Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study

1130-0108/2022/114/6/335-342 • REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS © Copyright 2022. SEPD y © ARÁN EDICIONES, S.L. REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 Gómez-Bravo MÁ, Prieto M, Navasa M, Sánchez-Antolín G, Lladó L, Otero A, Serrano T, Jiménez-Romero C, García-González M, Valdivieso A, González-Diéguez ML, de la Mata M, Pons JA, Salcedo M, Rodrigo JM, Cuervas-Mons V, González A, Caralt M, Pardo F, Varo E, Crespo G, Rubin Á, Guilera M, Aldea A, Santoyo J; and the REDUCE Study Group. Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study. Rev Esp Enferm Dig 2022;114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study ORIGINAL PAPERS Miguel Á. Gómez-Bravo1, Martín Prieto2,3, Miquel Navasa4, Gloria Sánchez-Antolín5, Laura Lladó6, Alejandra Otero7, Trinidad Serrano8, Carlos Jiménez-Romero9, Miguel García-González10, Andrés Valdivieso11, María Luisa González-Diéguez12, Manuel de la Mata13, Jose A. Pons14, Magdalena Salcedo15, Juan M. Rodrigo16, Valentín Cuervas-Mons17, Antonio González18, Mireia Caralt19, Fernando Pardo20, Evaristo Varo21, Gonzalo Crespo4, Ángel Rubin2,3, Magda Guilera22, Anna Aldea22, Julio Santoyo16; and the REDUCE Study Group 1Hospital Universitario Virgen del Rocío. Sevilla, Spain. 2Liver Transplantation and Hepatology Unit. Hospital Universitari I Politècnic La Fe-IIS La Fe. Valencia, Spain. 3CIBERehd. Instituto de Salud Carlos III. Madrid, Spain. 4Liver Transplant Unit, Hospital Clínic. Universitat de Barcelona, IDIBAPS, CIBERehd. Barcelona, Spain. 5Hospital Universitario Río Hortega. Valladolid, Spain. 6Hospital Universitari de Bellvitge. Institut d’Investigació Biomèdica de Bellvitge. Barcelona, Spain. 7Hospital Universitario de A Coruña. A Coruña, Spain. 8Hospital Clínico Universitario Lozano Blesa. IIS Aragon. Zaragoza, Spain. 9Hospital Universitario 12 de Octubre. Madrid, Spain. 10Hospital Universitario Ramón y Cajal. Madrid, Spain. 11Hospital Universitario Cruces. Bilbao, Spain. 12Hospital Universitario Central de Asturias. Oviedo, Spain. 13HU Reina Sofía. CIBERehd, IMIBIC. Córdoba, Spain. 14Hospital Clínico Universitario Virgen de la Arrixaca. Murcia, Spain. 15Hospital Gregorio Marañón. Madrid, Spain. 16Hospital Regional Universitario. Málaga, Spain. 17Hospital Universitario Puerta de Hierro. Universidad Autónoma de Madrid. Madrid, Spain. 18Hospital Universitario Ntra. Sra. de Candelaria. Tenerife, Spain. 19Hospital Valle de Hebrón. Universidad Autónoma de Barcelona. Barcelona, Spain. 20Clínica Universitaria de Navarra. Pamplona, Spain. 21Hospital Clínico Universitario de Santiago de Compostela. Santiago de Compostela, A Coruña. Spain. 22Novartis Farmacéutica S.A. Barcelona, Spain Received: 29/12/2021 · Accepted: 05/04/2022 Correspondence: Martín Prieto. Liver Transplantation and Hepatology Unit. Hospital Universitari i Politècnic La Fe-IIS La Fe. Avinguda de Fernando Abril Martorell, 106. 46026 Valencia, Spain. e-mail: [email protected] Authorship statement: MN and JS participated in the research design, and conduction of the research; MAGB, MP, GSA, LLl, AO, TS, CJR, MGG, AV, MLGD, MM, JAP, MS, JMR, VCM, AG, MC, FP, EV, GC and AR participated in the conduction of the research; MG and AA participated in the research design and data analysis. Funding sources: the REDUCE study was funded by Novartis Farmacéutica S.A., Barcelona, Spain. Conflict of interest statement: the authors of this manuscript have the following conflicts of interest to disclose: MN received an unrestricted grant from Novartis, and acted as speaker/advisor for Astellas and Novartis. MAGB received an unrestricted grant from Novartis, and acted as speaker/advisor for Astellas, Chiesi and Novartis. MP acted as speaker/advisor for Astellas and Novartis. GSA acted as speaker/advisor for Astellas and Novartis. LL received an unrestricted grant from Novartis and Astellas, and acted as speaker/advisor for