Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study.

INTRODUCTION: The purpose of this study was to evaluate early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen. METHODS: Within 48 hr after transplantation, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of SRL (troughs >5 ng/mL; immunoassay), CsA, and ST. Those eligible (430) were randomly assigned (1:1) at 3 months +/- 2 weeks to remain on triple-drug therapy (SRL-CsA-ST group) or to have CsA withdrawn and SRL trough concentrations targeted to 20 to 30 ng/mL (SRL-ST group) until month 12, and 15 to 25 ng/mL thereafter. RESULTS: At 24 months, there were no statistically significant differences in patient survival (94.0% vs. 95.3%), graft survival (91.2% vs. 93.5%), acute rejection after randomization (5.1% vs. 9.8%) or discontinuations (34% vs. 33%) for SRL-CsA-ST versus SRL-ST, respectively. Serum creatinine level was significantly better in patients who had CsA withdrawn (167 vs. 128 micromol/L, P<0.001), as was the slope of 1/creatinine. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn (141 vs. 134 mm Hg, P<0.001). High-density lipoprotein cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. Hypertension, creatinine increase, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, cataracts, Herpes zoster, and malignancy were reported significantly more often in patients continuing CsA. Thrombocytopenia, hypokalemia, abnormal liver function tests, abnormal wound healing, ileus, and pneumonia were reported significantly more frequently with SRL-ST. CONCLUSION: Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.

Posttransplantation production of donor HLA-specific antibodies as a predictor of renal transplant outcome.

BACKGROUND: This study aimed to determine whether the production, in renal transplant recipients, of antibodies directed against donor HLA mismatches is predictive of transplant failure. METHODS: The failure study group comprised 112 adult recipients of primary renal transplants who had re-entered the transplant waiting list after failure of the first graft. A control group of 123 recipients with functioning transplants was selected from transplantations performed during the same time period, in which patients had equivalent HLA matching and immunosuppression and a minimum of 5 years of follow-up. Sera taken before transplantation and at 1, 3, and 6 months and annually after transplantation were tested by enzyme-linked immunoabsorbent assay (ELISA) for the presence of HLA class I- and class II-specific antibodies. Antibody specificity was defined by a combination of cytotoxicity, ELISA, and flow cytometry techniques to determine whether the antibodies were directed against donor mismatches. RESULTS: All recipients were negative for donor HLA-specific antibodies before transplantation. After transplantation, 57 (50.9%) of the 112 patients in the failure group produced donor HLA-specific antibodies compared with 2 (1.6%) of the 123 controls (P<0.0001; odds ratio [OR]=64.98; confidence interval [CI], 14.78-399.51). For 60% of the donor-specific antibody-positive patients, antibodies were detected before transplant failure. In 17 cases, these were class I specific; in 14 cases, class II specific; and in 3 cases, specific for both class I and II. CONCLUSIONS: This study has demonstrated that the production of posttransplantation antibodies directed against donor HLA-A, -B, -Cw, -DR, and -DQ mismatches are all strongly predictive of transplant failure.

Sirolimus (Rapamune) in renal transplantation.

There has been a necessary change in attitude to transplantation; there is much less concern with short-term outcome and more concern with long-term kidney function, overall health and quality of life. Nephrotoxicity is an invariable consequence of long-term treatment with calcineurin antagonists and it is one of the most underestimated causes of late graft loss; it has been reported as a serious threat to both patient and graft survival following heart, liver and bone marrow transplantation. Sirolimus has been shown in many recent studies to be of great value in allowing patients to be weaned from cyclosporine with excellent patient and graft survival at 24 months a significant improvement in renal function with resolution of hirsutism and gum hyperplasia. Patients maintained on the combined regime of cyclosporine and sirolimus had significantly higher blood pressure, much more cyclosporine nephrotoxicity and hyperuricaemia at 12 months. The experimental studies have found cyclosporine and sirolimus potentiate with each other's good and adverse effects. Cyclosporine therefore augments hyperlipidaemia caused by sirolimus, and sirolimus augments nephrotoxicity caused by cyclosporine. The results of these studies indicate that sirolimus is a suitable replacement for cyclosporine or tacrolimus for long-term maintenance therapy. By contrast the use of sirolimus in combination with cyclosporine results in potentiation of side effects. The principal disadvantages being increased cyclosporine associated nephrotoxicity and sirolimus associated hyperlipidaemia