1. Predictors of Early Cardiovascular Disease in Children with CKD
Hesham Safouh, MD
Prof. of Pediatrics and Pediatric Nephrology
Cairo University
Predictors of Early Cardiovascular Disease in Children with CKD

2. Good news……
Widespread availability of state-of-the-art renal replacement therapy!!
Safouh, MD

3. 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.

4. More than one decade ago….
CVD recognized as a major cause of death in children with advanced CKD.
Safouh, MD

5. Leading causes of death in the general pediatric population
and in children on renal replacement therapy.
Leading causes of death in general pediatric population and in children on renal replacement therapy. Data are presented as percentages. Data for dialysis and transplant patients are from the USRDS (2011).2 Data for general pediatric population are from Mathews et al. (2011).1
Mitsnefes M M JASN 2012;23:
Safouh, MD

6. ≠
A child is NOT a small adult!!

7. In older adults with ESRD
Coronary artery disease
Cardiomyopathy-associated congestive heart failure
Safouh, MD

8. Causes of cardiac death in children 0–19 years of age with CKD
In children, causes are different……
Causes of cardiac death in children 0–19 years of age with CKD
Safouh, MD

9. Arrhythmia….most common
Valvular heart disease (12%)
Cardiomyopathy (9%)
Cardiac arrest (3%)
USRDS 2011
Safouh, MD

10. RISK FACTORS FOR CVD

11. Common risk factors for CVD in children with CKD
Safouh, MD

12. Safouh, MD

13. 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.
Safouh, MD

14. Kidney transplantation
Elimination of uremia related risk factors
High risk for CVD from traditional risk factors.
Safouh, MD

15. MEASURING CARDIAC
AND VASCULAR CHANGES
IN CKD PATIENTS

16. Functional
Structural
Biochemical
Safouh, MD

17. Functional Studies

18. Functional studies Aortic pulse wave velocity
24-h ambulatory BP monitoring
Ambulatory arterial stiffness index
Heart rate variability (HRV)
Flow-mediated dilatation
Safouh, MD

19. Pulse wave velocity (PWV)
Carotid distensibility, aortic and brachioradial stiffness or loss of compliance.
Safouh, MD

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

21. Tissue Doppler imaging
Demonstrates impaired LV filling early in the progression of pediatric CKD.
Safouh, MD

22. 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
Safouh, MD

23. 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.
Safouh, MD

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

25. Safouh, MD

26. FMD was abnormal (<5%) in 24 patients (71%).
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%).
Safouh, MD

27. FMD and FMD/NTG-MD ratio were significantly lower in patients than in controls (p = and p = 0.01, respectively).
FMD correlated positively with serum calcium and negatively with alkaline phosphatase.
Safouh, MD

28. Endothelial dysfunction is present in children with CKD 4 on conservative treatment.
This may reflect increased atherogenic and thrombogenic properties of the endothelium.
Safouh, MD

29. Structural Changes

30. Structural changes LVH Carotid intima-media thickness
Coronary artery calcification score
Safouh, MD

31. LVH IS THE MOST COMMON CARDIAC ABNORMALITY IN CHILDREN WITH CKD
Safouh, MD

32. Echocardiography
Measures the presence, type, and degree of left ventricular hypertrophy (LVH)
Safouh, MD

34. High-resolution ultrasound
Measures carotid artery intima media thickness (cIMT), indicating structural changes in the arterial tree
Safouh, MD

36. Normal values of carotid intima-media thickness (cIMT) in healthy adolescents.
Cardiovascular risk assessment in children with chronic kidney disease
Shroff et al.
Pediatr Nephrol Oct, 2012

37. Coronary Artery Calcification Score
Safouh, MD

38. VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Safouh, 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 subjects
Safouh, MD

39. VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Methods
Doppler ultrasound for :
Carotid artery intima media thickness
Renal resistivity indices
Brachial artery flow mediated dilatation
Safouh, MD

40. VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Results
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)
Safouh, MD

41. VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Results
RRIs in the transplantation group were significantly higher than the control group (0.64 ± 0.06 vs ± 0.06, p=0.026).
Safouh, MD

42. VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Results
FMD % of the transplantation group was significantly higher than that of the dialysis group (12.01 ± 9.52 vs ± 6.78, p = 0.04) .
Safouh, MD

43. VASCULAR CHANGES IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS Conclusion
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.
Safouh, MD

44. 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.
Safouh, MD

45. Biochemical Markers

46. Surrogate Markers Ca PO4 PTH levels Hemoglobin
Cholesterol, lipid parameters
Serum creatinine
Vitamin D
Safouh, MD

47. 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.
Safouh, MD

48. Calcification inhibitors in CKD
They are not simply biomarkers but also mediators of CVD.
Fetuin-A
Osteoprotegerin (OPG),
Matrix γ-carboxyglutamic acid protein (MGP)
Pyrophosphate
Safouh, MD

49. Safouh, MD

50. Safouh, MD

51. Safouh, MD

52. Klotho The Greek Goddess of Fate, who spins the thread of life.
Safouh, MD

53. 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.
Safouh, MD

55. Klotho
Potential direct protective effects of Klotho on the vasculature
Is Klotho a robust biomarker for early CKD?
Safouh, MD

56. ≠
A child is NOT a small adult!!

57. 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.
Safouh, MD

58. 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.
Safouh, MD

59. 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
Safouh, MD

60. Best strategies…………. Slowing the progression of CKD
Avoiding long-term dialysis
Preemptive transplantation
Safouh, MD

61. Thanks for your attention!!
Hesham Safouh, MD Prof. of Pediatrics and Pediatric Nephrology Cairo University