Astellas, Novartis, and Pfizer. AO has no conflicts to disclose. TS received travel support and acted as speaker/advisor for Astellas and Novartis. CJR has no conflicts to disclose. MGG acted as speaker for Novartis. AV acted as speaker for Astellas and Novartis and advisor for Astellas. LGD received speaking and advisory fees from Gilead and speaker fee from Abbvie and Novartis. MM acted as a speaker for Astellas, Novartis, Bayer, Gilead and Abbvie. JAP acted as a speaker/advisor for Astellas, Gilead, and Novartis. MS acted as an advisor for Novartis and speaker for Novartis and Chiesi. JMR has no conflicts to disclose. VCM has no conflicts to disclose. AG received speaker’s honoraria from Novartis, Astellas, Gilead, Abbvie Bristol and is a member of advisory board with Gilead. MC has no conflicts to disclose. FP received speaker’s honoraria and travel support from Astellas, Novartis and Chiesi. EV received an unrestricted grant from Astellas, and acted as a speaker/advisor for Astellas, Novartis, and Roche. GC acted as a speaker/advisor for Astellas and Novartis. MG and AA are employees of Novartis Farmaceutica S.A. JS received an unrestricted grant from Novartis, and acted as a speaker/advisor for Astellas and Novartis. ABSTRACT Background and aim: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. Methods: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in M. Á. Gómez-Bravo et al. REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 336 de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels ≤ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. Results: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. Conclusion: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation. Keywords: Everolimus. De novo liver transplant. Renal function. eGFR. KDIGO. INTRODUCTION Approximately 7 % to 21 % of liver transplant (LT) recipients develop severe deterioration of renal function that may progress to end-stage chronic kidney disease (1). This is mostly due to prolonged calcineurin inhibitor (CNI) exposure (2). Mammalian target of rapamycin inhibitors (mTORi; everolimus [EVR] and sirolimus) protect against CNI-associated toxicities by facilitating CNI minimization. Several studies have shown that EVR-based CNI withdrawal (3-5) or CNI reduction regimes improve renal function (6-8). The aim of the REDUCE study was to evaluate the effect of early initiation of EVR with reduced tacrolimus (rTAC) on renal function when compared with mycophenolate mofetil (MMF) plus TAC in de novo LT recipients from Spanish transplant centers. PATIENTS AND METHODS Study design and conduct The REDUCE study (EudraCT No. 2013-001191-38) was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Details of study design and treatment regimens are presented in figure 1. The study was performed in accordance with the principles of the Declaration of Helsinki, with an independent ethics committee and institutional review board (HCP/2013/109). Written informed consent was obtained from all participants. Study population LT recipients who met the inclusion criteria 28 days after liver transplantation were eligible for enrolment into the study. Adult patients receiving their first LT from a deceased donor were eligible for screening. Patients with hepatocellular carcinoma were required to meet the Milan criteria at the time of inclusion on the waiting list. Patients with a functioning allograft (aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels ≤ 4 times the upper limit of normal [ULN]; alkaline phosphatase and gamma glutamyl transpeptidase levels ≤ 5 times the ULN) and estimated glomerular filtration rate (eGFR) ≥ 30 mL/ min/1.73 m2 were randomized. Exclusion criteria were proteinuria ≥ 1.0 g/24 h; cholesterol levels ≥ 350 mg/dL (≥ 9 mmol/L) or triglyceride levels ≥ 750 mg/dL; platelet count ≤ 50,000/mm3; absolute neutrophil count ≤ 1000/mm3 or white blood cell count ≤ 2000/ mm3; renal replacement therapy within 7 days before randomization