Abstract

Currently, the primary question facing renal transplantation is how to prolong renal allograft survival. Given the need to balance immunosuppressive requirements and potential drug toxicities, the optimal long-term therapeutic strategy remains uncertain. It is also unclear whether mTOR inhibitors offer unique advantages in maintaining normal allograft structure and function. Methods: In this prospective study, we examined the clinical and histological consequences of converting 63 low-risk adult renal transplant recipients (RTR). Those without subclinical rejection at 3 mos were converted to either low-dose tacrolimus (LoTAC) (4-6 ng/ml) or sirolimus (SLR) (5-10 ng/ml). Demographics for both groups were similar except that the LoTAC group had more ECD transplants (23% vs. 4%, p=0.05) and diabetic RTR (58% vs. 28%, p=0.02). Protocol biopsies were performed at implantation, 3 and 12 mos. All RTR received rabbit anti-thymocyte globulin induction therapy (3-5 mg/kg/total dose) along with standard dose TAC (levels 10-15 ng/ml), EC-MPS (Myfortic) and low-dose prednisone. Results: Seven patients were not randomized due to subclinical rejection present in the 3 mo. biopsy (Gr.1A n=1, Borderline, n= 6) leaving 26 randomized to SLR and 31 to LoTAC. Eight RTR in the SLR group were withdrawn due to adverse events including 1 AHR, 1 ACR, 3 infections, 1 hyperlipidemia and 2 proteinuria, but none had graft loss. Only 2 RTR in the LoTAC arm were withdrawn due to graft loss from BK and non-compliance (p=0.03). EC-MPS dose reductions occurred only in the SRL arm due to infections. Renal function (eGFR ml/min) was equal in the remaining LoTAC and SRL treated RTR (75±14 vs. 65±16 at 1 yr. and 68±17 vs. 67±18 at 2 yrs. respectively). Both groups exhibited equivalent increases in average IF/TA indices (LoTAC 0.09 - 0.58; SRL 0.01 - 0.86) and overall CADI scores (LoTAC 1.1 - 2.16; SRL 1.0 - 2.0) between the 3 and 12 mo. biopsies respectively. Three LoTAC and 4 SRL RTR had subclinical rejection in the 12 mo. biopsy. Conclusion: When combined with EC-MPS and steroids, early conversion to Lo-TAC is better tolerated with equivalent graft function and histology compared to SLR. Protocol biopsies are invaluable for risk assessment when altering or decreasing immunosuppressive therapy.

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