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2008 ASN Highlights: Kidney Transplantation

ASN Renal Weekends 2009. 2008 ASN Highlights: Kidney Transplantation. Donald E. Hricik, M.D. Professor of Medicine, Chief Division of Nephrology and Hypertension University Hospitals Case Medical Center Cleveland, Ohio Postgraduate Education Director, AST.

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2008 ASN Highlights: Kidney Transplantation

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  1. ASN Renal Weekends 2009 2008 ASN Highlights:Kidney Transplantation Donald E. Hricik, M.D. Professor of Medicine, Chief Division of Nephrology and Hypertension University Hospitals Case Medical Center Cleveland, Ohio Postgraduate Education Director, AST 2009 Renal Weekend Transplant Team: Donald Hricik, David Roth, Connie Davis

  2. ASN Renal Weekends 2009 Overview • Immunosuppression, including clinical trials • Desensitization protocols • Complications • Malignancy • Anemia • Proteinuria • The failed transplant/retransplantation

  3. ASN Renal Weekends 2009 Calcineurin Inhibitor Sparing Protocols:Is There Evidence that They Work? Henrik Ekberg Lund University, Malmö, Sweden

  4. ASN Renal Weekends 2009 Longitudinal assessment by protocol biopsy:CNI nephrotoxicity and subclinical rejection Brian Nankivell Timeline of biopsy protocol 0 3 12 mo. 2 3 4 5 6 7 8 9 10 years • 961 protocol kidney biopsies • 120 kidney/pancreas recipients • Young donors NEJM 2003; 349: 2326-33

  5. ASN Renal Weekends 2009 Histological features of Cyclosporine Nephrotoxicity

  6. ASN Renal Weekends 2009 ASN Renal Weekends 2009 The objectives of CNI sparing protocols: • To reduce CNI nephrotoxicity and chronic graft injury: and thereby • improve renal graft function • reduce overall toxicity • improve long-term graft survival • But maintain efficacy in terms of acute and subclinical rejection

  7. ASN Renal Weekends 2009 CNI sparing strategies • CNI avoidance • CNI withdrawal • CNI dose reduction • CNI replacement using mToR inhibitors

  8. ASN Renal Weekends 2009 CNI avoidance Daclizumab + CsA + MMF + CS Excellent Renal Function 53 % Acute rejection at 12 mo. 1° 2° 2 1 Daclizumab MMF 3g/day 2g/day Steroids n = 98 12 mo. Tx 6 mo. Vincenti F et al. Transplantation 2001; 71:1282–7.

  9. 6 12 mo 0 ASN Renal Weekends 2009 CAESAR study design 50-100 ng/mL Withdrawal 4-6 mo. Daclizumab Low CsA w/d Low-CsA w/d MMF Steroids 50-100 ng/mL Daclizumab Low-CsA Low CsA MMF Steroids 150-300 ng/mL, 4 mo.: 100-200 Standard CsA Stand CsA MMF Steroids Ekberg H et al. Am J Transplant 2007; 7 (3): 560.

  10. ASN Renal Weekends 2009 CAESAR studyRenal function at 12 months No significant difference No improvement in GFR by dose-reduction or w/d of CsA Two values for GFR > 200 ml/min/1.73 m2 excluded Ekberg H et al. Am J Transplant 2007; 7 (3): 560.

  11. ASN Renal Weekends 2009 CAESAR studyBPAR at 6 and 12 months 38 % Acute Rejection at 12 mo. 25 % Acute Rejection at 6 mo. after w/d Ekberg H et al. Am J Transplant 2007, 7 (3): 560.

