1. © 2014 Direct One Communications, Inc. All rights reserved. 1 How to Maximize Outcomes and Minimize Graft Failure Thin Thin Maw, MBBS Washington University School of Medicine in St. Louis, St. Louis, Missouri A REPORT FROM THE 2014 WORLD TRANSPLANT CONGRESS

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Trends in Renal Allograft Survival Over the past decade, 1-year renal allograft survival improved significantly; however, chronic allograft loss remains common. The major improvement in first-year renal allograft survival has been due to reduced early attrition. Attrition rates have not improved dramatically, even though a significant reduction in early attrition. The reasons for the lack of improvement in long- term survival remain unclear and are probably multifactorial.

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Trends in Renal Allograft Survival continued The overall rate of graft failure (return to dialysis, retransplant, death with a functioning graft) among renal-transplant recipients has continued to trend downward, reaching 6.2/100 patient-years in 2011, although death with a functioning graft has plateaued. 2013 USRDS Annual Data Report

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 Trends in Renal Allograft Survival continued Over the past 20 years, the major improvement in first-year renal-allograft survival has been due to a reduction in early attrition. 2013 USRDS Annual Data Report

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Causes of Allograft Loss El-Zoghby et al investigated the causes of graft loss in 1,317 kidney allografts transplanted between January 1,1996 and July 1,2006. A total of 330 grafts (25.1%) were lost: » 138 (10.5%) due to death with function » 39 (3%) due to primary nonfunction » 153 (11.6%) due to graft failure censored for death More than half (53.6%) of the graft losses were due to death with function and primary nonfunction. El-Zoghby ZM et al. Am J Transplant. 2009;9:527

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Renal Allograft Loss Causes of death with a functioning kidney graft: Cardiovascular disease (28.2%) Infection (15.2%) Malignancy (13.8%) Other (11.6%) Unknown (31.2%) 2013 USRDS Annual Data Report

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Risk Factors for Chronic Allograft Injury Both immunologic and nonimmunologic risk factors may contribute to chronic allograft dysfunction. The immunologic factors include poor HLA matching, prior sensitization, history of acute graft rejection, inadequate immunosuppression, and medication nonadherence. The nonimmunologic risk factors include existing comorbidities (hypertension, diabetes, obesity), older donor or poor organ quality, acute peritransplant injuries, chronic calcineurin inhibitor (CNI) toxicity, and BK virus nephropathy.

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Immunosuppression: Induction Therapy The 2009 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines recommend including a biologic agent as part of the initial immunosuppressive regimen for kidney- transplant recipients. The KDIGO guidelines also recommend using an IL-2 receptor antagonist, either daclizumab (no longer available) or basiliximab, as first-line therapy. The guidelines further suggest using a lymphocyte- depleting agent for kidney-transplant recipients who are at high immunologic risk or have risk factors for acute rejection. Kidney Disease: Improving Global Outcomes Transplant Work Group. Am J Transplant. 2009;9(suppl 3):S1; Matas AJ et al. Am J Transplant. 2013;13(suppl 1):11

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Immunosuppression: Maintenance Therapy Maintenance immunosuppression represents the cornerstone of long-term antirejection therapy. Immunosuppressants currently being used in various combination maintenance regimens (dual or triple therapy) include corticosteroids, azathioprine, mycophenolate mofetil (MMF), mycophenolate sodium, cyclosporine, tacrolimus, sirolimus, everolimus, and belatacept. In the United States, approximately 85% of kidney- transplant recipients were discharged on tacrolimus and MMF, either with (58%) or without (42%) glucocorticoids. Matas AJ et al. Am J Transplant. 2013;13(suppl 1):11

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Immunosuppression: CNI-Sparing Regimens CAESAR Study At 12 months post transplant, no statistically significant difference in mean glomerular filtration rate (GFR) was detected between kidney-transplant recipients who were weaned from cyclosporine 4–6 months after transplantation and those patients who were continued on a low-dose or standard-dose cyclosporine regimen for the entire 12 months. However, the incidence of biopsy-proven acute rejection was significantly higher in the cyclosporine-withdrawal group (38%) than in the low-dose (25.4%) or standard- dose (27.5%) cyclosporine groups. Ekberg H et al. Am J Transplant. 2007;7:560

