive medial vascular calcification, which confounds the interpretation of the test. Medial vascular calcification may not be associated with luminal atherosclerotic coronary disease.

• CCTA requires a minimum intravenous injection rate of iodinated radiocontrast media that may not be attainable in patients with poor peripheral venous access.

• Dialysis patients, particularly those who are just starting dialysis or are of relatively early vintage (ie, <2 years) may have significant residual kidney function. The loss of residual kidney function resulting from the administration of iodinated radiocontrast media could be deleterious and should be taken into consideration when deciding on CCTA.

• Increasing the frequency of dialysis sessions reduces LV mass and the risk of CV death and hospita-lizations.

• Patients undergoing home dialysis have a 41% lower risk of HF, fluid overload, and cardiomyopathy.

AA House et al.: HF in kidney disease: a KDIGO conference report. Kidney Int 2019

Annualized CVD mortality per 100 patient-years in the HD

and online HDF groups.

• Removal of MMW uraemic toxins

• Improved intradialytic haemodynamic stability

Blankestijn et al, Nephrol Dial Transplant 2018

Positioning of HF therapies according to LVEF and renal function

Pharmacotherapy for the prevention and treatment of

HFrEF in CKD progressing to ESKD.