PREDICTORS OF EARLY CARDIOVASCULAR DISEASE IN CHILDREN WITH CKD

Hesham Safouh, MDProf. of Pediatrics and Pediatric NephrologyCairo University

Good news…… Widespread availability of state-of-the-art renal replacement therapy!!

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Bad News…… For dialyzed children, all-cause

mortality rates have not changed significantly since the 1980s!!

Annual mortality rates per 1000 patient-years at risk, patients aged 0–19 years.

More than one decade ago…. CVD recognized as a major cause of

death in children with advanced CKD.

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Leading causes of death in the general pediatric population and in children on renal replacement therapy.

Mitsnefes M M JASN 2012;23:578-585

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≠A child is NOT a small adult!!

In older adults with ESRD Coronary artery disease

Cardiomyopathy-associated congestive heart failure

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Causes of cardiac death in children

0–19 years of age with CKD

In children, causes are different……

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Arrhythmia….most common Arrhythmia (20%) Valvular heart disease (12%) Cardiomyopathy (9%) Cardiac arrest (3%)

USRDS 2011

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RISK FACTORS FOR CVD

Common risk factors for CVD in children with CKD

Common risk factors for CVD

in children with CKDSafouh, MD

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Low Birth Weight (<2500 g) LBW is associated with a reduction

in nephron number. Increased risk for obesity, type II

diabetes and CVD. LBW or prematurity has been

associated with CVD risk factors in children without kidney disease.

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Kidney transplantation Elimination of uremia related risk

factors

High risk for CVD from traditional risk factors.

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MEASURING CARDIAC AND VASCULAR

CHANGES IN CKD PATIENTS

Functional

Structural

BiochemicalSafouh, MD

Functional Studies

Functional studies Aortic pulse wave velocity 24-h ambulatory BP monitoring

Ambulatory arterial stiffness index

Heart rate variability (HRV) Flow-mediated dilatationSafouh, MD

Pulse wave velocity (PWV) Carotid distensibility, aortic and

brachioradial stiffness or loss of compliance.

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Cardiovascular risk assessment in children with chronic kidney diseaseShroff et al.Pediatr Nephrol Oct, 2012 Safouh, MD

Tissue Doppler imaging Demonstrates impaired LV filling

early in the progression of pediatric CKD.

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Multi-slice CT Endothelium-dependent and

endothelium-independent flow-mediated dilatation to demonstrate direct evidence of calcification in the coronary arteries, cardiac valves, and aortic root

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The Effect of HDF on HRV in children with CKD Safouh, Essam and Attia HRV is an important predictor of

parasympathetic / sympathetic balance .

An increase in sympathetic tone becomes a predictor of sudden cardiac death, potentially through arrhythmias.

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The Effect of HDF on HRV in children with CKD Safouh, Essam and Attia

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Flow-mediated dilatation (FMD), nitro-glycerine mediated dilatation (NTG-MD) and FMD/NTG-MD ratio were estimated.

FMD was abnormal (<5%) in 24 patients (71%).

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FMD and FMD/NTG-MD ratio were significantly lower in patients than in controls (p = 0.001 and p = 0.01, respectively).

FMD correlated positively with serum calcium and negatively with alkaline phosphatase. Safouh, MD

Endothelial dysfunction is present in children with CKD 4 on conservative treatment.

This may reflect increased atherogenic and thrombogenic properties of the endothelium.

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Structural Changes

Structural changesLVH Carotid intima-media thickness

Coronary artery calcification score

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LVH IS THE MOST COMMON CARDIAC ABNORMALITY IN CHILDREN WITH CKD

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Echocardiography Measures the presence, type, and

degree of left ventricular hypertrophy (LVH)

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High-resolution ultrasound Measures carotid artery intima

media thickness (cIMT), indicating structural changes in the arterial tree

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Normal values of carotid intima-media thickness (cIMT) in healthy adolescents.

Cardiovascular risk assessment in children with chronic kidney diseaseShroff et al.Pediatr Nephrol Oct, 2012

Coronary Artery Calcification Score

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VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTSSafouh, Fadel, Bazaraa, Hashem and Salah 36 pediatric renal transplant recipients,

at the end of their 1st post - transplantation year

30 patients with ESRD on regular hemodialysis

30 normal subjectsSafouh, MD

VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Methods Doppler ultrasound for :

Carotid artery intima media thickness

Renal resistivity indices Brachial artery flow mediated dilatation

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Carotid artery IMT measurements in the transplantation group were significantly lower than the dialysis group (0.43 ± 0.08 mm vs. 0.5 ± 0.1 mm, p = 0.001)

VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Results

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RRIs in the transplantation group were significantly higher than the control group (0.64 ± 0.06 vs. 0.61 ± 0.06, p=0.026).

VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Results

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FMD % of the transplantation group was significantly higher than that of the dialysis group (12.01 ± 9.52 vs. 7.58 ± 6.78, p = 0.04) .

VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Results

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IMT, RRIs and FMD % in pediatric renal transplant recipients tend to show evidence of vascular dysfunction, despite being significantly lower than those of patients on regular hemodialysis.

VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Conclusion

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Not sensitive enough!! Currently available clinical measures are not sensitive enough to detect early stages of calcification.

Normal/negative test should be interpreted with caution.

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Biochemical Markers

Surrogate Markers Ca PO4 PTH levels Hemoglobin Cholesterol, lipid parameters Serum creatinine Vitamin D

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Low and high levels of 1,25-(OH)-D Both are associated with high cIMT

Due to both the effects of vitamin D on calcium-phosphorus homeostasis and its pro-inflammatory properties.

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Calcification inhibitors in CKD They are not simply

biomarkers but also mediators of CVD. Fetuin-A Osteoprotegerin (OPG), Matrix γ-carboxyglutamic acid

protein (MGP) PyrophosphateSafouh, MD

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KlothoThe Greek Goddess of Fate, who spins thethread of life.

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FGF-23 Potent phosphaturic hormone. Inhibits renal production of

1,25(OH)2D. Independently associated with LVH. Significantly elevated in stage 3

CKD. Potential biomarker.

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Klotho Potential direct protective

effects of Klotho on the vasculature

Is Klotho a robust biomarker for early CKD?

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≠A child is NOT a small adult!!

Children have an advantage… As a population without

preexisting symptomatic cardiac disease, children with CKD potentially receive significant benefit from aggressive attempts to prevent and treat CVD.

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Kt/V Unfortunately, the prescription of

adequate dialysis, as measured by Kt/V, will not necessarily decrease the risks associated with these CKD-associated complications.

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More frequent dialysis Clinically important improvements in

cardiac hypertrophy and function when children receive dialysis more frequently than the traditional, thrice-weekly in-center schedule

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Best strategies…………. Slowing the progression of CKD

Avoiding long-term dialysis

Preemptive transplantation

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HESHAM SAFOUH, MDPROF. OF PEDIATRICS AND PEDIATRIC NEPHROLOGYCAIRO UNIVERSITY

Thanks for your attention!!