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Immunosuppression: CNI-Sparing Regimens continued SYMPHONY Study At 3 years after transplant, a regimen based on daclizumab induction, 2 g of MMF, low-dose tacrolimus, and a corticosteroid resulted in better renal function (as measured by the GFR) and lower acute rejection and graft- loss rates than did a regimen using a low dose of cyclosporine or sirolimus instead of tacrolimus and another involving no induction therapy and standard doses of cyclosporine. Ekberg H et al. N Engl J Med. 2007;357:2562

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 Immunosuppression: CNI-Sparing Regimens continued CONVERT Study A total of 830 renal-transplant recipients receiving cyclosporine or tacrolimus for maintenance immunosuppression were randomly assigned to continue on their CNI regimen or converted to sirolimus 6–120 months post transplant. After 2 years, sirolimus conversion among patients with a baseline GFR > 40 mL/min was associated with excellent patient and graft survival, no difference in biopsy-proven acute rejection rate, increased urinary protein excretion, and a lower frequency of malignancy when compared with CNI continuation. Schena FP et al. Transplantation. 2009;87:233

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 Immunosuppression: CNI-Sparing Regimens continued BENEFIT Study In a randomized, active-controlled, multicenter trial comparing a more-intensive (MI) or less-intensive (LI) belatacept regimen with the use of cyclosporine immunosuppression in kidney- transplant recipients, patient and graft survival at 1 year in patients receiving either belatacept regimen was similar to that of patients receiving cyclosporine. However, patients receiving either belatacept regimen had superior renal function, as measured by a composite renal impairment end point (MI belatacept, 55%; LI belatacept, 54%; cyclosporine, 78%; P < 0.001) Belatacept-treated patients also experienced a higher rate of early acute rejection and a higher frequency of posttransplant lymphoproliferative disorder (PTLD). Vincenti F et al. Am J Transplant. 2010;10:535

14. © 2014 Direct One Communications, Inc. All rights reserved. 14 Medication Nonadherence Medication nonadherence is an important risk factor for renal allograft loss. Post-transplant nonadherence to immunosuppressive is common. From 5% to 45% of renal-transplant patients are nonadherent to immunosuppressive medication. Nonadherence rates increase dramatically > 6 months post transplantation. Nevertheless, medication nonadherence is probably underestimated because many studies are based on patient self-reporting.

15. © 2014 Direct One Communications, Inc. All rights reserved. 15 Impact of Medication Nonadherence Medication nonadherence has been linked to graft dysfunction, chronic graft rejection, graft loss, and donor-specific antibody formation. Sellarés et al found that medication nonadherence was 10 times more frequent among patients whose grafts progressed to failure (32%) than among those with viable grafts (3%). Medication nonadherence also has a significant impact on graft survival. Sellar é s J et al. Am J Transplant. 2012;12:388

16. © 2014 Direct One Communications, Inc. All rights reserved. 16 Medication Nonadherence and ABMR Role of antibody-mediated rejection (ABMR) and medication nonadherence among 315 kidney-transplant recipients. Almost one half of these episodes (47%) were due to nonadherence. Sellar é s J et al. Am J Transplant. 2012;12:388

17. © 2014 Direct One Communications, Inc. All rights reserved. 17 Approaches to Managing Nonadherence Because there is no single cause for nonadherence, it is difficult to have one effective intervention. A team approach is essential to achieve a successful intervention to improve medication adherence. Several studies have shown once-daily dosing to be significantly associated with improved adherence, compared with twice-daily or more frequent dosing. Clinicians should pay attention to medication nonadherence and discuss and monitor adherence with transplant recipients to improve long-term outcomes. De Bleser L et al. Transpl Int. 2009;22:780; Kuypers DR et al. Transplantation. 2013;95:333

18. © 2014 Direct One Communications, Inc. All rights reserved. 18 Improving Long-Term Outcomes Identifying factors that may predict allograft loss is an essential step toward prolonging kidney allograft survival. A new paradigm in immunosuppression is required to improve long-term outcomes. Introducing novel and less-nephrotoxic agents or regimens, decreasing medication nonadherence, and addressing cardiovascular comorbidities (such as hypertension, hyperlipidemia, and hyperglycemia) should help to minimize graft failure and improve long-term outcomes.