A CONCENTRATION-CONTROLLED REGIMEN OF HIGH SIROLIMUS EXPOSURE SUPPORTS FUNCTIONAL RECOVERY OF HUMAN RENAL ALLOGRAFTS FROM DECEASED DONORS

Abstract

O83 Aim: To assess the benefit of a concentration-controlled strategy of de novo sirolimus (SRL) administration, the evolution of renal function among a cohort of deceased donor kidneys at high risk for delayed graft function (DGF) was compared with the outcomes in the Scientific Registry of Transplant Recipients (SRTR). Methods: Between 3/22/1999 and 12/31/2001, 200 local recipients (Group I) were deemed to be at high risk for DGF, due to use of extended donors (n=197) or high PRA/presensitization (n=3). In addition to SRL (target C0=10-20ng/mL), induction therapy included steroids plus either basiliximab (20mgx2; low immune responder: primary graft in Caucasian/Hispanic; n=141 [70%]) or rabbit antihuman thymocyte globulin (1.5mg/kg/dx7; high responder: African American, re-transplant, >50% PRA; n=59 [30%]). When the serum creatinine (Scr) fell to 2.5mg/dL, cyclosporine (CsA; 1.5mg/kg/d) was initiated and adjusted to C2=200ng/mL for low- or 400ng/mL for high-risk patients. CsA exposure was tapered based upon renal function. The 12-mo evolutions of Scr and glomerular filtration rate (GFR; MDRD calculation) among Group I patients were compared with contemporaneous cohorts in the SRTR, who had been induced with (Group IIA; n=2674 including 15% expanded donors and 11.4% African Americans) or without (Group IIB; n=2752 including 13.9% expanded donors and 10.3% African Americans) SRL. SRTR groups were matched within centers by age and year of transplant, excluding centers not using SRL. Differences were evaluated for statistical significance by chi-square tests. Logistic regression models were used to assess the impact of drug concentrations on GFR. Results: Group I patients displayed superior function to Group IIA and equal to group IIB patients. The incidences of Scr <1.5mg/dL at 12 mo were 63.3 vs 52.8 (p=0.01) vs 61.8 (p=NS); of GFR >70mL/min, 25.2 vs 19.8 vs 21.9, and of GFR >55mL/min, 54.5 vs 42.5 vs 47.2, respectively. These results were observed despite Group I patients showing demographic features that forecast poorer allograft function—a higher incidence of DGF (44.9 vs 31.7; p=0.002 or 23.7; p<0.0001), older age, higher body mass index, and longer time on dialysis. Also, among Group I patients the frequencies of Scr <1.5mg/dL and GFR >55mL/min were similar at 1 and 12 mo; namely, 60.3 vs 63.3 and 51.8 vs 54.5, respectively. A high % coefficient of variation (%CV) of SRL C0 (>30%) produced no detriment in GFR values. Logistic models revealed a positive impact of increasing SRL concentrations (odds ratio [OR])=1.31 per ng/mL SRL C0 (p=0.003) on the odds of GFR >40 at 1 mo. An OR of 3.09 for GFR >40 at 1 mo was determined for patients with mean SRL concentrations ≥16ng/mL (p=0.02). Logistic models revealed a significant interaction between mean SRL C0 and CsA average concentrations. Conclusion: Our single-center experience with tailored antibody induction and delayed introduction of markedly reduced CsA exposure demonstrates that high SRL concentrations are associated with increased GFRs among deceased donor kidneys at increased risk of DGF.