30-Year Retrospective on Organ Transplant Immunosuppression in the

Document Sample
30-Year Retrospective on Organ Transplant Immunosuppression in the Powered By Docstoc
					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
   Early Clinical Trial Demonstrating Improved 1-Year
   Allograft Survival in Cyclosporine-Treated
   Deceased-Donor Kidney Transplant Recipients




Data from Starzl TE, et al. Surg Gynecol Obstet. 1981;153:486-494.
   5-Year Comparison of Tacrolimus With
   Cyclosporine in Kidney Transplantation

                                                         The Kaplan-Meier
                                                         estimates of 5-year patient
                                                         and allograft survival rates
                                                         were equivalent
                                                         in the tacrolimus and
                                                         cyclosporine treatment
                                                         arms.




Data from Vincenti F, et al. Transplantation. 2002;73:775-782.
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




Organ Procurement Transplantation Network/Scientific Registry of
Transplant Recipients. OPTN/SRTR Annual Report.
   Daclizumab vs Placebo




Data from Nashan B, et al. Transplantation. 1999;67:110-115.
   Cox Model Hazard Estimates of Relative Risk
   for Overall Allograft Loss by Donor Type




Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:378-383.
   Overall Unadjusted Graft Survival Rates by
   Renal Functiona Status After Acute Rejection




aEstimatedglomerular filtration rate
Data from Meier-Kriesche HU, et al. Am J Transplant. 2004;4:378-383.
   Survival Trends in Long-term Primary
   Deceased-Donor Kidney Transplants




Data from Gjertson DW. Clin Transpl. 1991:225-235.
   Overall Allograft Survival in Primary
   Deceased-Donor Kidney Transplants




Data from Meier-Kriesche H-U, et al. Am J Transplant. 2004;4:1289-1295.
   Overall Allograft Survival Rates by Discharge
   Immunosuppressive Regimen for Deceased-Donor
   Kidney Transplants




Data from Srinivas TR, et al. Am J Transplant. 2007;7:586-594.
   Early Cyclosporine Withdrawal From a
   Sirolimus-Based Regimen




Data from Oberbauer R, et al. Transpl Int. 2005;18:22-28.
   SYMPHONY Study: Reduced Exposure to
   Calcineurin Inhibitors in Kidney Transplantation




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;357:2562-2575.
   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.
   Spare-the-Nephron Trial Results*

        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
    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.
   CONCEPT Study

        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.
   CONVERT Trial Resultsa

        Aim: Evaluate the efficacy and safety of converting
        maintenance
              Endpoint                Group A         Group B        P value
              GFR (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/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;87:233-242.
   CAESAR Trial Results

         Aim: Evaluate CNI withdrawal under MMF-based
         immunosuppression

  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
                                             49.6   49.0    45.4      NS
  (mL/min/1.73 m2)
  Serum creatinine at 12 mo                  1.7    1.5     1.6       NS
                                                                   P = .027a
  BPAR (%) at 12 mo                           38    25.4    27.5
                                                                   P = .040b


aGroup A vs Group B
bGroup A vs Group C

Ekberg H, et al. Am J Transplant. 2007;7:560-570.
   Low-Dose Steroid Therapy: The Canadian
   Multicentre Transplant Study Group




Data from Sinclair NR. CMAJ. 1992;147:645-657.
   Chronic Low-Dose Steroid Therapy




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

        Aim: Demonstrate noninferiority of 12-month GFR in the
        steroid-free or steroid-withdrawal groups vs standard steroids


    Endpoint                              Group A Group B Group C P value
    GFR (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




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




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

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:47
posted:11/23/2011
language:English
pages:24