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    • Minimizing Cardiovascular Concerns Posttransplant Andrew D. Howard, MD, FACP Metropolitan Nephrology Associates Alexandria, Virginia
    • Introduction
      • Renal transplant recipients continue to experience improvements in short-term graft and patient survival
      • Long-term outcomes have shown much slower rates of improvement
      • Developments in immunosuppression which have been so critical in achieving short-term gains have likely contributed to the risk of cardiovascular disease (CVD)
      • CVD remains the most important cause of mortality in renal transplant recipients
    • Number of Transplants And Patients on Waiting List USRDS 2000 Annual Data Report (113,866 as of 12/31/01) (62,411 as of 8/20/04)
    • Distribution of RTR by CKD Stage CKD= chronic kidney disease; RTR=renal transplant recipients Djamali et.al. Kidney Intern. 2003; 64:1800-1807. RTR (N=890) University of Wisconsin 1985-2001 % Patients 0 5 10 15 20 25 30 35 40 45 50 Stage 1 Stage 2 Stage 3 Stage 4
    • Overall Survival Rates CKD RTR Adjusted for Age, Gender and CKD Stage CKD= chronic kidney disease; RTR=renal transplant recipients Djamali et.al. Kidney Intern. 2003; 64:1800-1807. % Patients 0 10 20 30 40 50 60 70 80 90 Kidney Survival Patient Survival P =.25 P =<.001
    • Complications of CKD: Cardiovascular Disease Mortality 0.3 0.3 0.3 0.3 0.2 0.8 11.1 9.2 10.3 8.1 10.8 6.1 13.2 0.5 0.6 0.4 0.5 0.6 1.1 6.7 11.2 8.8 9.4 9.1 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 General Population Hemodialysis Population Peritoneal Dialysis Population Renal Transplant Recipient Adapted from Meyer KB, Levey AS. J Am Soc Nephrol. 1998;9(suppl):S31-S42. Annual Mortality (%) Total Population Male Female White Black Diabetic
    • Shlipak, M. G. et. al. Ann Intern Med. 2002;137:555-562. Survival After Myocardial Infarction by Creatinine Clearance P <.001 by log-rank test for differences Medicare beneficiaries ≥65 admitted between April 1994 – July 1995 >55 mL/min 33–55 mL/min <33 mL/min
    • Wright, R S. et. al. Ann Intern Med . 2002;137:563-570. P <.001 In-hospital Mortality As a Function of Creatinine Clearance 3106 consecutive patients with an acute MI at the Mayo Clinic between 1988-2000
    • Complications of CKD: Cardiovascular Disease
      • Cardiovascular disease (CAD, cerebrovascular disease, PVD, CHF) more prevalent in patients with CKD than in the general population
        • 40% of patients have CAD or CHF at start of dialysis
        • Only 15% of patients have normal LV structure and function
        • Framingham heart study – SCr 1.4-3.0, CVD prevalence 18-20% vs 8-14%
        • HOPE study – 980 pts with 1.4 <SCr< 2.3, higher incidence of CV death, MI, stroke
        • Higher incidence of traditional risk factors:DM, HTN, hyperlipidemia, older age
      USRDS 1998 Annual Data Report; Kidney Int 1995;47:186-193.; Kidney Int. 1999;56:2214-2219.; Ann Intern Med. 2001;134:629-636.; Arch Intern Med 2001 ; 161:1207-1216. CAD=coronary artery disease; CHF=congestive heart failure; CKD=chronic kidney disease; DM=diabetes mellitus; HTN=hypertension; PVD=peripheral vascular disease; SCr=serum creatinine;
    • Complications of CKD: Cardiovascular Disease
      • Decreasing GFR & proteinuria are independent risk factors for CVD
      • The relative contribution of other CKD related risk factors to CVD is highly suggestive but is not yet conclusive
        • RAS activity/volume overload
        • Abnormal Ca and Phos metabolism
        • Anemia
        • Malnutrition
        • Inflammation/infection
        • Thrombogenic factors
        • Oxidative stress
        • Homocysteine
      K/DOQI. Am J of Kidney Dis . 2000;35:S1-S140.
