30-Year Retrospective on Organ Transplant Immunosuppression in the Era of Calcineurin Inhibitors Herwig-Ulf Meier-Kriesche, MD Professor of Medicine Department of Nephrology University of Florida College of Medicine Director of Kidney Transplant Program Department of Transplant Nephrology, Shands University of Florida Gainesville, Florida Sundus Lodhi, MD Clinical Fellow Division of Nephrology, Hypertension and Transplantation University of Florida Gainesville, Florida

Data from Starzl TE, et al. Surg Gynecol Obstet. 1981;153: Early Clinical Trial Demonstrating Improved 1-Year Allograft Survival in Cyclosporine-Treated Deceased-Donor Kidney Transplant Recipients

Data from Vincenti F, et al. Transplantation. 2002;73: The Kaplan-Meier estimates of 5-year patient and allograft survival rates were equivalent in the tacrolimus and cyclosporine treatment arms. 5-Year Comparison of Tacrolimus With Cyclosporine in Kidney Transplantation

Chronology of Approval of Maintenance and Induction Agents for Use in Solid Organ Transplantation

Trends in the Use of Approved Maintenance Immunosuppressive Agents in the Modern Era Organ Procurement Transplantation Network/Scientific Registry of Transplant Recipients. OPTN/SRTR Annual Report.

Trends in the Use of Approved Induction Agents in the Modern Era

Daclizumab vs Placebo Data from Nashan B, et al. Transplantation. 1999;67:

Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4: Cox Model Hazard Estimates of Relative Risk for Overall Allograft Loss by Donor Type

Overall Unadjusted Graft Survival Rates by Renal Function a Status After Acute Rejection a Estimated glomerular filtration rate Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:

Data from Gjertson DW. Clin Transpl. 1991: Survival Trends in Long-term Primary Deceased-Donor Kidney Transplants

Data from Meier-Kriesche H-U, et al. Am J Transplant. 2004;4: Overall Allograft Survival in Primary Deceased-Donor Kidney Transplants

Data from Srinivas TR, et al. Am J Transplant. 2007;7: Overall Allograft Survival Rates by Discharge Immunosuppressive Regimen for Deceased-Donor Kidney Transplants

Early Cyclosporine Withdrawal From a Sirolimus-Based Regimen Data from Oberbauer R, et al. Transpl Int. 2005;18:22-28.

SYMPHONY = Efficacy Limiting Toxicity Elimination (ELITE) SYMPHONY The dashed lines represent the upper and lower limits of the respective target trough levels. Data from Ekberg H, et al. N Engl J Med. 2007;357: SYMPHONY Study: Reduced Exposure to Calcineurin Inhibitors in Kidney Transplantation

SYMPHONY Study Results EndpointGroup AGroup BGroup CGroup DP value eGFR (mL/min) at 12 mo P <.001 BPAR (%) P <.001 Allograft survival (%) P =.02 BPAR = biopsy-proven acute rejection Ekberg H, et al. N Engl J Med. 2007;357:

EndpointsGroup AGroup BP value BPAR (%)6.57.1ND Allograft loss (%)1.62.4ND Death (%)02.4ND Change in GFR (%) ND ND = data not provided *The authors concluded that MMF/SRL maintenance therapy appears to be associated with improved renal function when compared with MMF/CNI-containing regimens without increasing the risk for acute rejection and is tolerated in almost 80% of patients. Pearson TC, et al. Am J Transplant. 2008;8(suppl 2):213. Aim: Evaluate the efficacy and safety of a maintenance immunosuppressive regimen of MMF and SRL compared with MMF and a CNI in kidney allograft recipients Spare-the-Nephron Trial Results*

Aim: Evaluate conversion from a CsA-based regimen to a SRL-based regimen 3 months after transplantation EndpointsGroup AGroup BP value eGFR (mL/min) P =.017 BPAR NS Lebranchu Y, et al. Am J Transplant. 2009;9: CONCEPT Study

EndpointGroup AGroup BP value GFR (mL/min) P =.009 BPAR b NS Allograft survival b NS Patient survival b NS a On-therapy patients with baseline GFR > 40 mL/min b % of patients who met composite and individual safety endpoints at 12 months after randomization Note: Enrollment in the 20- to 40-mL/min stratum was halted prematurely due to a higher incidence of safety endpoints in the SRL conversion arm. Schena FP, et al. Transplantation. 2009;87: Aim: Evaluate the efficacy and safety of converting maintenance CONVERT Trial Results a

EndpointsGroup AGroup BGroup CP value Mean eGFR (mL/min/1.73 m 2 ) NS Measured GFR at 3 mo (mL/min/1.73 m 2 ) NS Serum creatinine at 12 mo NS BPAR (%) at 12 mo P =.027 a P =.040 b a Group A vs Group B b Group A vs Group C Ekberg H, et al. Am J Transplant. 2007;7: Aim: Evaluate CNI withdrawal under MMF-based immunosuppression CAESAR Trial Results

Data from Sinclair NR. CMAJ. 1992;147: Low-Dose Steroid Therapy: The Canadian Multicentre Transplant Study Group

Data from Woodle ES, et al. Ann Surg. 2008;248: Chronic Low-Dose Steroid Therapy

FREEDOM Study Results EndpointGroup AGroup BGroup CP value GFR (mL/min/1.73 m 2 ) NS Composite endpoint at 3 mo P =.032 BPAR at 3 mo P =.017 Aim: Demonstrate noninferiority of 12-month GFR in the steroid-free or steroid-withdrawal groups vs standard steroids Vincenti F, et al. Am J Transplant. 2008;8:

Emerging Therapy − The BENEFIT Study: Belatacept-Based Immunosuppression Regimens vs Cyclosporine in Kidney Transplant Recipients Data from Vincenti F, et al. Am J Transplant. 2010;10:

Data from Busque S, et al. Am J Transplant. 2009;9: Emerging Therapy − CP-690,550 in Kidney Allograft Recipients