D. Lyubashevsky1, A. Shetty2, J. Leventhal2, M. J. Ansari2, V. Mas3, J. Matthew2, L. Gallon2 3Virginia Commonwealth University,Department Of Surgery,Richmond, VA, USA 1New York Medical College,Valhalla, NY, USA 2Northwestern University,Chicago, IL, USA
Introduction:
Calcineurin inhibitors (CNIs) such as Tacrolimus (FK) are considered mainstay of immunosuppression (IS) after kidney transplantation. However, CNIs are also known to have nephrotoxic properties: potent renal vasoconstriction can lead to irreversible and progressive tubulo-interstitial injury and glomerulosclerosis. One approach to circumvent this problem, is CNI minimization or ‘sparing’ by substitution or addition of a non-CNI immunosuppressive agent like mycophenolate mofetil (MMF) or a mammalian Target of Rapamycin inhibitor (mTORi). We hypothesize that combining low dose FK with the mTORi Everolimus may improve renal allograft outcomes, namely allograft survival and estimated GFR (eGFR).
Methods:
40 adult kidney transplant recipients were randomized at time of transplant to 2 groups: Low-dose FK with Everolimus, and standard dose FK with MMF. All patients received Alemtuzumab (Campath) induction and rapid steroid elimination. Everolimus levels were maintained between 3-8 ng/ml. Blood samples were taken at time of transplant, 3, 6, 12, 18, and 24 months post-randomization to record estimated GFR (eGFR) and serum drug concentration. Kidney biopsy data was gathered at transplant, 3, 12 and 24 months post. Primary outcomes were rejection-free graft survival and eGFR.
Results:
Mean follow-up time was similar between groups: 26 ± 8.5 months for FK/Everolimus, and 26 ± 10.9 for FK/MMF (p = 0.975). Baseline characteristics such as demographics, HLA match, and time on dialysis were statistically similar between the two groups. FK levels in the FK/Everolimus group (4.2 ± 1.56 ng/mL) were significantly lower (p=0.003) than in the FK/MMF group (6.45 ± 1.96 ng/mL). The FK/Everolimus group experienced 1 episode of acute rejection compared to 4 episodes in the FK/MMF group: Using Cox-proportional hazards survival analysis, rejection-free graft survival (Fig 1A) was statistically similar between groups. eGFRs (FK/Everolimus = 61.535 ± 3.44 mL/min/1.73 m2; FK/MMF = 59.03 ± 3.24 mL/min/1.73 m2) were statistically similar between groups (Fig 1B); as were adverse events, including proteinuria, infectious events and death.
Conclusion:
A combination of low dose FK with Everolimus may be an alternative immunosuppressive strategy to the standard of care FK+ MMF combination in a steroid free maintenance IS program. The favorable impact of mTORi on T-regulatory cells may provide added protection against rejection episodes. Longer clinical follow up, a larger sample size, and evaluation of renal biopsy data and circulating T-regulatory cell populations are warranted for future investigation.
