Effects of Kidney Disease on Cardiovascular Morbidity and Mortality Joachim H. Ix, MD, MAS Assistant Professor in Residence Division of Nephrology University of California San Diego, and Veterans Affairs San Diego Healthcare System
Outline Epidemiology of cardiovascular death in ESRD. Novel mechanisms of cardiovascular death in ESRD. Vascular Stiffness Phosphate Sudden Death Epidemiology of cardiovascular death in early kidney disease. Novel mechanisms of cardiovascular death in early kidney disease. Vascular Stiffness Phosphate Sudden Death
Epidemiology in 1999-2001 235 deaths / 1000 patient years 43 % of deaths due to cardiac disease. Not explained entirely by higher prevalence of diabetes, hypertension, or other CVD risk factors. USRDS 2003 Annual Data Report, NIDDK, 2003
USRDS 1000-fold 80 years Foley RN, et al. Am J Kidney Dis 1998; 32: S112-19.
Herzog CA, et al. N Engl J Med 1998; 339:799-805. Estimated Cumulative Mortality after Acute Myocardial Infarction among Patients on Dialysis. Herzog, C. A. et al. N Engl J Med 1998;339:799-805
The Cause of the High CVD Mortality in ESRD is Unknown End of talk
The Cause of the High CVD Mortality in ESRD is Unknown Some new hypotheses.
The 4-D Study Randomized, double blinded, placebo controlled study. 1255 subjects with ESRD due to diabetes, undergoing maintenance dialysis. Randomized to atorvastatin 20mg vs. matched placebo. Primary outcome: Composite of death from cardiac cause, acute myocardial infarction, or stroke. Wanner C, et al. N Engl J Med, 2005
The 4D Study - Results 42% reduction in LDL in treatment arm, 1% in controls. Subjects followed for 4 years. 469 patients (37%) reached the primary end-point. Wanner C, et al. N Engl J Med, 2005
4D Study - Results RR 0.92; 95% CI 0.8 1.1; P=0.37 Wanner C, et al. N Engl J Med, 2005
Reverse Epidemiology in ESRD Higher BMI is associated with lower mortality in ESRD. Higher cholesterol is associated with lower mortality in ESRD. Higher diastolic blood pressure is associated with lower mortality in ESRD. Khalantar-Zadeh, et al. Kidney Int., 2003
ESRD and CVD: Beyond Traditional Atherosclerosis Vascular Calcification Arrhythmia RAAS system activation Sympathetic tone Endothelial dysfunction Inflammation Hyperhomocystenemia Oxidative stress Platelet activation Anemia
ESRD and CVD: Beyond Traditional Atherosclerosis Vascular Calcification Arrhythmia RAAS system activation Sympathetic tone Endothelial dysfunction Inflammation Hyperhomocystenemia Oxidative stress Platelet activation Anemia
Prevalence of Vascular Calcification in Advanced Kidney Disease Prevalence 100 90 80 70 60 50 40 30 20 10 0 Stage IV CKD Incident ESRD Prevalent ESRD Russo D, AJDK, 2004 Block GA, Kidney Int, 2007 Chertow GM, Kidney Int, 2002
Presence and Severity of Coronary Calcification Predicts Mortality in ESRD Block GA, Kidney Int, 2007
ESRD and CVD: Beyond Traditional Atherosclerosis Khogali SS, et al. N Engl J Med 2002; 347: 1548.
Medial vs. Intimal Arterial Calcification library.med.utah.edu/webpath/cow/cow086.html www.opt.indiana.edu/v543/slides/70bf.html
www.clevelandclinic.org/heartcenter/pub/guide/disease/aorta_marfan/aortaillust.htm
Vascular Calcification and Pulse Wave Velocity are Directly Correlated in ESRD Raggi P, Kidney Int, 2007
PO 4 - Na + Phosphorus as a Novel Vascular Toxin: Not Simply Passive Crystallization Arsenate, phosphonoformic acid NPC Pi Human aortic smooth muscle cell (SMC) Matrix Vesicles Cbfa-1 SMC-genes Cbfa-1 = core-binding factor-1 (central transcription factor for osteogenic differentiation) Alkaline P ase BIOAPATITE Ca 2+ -binding proteins (osteocalcin, osteopontin) Collagen-rich extracellular matrix Giachelli et al., Am J Kidney Dis 2001; Jono et al., Circ Res 2000
Phosphorus and RR Death 2 1.8 1.6 1.4 1.2 1 0.8 0.6 <3.0 3.0-4.0 4.0-5.0 5.0-6.0 6.0-7.0 7.0-8.0 8.0-9.0 >9.0 Adjusted for age, sex, race, diabetes, vintage, body size, dialysis dose, creatinine, BUN, albumin, bicarbonate, hemoglobin, ferritin, calcium, cium, aluminum, PTH. Block GA et al., JASN 2004; 15: 2208-18.