and ≥ 2 corticosteroid-sensitive acute rejection (AR) episodes. Immunosuppression All patients received interleukin-2 receptor antagonist + TAC (trough level [C0] 6-10 ng/mL) + MMF (500- 1000 mg/12 hour) + corticosteroids before randomization. A centralized randomization system included in the electronic case report form was used. EVR was started within EVR+rTAC (n = 105) EVR+rTAC+Corticosteroids EVR (3-8 ng/mL) TAC (C0 ≤5 ng/mL) MMF+TAC (n = 106) MMF+rTAC+Corticosteroids MMF (500-1000 mg/12 h) TAC (C0 6-10 ng/mL) 12-month follow-up post-transplant Visit 4 (Day 28 −5/+15 days) Randomization Week 52 End of study Recipients of first liver transplant (N = 291) IL-2RA + TAC (C0 6-10 ng/mL) + MMF (500-1000 mg/12 h) + Corticosteroids Randomization Day 3 to 7 Baseline Day 0 Screening Fig. 1. Study design. Corticosteroids were withdrawn by week 24 post-transplantation, except in patients with baseline autoimmune liver disease (EVR: everolimus; IL-2RA: interleukin-2 receptor antagonist; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; TAC: tacrolimus). Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 337 24 hours of randomization in the EVR + rTAC group, at a dose of 1 mg twice daily and adjusted to a target C0 of 3 to 8 ng/mL. Upon achieving the required EVR C0, a reduction of TAC dose was initiated to achieve a target C0 of ≤ 5 ng/mL within 4 weeks post-randomization, and these levels were maintained until week 52. In the MMF + TAC group, TAC C0 was maintained within the range of 6 to 10 ng/mL according to the levels shown in the TAC minimization studies with MMF. TAC capsules were used according to normal clinical practice to adjust the dose of TAC until week 3 post-trans- plant, at the latest. Beginning at week 3, all patients had to be in treatment with prolonged release TAC capsules in order to have stable levels of TAC prior to randomization. Study objectives The study assessed the evolution of kidney function from randomization (week 4) to the end of the study (week 52) in the EVR + rTAC vs the MMF + TAC group. Clinical benefit in renal function was defined by either (i) an improvement in 1 or 2 ranges of eGFR at week 52 post transplantation in patients with values of 30 to < 45 (Kidney Disease: Improving Global Outcomes [KDIGO] category G3b) or 45 to < 60 mL/min/1.73 m2 (G3a) at randomization, or (ii) stabilization of eGFR at week 52 post transplantation in patients with eGFR ≥ 60 mL/min/1.73 m2 (G2, G1) at randomization (9). Kidney function was also assessed by evaluating the mean eGFR changes throughout the study. The study also evaluated incidence, time to rejection and severity of biopsy-proven AR (BPAR); graft loss and death; new onset of clinical events of interest and the incidence of adverse events (AEs) and serious AEs (SAEs). Statistical analysis In this study, the aim was to reject the null hypothesis of no difference in kidney function between the groups with a bilateral level of significance of 0.05. The plan was to recruit 250 de novo LT recipients, considering 10 % of screening failures and 20 % for patient discontinuation rate. Fisher’s exact test or the chi-squared test were used for categorical variables, and the t-test or Mann-Whitney U-test was used for treatment comparisons between continuous variables. Renal function was analyzed using an analysis of covariance (ANCOVA) model with levels of each variable at randomization as a concomitant variable. RESULTS Patients From December 2013 to February 2016, patients were recruited from 20 centers across Spain. Of the 291 patients screened, 217 were randomized 4 weeks after transplantation to receive EVR + rTAC (n = 108) or MMF + TAC (n = 109). Patients prematurely discontinuing the study medication were similar in the study groups (Fig. 2). The demographic and baseline characteristics including mean eGFR were similar in the study groups, with the exception of recipient age which was significantly higher in the EVR + rTAC group (Table 1). Immunosuppression In the EVR + rTAC group, the mean (standard deviation, SD) everolimus C0 was 3.6 (2.0) ng/mL at week 5, 4.7 (2.4) ng/ mL at week 8, 5.7 (2.7) ng/mL at week 24, and 4.9 (1.7) ng/ mL at week 52. Everolimus C0 was within the target range in 36.2 %, 72.4 %, 67.6 %, and 60.0 % of patients at weeks 5, 8, 24 and 52, respectively. Tacrolimus C0 at randomization in the EVR + rTAC and MMF + TAC groups were 8.3 (3.1) ng/mL and 8.2 (2.9) ng/mL, respectively (p = NS). In the EVR + rTAC group, TAC C0 was reduced, reaching < 6 ng/mL in 32.4 %, 64.8 %, 71.4 %, and 62.9 % of the patients at weeks 5, 8, 24 and 52, respectively. The mean TAC C0 in this group was 6.9 (2.9) ng/mL at week 5, 5.3 (2.5) ng/mL at week 8, 4.7 (1.8) ng/mL at week 24, and 4.3 (1.9) ng/mL at week 52 (lower than the TAC levels in the MMF + TAC group at each time point) (Fig. 3). There was a 30 % reduction in the mean TAC levels in the EVR + rTAC vs MMF + TAC group as early as 2 weeks after randomization, with a 41 % reduction at week 52. Renal function Clinical benefit in renal function was observed in 81.9 % and 84.0 % of patients in the EVR + rTAC and MMF + TAC groups, respectively (p = NS). Improvement of renal function was seen in 18.6 % vs 19.1 %, and stabilization was achieved in 81.4 % vs 80.9 % of patients in the EVR + rTAC vs MMF + TAC group, respectively (p = NS). There were no statistical differences in the clinical benefit in renal function by eGFR stratification (Table 2). The EVR + rTAC group had a lower (albeit not significantly different) mean eGFR value at randomization compared with the MMF + TAC group, and it improved as the study progressed. Conversely, the mean eGFR of the MMF + TAC group decreased during the subsequent study visits (Fig. 4A). A significant difference was reported in the mean change in eGFR from randomization to week 52 between the EVR + rTAC and MMF + TAC groups at all visits (p < 0.05 for all visits) (Fig. 4B). Proteinuria (> 0.5 g/day) was reported in 21 (9.95 %) patients during the study period and was more common in the EVR + rTAC group (13.3 % vs 6.6 %, p = NS). BPAR, graft loss, and death BPAR was reported in 6 (5.7 %) patients in the EVR + rTAC and in 4 (3.8 %) patients in the MMF + TAC group (p = NS) (Table 2). Graft loss was observed in 2 (1.9 %) patients in the EVR + rTAC and 1 (0.9 %) patient in the MMF + TAC group (p = NS). Nine deaths (6 in the EVR + rTAC group and 3 in the MMF + TAC group, p = NS) were reported between randomization and week 52. None of the deaths were related to the study drug (Table 2). Safety Over the 12-month study period, the overall rates of AEs and SAEs were similar between the study groups. With regard to new onset events of clinical interest, dyslipidemia M. Á. Gómez-Bravo et al. REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 338 Fig. 2. Patient disposition (EVR: everolimus; ITT: intention-to-treat; MDRD4: 4-variable modification of diet in renal disease; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; TAC: tacrolimus). 74 not randomized 9 adverse events 5 protocol deviation 7 death 7 graft loss/re-transplant 6 prohibited medication 1 unsatisfactory therapeutic effect 20 abnormal laboratory values 19 other reasons 2 patients did not receive treatment 1 patient without MDRD-4 values after randomization 40 discontinued study medication* 22 adverse events 9 abnormal laboratory value 4 protocol deviation 2 unsatisfactory therapeutic effect 3 death 0 re-transplant 3 proteinuria >1 g/24 h 3 abnormal results from the analytical procedure 14 prohibited medication *A single patient could present more than one reason 3 patients without MDRD-4 values after randomization 39 discontinued study medication* 15 adverse events 14 abnormal laboratory value 10 protocol deviation 2 unsatisfactory therapeutic effect 3 death 1 re-transplant 0 proteinuria >1 g/24 h 3 abnormal results from the analytical procedure 12 prohibited medication *A single patient