  12. ASN Renal Weekends 2009 CNI sparing strategies So: • CNI avoidance – did not work • CNI withdrawal (at 4-6 mo.) – did not work • CsA dose reduction …

  13. 3–7ng/mL Daclizumab C Low-dose TAC MMF Steroids 4–8ng/mL Daclizumab D Low-dose SRL MMF Steroids ASN Renal Weekends 2009 SYMPHONY Study Design1645 patients at 83 sites in 15 countries 150–300ng/mL for 3 months 100–200ng/mL thereafter A Standard-dose CsA MMF Steroids 50–100ng/mL Daclizumab B Low-dose CsA MMF Steroids 12 months 6 months Transplantation Ekberg H, et al. NEJM2007;357:2562–75

  14. p=0.0014 p<0.0001 p<0.0001 ASN Renal Weekends 2009 Graft function was superior with Low-dose TacCalculated GFR Cockcroft-Gault 100 90 80 Standard-dose CsA 65 70 59 Low-dose CsA 57 57 60 Low-dose TAC GFR (Cockcroft Gault) (ml/min) 50 Low-dose SRL 40 30 No significant difference between CsA and Low-CsA 20 10 0 12 months post-Tx Ekberg H et al NEJM 2007; 357: 2562.

  15. p = NS p=0.0143 p=0.0147 100 98% 100 97% 97% 97% 94% 93% 89% 89% 90 90 Patient survival (%) Graft survival (%) 80 80 70 70 12 months post-Tx 12 months post-Tx ASN Renal Weekends 2009 Graft Survival was superior with Low-dose Tac Standard-dose CsA Low-dose CsA Low-dose TAC Low-dose SRL

  16. p<0.0001 p<0.0001 ASN Renal Weekends 2009 Less Biopsy Proven Acute Rejectionwith Low-dose Tac (ITT, Excluding Borderline) 50 37% 40 Standard-dose CsA Low-dose CsA 26% 30 24% Low-dose TAC BPAR (% of patients) Low-dose SRL 20 12% No significant difference between CsA and Low-CsA; about 25% 10 0 12 months post-Tx Ekberg H et al NEJM 2007; 357: 2562.

  17. ASN Renal Weekends 2009 The CNI-free alternative:Was the target 4-8 ng/ml for Low-dose SRL too low? -16% Low-SRL was not efficient enough,but still not without toxicity Vincenti F et al. Transplantation 2001; 71:1282. Ekberg H et al NEJM 2007; 357: 2562.

  18. ASN Renal Weekends 2009 Probability of One-Year Acute Rejection by Drug Exposure at 1 month .35 Low-SRL 0 5 .30 10 15 20 25 30 .25 .20 Probability of One-year AR Cyclosporine .15 0 100 200 300 400 500 .10 600 700 800 Low-Tac .05 0 2 4 6 8 10 12 14 16 18 0 Values indicate average 1-month trough levels

  19. ASN Renal Weekends 2009 3-year Follow-up Study Core study (12 months) 1645 Enrolled: 1602 Safety (received Rx): 1589 ITT (received Rx, transplanted): Approx. 60% of patients Follow-up study (data at 36 months) 955 FU-Enrolled: 954 FU-Safety: 954 FU-ITT:

  20. ASN Renal Weekends 2009 Many patients switched treatments during the 1st year - 3% Dotted bars: Day 0 Striped bars: Month 12 + 9% - 8% Switches from SRL to Tac occurred due to treatment failure, mainly AR

  21. p<0.0001 p<0.0001 p<0.0001 ASN Renal Weekends 2009 Incidence of BPAR remained lowestin Low-Tac group at 3 years BPAR (% of patients)

  22. ASN Renal Weekends 2009 Graft survival* remained superiorin Low-Tac group at 3 years p>0.05 Graft loss (% of patients) * Graft survival not censored for patient death

  23. Interim 1-Year Outcomes of the Spare-the-Nephron (STN) Trial: An MMF-Based Regimen Combined With Sirolimus to Spare Renal Function ASN Renal Weekends 2009 Roberto Kalil, MD University of Iowa Hospitals and Clinics, Iowa City, Iowa T. C. Pearson, S. Mulgaonkar,A.Patel, H. Shidban, M. Weir, D. Patel, and J. Scandling

  24. Trial Design Pre-randomization* Post-randomization MMF + tacrolimus 30 – 180 D A Y S P O S T - T X MMF + tacrolimus MMF + sirolimus MMF + cyclosporine MMF + cyclosporine MMF + sirolimus Patient screening and enrollment 2 years 1 year ASN Renal Weekends 2009 *Randomization pre-stratified by CNI type at screening Target population = 305 single-organ renal allograft recipients

