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

4. CKD is prevalent in CVD 46% 43% Patients With CKD (%) 33% 23%
CAD, N=431
AMI, N=14,527
CHF, N=6800
CAD CrCl ≤60 mL/min
AMI
GFR <60 mL/min
CHF
GFR ≤60 mL/min
CVA
GFR ≤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. Mean Coronary Calcium Score
Dialysis Patients have higher Coronary Calcification Score compared to CAD patients
2500
CAD-no ESRD
2000
Dialysis
1500
Mean Coronary Calcium Score
1000
Coronary calcification is much more marked in dialysis patients than in either patients with coronary artery disease (not on dialysis) or the general population.
500
28-39
40-49
50-59
60-69
Age (years)
Adapted from Braun J et al. Am J Kid Dis. 1996;27:

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. Pathological abnormalities; or
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. Major mechanisms of vascular calcification
Major mechanisms of vascular calcification. Six different mechanisms that have been proposed to regulate the initiation
or progression of vascular calcification are illustrated, along with key molecular mediators where known. The extent to which each of these
mechanisms plays a role in vascular calcification in various disease states, including hyperphosphatemia and ESRD, is currently unknown.
cMGP; gamma carboxylated matrix gla protein, pOPN; phosphorylated osteopontin.
Giachelli, KI 2009

12. Ca load in the vessel wall is high in patients on dialysis
Calcium accumulation in the vessel wall begins predialysis
Figure 1. Quantification of Ca load in the vessel wall. (A) Dialysis
vessels had a significantly higher Ca load compared with
predialysis or normal vessels (P0.0001, ANOVA). (B) von
Kossa staining demonstrated the absence of calcification in
controls, whereas dialysis vessel showed speckled calcification
(arrows) in the media and along the internal elastic lamina. M
indicates media; Ad, adventitia; and Ca, calcium.
Medium-sized muscular arteries routinely removed at omentectomy
during a peritoneal dialysis catheter insertion or at renal transplantation
in 34 patients with CKD were compared with mesenteric
arteries removed at planned intra-abdominal surgery in 6 disease free,
age-matched controls.
Shroff et al . Dialysis Induces Apoptosis and Vascular Calcification. Circulation. 2008;118;

13. Dialysis leads to VSMC apoptosis Shroff et al . Circulation 2008
Figure 3. Cell number and apoptosis in vessels. (A)VSMC nuclei per unit area of vessel were counted on a hematoxylin-eosin stained sample to determine the number of VSMCs in different vessel types. There was no reduction in the number of VSMCs in predialysis compared with control vessels, but cell numbers were significantly reduced in dialysis vessels. (B) There was no increase in the
number of apoptotic cells in predialysis as compared with normal vessels, but dialysis vessels showed significantly more apoptosis. (C) Staining for smooth muscle cell actin (top) was reduced, as was cell number in dialysis vessels compared with controls. Arrows indicate areas of cell loss in the dialysis vessel. TUNEL staining (middle) was present in dialysis vessels but absent in controls.
Von Kossa staining (bottom) showed that areas of medial calcification in dialysis vessels localized to regions that were also TUNEL-positive in adjacent
sections. No TUNEL positivity or calcification were observed in control vessels. VSMC indicates vascular smooth muscle cells; M, media; Ad, adventitia; -SM actin, smooth muscle cell actin; and TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end abeling.
Figure 5. Deposition of calcification inhibitors.(A) Dialysis vessels showed maximum fetuin-A positivity as compared with predialysis or normal vessels (P0.03). (B) Dialysis vessels had more Glu compared with Gla MGP: Gla/ Glu compared with predialysis
( ) or normal (1.50.2) vessels (P0.02). (C) Immunohistochemistry for fetuin-A (top) confirmed significantly
greater fetuin-A positivity in dialysis as compared with predialysis or normal vessels. Immunohistochemistry for Gla and
Glu MGP (middle and bottom) showed increased amounts of Glu compared with
Gla-MGP in dialysis, whereas control vessels had predominantly Gla-MGP. Gla indicates carboxylated; Glu, undercarboxylated; MGP, matrix Gla-protein; M, media; and Ad, adventitia.

14. Dialysis leads to VSMC apoptosis Shroff et al . Circulation 2008
heteropycnotic nuclei
Cytoplasmic vacuoles and matrix vesicles
Normal
vesicular debris
TEM showed (a) a normal contractile VSMC showing a normal nucleus with heterochromatic areas localized predominantly around the
nuclear envelope. The euchromatin is interspersed with heterochromatin in the
deeper regions of the nucleus. Arrowheads indicate dense bodies indicative of a contractile cell. (b) Interspersed with
normal VSMCs were contractile cells with evidence of damage showing heteropycnotic nuclei (large arrow), with
highly increased electron density of heterochromatin and much less euchromatin. Cytoplasmic vacuoles and matrix
vesicles were deposited in the extracellular matrix adjacent to the plasma membrane. Boxed area is enlarged to show vesicles. (c) Many cells had undergone cell death leaving cellular debris, including vesicular debris (boxed area enlarged). (d) In some areas, vesicles
stained with high contrast, indicating the presence of mineral (arrow). (e) The origin
of vesicles from budding of the plasma membrane is shown (arrow).
Bar1 m. M indicates media; Ad, adventitia; TEM, transmission electron microscopy.

15. Risk Factors for Vascular Calcification in CKD
Intima
Media
Dyslipidemia √
Advanced age
HTN
Reciprocal
Male
Smoking
Diabetes
Inflammation
√ (local)
√ (systemic)
Goodman et al, AJKD 2004

16. Risk Factors for Vascular Calcification in CKD
Intima
Media
Reduced GFR √
Hypercalcemia
Positive Ca balance
Hyperphosphatemia
PTH abnormalities
Vitamin D administration
Duration of treatment with dialysis
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)
>

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

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

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