Triple Therapy in Cadaveric Renal Transplantation: Role of Induction Cyclosporine and Targeted Levels to Avoid Rejection

Abstract

The updated data on 61 consecutive cadaveric transplants performed at our institution from 1987 to 1990 (followup 31 to 82 months, median 54 months) were analyzed with emphasis on cyclosporine monitoring and long-term results. All patients received triple therapy with cyclosporine induction, azathioprine and prednisone regardless of graft function, and they were preferentially placed on the calcium blocker nifedipine. We monitored 12-hour cyclosporine trough levels in whole blood using high performance liquid chromatography and the dose was adjusted to maintain levels at 150 ng./ml. or greater for the first 3 months. In 17 of 61 patients (28%) 22 rejection episodes occurred and 20 nephrotoxicity episodes occurred in 17 of 61 patients (28%). There was no significant difference in the mean cyclosporine levels among 32 rejection, nonrejection, nephrotoxic and nonnephrotoxic cases at any interval. Rejection occurred by 1 month in 13 (76%) and by 3 months in 15 (88%) of 17 patients. Comparisons were made in the first month to define the desirable cyclosporine levels by calculating the mean cyclosporine only within 10 to 14 days of rejection or nephrotoxicity events. The mean cyclosporine level before rejection was significantly lower than that for nephrotoxicity (188 +/- 113 versus 304 +/- 62 ng./ml., p < 0.01). The median cyclosporine level for first month rejection was also significantly lower than that for nonrejection (156 versus 218 ng./ml., p < 0.05) and it was significantly greater for nephrotoxicity versus nonnephrotoxicity (272 versus 218 ng./ml., p < 0.05). Of 13 rejections in the first month 10 (77%) were associated with mean levels of less than 210 ng./ml. Actuarial graft survival at 1, 3 and 5 years was 93.4%, 87.8% and 78.5%, respectively. The 3-year graft survival was significantly worse for patients who experienced acute rejection episodes versus those who did not (68.8% versus 96.7%, p < 0.05) but it was not different for nephrotoxic versus nonnephrotoxic groups (85.6% versus 79.6%). Long-term function was not influenced by the occurrence of acute nephrotoxicity events. These findings confirm the efficacy of triple therapy with induction cyclosporine in cadaveric transplantation, yielding improved short-term and intermediate graft survival without any adverse effects on long-term graft function. Specific cyclosporine level monitoring is invaluable, particularly initially, with high target levels of 200 ng./ml. or greater. The use of calcium blockers may have allowed higher cyclosporine dosing in the first 3 months, mitigating against cyclosporine associated chronic nephrotoxicity.

Issues in Cyclosporine Drug Substitution: Implications for Patient Management

“…Several studies have demonstrated different therapeutic ranges for cyclosporine in which overexposure or underexposure has been correlated with poor transplant outcomes. [14][15][16][17][18][19] Going outside the therapeutic range for immunosuppressive drugs can lead to serious clinical consequences for the transplant recipient. Underexposure to cyclosporine or tacrolimus may contribute to an increased incidence of acute rejection and subsequent graft loss, whereas overexposure can result in nephrotoxicity, infections, and malignancies.…”