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ESRD: State of the Art Conference Optimal CV-Renal Therapy Over the Next 5 Years William L. Henrich, MD University of Texas Health Science Center at San Antonio The Problem – Causes of Death in CKD Patients Estimated Event Rate (%) 60 75 GFR (mL/min/1.73 m2) P<.001 50 60-74.9 GFR 40 45-59.9 GFR (mL/min/1.73 (mL/min/1.73 m2) (mL/min/1.73 m2) 30 <45 GFR (mL/min/1.73 m2) 20 10 0 Death From CV Causes Re-infarction CV CHF Stroke Resuscitation Composite End Point *14,527 patients with HF or LV dysfunction post-MI NEJM 2004;351:1285-1295. Courtesy of Allen R. Nissenson, MD, FACP AJKD Vol 45, No 4, Suppl 3, April 2005 Hypothetical CV Risk Factors and Event Rates in Various Stages of CKD Literature GFR Cheung, 2004 CVD/ESRD Pathophysiology • Multifactorial • Traditional factors (Htn, volume overload, smoking, HDL, oxidative stress) • Non-Traditional (HCY, ADMA, Ca/P, ET) • Common pathways: • Stiff blood vessels • Ischemia Modifiable Uremia-related Risk Factors Traditional Risk Factors Non-modifiable Qunibi, Henrich, Berl Age Make Gender Family History Diabetes Hypertension Dyslipidemia Smoking Hyperhomocystinemia Oxidative stress Inflammation Low serum albumin Anemia High PTH High PO4 Low GFR Increased ET High CRP Albuminuria CHF LVH Arterial Stiffness PVD CAD MI Suggestions and Observations by Experts on Priorities Eberhard Ritz a. Sudden death accounts for 59% of deaths now— focus on that problem! b. Lower BP via a reduction in ECF volume Concentric LVH HTN increased afterload Left Ventricle Uremic cardiomyopathy Altered myocardial metabolism Anemia Hyperparathyroid Angiotensin II Progression of CKD Myocyte dropout Arteriolar wall thickening Myocyte/capillary mismatch Increased cardiac output Volume overload Courtesy: J. Fink, M.D. Eccentric LVH • Ischemia • Cardiac arrest • CHF • Death Eccentric and Concentric LVH Ecc LVH Concen LVH 65% N/A ESRD – Incident 44% Dialysis** *Prevalence changes over time ** Prevalence of LVH 75%-80% 42% Early CKD* AJKD 34:125, 1999 Sem in Dialy 16:85, 2003 Correlation of LV Anatomy and LV Function in ESRD Patients n = 41 • % of patients with LVH (defined as PW or IVS 1.2 cm): 62% • % of patients without LVH, SD or DD: 9.5% • % of patients with isolated SD (with LVH): 5% • % of patients with both SD and DD: 24% • % of patients with isolated DD: 57% – 58% of this group had LVH – 42% of this group did not have LVH JASN 9:275, 1998 Left Ventricular Diastolic Pressure (mmHg) Diastolic Pressure-Volume Relation in Patients with Diastolic Heart Failure and in Controls Patients with diastolic heart failure Controls Left Ventricular Diastolic Volume (ml) NEJM 350:1953, 2004 Risk of CV Death Related to Systolic Function and LVH in 254 ESRD Patients 8 7 *P= 0.001 HR and 95% CI 6 5 4 3 2 1 0 No LVH and Normal Ejection Fraction JASN 15:1029, 2004 LVH or Reduced Ejection Fraction LVH and Reduced Ejection Fraction LVH, Sudden Death and Dialysis • Abnormalities in coronary microcirculation (myocyte/capillary mismatch) • Impaired coronary reserve • Reduced aortic compliance • activity of the SNS • activity of the renin-angiotensin system • Sudden changes in [K]+, [Ca]++, [Mg]++ Number of cardiac arrests Cardiac Arrests Occur Most Often on Monday Day relative to facility being closed Number of cardiac arrests relative to the day of the week of dialysis facility closure. *25 cases versus expected number of 15.7, P = 0.011, significance based on X2-test. Kidney Int’l 73(8): 935, 2008 