could present more than one reason 70 completed study 68 completed study medication 74 completed study 70 completed study medication 291 screened 217 randomized ITT population EVR+rTAC (n = 105) ITT population MMF+TAC (n = 106) 108 EVR+rTAC 109 MMF+TAC Table 1. Demographics and baseline characteristics (ITT population) EVR + rTAC (n = 105) MMF + TAC (n = 106) p-value Demographic characteristics Age (years), mean (SD) 58.4 (6.4) 55.8 (7.5) 0.007 Gender (male), n (%) 91 (86.7) 90 (84.9) 0.866 Cytomegalovirus positive, n (%) 83 (79.1) 80 (75.5) 0.649 Screening eGFR (MDRD4), mL/min/1.73 m2, mean (SD) 100.2 (38.7) 99.4 (43.1) 0.890 MELD, mean (SD) 15.0 (6.2) 15.0 (6.3) 0.999 Medical history/relevant comorbidities Diabetes mellitus, n (%) 37 (35.2) 30 (28.3) 0.350 Hypertension, n (%) 31 (29.5) 34 (32.1) 0.801 Main reasons for transplantation Cirrhosis, n (%) 96 (91.4) 98 (92.5) 0.984 HCC, n (%)* 46 (43.8) 53 (50.0) 0.445 Donor characteristics Age (years), mean (SD) 60.8 (13.8) 62.4 (16.5) 0.443 Gender (male), n (%) 64 (61.0) 58 (54.7) 0.437 *Most patients with HCC also belong to the cirrhosis group. eGFR: estimated glomerular filtration rate; EVR: everolimus; HCC: hepatocellular carcinoma; ITT: intention-to-treat; MDRD4: 4-variable modification of diet in renal disease; MELD: model for end stage liver disease; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; SD: standard deviation; TAC: tacrolimus. Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 339 and diabetes were more common in the EVR + rTAC group. The incidence of cytomegalovirus infections was lower in the EVR + rTAC group (Table 3). DISCUSSION The present study shows that the concomitant administration of EVR allows the safe reduction of TAC exposure to C0 below 6 ng/mL at month 1 after liver transplantation. As a result, a clinically significant reduction of almost 30 % of the TAC C0 was achieved in the EVR + rTAC group as early as 2 weeks after randomization, in comparison with the TAC C0 in the MMF + TAC group. Furthermore, this reduction increased during the study period and reached 41 % at week 52. These differences were greater than the reduction in the exposure to TAC achieved in the H2304 study (26 % to 38 % in the EVR + rTAC group) (6), and the TAC lev- 0 20 40 60 80 100 120 140 160 180 SCR 1 4 12 24 36 52 Post-transplant time (weeks) Randomization Mean eGFR (mL/min/1.73 m2) 104/105 103/106 105/106 94/98 86/89 80/77 76/77 EVR+rTAC MMF+TAC 4A) 3) 100.2 112.9 82.2 86.0 86.0 87.7 86.1 99.4 112.2 88.4 83.6 82.0 83.0 83.2 Mean change in eGFR (mL/min/1.73 m2) Post-transplant time (weeks) Week 12 Week 24 Week 36 Week 52 4B) 8 6 4 2 0 −2 −4 −6 −8 −10 p = 0.0025 p = 0.0098 p = 0.0091 p = 0.0052 4.6 −5.0 −7.7 −9.3 −8.8 3.4 4.0 2.6 0 EVR+rTAC MMF+TAC 7.2 (SD 2.1) 7.2 (SD 2.5) 7.4 (SD 2.3) 8.0 (SD 3.2) 8.2 (SD 2.9) 7.5 (SD 2.1) 8.4 (SD 3.7) 8.2 (SD 2.9) Mean TAC levels [ng/mL] Post-transplant time (weeks) 0 1 3 5 7 9 5 6 8 12 18 24 36 52 98 103 98 94 4 105 105 77 71 95 98 93 92 88 89 76 74 77 76 2 4 6 8 10 EVR+rTAC MMF+TAC 8.1 (SD 3.2) 8.3 (SD 3.1) 6.9 (SD 2.9) 5.9 (SD 2.3) 5.3 (SD 2.5) 5.2 (SD 2.8) 5.3 (SD 2.8) 4.7 (SD 1.8) 4.6 (SD 1.8) 4.3 (SD 1.9) n Fig. 3. Mean tacrolimus trough levels (EVR: everolimus; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; SD: standard deviation; TAC: tacrolimus). Table 2. Renal function and key efficacy endpoints (ITT population) EVR + rTAC (n = 105) MMF + TAC (n = 106) p-value Clinical benefit in renal function, n (%) 86 (81.9) 89 (84.0) 0.691 Improvement 16 (18.6) 17 (19.1) 0.933 Stabilization 70 (81.4) 72 (80.9) Clinical benefit in renal function by eGFR (mL/min/1.73 m2) stratification, n (%) 30 to < 45 6 (85.7) 7 (70.0) 0.452 45 to < 60 10 (52.6) 10 (58.8) 0.709 ≥ 60 70 (88.6) 72 (91.1) 0.598 Change in eGFR (mL/min/1.73 m2) from randomization to week 52, mean (SD) 2.6 (24.6) −8.8 (24.4) 0.005 eGFR (MDRD4), mL/min/1.73 m2, mean (SD) Randomization 82.2 (28.5) 88.4 (34.3) 0.154 Week 52 86.1 (27.9) 83.2 (25.2) 