Efficacy and Safety of Delayed Prolonged-Release Tacrolimus Initiation in De Novo Hepatitis C Virus-Negative Orthotopic Liver Transplant Recipients: A Single-Center, Single-Arm, Prospective Study

Abstract

BackgroundDelaying initiation of tacrolimus after liver transplantation (LT) is a potential renal-sparing strategy. We assessed safety and efficacy of delayed initiation of prolonged-release tacrolimus (PR-T) in de novo LT.Material/MethodsThis was a single-center, single-arm, prospective, 12-month observational study of hepatitis C virus-negative orthotopic LT patients. Immunosuppression included PR-T (initially 0.1 or 0.2 mg/kg/day) initiated on Day 3 post LT, basiliximab (20 mg) on post-transplantation Day 0 and Day 4, and intraoperative corticosteroids (500 mg). Patients received maintenance corticosteroids and mycophenolate mofetil (MMF) according to center protocol. MMF dose was adjusted according to thrombocyte count. The primary endpoint was the estimated glomerular filtration rate (eGFR) measured using the Modification of Diet in Renal Disease 4-variable formula at 12 months. Secondary endpoints included biopsy-confirmed acute rejection (BCAR) and dialysis requirement. Adverse events were recorded.ResultsSixty-nine patients (mean age 55.0 years) were included. Most patients started MMF on Day 1 (60.9%) or Day 2 (10.1%), and PR-T on Day 3 (55.1%) or Day 4 (29.0%). Mean tacrolimus trough levels (ng/mL) were: Day 7, 9.5±6.3; Day 10, 9.4±5.4; Month 1, 8.0±3.1; Month 3, 7.8±3.7; Month 6, 8.0±4.1; and Month 12, 7.2±3.1. Mean 12-month eGFR was 77.2±24.5 mL/min/1.73 m2; 72.5% of patients had eGFR >60 mL/min/1.73 m2 at 12 months; 89.9% had no eGFR measurements <40 mL/min/1.73 m2 during the study. Renal insufficiency (any eGFR <60 mL/min/1.73 m2) was diagnosed in 27.5% of patients; one patient required dialysis. There were no BCAR episodes; the infection rate was 36.2%, and 3 patients died. Overall, 19 patients (27.5%) developed de novo diabetes mellitus, 18 patients (26.1%) had hypercholesterolemia, and 12 patients (17.4%) had hypertriglyceridemia.ConclusionsQuadruple therapy with delayed administration of PR-T was well tolerated and efficacious, and was associated with acceptable renal function over 12 months.

A Systematic Review of the Literature on Chronic Kidney Disease Following Liver Transplantation

“…When information was available, ≥78.1% of patients were White; the exception was Chauhan et al, in which 36.3–43.3% of patients across study arms were White [ 20 ]. The primary diseases at baseline varied between studies and study arms ( Table 4 ), but included alcoholism or ethanol abuse (23.1–71.4% across 3 studies [ 23 , 24 , 29 ]) hepatitis C virus infection (0–41.8% in 11 studies [ 7 , 19 , 20 , 22 – 26 , 28 – 30 ]), and hepatocellular carcinoma (2.3–63.6% in 10 studies [ 7 , 19 – 22 , 24 , 27 – 30 ]).…”

“…Mean GFR/eGFR decreased numerically over time in at least 1 study arm from 6 publications where data were reported according to study arm [ 19 , 22 – 24 , 26 , 27 ]. Where mean data were available, eGFR ranged from 71.4 to 119.6 mL/min/1.73 m 2 (means within CKD stage 2 to stage 1) across studies at baseline, from 76.0 to 85.2 mL/min/1.73 m 2 (CKD stage 2) at 6 months [ 22 , 26 , 27 ], and was 77.2 and 79.1 mL/min/1.73 m 2 (CKD stage 2) in 2 studies at 12 months [ 24 , 26 ]. Median data from Pascher et al at 6 months were consistent with this, irrespective of study arm ( Table 5 ) [ 30 ].…”

“…Five studies reported the prevalence of CKD (it was unclear if these were new cases after transplantation), and Lim et al reported the incidence of new-onset CKD [ 7 , 19 , 22 , 24 , 26 , 28 ] ( Table 6 ). Of the 2 studies reporting the prevalence of CKD at baseline and follow-up, there was an increase in the proportion of patients with CKD [ 7 ].…”

“…Defining CKD as stage 3a or higher (GFR/eGFR <60 mL/min/1.73 m 2 ), 5.4–32.6% of patients had CKD at 6 months across 3 study arms in 2 studies ( Table 6 ) [ 19 , 22 ]. Across 3 study arms in 2 studies, 23.2–36.8% of patients had CKD at 12 months, with the highest proportion reported in patients with post-transplantation AKI ( Table 6 ) [ 26 , 28 ].…”

“…Ten studies reported data for patient deaths ( Table 7 ) [ 7 , 19 , 20 , 22 , 23 , 26 – 30 ]. The incidence of patient deaths at 6 months was generally between 0% and 3.8%, with the exception of the sotrastaurin arms of Pascher et al, in which death rates of up to 14.3% were cited ( Table 7 ) [ 30 ].…”