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Clinical Care of Renal Transplant Recipients: An Internist’s Guide

Clinical Care of Renal Transplant Recipients: An Internist’s Guide. Matthew R. Weir, M.D. Professor and Director Division of Nephrology University of Maryland School of Medicine. Overview. Short-term risks Long-term risks Erosion of graft function Cardiovascular disease malignancy

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Clinical Care of Renal Transplant Recipients: An Internist’s Guide

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  1. Clinical Care of Renal Transplant Recipients: An Internist’s Guide Matthew R. Weir, M.D. Professor and Director Division of Nephrology University of Maryland School of Medicine

  2. Overview • Short-term risks • Long-term risks • Erosion of graft function • Cardiovascular disease • malignancy • Drug – Drug interactions • Future opportunities

  3. Overview • Short-term risks • Long-term risks • Erosion of graft function • Cardiovascular disease • malignancy • Drug – Drug interactions • Future opportunities

  4. What are the short-term risks? • Rejection • Donor factors leading to poorer outcome • Recipient death • Operative complications • Infection • Malignancy • Cardiovascular disease • Complications of immunosuppressive therapy

  5. Short-Term Risks: Infection • First 6 weeks: standard post-surgical issues including UTI, line infection, thrombophlebitis, pneumonia/atelectasis, wound infection, thrush • After 6 weeks: opportunistic infection including CMV, EBV, PCP, listeria, aspergillus, etc. • Chemoprophylaxis: clotrimazole, TMS, valganciclovir

  6. Overview • Short-term risks • Long-term risks • Erosion of graft function • Cardiovascular disease • malignancy • Drug – Drug interactions • Future opportunities

  7. Acute rejection rates at one year have improved considerably since the mid-1990s1,2 60 50 40 30 Incidence (%) 20 10 0 2005 1996 1997 1998 1999 2000 2001 2002 2003 2004 Year 1. OPTN/SRTR 2006 Annual Report. 2. OPTN/SRTR 2007 Annual Report.

  8. Longer-term outcomes remain a challenge in kidney transplantation Primary graft survival of deceased donors by year of transplant to 31/12/07: Australia and NZ ANZDATA 31st annual report 2008 (http://www.anzdata.org.au/anzdata/AnzdataReport/31stReport/Ch08Txpart2.pdf)

  9. Possible reasons why short-term improvements have not changed the long-term attrition rate • Increased immunosuppression to prevent early acute rejection generates subsequent graft loss from over-immunosuppression • Long-term attrition rate is a separate process driven by calcineurin inhibitors or other chronic injury • Late immunosuppression minimization and/or non-compliance may play a role Meier-Kriesche H-U WTC 2006.

  10. Immunosuppression may have early benefits but late adverse effects on graft survival Late graft failure may occur via mechanisms unrelated to immune injury Immunosuppression may be inadequate late because of nonadherence and minimization regimens Why hasn't improved early graft survival resulted in better late graft survival? BK nephropathy, other late infections, malignancies, CVD CNI nephrotoxicity, recurrent disease, senescence Multiple and/or late acute rejection episodes, subclinical rejection, AMR

  11. ALTERNATIVE MECHANISMS FOREARLY KIDNEY GRAFT FAILURE Good Function Ccr Accelerated Slope Reduced Intercept Ccr at return to dialysis Time

  12. Disease and medical trends: Keys to long-term success • Graft survival • Acute rejection renal function1 • One year survival long-term survival2 • Patient survival • Cardiovascular disease3 • Post-transplant malignancy4 1. Meier-Kreische HU, et al. Am J Transplant. 2004;4:378–383. 2.Hariharan S, et al. Kidney Intl. 2002;62:311–318. 3. Meier-Kreische HU, et al. Transplantation. 2003;75:1291–1295. 4. Campistol J, et al. JASN. 2006; 17: 581–589.