0.435 Clinically suspected AR, n (%) 18 (17.1) 16 (15.1) 0.686 BPAR, n (%) 6 (5.7) 4 (3.8) 0.734 tBPAR, n (%) 5 (4.8) 2 (1.9) 0.434 Time to tBPAR (months), mean (SD) 2.7 (1.5) 3.9 (5.3) 0.619 Graft loss, n (%) 2 (1.9) 1 (0.9) 0.993 Death, n (%) 6 (5.7) 3 (2.8) 0.486 AR: acute rejection; BPAR: biopsy-proven AR; eGFR: estimated glomerular filtration rate; EVR: everolimus; ITT: intention-to-treat; MDRD4: 4-variable modification of diet in renal disease; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; SD: standard deviation; TAC: tacrolimus; tBPAR: treated BPAR. M. Á. Gómez-Bravo et al. REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 340 Fig. 4. A. Evolution of renal function (eGFR, MDRD4). B. Mean change in eGFR from randomization. Vertical bars (in 4A) indicate the respective standard deviations (eGFR: estimated glomerular filtration rate; EVR: everolimus; MDRD4: 4-variable modification of diet in renal disease; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; TAC: tacrolimus). Table 3. Safety evaluation (safety population) EVR + rTAC (n = 106) MMF + TAC (n = 109) p-value AEs, n (%) Patients with any AE 105 (99.1) 109 (100.0) 0.989 Patients with any SAE 55 (51.9) 48 (44.0) 0.310 Renal failure 13 (12.3) 19 (17.4) 0.287 Peripheral edema 39 (36.8) 27 (24.8) 0.056 Anemia 31 (29.3) 36 (33.0) 0.652 Leukopenia 14 (13.2) 10 (9.2) 0.348 Thrombocytopenia 25 (23.6) 22 (20.2) 0.546 Hepatic artery and portal vein thrombosis 3 (2.8) 2 (1.8) 0.680 New onset events of clinical interest Dyslipidemia 78 (73.6) 55 (50.5) 0.0005 Hypertension 66 (62.3) 59 (54.1) 0.284 Diabetes 36 (34.0) 24 (22.0) 0.051 Neoplasia 3 (2.8) 2 (1.8) 0.680 Cytomegalovirus infection 25 (23.6) 41 (37.6) 0.026 AE: adverse events; EVR: everolimus; MMF: mycophenolate mofetil; rTAC: reduced tacrolimus; SAE: serious adverse events; TAC: tacrolimus. 0 20 40 60 80 100 120 140 160 180 SCR 1 4 12 24 36 52 Post-transplant time (weeks) Randomization Mean eGFR (mL/min/1.73 m2) 104/105 103/106 105/106 94/98 86/89 80/77 76/77 EVR+rTAC MMF+TAC 4A) 3) 100.2 112.9 82.2 86.0 86.0 87.7 86.1 99.4 112.2 88.4 83.6 82.0 83.0 83.2 Mean change in eGFR (mL/min/1.73 m2) Post-transplant time (weeks) Week 12 Week 24 Week 36 Week 52 4B) 8 6 4 2 0 −2 −4 −6 −8 −10 p = 0.0025 p = 0.0098 p = 0.0091 p = 0.0052 4.6 −5.0 −7.7 −9.3 −8.8 3.4 4.0 2.6 0 EVR+rTAC MMF+TAC 7.2 (SD 2.1) 7.2 (SD 2.5) 7.4 (SD 2.3) 8.0 (SD 3.2) 8.2 (SD 2.9) 7.5 (SD 2.1) 8.4 (SD 3.7) 8.2 (SD 2.9) Mean TAC levels [ng/mL] Post-transplant time (weeks) 0 1 3 5 7 9 5 6 8 12 18 24 36 52 98 103 98 94 4 105 105 77 71 95 98 93 92 88 89 76 74 77 76 2 4 6 8 10 EVR+rTAC MMF+TAC 8.1 (SD 3.2) 8.3 (SD 3.1) 6.9 (SD 2.9) 5.9 (SD 2.3) 5.3 (SD 2.5) 5.2 (SD 2.8) 5.3 (SD 2.8) 4.7 (SD 1.8) 4.6 (SD 1.8) 4.3 (SD 1.9) n B A Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study REV ESP ENFERM DIG 2022:114(6):335-342 DOI: 10.17235/reed.2022.8549/2021 341 els were clearly lower than those described in randomized studies using the combination of MMF + TAC (10-14) and in those reflecting real-world experience aimed at minimization of CNI (15,16). The results of the current study also show that despite the important and significant reduction in TAC exposure achieved in the EVR + rTAC group, clinical renal function benefits were similar with both regimens. This could due to the fact that both groups had effective TAC reduction, which reinforces the fact that this reduction is key to preserving kidney function after liver transplantation. With a more pronounced TAC reduction in the EVR + rTAC group, the mean eGFR from randomization to week 52 significantly improved. In contrast, it worsened in the MMF + TAC group from week 12 onwards, even though the patients in the EVR + rTAC group had a lower eGFR at randomization. When we consider the evolution of eGFR during the entire study period (pre, peri, and post transplantation), once the initial decrease in GFR after liver transplantation was established, the reduction in CNI exposure to