30-Year Retrospective on Organ Transplant Immunosuppression in the Era of Calcineurin Inhibitors

Herwig-Ulf Meier-Kriesche, MDProfessor of MedicineDepartment of NephrologyUniversity of Florida College of MedicineDirector of Kidney Transplant ProgramDepartment of Transplant Nephrology, Shands University of FloridaGainesville, Florida

Sundus Lodhi, MDClinical FellowDivision of Nephrology, Hypertension and TransplantationUniversity of FloridaGainesville, Florida

Data from Starzl TE, et al. Surg Gynecol Obstet. 1981;153:486-494.

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;73:775-782.

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.

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;67:110-115.

Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:378-383.

Cox Model Hazard Estimates of Relative Risk for Overall Allograft Loss by Donor Type

Overall Unadjusted Graft Survival Rates by Renal Functiona Status After Acute Rejection

aEstimated glomerular filtration rateData from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:378-383.

Data from Gjertson DW. Clin Transpl. 1991:225-235.

Survival Trends in Long-term Primary Deceased-Donor Kidney Transplants

Data from Meier-Kriesche H-U, et al. Am J Transplant. 2004;4:1289-1295.

Overall Allograft Survival in Primary Deceased-Donor Kidney Transplants

Data from Srinivas TR, et al. Am J Transplant. 2007;7:586-594.

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) SYMPHONYThe 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;357:2562-2575.

SYMPHONY Study: Reduced Exposure to Calcineurin Inhibitors in Kidney Transplantation

SYMPHONY Study Results

Endpoint Group A Group B Group C Group D P value

eGFR (mL/min) at 12 mo 57.1 59.4 65.4 56.7 P < .001

BPAR (%) 25.8 24.0 12.3 37.2 P < .001

Allograft survival (%) 89.3 93.1 94.2 89.3 P = .02

BPAR = biopsy-proven acute rejection

Ekberg H, et al. N Engl J Med. 2007;357:2562-2575.

Endpoints Group A Group B P value

BPAR (%) 6.5 7.1 ND

Allograft loss (%) 1.6 2.4 ND

Death (%) 0 2.4 ND

Change in GFR (%) 25.8 11.3 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

Endpoints Group A Group B P value

eGFR (mL/min) 64.4 68.9 P = .017

BPAR 8.2 16.8 NS

Lebranchu Y, et al. Am J Transplant. 2009;9:1115-1123.

CONCEPT Study

Endpoint Group A Group B P valueGFR (mL/min) 59.9 62.6 P = .009

BPARb 1.6 2.6 NS

Allograft survivalb 98 96.8 NS

Patient survivalb 99.2 97.8 NS

aOn-therapy patients with baseline GFR > 40 mL/minb% of patients who met composite and individual safety endpoints at 12 months after randomizationNote: 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;87:233-242.

Aim: Evaluate the efficacy and safety of converting maintenance

CONVERT Trial Resultsa

Endpoints Group A Group B Group C P value

Mean eGFR (mL/min/1.73 m2) 50.9 50.9 48.6 NS

Measured GFR at 3 mo(mL/min/1.73 m2) 49.6 49.0 45.4 NS

Serum creatinine at 12 mo 1.7 1.5 1.6 NS

BPAR (%) at 12 mo 38 25.4 27.5 P = .027a

P = .040b

aGroup A vs Group BbGroup A vs Group CEkberg H, et al. Am J Transplant. 2007;7:560-570.

Aim: Evaluate CNI withdrawal under MMF-based immunosuppression

CAESAR Trial Results

Data from Sinclair NR. CMAJ. 1992;147:645-657.

Low-Dose Steroid Therapy: The Canadian Multicentre Transplant Study Group

Data from Woodle ES, et al. Ann Surg. 2008;248:564-577.

Chronic Low-Dose Steroid Therapy

FREEDOM Study Results

Endpoint Group A Group B Group C P valueGFR (mL/min/1.73 m2) 58.6 59.1 60.8 NS

Composite endpoint at 3 mo 27.9 -- 11.0 P = .032

BPAR at 3 mo 25.2 18.3 7.3 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;8:307-316.

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;10:535-546.

Data from Busque S, et al. Am J Transplant. 2009;9:1936-1945.

Emerging Therapy − CP-690,550 in Kidney Allograft Recipients