  25. Patient Allocation (Intent-to-Treat)* ASN Renal Weekends 2009 Randomized N=298 MMF/SRL N=148 MMF/CNI N=150 Tacrolimus Withdrawal N=122 Cyclosporine Withdrawal N=26 Tacrolimus N=119 Cyclosporine N=31 *81% received tacrolimus and 19% received cyclosporine

  26. Efficacy Outcomes, n (%) ASN Renal Weekends 2009 *P = NS for MMF/SRL vs. MMF/CNI.

  27. Treatment Failure, n (%) ASN Renal Weekends 2009 Events are mutually exclusive; only the first event counted per patient. *P = NS for MMF/SRL vs. MMF/CNI.

  28. Mean % Change in Measured GFR ASN Renal Weekends 2009 Baseline to Month 12 P=0.013 35 MMF/SRL 30 MMF/CNI 25 25.7 20 Mean Percent Change ± SEM 15 10 7.8 5 0 N = 118 N = 109 -5 Baseline GFR (mL/min/1.7 m2)  SEM 59.5  2.0 58.7  2.2

  29. Urinary Protein/Creatinine Ratio ASN Renal Weekends 2009 MMF/SRL vs. MMF/CNI: baseline, P=NS; 12 months, *P=0.096; **P=0.043.

  30. ASN Renal Weekends 2009 Desensitization Protocols

  31. ASN Renal Weekends 2009 Approaches to Desensitization Mark D. Stegall, M.D. Mayo Clinic, Rochester, MN ASN Renal Week November 7, 2008

  32. ASN Renal Weekends 2009 Desensitization What is it? • Removing or blocking donor specific antibody (almost always anti-HLA) • High Dose IVIG versus low dose IVIG and plasmapheresis with or without rituximab Goal? Prevention of: • Hyperacute rejection • Acute humoral rejection • Transplant glomerulopathy (chronic damage) Efficacy? • Few comparative studies of different approaches

  33. ASN Renal Weekends 2009 IVIG + Rituximab ProtocolVo et al NEJM 2008;359:242-51 • 20 sensitized patients underwent IVIG desensitization • IVIG 2 g/kg day 0, 30 and Rituximab 1g on day 7 and 22) • Required a T cell AHG – at 1:2 and a T flow crossmatch <250. • 18 transplanted (8 deceased donor and 10 living donor) • Alemtuzumab, Tacrolimus, MMF, Pred

  34. ASN Renal Weekends 2009 IVIG and Acute Rejection • Acute rejection • 50% • 31% C4d+ AMR • Treatment • Banff I or II: methylprednisolone, IVIG (2 g/kg) and rituximab (375 mg/BSA) • Banff III: Plasmapheresis (3-5 sessions) IVIG and rituximab (375 mg/BSA)

  35. ASN Renal Weekends 2009

  36. ASN Renal Weekends 2009

  37. ASN Renal Weekends 2009 RATIONAL DESENSITIZATION PROTOCOLS: TREATMENT ACCORDING TO MEDIAN FLUORESCENCE INTENSITY VALUES OF LUMINEX FLOW BEADS Akalin E, Dinavahi R, de Boccardo G, Schroppel B, Sehgal V, Murphy B, and Bromberg JS Mount Sinai School of Medicine Renal Division Recanati/Miller Transplantation Institute New York, NY NO. I HAVE NOTHING TO DISCLOSE.

  38. CLINICAL OUTCOMES PER LUMINEX MFI VALUES ASN Renal Weekends 2009 IVIG only IVIG only IVIG/PP____ DSA MFI < 6,000 DSA MFI > 6,000 DSA MFI>6,000 (n=33) (n=17) (n=20) ______________________________________________________________________ Median F/U (mos) 30 (4-80) 40 (14-53) 16 (12-28) Patient survival 100% 100% 90% Graft survival 97% 65% 75% Living 100% 67% 88% Deceased-donor 88% 64% 67% Acute rejection 0% 59% 20% AMR 0% 47% 15% ACR 0% 12% 5% Biopsy proven CAN 6% 36% 20% Transplant glomerulopathy 6% 12% 10% Median Cr (mg/dl) 1.1 (0.6-3.1) 1.2 (1.0-3.1) 1.4 (0.8-1.9) Patients with Cr < 1.4 81% 73% 87% DSA loss during F/U 77% 31% 36%