Myocardial Ultrasound Tissue Characterization in Patients with Chronic Renal Failure Massimo Salvetti, Maria Lorenza Muiesan, Anna Pain, Cristina Monteduro, Bianca Bonz, Gloria Galbassini, Eugenia Belotti, Ezio Movilli , Giovanni Cancarini and Enrico Agabiti-Rosei JASN 18(6): 1953, 2007 Objective To detect ultrastructural changes in myocardium related to collagen content by U.S. in patients with CKD and uncomplicated hypertensive patients Patients 25 ESRD, 25 CKD, 10 HTN matched for age, BP, LVMI and EF Methods Key new measurement called integrated backscatter signal (IBS) analyzed by acoustic densitometry JASN 18(6):1953, 2007 Results IBS is a measure of increased myocardial collagen and was significantly increase in HD and CKD patients. It correlated positively with serum creatinine. JASN 18(6):1953, 2007 JASN 18(6):1953, 2007 Conclusion Interstitial collagen appears early in CKD and acoustic densitometry is a useful tool for detection. Pathological Characteristics of Cardiomyopathy in Dialysis Patients • 40 dialysis patients and 50 “control” patients with dilated cardiomyopathy had endomyocardial biopsies • Both groups had a decrease in EF (34/35%) • Classification by NYHA (%) Control I 8 II 40 III 36 IV 16 Kidney Int’l 67:333, 2005 HD 0 28 48 25 A 63 yo Man on HD for 7.3 years Bizarrely Shaped Myocytes with Irregular Enlarged Nuclei Kidney Int’l 67:333, 2005 56 yo Man on HD for 7.1 years Widespread Fibrosis Present; Patient Died of Ventricular Arrhythmia 1.1 Year after Biopsy KI 67:333, 2005 56 yo Man on HD for 6.8 Years. Small Amount of Fibrosis Present and No Cardiac Event 3.8 Years After Biopsy KI 67:333, 2005 Cumulative Survival for Cardiac Death Stratified by Extent of Fibrosis Kidney Int’l 67:333, 2005 Conclusions 1. Uremic cardiomyopathy is characterized by a derangement in myocardial myocyte organization. 2. Uremic cardiomyopathy associated with LVH is characterized by an increase in intermyocyte fibrosis. 3. An increase in myocardial fibrosis is associated with an increase in cardiac deaths. Uremia Stimulates Collagen Formation in the Heart Secondary to Marinobufagenin Procollagen-1 Expression (arb units) 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Sham PNx MBG 0PNxIM PNx=Uremia MBG= Mini Pump OPNx-IM-Immunized to MBG Hypertension 49(6):215, 2007 Rapamycin Prevents Uremic Cardiac Fibrosis Independent of BP SHAM Nx NxV NxR Kidney Int 75(8):800, 2009 Rapamycin Prevents Uremic Cardiac Fibrosis Independent of BP Kidney Int 75(8):800, 2009 Effects of Short Daily vs. Conventional Hemodialysis on Left Ventricular Hypertrophy and Inflammatory Biomarkers • Non randomized, controlled trial • Short daily = 3 hr / HD x 6 d • 4 hr / HD x 3 d • n = 26 SD • n = 51 Conventional • Follow-up @12 months JASN 16: 2778, 2005 Change in LVMI over 12 Months 210 190 LVMI (g/m2) 170 p<.01 P=NS 150 130 Baseline 12 Month 110 90 70 50 SDHD CHD Group JASN 16: 2778, 2005 Impaired Systolic Function Pre/Post Transplant • 103 ESRD patients with LVEF < 40%, restudied @ 6 and 12 months post - tx • Mean LVEF 31.6 (± 7)% pre tx to 52.2 (± 12)% post - tx; NYHA Class also improved • No preoperative deaths • Longer duration of dialysis pre- tx decreased the likelihood of normalization of LVEF post - tx JACC 45:1051, 2005 Pre -Tx Cx’s of 79 Patients Age All Patients n = 79 54 Post - Tx EF < 40% n = 25 54 Post - Tx EF > 50% n = 54 55 % AA 59% 60% 60% % Male 71% 60% 72% % CAD 51% 52% 50% 24 39* 17* 57% 56% 57% Time on HD (mos) % NYHAIV Pre/Post Tx LVEF in