    • Cause of Death in Renal Transplant Recipients 26% 7% 13% 21% 20% 13% *Excludes patients whose cause of death was unknown USRDS: 1999 Annual Data Report CVD 46% (1995-1997)* Cerebrovascular disease Myocardial infarction Other cardiovascular Infection Malignancy Other
    • Cardiovascular Mortality*: RTR vs General Population 0.001 0.01 0.1 1 10 25-34 35-44 45-54 55-64 65-74 75-84 Age (years) Annual Mortality (%) Renal transplant recipients (1994-1996) General population (1993) *Cardiovascular mortality is underestimated in transplant recipients because of incomplete ascertainment of cause of death in these patients. Foley RN, et al. Am J Kidney Dis . 1998;32(suppl 3):S112-S119
    • Cardiovascular Risk Factors: General Population 1. Eckel RH. Circulation. 1997;96:3248-3250 BP=blood pressure; CRP= C-reactive protein; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); TGs=triglycerides; Total-C=total cholesterol;
      • Conditional
      • Risk Factors
      •  TGs
      • Small LDL
      •  Homocysteine
      •  Lp(a)
      • Prothrombotic factors (fibrinogen)
      • Inflammatory markers (CRP)
      • Predisposing Risk Factors
      • Obesity 1
      • Physical inactivity 1
      • Family history of premature CHD
      • Ethnic characteristics
      • Psychosocial factors
      • Independent Risk Factors (Major)
      • Hypertension
      • Diabetes mellitus
      • Hyperlipidemia
      • Smoking
      • Advancing age
    • Relative Risk for Cardiovascular Death in Renal Transplant Recipients:Cox Model Meier-Kriesche H-U, et al. Transplantation. 2003:75;1291-1295. < .001 1.38 – 3.03 1.67 2.2 – 2.5 < 0.001 1.25 – 1.76 1.49 1.9 – 2.1 < .001 1.85 – 2.75 2.26 2.6 – 4.0 < .001 1.16 – 1.62 1.37 1.7 – 1.8 .025 1.02 – 1.39 1.19 1.5 – 1.6 .69 0.89 – 1.20 1.03 1.3 – 1.4 Cr at 1 year < .001 1.26 – 1.81 1.51 >24 months .001 1.14 – 1.64 1.37 12–24 months .009 1.07 – 1.57 1.30 6-12 months .018 1.04 – 1.57 1.28 <6 months ESRD Time < .001 3.26 – 4.38 3.78 Diabetes < .001 1.36 – 1.92 1.61 Hypertension < .001 1.049 – 1.058 1.053 Age P CI RR Variable
    • Classification of Blood Pressure for Adults ≥18 Years (JNC-VII) JNC-VII . JAMA. 2003;289:2560-2572. ≥ 100 Or
      • 160
      Stage 2 HTN 90-99 Or 140-159 Stage 1 HTN 80-89 Or 120-139 Prehypertension <80 And <120 Normal DBP (mm Hg) SBP (mm Hg) Category
    • Hypertension in Renal Transplant Recipients
      • Present in >95% of renal transplant recipients after 1 year (only 3.5% of patients had normal BP without medication)
      • Associations with transplant-related hypertension include:
        • Male sex, age, diabetes & BMI
        • Native kidneys
        • Immunosuppressive agents, such as corticosteroids and calcineurin inhibitors
        • Acute rejection and delayed graft function
      Kasiske BL, et al. Amer J Kid Dis . 2004;6:1071-1081.
