Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine.
BACKGROUND
Progressive nephrotoxicity caused by calcineurin inhibitor drugs contributes to the long-term decline in renal function in kidney transplant patients.


METHODS
We conducted a randomized, prospective trial of calcineurin inhibitor drug avoidance in 61 adult primary kidney transplant recipients. Each patient received induction therapy with 20 mg basiliximab on days 0 and 4, and maintenance therapy with mycophenolate mofetil 1 g two times per day and steroids. Thirty-one patients received sirolimus, 5 mg daily after a 15-mg loading dose. Doses were then concentration-controlled to keep 24-hr trough levels at 10 to 12 ng/mL for 6 months and 5 to 10 ng/mL thereafter. Thirty patients began cyclosporine therapy at 6 to 8 mg/kg per day in divided doses and were then concentration-controlled to keep 12-hr troughs of 200 to 250 ng/mL.


RESULTS
Mean follow-up is 18.1 months (range, 12-26 months). The percentages of 1-year patient survival, graft survival, and biopsy-confirmed acute rejection rates were not significantly different between the sirolimus-treated patients (96.7%, 96.7%, and 6.4%, respectively) and the cyclosporine-treated patients (100%, 95.4%, and 16.6%, respectively). At 6 and 12 months, respectively, the sirolimus-treated patients enjoyed significantly better (P=0.008 and P=0.004) mean serum creatinine levels (1.29 and 1.32 mg/dL) and calculated creatinine clearances (77.8 and 81.1 mL/min) than cyclosporine-treated patients (1.74 and 1.78 mg/dL, and 64.1 and 61.1 mL/min, respectively). Sirolimus-treated recipients have significantly (P=0.001) higher 1-year trough levels of mycophenolic acid (4.16 ng/mL) than cyclosporine-treated patients (1.93 ng/mL). Sirolimus also delays the repopulation of basiliximab-depleted CD25 T cells compared with cyclosporine.


CONCLUSIONS
Calcineurin inhibitor drug avoidance with basiliximab induction and sirolimus provides comparable 1-year transplant outcomes, with significantly better renal function in primary renal allograft recipients.
Flechner
Stuart M
SM
Urological Institute and Transplant Center A110, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. flechns@ccf.org.
Goldfarb
David
D
Modlin
Charles
C
Feng
Jingyuan
J
Krishnamurthi
Venkatesh
V
Mastroianni
Barbara
B
Savas
Kathy
K
Cook
Daniel J
DJ
Novick
Andrew C
AC
D000293:Adolescent; D000328:Adult; D000368:Aged; D016516:CD4-CD8 Ratio; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy / Q000201:enzymology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000502:physiology; D007676:Kidney Failure, Chronic / Q000201:enzymology / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011183:Postoperative Complications; D011446:Prospective Studies; D020123:Sirolimus / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D020123:Sirolimus