Long-Term Benefits with Sirolimus-Based Therapy after Early Cyclosporine Withdrawal

Abstract

Abstract. Graft function at 6 or 12 mo is positively correlated with renal transplant survival. The 36-mo results of a study that tested whether withdrawing cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would affect renal graft survival are reported. Eligible patients (n ϭ 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group). At 36 mo, the calculated GFR was significantly better with SRL-ST (47.3 versus 59.4 ml/min; P Ͻ 0.001) as was the slope of the GFR (Ϫ3.6 versus 0.8 ml/min; P Ͻ 0.001). This was accompanied by growing trend for improved graft survival in the SRL-ST group (85.1% versus 91.2%, P ϭ 0.052 at 36 mo; 81.4% versus 91.2%, P ϭ 0.015 in a cumulative data analysis up to 54 mo), despite numerically more biopsy-proven acute rejections after randomization (5.6% versus 10.2%; P ϭ 0.107). Lipid parameters were similar between groups, whereas both systolic and diastolic BP were significantly lower in the SRL-ST group. Investigator-reported hypertension, abnormal kidney function, edema, hyperuricemia, hyperkalemia, gingival hyperplasia, and Herpes zoster occurred significantly more often in SRL-CsA-ST patients. Abnormal liver function test results, hypokalemia, thrombocytopenia, and abnormal healing were reported significantly more often with SRL-ST. The discontinuation rate was significantly higher for SRLCsA-ST (48% versus 38%; P ϭ 0.041). In conclusion, withdrawing CsA from a SRL-CsA-ST regimen at 3 mo after transplantation resulted in long-term benefits for renal transplant recipients.Multiple risk factors, including donor origin and age, acute rejection, human leukocyte antigen (HLA) mismatches, ethnic origin, and diabetes, influence long-term graft survival in renal transplantation. The calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are immunosuppressive agents that have been associated with a reduced incidence of acute rejection and improved graft survival during the first year (1). CNI, however, increase BP, decrease GFR, and contribute to chronic allograft nephropathy. Studies have shown that renal function (2, 3) and BP control (4) are important predictors of graft survival. Therefore, an intervention to improve renal function and BP control by eliminating CNI-related toxicity may result in an improvement in graft survival.

Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation

“…As we have described in the initial (12) and subsequent reports (13)(14)(15)(16), this study has shown that early CsA withdrawal has resulted in lower BP, better renal function, and improved graft survival along with improved graft structure and better quality-of-life indices. We report the 5-yr malignancy data from this study and place these findings in perspective with regard to the problem of malignancy in transplant recipients.…”

“…A total of 94.5% of the recipients were of white ethnic origin, reflecting the ethnic composition of countries in which the trial was conducted. On the basis of the month 36 and cumulative data available at that time (13), the protocol was amended to discontinue protocol-assigned treatment in the SRL-CsA-ST group. This amendment began affecting the discontinuation rate beginning at the month 48 visit.…”

Therapeutic targets: MTOR and related pathways

“…62 In addition, sirolimus appears to be associated with a lower risk of developing and successful treatment of post-transplant malignancies including PTLD, skin carcinomas and Karposi's sarcoma. [63][64][65][66][67][68] These results suggest that sirolimus may minimize the risk of developing post-transplant malignancies while maintaining organ transplant viability and may be used to continue immunosuppression and inhibit malignancies recurrence in successfully treated patients.…”

Long-term Medical Management of the Liver Transplant Recipient: What the Primary Care Physician Needs to Know

“…Options include reduction in corticosteroids, 17 substituting tacrolimus for cyclosporine, 18 reducing CNI doses by adding mycophenolate mofetil (MMF), 19 or converting to sirolimus-based immunosuppression. 20 These decisions should be made with the transplant hepatologist involved.…”

“…33 In cases of diabetes that is poorly controlled despite aggressive medical management, the transplant hepatologist may consider withdrawing corticosteroids or possibly adding MMF to reduce CNI or mTOR inhibitor doses. 20 Switching from tacrolimus to cyclosporine has not been reliably effective in reducing glucose levels and has the cost of worse hypertension and dyslipidemia. 18,34 Dyslipidemia Dyslipidemia is unusual in patients with cirrhosis, which usually results in marked decline in cholesterol levels due to impaired hepatic synthesis.…”