  39. ASN Renal Weekends 2009 • IVIg and Plasmapheresis: • “The azathioprine and prednisone of desensitization”: • Major Problem: Current protocols do not control antibody production • Solution: We need to understand antibody production better • New Paradigms • Prevent antibody production • Prevent the impact of antibody (complement inhibition)

  40. ASN Renal Weekends 2009 Proteasome Inhibition • Proteasome is a group of enzymes that “recycles” proteins in eukaryotic cells • Very active in highly-secretory cells • Velcade (bortezomib)—FDA approved proteasome inhibitor approved for treatment of resistant myeloma • Kills by apoptosis

  41. ASN Renal Weekends 2009 DAPI staining demonstrating apoptosis of Velcade treated cells Control Velcade

  42. The Complement Cascade: Targeted Inhibition Classical Pathway Antigen/Antibody Complexes ASN Renal Weekends 2009 Lectin Pathway Carbohydrate Structures Potent Anaphylatoxin Chemotaxis Cell Activation Activated C1 C4+C2 C3 Convertase C5 Convertase Activated MBL C4b2a C4b2a3b Cell Activation Neisseria Clearance RBC Lysis C5a Weak Anaphylatoxin C3a X C5 C5b-9 Immune Complex Microbial Opsonization C3 C3b C5b C6 C7 C8 C9 Alternative Pathway M/O and Mammalian Cell Membranes C3bBb3b C3b C3bBb C3 Convertase C5 Convertase Eculizumab Target Factor B+D C3H20 Tickover

  43. Anti-C5 AntibodyEculizumab Humanized monoclonal antibody FDA approved for treatment of paroxysmal nocturnal hemoglobinuria Blocks formation of C5a and C5b-9 May also decrease more proximal complement activation via feedback loop inhibition ½ life = ?? Partially removed by plasmapheresis ASN Renal Weekends 2009

  44. Anti-C5 Study ASN Renal Weekends 2009 Combine anti-C5 Ab with current protocol Goal: Decrease incidence of AHR compared to historical untreated controls Expected Findings: High antibody levels (and C4d+) without histologic injury/graft dysfunction

  45. ASN Renal Weekends 2009 Kidney Transplantation:Complications

  46. ASN Renal Weekends 2009 Immunosuppression Management in the Patient with Cancer: Role of Sirolimus Bertrand Kasiske University of Minnesota

  47. ASN Renal Weekends 2009 Sirolimus for Kaposi’s Sarcoma • 15 kidney transplant recipients • Biopsy-proven Kaposi’s Sarcoma • Treatment: • CsA was discontinued • Sirolimus was begun • Outcome: • No lesions at 3 months • Confirmed by biopsy Before After Stallone G, et al. New Engl J Med 2005;352:1317

  48. ASN Renal Weekends 2009 Everolimus in Advanced Renal Cell Carcinoma: A Double Blind RCT Progression-Free Survival (Everolimus dose =10 mg/day) N=272 N=138 Motzer RJ, et al. Lancet 2008;372:449

  49. ASN Renal Weekends 2009 mTOR Inhibitors and Non-Skin Cancers in Kidney Recipients: OPTN Data Transplanted 2000-20052 Transplanted 1996-20011 P=0.0002 Relative Risk Relative Risk REFERENCE REFERENCE CsA/Tac SRL/EVL Tac CsA SRL SRL+CsA SRL+Tac N= 30,424 2,825 37,829 18,783 2,257 2,664 4,659 1Kauffman HM, et al. Transplantation 2005;80:883 2Wida SC, et al. American Transplant Congress, June 2008 Abstract #294

  50. ASN Renal Weekends 2009 mTOR Inhibitors and Malignancies: A Meta-Analysis of RCTs CNIs v. mTOR Antimetabolites v. mTOR Relative Risk Relative Risk CNI mTOR Antimetabolite mTOR 4 Trials (N=447) 6 Trials (N=2,944) Webster AC, et al. Am J Transplant 2006;81:1234

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