    • Hypertension Long Term Control Posttransplant Normal Stage 1 1976-92 1993-02 JNC 7 hypertension stage at 5 years posttransplant Kasiske BL, et al. Amer J Kid Dis . 2004;6:1071-1081. Pre-HTN Stage 2 % Patients 0 5 10 15 20 25 30 35 40
    • Hypertension Long Term Control Posttransplant 0 2 ≥ 4 Number of blood pressure medications at 5 years posttransplant Kasiske BL, et al. Amer J Kid Dis . 2004;6:1071-1081. 1976-92 1993-02 1 3 0 5 10 15 20 25 30 35 40
      • No antihypertensive agent is absolutely contraindicated in renal transplantation
      • Lifestyle modification
        • Sodium restriction
        • Weight reduction
        • Smoking cessation
        • Exercise
      • Diuretics
        • Volume overload and hyperkalemia
      • Beta-blockers
        • Cornerstone of therapy in CVD
        • Overall usage remains low & decreases with time
      • Use of calcium channel blockers with appropriate adjustments in cyclosporin, tacrolimus, sirolimus
      Midtvedt K, et al. Transplantation. 2001;72:1787-1792. Treatment of Hypertension in Renal Transplant Recipients
      • Reduction or elimination of corticosteroids
      • Reduction or conversion of cyclosporin
      • ACE inhibitors
        • Risks: reversible decline in GFR, hyperkalemia, anemia
        • Usage increasing but remains only 30% after 1 year
      • Angiotensin receptor blockers
        • Possible decrease in production of TGF-ß
        • Usage ≤ 5% up to 5 years
      Treatment of Hypertension in Renal Transplant Recipients Kasiske BL, et al. Amer J Kid Dis . 2004;6:1071-1081.
      • Goals: <130/80 mm Hg
      • No preferred agents
      • Possible options
        • Diuretics
          • Necessary in most; choice dependent on GFR
        • Beta-blockers
        • CCB
        • ACEI/ARB
          • First choice for all diabetics and non-diabetics with spot protein/creatinine ≥ 200 mg/g
      Treatment of Hypertension in Renal Transplant Recipients K/DOQI. Amer J Kid Dis . 2004;43(Suppl 1):S16-S41. K/DOQI Clinical Practice Guidelines on HTN and antihypertensive agents in chronic kidney disease
    • Conversion From Cyclosporine to Tacrolimus Mean Day Mean Night Systolic BP (mm Hg) Cyclosporin Following conversion to tacrolimus Return to cyclosporin Ligtenberg G, et al. J Am Soc Nephrol . 2001;12:368-373. * * * P <.05 Improved hypertension in stable renal transplant recipients 100 115 130 145 160
      • An estimated 16 million individuals in the U.S. have diabetes (diagnosed + undiagnosed)
      • Direct and indirect costs were estimated at $98 billion in 1997
      • 25% of renal transplant recipients have preexisting diabetes (33% increase since 1992)
      • 15-20 % of renal transplant recipients will develop new onset glucose intolerance after transplantation
      Gaston RS, et al. Am J Kid Dis. 2004 ; 44:529-542. Diabetes and Renal Transplant Recipients
    • ADA Guidelines for Diagnosis of Diabetes
      • Diabetes mellitus
        • FBS ≥126 mg/dL
        • Symptoms + casual glucose ≥200 mg/dL
        • 2-h postprandial glucose ≥200 mg/dL after 75 g glucose load
      • Impaired fasting glucose
        • FBS >100 & <126 mg/dL
      • Impaired glucose tolerance
        • 2-h postprandial glucose ≥140 and
        • <200 mg/dL
      Diabetes Care 2003;26:S33-S50.
    • Posttransplant Diabetes Mellitus
      • De novo development of diabetes after transplant is common, appears to be increasing in frequency and compromises patient and graft survival
      • Determining the true incidence of PTDM is difficult because of variable diagnostic criteria
      • Most often develops during the initial 3-6 months posttransplant but can occur at any time
      • PTDM likely exerts the same adverse consequences as preexisting diabetes over 8-10 years posttransplant (CVD risk)
      Gaston RS, et al. Am J Kid Dis. 2004;44:529-542.
