Effect of Early Everolimus-Facilitated Reduction of Tacrolimus on Efficacy and Renal Function in De Novo Liver Transplant Recipients

Abstract

BackgroundA recent randomized phase III study of 719 de novo liver transplant recipients showed that early everolimus plus reduced-dose tacrolimus (EVR + rTAC) led to significantly better kidney function than standard TAC (TAC-C), without compromising efficacy. In that study, patients from North America (n = 211) had increased risk factors for posttransplant renal insufficiency at study start, relative to patients from Europe and rest of world (eg, worse renal function, more diabetes, older age).MethodsA post hoc analysis was performed to assess whether these regional disparities affected study outcomes in North American patients.ResultsIn this subpopulation, estimated glomerular filtration rates at randomization were higher in TAC-C over EVR + rTAC (76.4 vs 69.3 mL/min per 1.73 m2). Mean changes in estimated glomerular filtration rate values (mL/min per 1.73 m2) favored EVR + rTAC over TAC-C at months 12 (+3.7 vs −4.5; P = 0.032), 24 (+2.7 vs −6.6; P = 0.042), and 36 (+4.3 vs −8.1; P = 0.059). The composite efficacy endpoint of treated biopsy-proven acute rejection, graft loss, or death was 10.9%, 14.1%, and 14.1% for EVR + rTAC and 13.1%, 17.2%, and 19.3% for TAC-C at months 12, 24, and 36, respectively.ConclusionsAlthough the North American cohort had more comorbidities, results were consistent with the overall population for efficacy and renal function.

Real-Life Experience of mTOR Inhibitors in Liver Transplant Recipients in a Region Where Living Donation Is Predominant

“…The rejection rate in our cohort was low because 75% of patients maintained a low dose of TAC after mTOR inhibitor initiation and 20% of patients maintained a low dose of MMF. In the current population, the adverse event profile was similar with that reported in other mTOR inhibitor-treated populations ( Chapman et al, 2017 ). In a recent observational CERTITUDE study ( Saliba et al, 2019 ), the rate of stopping mTOR inhibitors due to the adverse events was relatively high, affecting approximately one quarter of patients ( Nashan, 2018 ).…”

Effects of Conversion From Calcineurin Inhibitors to Sirolimus or Everolimus on Renal Function and Possible Mechanisms in Liver Transplant Recipients

“…The timing of mTORI conversion remains under debate. The decrease of eGFR under conventional CNI‐based regimens could be considerable in the first year after liver transplantation, ranging from –2.8 to –14.8 mL/min/1.73 m 2 . The mean eGFR changes after 1 year in our cohort were –2.26 and –2.81 mL/min/1.73 m 2 in the sirolimus and everolimus groups, respectively, which were no worse than those of the CNI‐based regimen.…”

“…The decrease of eGFR under conventional CNI-based regimens could be considerable in the first year after liver transplantation, ranging from -2.8 to -14.8 mL/min/1.73 m 2 . 12,28 The mean eGFR changes after 1 year in our cohort were -2.26 and -2.81 mL/min/1.73 m 2 in the sirolimus and everolimus groups, respectively, which were no worse than those of the CNI-based regimen. Although many studies have demonstrated that mTORI conversion conferred renoprotective effects in both sirolimus-or everolimus-based therapy, [29][30][31] some reported no change of renal function compared with conventional CNI-based regiment.…”

“…However, conversion from CNIs to mTORIs yields only limited or short-term improvement in the estimated glomerular filtration rate (eGFR) among some populations. [10][11][12] Prior studies also have raised concerns regarding renal fibrosis and tubular injury with use of mTORIs in renal and heart transplant recipients. 13,14 Although serum creatinine (SCr)-based eGFR is considered the best indicator of kidney function in practice, the SCr or eGFR alone may not reflect the actual degree of kidney function or injury.…”

“…To minimize CNI‐related nephrotoxicity and preserve long‐term renal function, mTORIs have been used to reduce CNI exposure through early discontinuation of CNIs or dose reduction in maintenance therapy. However, conversion from CNIs to mTORIs yields only limited or short‐term improvement in the estimated glomerular filtration rate (eGFR) among some populations . Prior studies also have raised concerns regarding renal fibrosis and tubular injury with use of mTORIs in renal and heart transplant recipients …”