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Benefits and Risks of Introduction of Everolimus in Long-Term Kidney Transplant Recipients

Asai, Toshihiro1; Tanaka, Hisao1; Nishikawa, Noriaki1; Hasaka, Tomohiro1; Kitamoto, Koichiro1; Ishii, Keiichi1; Kamikawa, Sadanori1; Sugimoto, Toshikado1; Kim, Taku2; Kumada, Norihiko3

doi: 10.1097/

1Urology, Osaka City General Hospital, Osaka, Japan; 2Kidney Transplant and Dialysis, Osaka City General Hospital, Osaka, Japan; 3Urology, Suita Municipal Hospital, Suita, Japan.

Background: The progression of calcineurin inhibitor (CNI) nephrotoxicity is ameliorated if CNI is withdrawn during the first 6 months posttransplant. However, it has been reported that introducing everolimus (EVR) with CNI minimization in longer term kidney transplant recipients showed no beneficial effect on renal function in ASCERTAIN study. Therefore, the literature on late phase CNI minimization, not elimination with EVR is very scant.

Methods: To investigate benefits and risks of late introduction of EVR, 22 maintenance renal transplant recipients were enrolled. Exclusion criteria were biopsy-proven acute rejection (BPAR), presence of HLA antibodies, proteinuria >1 g/gCre, focal segmental glomerulosclerosis. The initial immunosuppressive regimen combined steroid, CNI and MMF. EVR was converted from MMF thereafter (triple maintenance immunosuppression). On the day of conversion, patients received 50% reduced MMF dose with EVR (0.25 mg TID). On day 7, they were given no MMF with EVR (0.75 mg BID), after which the dose was adjusted to a target trough level of 3 to 6 ng/ml. Dose of CNI was decreased to 50-60%. The median time from transplantation to EVR introduction with CNI minimization was 62 (6–230) months. The reasons for EVR use were nephrotoxicity (n = 14), neoplasms (n = 5), infection (n = 2), and cardiovascular disease in one patient.

Results: Seven patients discontinued EVR due to adverse events: overt proteinuria in 4 patients, increased serum creatininine in 3 patients. Out of these 7 patients, 3 patients also developed BPAR, thrombocytopenia and death with functioning graft, leaving 15 patients for analysis. At month 12, eGFR was significantly increased from baseline (38.8 ± 17.2 ml/min/1.73m2) to 42.3 ± 18.4 ml/min/1.73m2 (p=0.0025). On the other hand, urinary protein was increased from 0.25 ± 0.27 g/gCr at baseline to 0.45 ± 0.44 g/gCr at month12.

Conclusions: In maintenance renal transplant recipients with high-grade proteinuria, graft function may deteriorate by introducing EVR. The cut-off point of urinary protein for safety use of EVR has not yet been determined. Our study showed that some patients may, however, benefit from EVR use even at a late stage posttransplant.

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