    • Incidence of PTDM Multivariate Analysis Study Cosio FG, et al. Kidney Int. 2001;59:732-737.
    • Posttransplant Diabetes Mellitus: Risk Factors
      • Older age of recipient
      • Body weight
        • Risk increases with rising BMI
      • Ethnicity
        • African American, Hispanic, Native American
      • Preexistent diabetes or glucose intolerance
      • Family history of type 2 diabetes
      • Hepatitis C
      • Dyslipidemia
      • Immunosuppression
        • Steroids,
        • Calcineurin inhibitors
      Gaston RS, et al. Am J Kid Dis. 2004;44:529-542.
    • Diabetes Screening Posttransplant
      • The American Society of Transplantation recommends posttransplant screening
        • Weekly for months 1-3
        • Every other week for months 4-6
        • Monthly for months 6-12
        • 3-4 months thereafter
      Kasiske BL, et.al. J Am Soc Nephrol. 2000;11:S1-S86.
    • Management After Transplantation
      • Likely an expression of peripheral insulin resistance and low insulin production due to medication effect
      • Complicated by the competing effects of changing renal function and diabetogenic immunosuppressants
      • As renal function improves posttransplantation, insulin requirements increase
      • Posttransplant infections profoundly impact therapeutic approaches to diabetes
      • No superior immunosuppressive regimen exists
      • Provision of immunosuppression adequate to prevent rejection and maintain allograft function is critical
    • Diabetes and Immunosuppressive Regimens *Number of patients not diabetic at time of transplantation 2.0 273 CsA + AZA + steroids 4.5 287 Prospective, randomized, parallel-group, open-label [Margreiter R, et al. Lancet . 2002;359:741-756.] TAC + AZA + steroids 6.4 328 CsA + AZA + steroids 6.4 77 Posttransplant evaluation of consecutive transplant recipients [Romagnoli J, et al. Poster abstract presented at: 2002 Congress of The Transplantation Society; August 29-30, 2002; Miami, Fl. Abstract 2104.] TAC + steroids 4.7 66 CsA + adjuvant agents 5.7 131 Randomized, multicenter, open-label [Waid T, et al. Protocol 20-98-002. IRB# 99-40118] TAC + adjuvant agents 3.2 15.0 3.3 5.7 6.5 14.0 6.5 Incidence (%) 121* CsA + adjuvant agents 245* Retrospective, multivariate, multicenter analysis [First MR, et al. Transplantation. 2002;73:379-386.] TAC + adjuvant agents 57* TAC + AZA 46* CsA + MMF 40 SIR + CNI + steroids 62 AZA + steroids 42* Randomized, 3-arm, parallel group, open label, prospective trial, 2000 [ Johnson C, et al. Transplantation . 2000;69:834-841.] TAC + MMF # Patients Study Design Protocol
    • Diabetes: Long-term Treatment
      • Tight glycemic control posttransplant is as important to patients with diabetes as in other settings
        • DCCT & UKPDS results
        • Results of pancreatic transplants in kidney recipients
      • Metformin may be problematic
      • Early administration of insulin may preserve residual islet function
      • HbA1c <7% checked 4 times a year
      • Glucose self-monitoring
        • FBS 80-120 mg/dL
        • postprandial glucose <140-160 mg/dL
      • Ophthalmologic & foot examinations
      • Microalbuminuria test unless frank proteinuria present
    • Hyperlipidemia
      • Common in patients with chronic kidney disease and even more so in renal transplant recipients
      • Characterized by a significant increase in
        • total cholesterol (>200 mg/dL)
        • LDL cholesterol (>130 mg/dL)
        • Triglycerides (>150 mg/dL)
        • VLDL (>35mg/dL)