Different Subgroups of Patients 60 50 LVEF% 40 30 Pre LVEF Post LVEF 20 JACC 45:1051, 2005 DM No DM PTCA No PTCA CABG No CABG CAD No CAD 0 All 10 Importance of Dry Weight Reduction for BP Control 494 Patients were screened 346 were eligible 250 were consented 150 were randomized 100 were assigned to receive Additional ultra filtration 9 patients did not Complete the study 5 withdrew consent 3 were hospitalized 1 had high BP 91 completed the study Hypertension 53: 500, 2009 50 were assigned to a Control group 7 patients did not Complete the study 1 withdrew consent 1 was transplanted 5 had high BP 43 completed the study Importance of Dry Weight Reduction for BP Control UF Control n 100 50 Age 54 55 % AA 85 92 Pre BP 160/86 159/87 Post BP 143/78 143/78 % DM 40 38 Hypertension 53: 500, 2009 Importance of Dry Weight Reduction for BP Control • Ambulatory BP monitoring used in the study • Goal UF was 0 – 1 kg per 10 kg in wt • No deterioration in QOL by survey Hypertension 53: 500, 2009 Importance of Dry Weight Reduction for BP Control The effects of dry-weight reduction on interdialytic ambulatory systolic (A) and diastolic BP (B) in hypertensive hemodialysis patients. Hypertension 53: 500, 2009 Importance of Dry Weight Reduction for BP Control • Reduction in dry weight is a simple, efficacious and well-tolerated maneuver to improve BP in ESRD patients. Hypertension 53: 500, 2009 Suggestions/Observations, Con’t George Bakiris Lower intradialytic BP Fosinopril Study • RCT, n = 397; all had LVH on HD for 24 mos. • 5 – 20 mg Fosinopril • End-point= CVE’s • 196 patients treated with Fosinopril 201 with placebo for 24 months Kidney Int’l 70: 1318, 2006 ACEI Use in ESRD: Fosinopril of Benefit Kidney Int’l 70: 1318, 2006 Suggestions/Observations, Con’t Richard Glassock a. Euvolemia b. ACE/ARB c. Control [Phosphate] d. Replete Vit D, Pth to <500 pg/ml e. Monitor LVH by Echo/MRI Q12 to 36 mos. f. QD/Nocturnal HD Suggestions/Observations, Con’t Alfred Cheung Renal diplipidemias— Not responsive to statins (↑ TG’s, low LDL, High Lp(a), abnormal LDL, oxidized LDL) 4D Study • 1,255 patients, type 2 DM on HD • 20 mg. lipitor vs. placebo • Primary end point: composite of death from cardiac causes, nonfatal MI and stroke • Secondary end points: death from all causes and all cardiac and cerebrovascular end points combined Median Change in LDL in 4D Study Median LDL Cholesterol (mg/dl) 130 120 110 Placebo 100 90 80 70 60 Atorvastatin 50 40 30 20 10 0 Baseline 6 12 18 24 30 36 42 48 60 54 Month NEJM 353(3):238, 2005 No. at Risk Placebo Atorvastatin 636 611 544 619 597 539 493 427 327 264 484 413 343 279 208 218 147 157 105 117 60 74 37 44 Cumulative Incidence of the Primary Composite End Point (%) Cumulative Incidence of Primary End Point 60 50 40 30 20 10 0 0 1 2 3 Year NEJM 353(3):238, 2005 4 5 6 Conclusions from 4D No significant effect of atorvastatin on primary end point in ESRD patients. Rosuvastatin (10 mg) and CVE in ESRD • RCT, n=2,776, age 50 to 80 • Primary End-Point: CVE’s, death from CVD NEJM 360(14):1395, 2009 Changes in Levels of LDL NEJM 360(14):1395, 2009 Changes in Levels of TG’s NEJM 360(14):1395, 2009 Changes in Levels of HDL NEJM 360(14):1395, 2009 No Difference Between R and P Groups NEJM 360(14):1395, 2009 Conclusion Two well-done RCT’s with a negative result. Should we d/c statin therapy in ESRD patients? Should we not start it in ERSD patients who have not yet been treated? Suggestions/Observations, Con’t Ravi Thadhani A major consequence