Sudden Death in ESRD Cardiovascular Death in ESRD 20 % due to Acute MI 61% due to Cardiac Arrest, Cause Unknown. Limited by administrative data source. Etiology arrhythmia may differ from the general population. Large volume shifts 3X per week Electrolyte abnormalities Hyperkalemia / hypokalemia Prevalent structural heart disease
Structural Heart Disease in ESRD 433 incident ESRD patients. All subjects had TTE, and were followed longitudinally. 15% had Systolic Dysfunction 74% had Left Ventricular Hypertrophy. LV Mass Index was independently associated with mortality. Foley RN, et al., Kidney International, 1995
Potential Mechanism Kidney Disease Hypervolemia Vascular Stiffness Hypertension Cardiac Remodeling / LVH / Fibrosis Arrhythmia / Sudden Death
Charles Nolan, MD
ESRD is the Tip of the Iceberg Stage V (ESRD) = 250,000 Stage IV = 1.2 Million Stage III = 8.9 Million USRDS 2003 Annual Data Report, NIDDK, 2003 and Coresh J, AJKD, 2003
Pre-Dialysis Kidney Disease and Cardiovascular Disease Mortality Cardiovascular Events Age-Adjusted Event Rate (per 100 personyr) 40 35 30 25 20 15 10 5 0 60 45-59 30-44 15-29 < 15 Estimated GFR (ml/min/1.73m2) Go AS, NEJM, 2004
Problems with Creatinine Levey A, Annals Int. Med, 1999
Roos JF, Clin Biochem, 2007 Cystatin C A Renal Troponin? 13KDa protein Produced by all nucleated cells Not dependent on muscle mass. Freely filtered 99% metabolized by the proximal tubule. More accurately reflects true GFR than serum creatinine.
Cystatin C is more sensitive to early decrements in kidney function Adapted from Perkins BA, et al. J Am Soc Nephrol 2005
Association of Cystatin C and Cardiovascular Events in Elderly Persons Shlipak MG, Annals Int. Med, 2006
Why is Mild Kidney Disease Associated with Cardiovascular Disease? Mechanisms are unknown Not accounted for by higher prevalence to traditional cardiovascular risk factors. Possibilities: A sensitive marker of generalized atherosclerotic vascular disease Phosphorus Structural heart disease
Tonelli, Circulation, 2005 Phosphorus and Cardiovascular Events in Non-ESRD Populations Post-hoc analysis of the CARE trial RCT of pravastatin vs. placebo 4127 subjects with hypercholesterolemia and history of myocardial infarction. Mean Cr 1.1 mg/dl (mean egfr 71 ml/min/1.73m2) Mean Phosphorus = 3.3 ± 0.5 mg/dl
Phosphorus and Cardiovascular Events in CARE study participants Tonelli, Circulation, 2005
Early Kidney Function and Left Ventricular Hypertrophy Prevalence of Left Ventricular Hypertrophy 70 60 50 40 30 20 10 0 egfr > 60, Cystatin < 1 P < 0.001 egfr > 60, Cystatin > 1 egfr < 60 Kidney Disease Categories Ix, J Cardiac Failure, 2006
Association of Cystatin C with Sudden Cardiac Death Recently evaluated in the Cardiovascular Health Study Outcomes - Sudden Cardiac Death Sudden pulseless condition from a cardiac origin in a previously stable person occurring out of the hospital / ER Deo R, AHA (Abstract), Scientific Sessions, 2007
Deo R, AHA (Abstract), Scientific Sessions, 2007 + MI and CHF (time dependent covariates) Cystatin C (mg/l) < 0.9 0.9-1.1 > 1.1 No at risk 1584 1592 1306 No of SCD events HR for SCD (95% CI) Unadjusted 1.00 Adjusted* 1.00 1.00 + LVEF 1.00 15 40 2.89 (1.57-5.32) 5.32) 2.80 (1.51-5.18) 5.18) 2.75 (1.49-5.10) 3.21 (1.58-6.52) 36 3.71 (1.99-6.94) 3.13 (1.63-6.01) 6.01) 3.04 (1.58-5.85) 5.85) 3.22 (1.51-6.85) *Age, gender, race, DM, SBP, DBP, calcium channel blockers, diuretics, aspirin, LVH
Take Home Points Kidney disease, across the spectrum, is strongly and independently associated with cardiovascular mortality. The etiology is unexplained, but may be more complex than accelerated atherosclerosis. Vascular calcification and left ventricular hypertrophy represent candidate mechanisms.