maintain kidney function thereafter is mandatory. From the results of the present study, it is not clear whether the trend to improvement in kidney function in the EVR + rTAC group in contrast to the trend to stabilization or even decrease of eGFR in the MMF + TAC group, would translate to clinically significant differences in renal function with a longer follow-up. The current study confirms the possibility of safely using TAC levels below 6 ng/mL in the relatively early post-trans- plant period. The EVR + rTAC group showed a similar incidence of BPAR, treated BPAR, graft loss and death as that of the MMF + TAC group. In addition, the incidence of AEs and study medication discontinuation rates were similar in both groups. Interestingly, the 19 % discontinuation rate using EVR was lower than the approximate 30 % rate reported in previous studies (3,6). Better control of EVR levels and lower target levels could probably explain the low rate of discontinuation and reinforce early EVR introduction with low TAC exposure. The incidence of proteinuria and AEs was similar in both groups, except for a higher incidence of dyslipidemia and diabetes in the EVR + rTAC group and a higher incidence of cytomegalovirus infection in the MMF + TAC group. This study opens several lines for further exploration, namely assessing the effects of early low exposure to CNI on kidney function with a longer follow-up; evaluating whether the decreased exposure to CNI can improve the incidence of medium- and long-term cardiovascular events and assessing whether this immunosuppressive regime can reduce the incidence of de novo neoplasia. A limitation of the REDUCE study was that the target TAC C0 ≤ 5 ng/mL was not achieved within 4 weeks post-ran- domization. Another limitation was that, due to scarce data on renal function benefit at the time of the study design, the sample size was calculated based on the benefit shown in a previous study evaluating TAC monotherapy as the control group (2). However, most patients in both groups had an eGFR > 60 mL/min/1.73 m2 at randomization, which did not allow the assessment of whether patients with an eGFR < 60 mL/min/1.73 m2 could have had an improvement in renal function. The distribution of the patients in the different subgroups according to the baseline renal function indicates that the sample size may be too small to provide accurate results. Future studies of superiority are needed to derive more consistent conclusions. Secondly, considering the difference in changes in eGFR between the groups, a long-term follow-up may have been better to show additional changes in renal function. In summary, the REDUCE study shows that the early introduction of EVR allows a significant reduction in the mean TAC C0, which in turn is associated with a significant improvement in eGFR 1 year after liver transplantation, without compromising safety. Whether this may have longterm benefits in LT recipients remains to be explored in future studies. ACKNOWLEDGMENTS This study was funded by Novartis Farmaceutica S.A, Spain. The authors thank all the study investigators and their teams for their contribution to the study, Aruna Meka, Aparajita Mandal, and Kshama Chitnis of Novartis Healthcare Pvt Ltd for providing medical writing and editorial support in accordance with Good Publication Practice (GPP3) guidelines. REFERENCES 1. Allen AM, Kim WR, Therneau TM, et al. Chronic Kidney Disease and Associated Mortality after Liver Transplantation – a Time-Dependent Analysis Using Measured Glomerular Filtration Rate. J Hepatol 2014;61(2):286-92. DOI: 10.1016/j.jhep.2014.03.034 2. Rodríguez-Perálvarez M, Guerrero M, De Luca L, et al. Area under trough concentrations of tacrolimus as a predictor of progressive renal impairment after liver transplantation. Transplantation 2019;103(12):2539-48. DOI: 10.1097/TP.0000000000002760 3. Fischer L, Klempnauer J, Beckebaum S, et al. 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