      • Other changes that occur in the lipid profile of the renal transplant recipient
        • variable effects on HDL cholesterol and Lp(a)
        • accumulation of atherogenic remnants (eg, IDL)
    • Hypercholesterolemia: Independent Risk Factor for Graft Loss Wissing KM, et al. Transplantation . 2000;70:464-472. Years 0 10 20 30 40 50 60 70 0 1 2 3 4 5 6 7 8 9 10 % Overall Kidney Graft Loss Acute rejection, C>250 mg/dL Acute rejection, C<250 mg/dL
    • Hypercholesterolemia:Risk Factor for Renal Allograft Dysfunction Years Posttransplant 1 3 5 7 % Probability of Doubling Serum Creatinine Carvalho MF, et al. Clin Transplant. 2001;15:48-52. 0 0.25 0.5 High cholesterol Normal cholesterol
    • Hypertriglyceridemia: Risk Factor for Renal Allograft Dysfunction 0 0.25 0.5 Years Posttransplant % Probability of Doubling Serum Creatinine Carvalho MF, et al. Clin Transplant. 2001;15:48-52. 1 3 5 7 High TGC Normal TGC
    • Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      • CHD risk equivalents
        • Clinical CHD
        • Symptomatic carotid disease
        • Peripheral arterial disease
        • Abdominal aortic aneurysm
        • Diabetes mellitus
      • Major risk factors
        • Cigarette smoking
        • Hypertension (  140/90)
        • HDL <40 mg/dL
        • Family history of early CHD
        • Age (men  45; women  55)
      • The National Cholesterol Education Program recommendations include maintaining:
        • total cholesterol and LDL cholesterol below 200 and 130 mg/dL, respectively
        • HDL cholesterol above 35 mg/dL
        • triglycerides below 200 mg/dL
      National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III ). Bethesda, Md: National Heart, Lung, and Blood Institute; 2001. NIH publication 01-3670.
    • KDOQI Guidelines Management of Dyslipidemias in Adults With Chronic Kidney Disease Am J Kid Dis. 2003;41(Suppl 3):S39-S58. TLC + max. dose statin TLC + low dose statin Non-HDL <130 mg/dL TG ≥200 & non-HDL ≥130 mg/dL TLC + max. dose statin TLC + low dose statin LDL <100 mg/dL LDL ≥ 130 mg/dL TLC + low dose statin TLC LDL <100 mg/dL LDL 100-129 mg/dL TLC + fibrate or niacin TLC TG <500mg/dL TG ≥ 500 mg/dL Increase Initiate Goal Dyslipidemia
    • Lipid Lowering Agents LFT = liver function test; GI = gastrointestinal. Increased risk of myositis/rhabdomyolysis when used with statins, cyclosporine, and tacrolimus Myositis/rhabdomyolysis; GI upset Fibrates Use with cyclosporine, tacrolimus, and prednisone may exacerbate glucose intolerance Glucose intolerance; increased LFTs Nicotinic acid May interfere with cyclosporine and tacrolimus absorption May cause bloating/constipation Bile acid resin Interactions With Immunosuppressives Side Effects
    • Lipid Lowering Agents Interactions With Immunosuppressives Side Effects Increased risk of myositis/rhabdomyolysis when used with fibrates, cyclosporine, and tacrolimus Myositis/rhabdomyolysis; increased LFTs; GI upset Statins (HMG-CoA reductase inhibitors) Cyclosporin may increase levels Angioedema, diarrhea, abdominal pain Ezitimibe
    • Treatment for Hyperlipidemia in Renal Transplant Recipients
      • Diet
        • Saturated fat: < 7% of total calories
        • Polyunsaturated fat: up to 10% of total calories
        • Monounsaturated fat: up to 20% of total calories
        • Total fat: 25-35% of total calories
        • Complex carbohydrates: 50-60% of total calories
        • Fiber: 20-30 g/day
        • Cholesterol: < 200 mg/day
      Am J Kid Dis ;41(Suppl 3):S39-S58.
