Presentation on theme: "CKD in individuals with CKD"— Presentation transcript:
1 CKD in individuals with CKD Sylvia E. Rosas, MD, MSCEUniversity of PennsylvaniaPhiladelphia VA Medical Center3/19/2011
2 ObjectivesBrief 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=431AMI, N=14,527CHF, N=6800CAD CrCl ≤60 mL/minAMIGFR <60 mL/minCHFGFR ≤60 mL/minCVAGFR ≤60 mL/minIx, 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 patients2500CAD-no ESRD2000Dialysis1500Mean Coronary Calcium Score1000Coronary calcification is much more marked in dialysis patients than in either patients with coronary artery disease (not on dialysis) or the general population.50028-3940-4950-5960-69Age (years)Adapted from Braun J et al. Am J Kid Dis. 1996;27:
7 The people to test are those at greatest risk Diabetes mellitusHypertensionCardiovascular diseaseFamily members of patients with ESRDNote on pediatric patients:CKD may start with childhood obesityNo recommendations for routine testing
8 Pathological abnormalities; or Definition of CKDKidney damage for > 3 mo, as defined by structural or functional abnormalities of the kidney, with or w/o decreased GFR, manifest by eitherPathological abnormalities; orMarkers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging testsGFR < 60 ml/min/1.73m2 for > 3 mo, with or w/o kidney damage
9 Vascular Calcification Inductive vs. inhibitory processInductive processInhibitory processPyrophosphateMGP, Osteopontin and osteoprotegerinFetuin (a)Smad 6BMP2Cbfa1Phos, PTH and Vitamin D
10 Stages of Chronic Kidney Disease (CKD)1 Description GFR (ml/min/1.73m2) Stage1(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 initiationor progression of vascular calcification are illustrated, along with key molecular mediators where known. The extent to which each of thesemechanisms 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 predialysisFigure 1. Quantification of Ca load in the vessel wall. (A) Dialysisvessels had a significantly higher Ca load compared withpredialysis or normal vessels (P0.0001, ANOVA). (B) vonKossa staining demonstrated the absence of calcification incontrols, whereas dialysis vessel showed speckled calcification(arrows) in the media and along the internal elastic lamina. Mindicates media; Ad, adventitia; and Ca, calcium.Medium-sized muscular arteries routinely removed at omentectomyduring a peritoneal dialysis catheter insertion or at renal transplantationin 34 patients with CKD were compared with mesentericarteries 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 thenumber 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 adjacentsections. 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 significantlygreater fetuin-A positivity in dialysis as compared with predialysis or normal vessels. Immunohistochemistry for Gla andGlu MGP (middle and bottom) showed increased amounts of Glu compared withGla-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 nucleiCytoplasmic vacuoles and matrix vesiclesNormalvesicular debrisTEM showed (a) a normal contractile VSMC showing a normal nucleus with heterochromatic areas localized predominantly around thenuclear envelope. The euchromatin is interspersed with heterochromatin in thedeeper regions of the nucleus. Arrowheads indicate dense bodies indicative of a contractile cell. (b) Interspersed withnormal VSMCs were contractile cells with evidence of damage showing heteropycnotic nuclei (large arrow), withhighly increased electron density of heterochromatin and much less euchromatin. Cytoplasmic vacuoles and matrixvesicles 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, vesiclesstained with high contrast, indicating the presence of mineral (arrow). (e) The originof 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 IntimaMediaDyslipidemia√Advanced ageHTNReciprocalMaleSmokingDiabetesInflammation√ (local)√ (systemic)Goodman et al, AJKD 2004
16 Risk Factors for Vascular Calcification in CKD IntimaMediaReduced GFR√HypercalcemiaPositive Ca balanceHyperphosphatemiaPTH abnormalitiesVitamin D administrationDuration of treatment with dialysisGoodman et al, AJKD 2004