  13. What are the important laterisks? • Donor factors leading to poorer outcome • Recipient death • Cardiovascular disease • Malignancy • Infection • Late graft loss • Chronic allograft nephropathy • Subclinical ACR or AMR • Infection

  14. Other Recurrence 6% Noncompliance 4% 13% Chronic Death rejection 56% 21% Death with a functioning graft is the most common cause of graft loss in kidney transplant recipients beyond the first year after transplantation Cause of graft loss*1 Cause of death2 USRDS 1st kidney transplants 1995–2003(excluding 30% unknown) Other 19.4% Cardiovascular disease 43.5% Malignancy 10.7% Infection 26.3% *beyond the first year after transplantation 1. Peeters J, et al. Kidney Int. 1995;48(Suppl 52):S97S101. 2. Kasiske B L. et al. Coronary Artery Disease. Presented at the American Society of Nephrology Renal Week 2006 San Diego November, 14-19, 2006.

  15. Cardiovascular risk and kidney transplantation • Cardiovascular disease is much more common among renal transplant recipients compared to the general population • The greater incidence of CVD is not entirely explained by traditional risk factors, (blood pressure, cholesterol, glucose). Thus, other factors may be involved (immunosuppression, rejection, infection?) Kasiske BL et al. J Am Soc Nephrol 2000;11:1735-1743

  16. Observed and expected risk for ischemic heart disease after renal transplantation 1.00 0.90 0.80 10-year survival without IHD 0.70 0.60 0.50 0.40 Older Younger Older Younger Older Younger Older Younger --Diabetic-- -Non-Diabetic- Diabetic -Non-diabetic- ----------Smoker---------- ----------Non-Smoker----------

  17. 100 98 Scr mg/dl @1 /RR 96 1.0 1.03 1.19 1.371.49 1.67 2.26 <1.3 1.3-1.4 % Cardiovascular death free survival 1.5-1.6 1.7-1.8 94 1.9-2.1 2.2-2.5 92 2.6-4.0 90 12 24 36 48 60 72 84 96 108 120 0 Months post-transplant Cardiovascular Death Events in 48,832 KTX by SCr at One Year Post-Transplant Meier-Kriesche, Kaplan et al.Transplantation 2003.

  18. Relationship Between CKD and CVD1 CKD is a risk factor for CVD, and CVD may be a risk factor for the progression of CKD CKD Traditional CV risk factors Non-traditional CV risk factors CVD CKD = chronic kidney disease; CVD = cardiovascular disease; CV = cardiovascular. 1. Menon V et al. Am J Kidney Dis. 2005;45:223–232.

  19. Graded and Independent Relationship Between Estimated Glomerular Filtration Rate (GFR) and CVD Outcomes* *Adjusted for baseline age, sex, income, education, coronary disease, chronic heart failure, stroke or transient ischemic attack, peripheral artery disease, diabetes, hypertension, dyslipidemia, cancer, hypoalbuminemia, dementia, liver disease, proteinuria, prior hospitalizations, and subsequent dialysis requirement. Shastri S et al. Am J Kidney Dis. 2010 Jul 2. [Epub ahead of print].

  20. The key understanding is that patients with CKD benefit as much as non-CKD patients with appropriate medications and therapies, if not more, because of their increased risk!

  21. Decreased GFR has consistently been found to be an independent risk factor for CVD outcomes and all cause mortality!

  22. 100 GP Male GP Female 10 GP Black GP White 1 Dialysis Male 0.1 Dialysis Female Dialysis Black 0.01 Dialysis White Transplant 0.001 25-34 35-44 45-54 55-64 65-74 75-84 ≥85 Cardiovascular Mortality Is Higher in Patients With ESRD Annual mortality (%) Age (years) Adapted from Foley RN et al. Am J Kidney Dis. 1998;32(5 Suppl 3):S112–S119.

  23. Traditional and Nontraditional Risk Factors Increase CVD Event Risk in Patients With CKD1 Particular to individuals with CKD CVD = cardiovascular disease; CKD = chronic kidney disease; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; Apo = apolipoprotein. 1. Shastri S et al. Am J Kidney Dis. 2010;56:399-417.

  24. The Transplant Kidney • Optimal GFR 50-60 ml/min, less in situations of ischemia/reperfusion injury, marginal donors, nephrotoxic drugs or rejection • Risk for hyperfiltration injury • Pre-existing milieu of hypertension, diabetes and vascular disease

  25. Cardiovascular Risk Profile of the Renal Transplant Recipient • Hypertension • Diabetes • Dyslipidemia • Renal Disease

  26. Appreciate that we have no prospective randomized controlled trials to evaluate optimal treatment regimens and goals in patients with kidney transplants!

