Controversies in Renal Transplantation. The Controversial Questions. Patrick M. Klem, PharmD, BCPS University of Colorado Hospital

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1 Controversies in Renal Transplantation Patrick M. Klem, PharmD, BCPS University of Colorado Hospital The Controversial Questions Are newer immunosuppressants improving patient outcomes? Are corticosteroids still considered part of the standard of care immunosuppression? Are drug interaction with cyclosporine (Neoral) the same as with tacrolimus (Prograf)?

2 Induction therapy is increasing in popularity % Receiving induction therapy: 72%in 2004, increased from 49% in Thymoglobulin Simulect Zenapax Campath H.-U. Meier-Kriesche et al, Am J Transplant 2006; 6: 1111 Rejection Rates Meier-Kriesche H-U. Am J Transplantation 2004;4:378

3 Drug Development and Outcomes How far have we really come? AJT 2004;4:1289 Types of Immunosuppression Calcineurin Inhibitors cyclosporine (Neoral) Tacrolimus (Prograf) Antiproliferative Agents Mycophenolate (Myfortic) Mycophenolate (Cellcept) azathioprine (Imuran) Non-specific Immunosuppressants - prednisone Inhibition of Late T cell Function (mtor inhibition) - sirolimus (Rapamune) - everolimus (Zortress) Monoclonal Antibodies - OKT3 ( - daclizumab (Zenapax) - basiliximab (Simulect) Polyclonal Antibodies - antithymocyte globulin (Thymoglobulin, Atgam)

4 NEJM 04;351:2715 New Onset Diabetes After Transplant (NODAT) in the US Am J Transplantation 2003;3:178 Polyoma Virus (BK Virus) DNA virus which can cause interstitial nephritis (nephropathy) after renal transplant Can appear like acute rejection on biopsy Developing knowledge of pathogenesis Infection in 10 45% or renal transplant BK nephropathy incidence 1 10% High rate of graft failure with nephropathy Risk Factors Over immunosuppression, age, DM, - serostatus

5 NEJM 2002;346:580 Adverse Effects of Common Immunosuppressive Drugs Calcineurin inhibitors- TAC or CYA Hyperglycemia Dyslipidemia Hypertension Neurotoxicity Hyperkalemia Hemolytic Uremic Syndrome Nephrotoxicity Allopecia Hirsutism Gingival hyperplasia Adverse Effects of Common Immunosuppressive Drugs Corticosteroids Hyperglycemia Dyslipidemia Hypertension Insomnia Psychosis Osteoporosis Weight gain Infection PUD Cataracts Impaired wound healing

6 NEJM 2006;296:2827 Newer combination thearpy Attempts to decrease nephrotoxicity -Minimization of calcineurin inhibitors- Symphony Trial Randomized trial evaluating whether MMF based regimen with induction reduces toxicities without increasing rejection Non-US population, 92% Caucasian Low to normal immunologic risk patients Induction + MMF + prednisone + CSA standard: ng/ml x 3 mo, then ng/ml CSA low dose: ng/ml throughout Tac low dose: 3-7 ng/ml throughout Low dose sirolimus: 4-8 ng/ml troughout American Journal of Transplantation 09; 9:

7 3Year Results Standard CSA Low Dose CSA Low dose Tac Mean trough (ng/ml) GFR (ml/min) Acute rejection 27% 27% 14% 39% Graft survival 87% 89% 90% 85% NODAT 8% 5% 12% 8% Low dose Sir American Journal of Transplantation 09; 9: Large database analysis suggests CNI avoidance is not optimal, and TAC/MMF is preferred regimen Meier-Kriesche HU, et al, Am J Transplant 2007;7: 586 TAC/MMF has lowest discontinuation rate compared to other regimens 48% of patients discharged on TAC/ SRL had discontinued one/both medications, vs. 28% of TAC/MMFtreated subjects Meier-Kriesche HU, et al, Am J Transplant 2007;7: 586

8 Impact of Sirolimus on NODAT JASN 08;19:1411 mtor Inhibition: Prevention of Posttransplant Malignancies Study Yr Data Source Walter Reed 1 #Pts Analyzed FU (mo) Observations 2005 USRDS 25,127 MVA: MMF reduced PTLD risk Sirolimus no effect SRTR SRTR 33, MVA: Sirolimus* reduced risk of nonskin de novo (RR 0.45) or any de novo Ca (RR 0.40) UT 2005 Single Houston 3 Center Mathew Sirolimus Trials Campistol Randomized open-label 1, % Ca incidence 0.4% PTLD, 2.4% skin 1, Skin Ca incidence: Sirolimus 0%, CNI 5% Reduced risk of SCC, BCC, any skin Ca w/ early conversion from CyA- to SRL-based therapy *Included pts treated with either sirolimus or everolimus. All studies were of kidney transplant recipients only. FU=follow-up; MVA=multivariate analysis; Ca=cancer; CyA=cyclosporine; SRL=sirolimus. Transplantation. 2005;80: Transplantation. 2005;80: Transplantation. 2005;80: Clin Transplant. 2004;18: JASN 2006;17: Everolimus (Zortress )

