June 5, 2008 (Toronto) — Data presented here at the American Transplant Congress suggest that renal function is preserved in patients who are on a regimen of mycophenolate mofetil (MMF) with sirolimus (SRL) after kidney transplantation.

In an effort to explore the effect of avoiding the use of calcineurin inhibitors post-transplantation, investigators of the Spare-the-Nephron trial compared the efficacy and tolerability of 2 immunosuppressive regimens in an open-label, prospective multicenter design. One regimen consisted of MMF and SLR, and the other regimen consisted of a calcineurin inhibitor (CNI), either cyclosporine or tacrolimus (TAC), with MMF.

All participants were first treated with a combination therapy consisting of MMF and CNIs. Each of the 32 participating study sites in the trial put in place their own practice of antibody induction and/or administration of steroids.

Patients were not included in the trial if they had more than 1 biopsy-proven acute rejection at study entry, had total cholesterol levels of 300 mg/dL, or had greater or total triglyceride levels of 350 mg/dL or more. Patients who had serum creatinine (SCr) of 2.5 mg/dL or creatinine clearance (CrCl) of 30 mL/minute or less at study entry were also excluded.

Subjects were randomly assigned after 30 to 180 days subsequent to receiving their new kidney to either continuing the MMF/CNI regimen or switching their CNI therapy to SRL therapy. The mean time in both groups from transplantation to randomization was 117 days. The subjects were administered 1 to 1.5 g of MMF twice daily, along with 2 to 10 mg of SRL as a loading dose; subjects were maintained at trough levels of 5 ng/mL to 10 ng/mL.

Investigators employed multiple renal endpoints including mean percentage change in glomerular filtration rate (GFR) at 12 months' follow-up, mean percentage change in calculated GFR, mean percentage change in SCr, and mean calculated CrCl at 12 and 24 months. The researchers also measured biopsy-confirmed acute rejection, treatment failure, and safety.

A total of 148 patients were gradually withdrawn from CNI therapy after transplantation, whereas 150 continued to receive CNI therapy, with 119 of those (81%) receiving TAC (MMF/TAC).

Investigators found no statistically significant difference between the 2 groups in the measurement of mean percentage change in GFR (27.9% for the MMF/SRL group and 11.0% for the MMF/CNI group; P = .052). In looking at the 91 patients who received TAC, the researchers did conclude there was a statistically significant difference in the mean percentage change in GFR between the MMF/SRL group and the MMF/TAC subset (27.9% vs 6.1%; P = .0247).

Similarly, the mean percentage change in calculated GFR from baseline to month 12 was 7.4% for the MMF/SRL group, 1.3% for the MMF/CNI group, and −0.1% for the MMF/TAC subset, with a statistically significant difference between the MMF/SRL and MMF/CNI groups (P = .027). Patients receiving SRL demonstrated statistically significant greater changes in SCr from baseline compared with patients receiving TAC or cyclosporine, suggesting better kidney function (−2.0% MMF/SRL, 6.4% MMF/CNI, and 8.1% MMF/TAC; P = .004).

Patients receiving MMF/SRL experienced a mean 6% change from baseline in their calculated CrCl, whereas patients receiving MMF/CNI had a −0.7% change in their calculated CrCl level, and the MMF/TAC patients had a −1.9% change in their CrCl level from baseline to month 12, with a statistically significant difference between the MMF/SRL and MMF/CNI groups (P = .018).

"After 12 months of therapy, maintenance immunosuppression with MMF/SRL after CNI withdrawal appears to preserve renal function when compared with a MMF/CNI-containing regimen," writes Shamkant Mulgaonkar, MD, FASN, a nephrologist and chief of the renal and pancreas transplant division, St. Barnabas Medical Center in Livingston, New Jersey, and colleagues in their abstract.

Ron Shapiro, MD, professor of surgery in the Division of Transplantation, University of Pittsburgh School of Medicine, and director of Renal Pancreas and Islet Transplantation at the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh Medical Center, Pennsylvania, described the results as hopeful.

"It's a very positive finding and [is] encouraging that the renal function improved in patients who were converted to MMF and SRL and taken off a CNI," Dr. Shapiro told Medscape Transplantation, commenting on the research. "It would be nice to see how long the improvement in renal function continues."

Dr. Shapiro estimated that about 80% of kidney transplant patients are being administered TAC.

The study was funded by Roche. Dr. Mulgaonkar has received grant funding from Roche. Dr. Shapiro is a member of the data monitoring committee for Bristol-Myers Squibb.

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