Early Withdrawal of Calcineurin Inhibitors and Everolimus Monotherapy in de novo Liver Transplant Recipients Preserves Renal Function

Abstract

We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥3 (estimated glomerular filtration rate <60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.

Conversion to everolimus in maintenance liver transplant patients: A multicenter, retrospective analysis

“…Together, these studies suggest that liver transplant patients can receive a renal benefit from everolimus initiation with CNI withdrawal even at a relatively late stage after transplantation unless renal deterioration is profound. The remarkable improvement in eGFR (almost 30 mL/minute) reported by Masetti et al 16 after CNI withdrawal on day 30 in everolimus-treated patients versus CNI-treated patients highlights that early, preemptive conversion may be a more promising strategy. The second major indication for the introduction of everolimus was the prevention or treatment of malignancies; this reflects current interest in the role of mTOR inhibitors in the management of posttransplant tumors.…”

“…15 One randomized trial assessed the impact of converting 78 patients from CNI therapy to everolimus very early (day 30) after liver transplantation. 16 Renal function was significantly better at 1 year in the everolimus cohort, and this improvement was accompanied by a lower incidence of chronic kidney disease (stage 3 or higher); however, the rate of acute rejection was similar to the rate for the CNI arm. Single-arm studies have demonstrated that maintenance liver transplant patients can be converted from CNIs to everolimus safely at later time points with a low rate of acute rejection.…”

“…Single-arm studies have demonstrated that maintenance liver transplant patients can be converted from CNIs to everolimus safely at later time points with a low rate of acute rejection. [17][18][19][20][21][22] Like kidney transplant recipients, 23 liver transplant recipients with kidney dysfunction apparently need to be switched from CNI immunosuppression to everolimus either early after transplantation 16 or before the establishment of severe dysfunction. 17 In clinical practice, some centers now initiate everolimus in maintenance liver transplant patients who develop kidney dysfunction or, less frequently, posttransplant neoplasms and attempt to withdraw CNI therapy.…”

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

“…Furthermore, subsequent single-center observational studies (not clinical trials) comparing de novo sirolimus initiation at time of LTx have not shown an increased risk of graft failure or HAT as compared to other strategies, which underscore the importance of making the data of this multicenter study available to clinicians (15,20). Second, given emerging literature on the role of another mTOR inhibitor, everolimus, it is important to gauge whether similarities exist in the risk and benefit profile for these two medications (21)(22)(23)(24)(25)(26)(27). Above all, transparency in the full presentation of the results of the study are important given that it may impact our current approach to management of immunosuppression after LTx.…”

Clinical Immunosuppression

“…Promising protocols include sirolimus, MMF, and steroids or the combination of anti-CD25 antibodies, sirolimus, MMF, and steroids. These protocols have shown acceptable graft survival rates and acute rejection rates; however, these studies were small in size and further research is warranted [34]. In short, multiple regimens have been shown to be effective.…”