1. CKD in individuals with CKD Sylvia E. Rosas, MD, MSCE University of Pennsylvania Philadelphia VA Medical Center 3/19/2011

2. Objectives • Brief overview of pathophysiology of CKD.

3. All-cause Mortality and CV Events According to Estimated GFR Go, et al. NEJM 2004

4. CKD is prevalent in CVD 46% 43% 33% Patients With CKD (%) 23% CHF GFR ≤60 mL/min CVA GFR ≤60 mL/min AMI GFR <60 mL/min CADCrCl ≤60 mL/min Ix, et al., 2003; Anavekar, et al., 2004; Shlipak, et al., 2004, McClellan et al, 2006.

5. Cause of death with graft function (DWGF) among renal transplant recipients 1988-1997 Ojo, KI 2000

6. Dialysis Patients have higher Coronary Calcification Score compared to CAD patients 2500 CAD-no ESRD 2000 Dialysis 1500 Mean Coronary Calcium Score 1000 500 0 28-39 40-49 50-59 60-69 Age (years) Adapted from Braun J et al. Am J Kid Dis. 1996;27:394-401.

7. The people to test are those at greatest risk • Diabetes mellitus • Hypertension • Cardiovascular disease • Family members of patients with ESRD • Note on pediatric patients: • CKD may start with childhood obesity • No recommendations for routine testing

8. Definition of CKD • Kidney damage for > 3 mo, as defined by structural or functional abnormalities of the kidney, with or w/o decreased GFR, manifest by either • Pathological abnormalities; or • Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests • GFR < 60 ml/min/1.73m2 for > 3 mo, with or w/o kidney damage

9. Vascular Calcification Inductive vs. inhibitory process Inductive process Inhibitory process • Pyrophosphate • MGP, Osteopontin and osteoprotegerin • Fetuin (a) • Smad 6 BMP2 Cbfa1 Phos, PTH and Vitamin D

10. Stages of Chronic Kidney Disease (CKD)1 Description GFR (ml/min/1.73m2) Stage 1(National Kidney Foundation: K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 39[Suppl 1]: S1-S266, 2002)

11. Giachelli, KI 2009

12. Ca load in the vessel wall is high in patients on dialysis Calcium accumulation in the vessel wall begins predialysis Shroff et al . Dialysis Induces Apoptosis and Vascular Calcification. Circulation. 2008;118;1748-1757.

13. Dialysis leads to VSMC apoptosisShroff et al . Circulation 2008

14. Dialysis leads to VSMC apoptosisShroff et al . Circulation 2008 heteropycnotic nuclei Cytoplasmic vacuoles and matrix vesicles Normal vesicular debris

15. Risk Factors for Vascular Calcification in CKD Goodman et al, AJKD 2004

16. Risk Factors for Vascular Calcification in CKD Goodman et al, AJKD 2004

17. Electron Beam Tomography

18. EBCT Coronary Calcium Scoring Area = 15 mm2 Peak CT = 450 Score = 15 x 4 = 60 Area = 8 mm2 Peak CT = 290 Score = 8 x 2 = 16 Total Score = S Hn x-factor (Agatston Scoring) 130-199 1 200-299 2 300-399 3 >400 4

19. Types of Vascular Calcification Atherosclerosis Intimal Calcification Medial Calcificationor Mönckeberg’s sclerosis

20. Association between CRP and WBC quintiles and coronary calcification Roe, Rosas, Atherosclerosis, 2010

21. Mortality and cardiovascular event free survival in patients with and without CAC No CAC CAC Roe, Rosas, Atherosclerosis, 2010

22. Coronary calcification predicts cardiovascular events and mortality Roe, Rosas, Atherosclerosis, 2010

23. Change in CAC score over time in renal transplant recipients Schankel, Rosas AJT 2007

24. Schankel, Rosas AJT 2007

25. Coronary calcification progression predicts cardiovascular events and mortality n = 87 Roe, Rosas, Atherosclerosis, 2010

26. Sylvia.rosas@uphs.upenn.edu