  27. Pathogenesis of Hypertensionin Renal Transplant Recipients • Pre-existing essential hypertension • General-population risk factors(obesity, smoking, alcohol, excessive salt intake) • Renal dysfunction/rejection • Renal-transplant artery stenosis • Effects of native kidneys • Hypertensive donor • Immunosuppressive drugs Mailloux LU et al. Am J Kidney Dis. 1998;32(suppl 3):S120–S141. Kew CE II et al. J Renal Nutrition. 2000;10:3–6.

  28. 100 90 SBP No. pts < 120 2,805 120–129 4,488 130–139 5,961 80 70 140–149 6,670 150–159 4,443 60 160–169 2,925 170–179 1,217 50 ³ 180 1,242 0 Association of Hypertension at 1 YearWith Decreased Graft Survival % grafts surviving 0 1 2 3 4 5 6 7 Years post-transplantation SBP = systolic blood pressure Opelz G et al. Kidney Int. 1998;53:217–222.

  29. Does treatment of high blood pressure in renal transplant recipients reduce graft loss and patient death?

  30. Probably! • No outcome studies have been performed • It is likely that these high risk patients will derive benefit for the heart, brain and transplant kidney

  31. Drug Therapy: Treatment Diuretics: As needed to control volume: more studies need to focus on the advantages of thiazides vs loop diuretics Beta-blockers: Heart rate control, CAD Alpha blockers: BPH, outflow obstruction

  32. ACEI and ARB • Preferred treatment strategies antihypertensive antiproteinuric antiproliferative

  33. ACEI/ARB in Renal Transplantation • Retrospective open cohort study • N=2031, University of Vienna • 1990-2003, ACE use increased 9%-47%, ARB 0%-18% at the end of the observation period • Medication and co-morbidities were analyzed as time-dependent variables in cox regression analyses. • Ten year patient survival:74% ACE/ARB vs 55% in no ACE/ARB, p<.001 • Ten year graft survival: 59% in ACE/ARB group vs 41% in no ACE/ARB, p=.002 Heinze G, et al. JASN 2006;17:889-899

  34. Kaplan-Meier estimates of patient survival. Angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers (ACEI/ARB) users lived significantly longer compared with noACEI/ARB patients (log rank: P < 0.001).

  35. Kaplan-Meier estimates of actual graft survival counting death as event. ACEI/ARB therapy was associated with longer graft survival (log-rank: P = 0.002).

  36. Systematic Review of RAS Blockade in Kidney Transplantation • 21 randomized trials • n=1549 • Median follow-up: 27 months • eGFR decreased by 5.8 ml/min • Hct decreased by 3.5 % • Proteinuria decreased by 470 mg/day • No change in serum potassium • Not enough power to see an effect on patient or graft survival Hiremath S, et. al AmJ Transplant 2007; 7:2350-2360

  37. Calcium Channel Blockers • Robust antihypertensive properties, despite salt consumption • Afferent glomerular dilators ? Good effect with calcineurin inhibitors ? Deleterious effect with glomerular capillary pressure • Best combined with ACEI or ARB

  38. Diabetes in Kidney Transplant Patients • Associated with reduced patient survival • Associated with reduced graft survival Histologic appearance of diabetic kidney disease within 5 years.

  39. Impact of Intensive Glycemic TherapySummary of Major Clinical Trials Initial trial Long-term follow-up 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589. 3. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329;977-986. 4. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. 5. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. 6. Patel A, et al. N Engl J Med. 2008;358:2560-2572.7. Duckworth W, et al. N Engl J Med. 2009;360:129-139. 8. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

  40. Cumulative Incidence of the First Occurrence of Nonfatal MI, Stroke, or Death From CVD, T1D 0.12 0.10 Risk reduction 42% 95% CI: 9% to 63% P = 0.02 Conventional 0.08 Longer studies? Cumulative Incidence 0.06 0.04 Intensive Earlier intervention? 0.02 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 15 20 10 Years from Study Entry Nathan DM et al. N Engl J Med. 2005:353:2643-2653.

  41. Cumulative Incidence of an Impaired Glomerular Filtration Rate, According to Treatment Group. The DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-2376.