of renal calification is the increase in PWV. Risk Factors for Vascular Calcification Clinical Biochemical Medications Kidney Int’l: 1535, 2006 Age Duration of dialysis Kidney function/Uremia Diabetes Known coronary artery disease Abnormal bone Hyperphosphatemia Hypercalcemia Abnormal parathyroid hormone Low fetuin-A Elevated cytokines Oxidative stress Low pyrophosphate Decreased MGP Decreased BMP-7 Calcium-containing phosphate binders High-dose vitamin D Coumadin (decreases active MGP) Role of Phosphate and Calcium on Vascular Calcification in CKD Kidney Int’l 68:429, 2005. Comparison Between Calcification Score and the Maximum Degree of Vessel Occlusion in Coronary Arteries Measured by CT Angiography AJKD 43:313, 2004 Calcification Score Does Correlate with Severity of Disease in ESRD Patients • 82 patients asked to undergo CA and EBCT • Patients selected for CA because they were renal transplant candidates, had symptoms at rest, exertional CP or recent MI. • 62 agreed, and 46 had CA w/in 12 months of the CA • CA before EBCT, n = 36; EBCT before CA, n = 10 • > 50% luminal narrowing “significant” • 16 HD patients – 4 CAPD patients – 8 GFR < 25 – 18 post renal transplant NDT 19:2307, 2004 Calcium Score and Number of Coronary Vessels Involved Total Calcium Score 4000 3000 2000 1000 0 One NDT 19:2307, 2004 Two Number of Vessels Involved Three Survival distribution function Importance of CAC Score in Incident ESRD Patients P=0.02 CAC=0 CAC1-400 CAC>400 Months Kidney Int’l : 438, 2007 Pulse Pressure Increased in Setting of Increased Vessel Stiffness AJKD 45:965, 2005 Pulse Wave Velocity Increases as Renal Function Decreases p<0.001 for trend 12 11.6 10.4 10 8.9 7.5 PWV (m/s) 8 4 1 2 3 (n=24) (n=30) 4 5 0 (n=12) (n=15) Stage of Chronic Kidney Disease AJKD 45:494, 2005 (n=21) Effect of Vascular Calcification on PWV 2000 P – value = 0.002 Median calcium score 1800 1852.0 1600 1400 PWV < 12 m/s PWV > 12 m/s 1200 1000 800 600 P – value = 0.307 400 200 470.1 323.3 161.5 0 Coronary artery calcium score Kidney Int’l: 802, 2007 Thoracic aorta calcium score Conclusions • Vessel calcifications are common in ESRD • Having calcifications worse prognosis than not having calcifications • Vessel calcification in ESRD is located in intima and medial areas of vessel – unknown correlation with intimal narrowing • Badly need studies which: – Correlate calcification to outcomes/events prospectively – Correlate calcification to ischemia and anatomy prospectively – Intervene to reduce or retard calcification and then track CV outcomes prospectively Management - 1 • Maintain euvolemia (increased use of extra sessions, nocturnal or quotidian dialysis • Excellent BP control (pre-dialysis SBP <130/80), using ACEI/ARB as first line agents where needed • Monitor for LVH/LVMI with an echocardiogram or MRI (no contrast) Q 12-24 months • Manage Ca/P to a low pre-dialysis P, if possible, and a PTH of less than 500 pg/ml (or 1.5 to 2 times normal); replete Vitamin D where possible; controversy over Cacontaining vs. non-Ca-containing Phosphate binders at present. • Hematocrit to guidelines Management - 2 • Avoid catheters • Improved nutrition • LDL-C to <100 mg/dl, <70 in patients with documented CAD • Cautious used of B-Blockers for low EF Systolic Failure • Passive resistance exercise where feasible • Stay tuned for evidence of benefit of aldosterone blocking agents on myocardial fibrosis/sudden death “Actionable” Variables in ESRD: Effects on Mortality AJKD 53(1): 79, 2009