Promising results in a trial that avoids the use of calcineurin inhibitors.


SAN FRANCISCO—Pairing mycophenolate mofetil (MMF) with sirolimus instead of a calcineurin inhibitor (CNI) may provide superior renal benefits to kidney transplant patients, according to interim results from the Spare-the-Nephron trial.

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“Our goal is to determine the safest and most effective immunosuppressive therapy regimen that avoids the nephrotoxic effects of CNIs while preventing rejection,” said study investigator Matthew Weir, MD, professor and director of the division of nephrology at the University of Mary-land School of Medicine in Baltimore. “The preliminary study results are very encouraging.” He presented findings here at the 2007 World Transplant Congress.


In the two-year open-label, prospective, randomized, controlled multicenter study, patients maintained on MMF plus a CNI (either cyclosporine or tacrolimus, dosed according to center-specific target levels) were randomized 30-180 days after transplantation to either continue their current regimen or to receive MMF plus sirolimus (MMF/SRL). These patients received MMF at a dosage of 1-1.5 g/ twice a day and sirolimus at a dosage of 2-10 mg to achieve levels of 5-10 ng/mL (24-hour trough), followed by at least 2 mg/day. Antibody induction and/or corticosteroids were administered according to the practice at individual centers.


The efficacy end points for the trial are the proportions of patients with biopsy-proven acute rejection (BPAR), graft loss, and death. In addition, researchers are analyzing the percent of change in measured glomerular filtration rate (GFR). Of the 305 randomized patients, 208 have completed 12 months of follow-up (110 in the MMF/CNI group and 98 in the MMF/SRL group).


All baseline characteristics and measured GFR values were similar in both groups. Mean time post-transplantation to ran-domization was 115 days for the MMF/SRL group and 112 days the MMF/CNI group.


BPAR occurred in six (6.1%) of the 98 patients in the MMF/SRL group and eight (7.3%) of 110 patients in the MMF/CNI group. Graft loss occurred in two (2%) patients in the MMF/SRL group and four (3.6%) in the MMF/CNI group. No patients in the MMF/SRL have died versus two (1.8%) in the MMF/CNI group. Patients in the MMF/SRL group had a median 18.5% increase from baseline in GFR compared with a 4.4% decrease in the MMF/CNI group.


Researchers hope the Spare-the-Nephron trial will lead to the development of better immunosuppressant combination therapies that reduce or eliminate the need for CNIs, which are nephrotoxic, and steroids.


“We are trying to develop long-term immunosuppression strategies so that the kidneys will in a sense serve their owner for their life expectancy, rather than have them fail during a typical 12-, 13-, or 14-year period,” Dr. Weir said. “Then they have to re-enter the pool for new kidneys and obviously start to compete again with the people who have been on dialysis. This is about quality of life and the duration of life; that is really the critical issue.”