  42. Rationale for Lipid Lowering Clinical Trials in the CKD Population CKD and ESRD patients are at increased risk of cardiovascular complications CKD and ESRD patients have abnormal lipid profiles Secondary analyses of lipid lowering studies indicated statin treatment improved CV outcomes in CKD patients Secondary analyses of these studies also demonstrated slowing of CKD progression Need for randomized placebo-controlled statin trials in CKD and ESRD patients 1. Scandinavian Simvastatin Survival Study (4S). Lancet.1994;344(8934):1383–1389. 2. Shepherd J et al. N Engl J Med. 1995;333(20):1301–1307. 3. Heart Protection Study Collaborative Group. Lancet. 2002;360(9326):7–22. 4. Seliger SL et al. Kidney Int. 2002;61(1):297–304. 5. Liao JK. Am J Cardiol. 2005;96(5A):24F–33F. 6. Fellström BC et al. Kidney Int. 2003;63(Suppl 84):S204–S206.

  43. Mechanism of CVD Development in Patients With Uremia Uremia Oxidative stress (ROS, AGE, AOPP) Dyslipidemia (TG↑, ApoB↑, ApoA1 ↓, HDL↓) Immuno-deficiency (T- & B- cell, phagocytosis, Ig-formation Malnutrition Inflammatory activity T Atherogenic lipid fractions (ox_LDL, small dense LDL) ADMA↑ B Endothelial dysfunction Ab Accelerated Atherosclerosis TG, triglycerides; HDL, high density lipoprotein; LDL, low density lipoprotein; ROS, reactive oxygen species; AGEs, advanced glycation end products; AOPP, advanced oxidation of plasma proteins; ADMA, asymmetric dimethylarginine Fellström BC et al. Kidney Int. 2003;63(Suppl 84):S204–S206.

  44. ALERT • n = 2102 renal transplant recipients • Randomized controlled trial (60 months) • Primary endpoint: cardiac death, non-fatal MI, or cardiac procedures • Fluvastatin (40-80 mg) vs placebo • 17% RRR (p = 0.139), but fewer cardiac deaths and MI in treatment group (p = 0.005) Holdaas et al. Lancet 2003;361:2024-2031.

  45. SHARP: Eligibility • History of chronic kidney disease • not on dialysis: elevated creatinine on 2 occasions • Men: ≥1.7 mg/dL (150 µmol/L) • Women: ≥1.5 mg/dL (130 µmol/L) • on dialysis: haemodialysis or peritoneal dialysis • Age ≥40 years • No history of myocardial infarction or coronary revascularisation • Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated

  46. SHARP: Randomisation structure Randomised (9438) Simva/Eze (4193) Simvastatin (1054) Placebo (4191) Not re-randomised (168) Randomised (886) Placebo (4620) Simv/Eze (4650) Median follow-up 4.9 years Lost to mortality follow-up 1.5%

  47. SHARP: Atherosclerotic Events(Lancet 2011;377:2181) 25 20 Risk ratio 0.83 (0.74-0.94) Logrank 2P=0.0021 Placebo 15 Simv/Eze Proportion suffering event (%) 10 5 0 0 1 2 3 4 5 Years of follow-up

  48. Summary Nevertheless, given the data from the HPS and the SHARP study, we feel that there is a strong argument to abandon a threshold-based algorithm for treating hyperlipidemia. Rather it may be advisable to treat those with high risk for atherosclerotic cardiac events regardless of initial LDL level, and to treat with a potent dose of a statin alone or in combination with a second line drug to achieve a marked (at least 40%) reduction in LDL, at least to ATP-III LDL goal levels.

  49. CKD Resets the Focus on CV Risk Reduction Strategies • BP <130/80 mmHg? • Evaluate and treat lipids • Extinguish microalbuminuria/proteinuria? • Reduction in dietary salt/saturated fat • Intensify glycemic control • Control anemia • Control calcium / phosphorus balance • Anti-platelet therapy

  50. The increased risk of malignancy in kidney transplant patients Cancer rates vs. general population Colon, lung, prostate, gastric, esophagus, pancreas, ovary and breast Testes and urinary, bladder Cutaneous melanoma, leukemia, liver and gynecological tumors Kidney Kaposi sarcoma, PTLD, skin cancer 2 Moderate Risk 3 5 High risk 15 >20 Kasiske BL, et al. Am J Transplant. 2004;4:905–913.

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