9 24 month, open-label, muli-national noninferiority trial 833 renl transplant recipients EVR 1.5 mg (3-8 ng/ml) or 3 mg/day (6-12 ng/ml) + reduced exposure CsA +/- prednisone MPA (1.44 g/day) + standard CsA +/- prednisone All received basiliximab induction therapy Am J Transplantation 2010;10:1401 Primary Outcomes Am J Transplantation 2010;10:1401 egfr (MDRD calculation) Am J Transplantation 2010;10:1401

10 Newer Immunosuppresants Controversy Evaluate each patient to minimize complications Awaiting long term outcomes Current practice of revised protocols may yield best results Medications in pipeline Belatacept, JAK3 Inhibitor, alefacept, ISA 247 Are corticosteroids still considered part of the standard of care immunosuppression? Why Steroid Free? When patients were asked which drug they would like to discontinue CNI 19% MMF/AZA 16% Prednisone 65% Main complaints Weight gain Skin problems Bone/joint disease Clin Transplant 2003: 17:

11 Adverse Effects of Common Immunosuppressive Drugs Corticosteroids Hyperglycemia Dyslipidemia Hypertension Insomnia Psychosis Osteoporosis Weight gain Infection PUD Cataracts Impaired wound healing Withdrawal Better n = 64 n = 66 n = 67 n = 84 n = 85 n = 100 n = 229 n = 266 n = 500 n = 1461 Withdrawal Worse Pooled difference = % Cl = Difference in Proportion with Acute Rejection Kasiske BL, et al. JASN 2000;11: Withdrawal Better Withdrawal Worse n = 64 n = 66 n = 67 n = 84 n = 85 n = 100 n = 229 n = n = 500 n = 523 n = Pooled difference = % Cl = Relative Risk of Graft Failure Kasiske BL, et al. JASN 2000;11:

12 Steroid withdrawal: U.S. trial CsA/MMF/Prednisone Randomized at 3 months if no acute rejection Power: 500 in each arm 20% African Americans Low rates of induction (33%) Stopped early (266 patients) Ahsan N et al., Transplantation Dec 1999 U.S.: Biopsy proven AR or treatment failure Ahsan N et al., Transplantation Dec 1999 Steroid withdrawal: U.S. Increase in acute rejection with prednisone withdrawal in CsA-based regiments Prohibitive incidence of actue rejection or treatment failure in African-Americans Unclear if induction therapy might have made a difference

13 Astellas Corticosteroid Withdrawal Study Group Double-blind, multicenter, 5 year study Induction + tacrolimus + MMF +/- steroids Steroid tapered over 7 days N = st transplant, no delayed graft function, PRA <50%, living and deceased donor transplants 20% AA Primary outcomes: Death, graft loss, moderate/severe rejection Annals of Surgery 2008;248: Year Results Steroids Withdrawal P value Primary outcomes 14.4% 15.7% nss Biopsy proven AR 10.8% 17.8% 0.04 Patient survival 93% 94% nss Death censored graft loss 3.6% 5.8% nss Serum creatinine 1.5 mg/dl 1.5 mg/dl nss Annals of Surgery 2008;248: year differences Corticosteroid More bone fractures + avascular necrosis More serious adverse effects due to DM or infection More ATG for acute rejection Higher fasting triglyceride level Steroid Withdraw Higher AR rate Higher incidence of hyperkalemia and neutropenia Annals of Surgery 2008;248:564-77

14 5 Year Similarities LDL and HDL cholesterol Blood pressue Mean weight change Cataracts Opportunistic infections Malignancies GI toxicity New onset diabetes (20% incidence) Annals of Surgery 2008;248: Controversy of Steroid Withdrawal Strong opinions from center to center Current data shows increase acute rejection rate without improved graft/patient survival Tailor immunosuppression for individual patients Are drug interaction with cyclosporine (Neoral) the same as with tacrolimus (Prograf)?

15 Trends in immunosuppression regimens at hospital discharge Tac/MMF CyA/MMF Tac/Siro CyA/Siro H.-U. Meier-Kriesche et al, Am J Transplant 2006; 6: 1111 Cyclosporine Pharmacokinetics Am J Transplant 2005; 5: Cyclosporine hepatic metabolism RIF= rifampin PXR=pregnane X receptor Am J Transplant 2005; 5:207-17

16 Tacrolimus vs. cyclosporine in combinatinon with atorvastatin Triangles: CYA + Atorvastatin Circles: Tac + Atorvastatin Am J Transplantation 2005;5:2236 Statin use in CKD and with CYA *PI for simvastatin (Zocor) recommends max dose of 10 mg daily with cyclosporine Statins with CYA Am J Transplantation 2004;4:13-53

17 INTERACTIONS - Increase creatinine - Nephrotoxicity - Decrease metabolism - Increase metabolism CJASN 2010;5:1-12 Drug interaction controversy Tacrolimus and cyclosporine undergo similar metabolism (cytochrome p450 system) Cyclosporine stronger inhibitor of cytochrome P450 Close monitoring is prudent for both agents with adding a known enzyme inhibitor/ inducer Who wants to be a millionaire?