    • Treatment for Hyperlipidemia in Renal Transplant Recipients
      • BMI
        • 25-28 kg/m 2
      • Moderate physical activity
        • 20-30 minutes 3-4 x/week
      • Alcohol in moderation
      • Smoking cessation
      Am J Kid Dis 41(Suppl 3):S39-S58.
    • Treatment for Hyperlipidemia in Renal Transplant Recipients
      • Statins are the drugs of choice to lower LDL cholesterol
        • Begin with lower doses if on therapy with a CNI (esp CYA, ?TAC)
        • No data on SRL
      • Use caution if adding a fibrate and begin with reduced dosages with GFR <90 unless using gemfibrozil
      Am J Kid Dis 41(Suppl 3):S39-S58.
    • Treatment for Hyperlipidemia in Renal Transplant Recipients
      • If LDL remains ≥100 mg/dL despite maximal medical management, consider
        • Tapering or discontinuing prednisone +/- adding or increasing the dose of AZA or MMF
        • Tapering or discontinuing CYA +/- adding or decreasing the dose of AZA or MMF
        • Replacing CYA with TAC
        • Discontinuing or replacing SRL
      • Bile acid sequestrants may interfere with the absorption of immunosuppressive agents (CNI)
    • Hyperlipidemia: Post-Hoc Subgroup Analysis of the ALERT Study
      • 2102 renal transplant patients treated with fluvastatin (40-80 mg) for 5-6 years
      • 32 % reduction in LDL cholesterol vs placebo
      • Incidence of cardiac death or nonfatal MI reduced from 104 to 70 events vs placebo
      • (RR 0.65, P =.005)
      • Statistically significant in multiple subgroups including patients at lower CV risk
      Jardine AG, et.al. Am J Trans. 2004; 4:988-995 .
    • Use of Lipid Reducing Drugs Over Time—Tacrolimus vs Cyclosporine Vincenti F, et al. Transplantation. 2002;73:775-782. 0 10 20 30 40 50 60 90 Days 1 Year 3 Years 5 Years % Patients P =NS P <.05 P <.05 P <.001 Tacrolimus Cyclosporin
    • Hypercholesterolemia After Conversion to Tacrolimus McCune TR, et al. Transplantation. 1998;65:87-92 0 50 100 150 200 250 300 Cholesterol LDL Cholesterol Apolipoprotein B Serum Lipid Levels (mg/dL) P =.0005 P =.0007 P =.0098 Tacrolimus Cyclosporin
    • Hyperhomocysteinemia
      • Common condition in renal transplant recipients
      • Testing for fasting homocysteine level might be a useful tool to identify patients at increased risk for development of vascular disease
      • Further long-term studies are needed to determine the best treatment
      • Effects of immunosuppressive therapy on hyperhomocysteinemia are also under investigation
    • Cardiovascular Risks Associated With Immunosuppressive Regimens MMF = mycophenolate mofetil, + = least association, ++++ = greatest association. ++++ Sirolimus (SRL) ++ + Tacrolimus (TAC) ++ + ++ Cyclosporin (CYA) +++ ++ +++ AZA or MMF + Pred + CYA ++ + ++ Prednisone (Pred) + + ++ +++ Diabetes ++++ ++ SRL + Pred + CYA +++ ++ SRL + Pred + TAC + ++ AZA or MMF + Pred + TAC MMF + Pred + SRL Azathioprine (AZA) or MMF Immunosuppressant +++ + Hyperlipidemia Hypertension
    • Conclusion
      • Cardiovascular disease after renal transplantation is related to a high prevalence and accumulation of risk factors before and after transplantation
      • Hypertension, diabetes and hyperlipidemia are well-recognized risk factors and are linked to immunosuppressive therapy
      • Reducing cardiovascular risk can only be accomplished by reducing the impact of these defined risk factors early after the onset of chronic kidney disease and effectively after renal transplantation