Study 1: an open-label pilot study evaluating the safety and efficacy of converting from calcineurin inhibitors to sirolimus in renal allograft recipients on a regimen of maintenance therapy with moderate renal insufficiency

T he purpose of this study was to determine the safety and efficacy of converting from a calcineurin inhibitor–based to a sirolimus (SRL)–based regimen in established renal transplant recipients who had moderate renal insufficiency. Patients enrolled in the study included 60 renal transplant recipients who were previously treated for a minimum of 3 months with calcineurin inhibitors and who had evidence of moderate renal insufficiency (serum creatinine level of 1.8-3.0 mg/dL and glomerular filtration rate between 30 and 60 mL/ min). SRL therapy was initiated with a loading dose on day 1, and the dose was adjusted to maintain a whole-blood trough concentration of 10 to 20 ng/mL thereafter. The dose of the calcineurin inhibitor was decreased by 50% on day 2 and discontinued when SRL trough concentration was 5 ng/mL. Concomitant therapy with mycophenolate mofetil (MMF) or azathioprine (AZA) and prednisone was continued. The primary efficacy end point included the incidence of biopsy-confirmed acute rejection after conversion. Secondary efficacy end points included patient survival, graft survival, and graft function. Sixty patients (67% male, 27% African American, 57% cadaveric recipients, mean age 45 years) were enrolled. SRL therapy was initiated at a mean of 61 months (range, 7-198 months) after transplantation. The incidence of acute rejection at 12 months after conversion was 3.3%. Patient survival and graft survival were 96.7%. The following values are reported as mean SEM. Trends toward improvement were noted in both mean serum creatinine level (baseline, 2.0 0.06 mg/dL; final, 1.97 0.13 mg/dL) and calculated creatinine clearance (baseline, 51.6 1.8mL/min; final, 54.2 2.31 mL/min). Mean SRL trough concentration was 10 ng/mL in patients with MMF or AZA and 11.7 ng/mL in patients without MMF or AZA. Preconversion and postconversion lipid (in milligrams per deciliter) values were as follows: total cholesterol, 186 4.2 and 208 7.3 (P .05); triglycerides, 177 13.2 and 203 17.7 (P .05), low-density lipoprotein 100 3.1 and 119 6.2 (P .01); high-density lipoprotein, 46 1.9 and 50 2.7 (P .05). After conversion, lipid-lowering therapy was instituted in 21% of patients who had not previously required therapy. Thirteen patients (21.7%) discontinued the study, with the incidence of one or more adverse events being the most commonly cited reason. The most frequently reported adverse events were hyperlipidemia (55%), diarrhea (37%), peripheral edema (35%), rash (31.7%), and anemia (26.7%). Three malignancies (2 skin, 1 renal cell) were reported at days 38, 21, and 82, respectively. Conclusion: At this 12-month interim analysis, conversion of renal transplant recipients with moderate renal insufficiency from a calcineurin inhibitor–based to an SRL-based regimen appears safe, without a significantly increased risk of acute rejection, and results in a trend toward improved renal function. From the Department of Nephrology, University of Cincinnati Medical Center, Cincinnati, OH; and Department of Nephrology, Columbia Presbyterian Medical Center, New York, NY. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.026