Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged‐Release Tacrolimus Regimens—The DIAMOND Study

DIAMOND: multicenter, 24‐week, randomized trial investigating the effect of different once‐daily, prolonged‐release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged‐release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged‐release tacrolimus (0.15–0.175mg/kg/day) plus basiliximab; Arm 3: prolonged‐release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan–Meier estimates of composite efficacy failure‐free survival were 72.0%, 77.6%, 73.9% in Arms 1–3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged‐release tacrolimus (0.15–0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged‐release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher‐dose prolonged‐release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.     

A Steady‐State Head‐to‐Head Pharmacokinetic Comparison of All FK‐506 (Tacrolimus) Formulations (ASTCOFF): An Open‐Label,Prospective, Randomized,Two‐Arm,Three‐Period Crossover Study

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (T_max) to peak concentration (C_max) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, C_max, T_max or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, ?30%; ER‐Tac:LCPT, ?36%. After exposure normalization, C_max was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; C_min was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac.     

Liver transplantation for hepatitis C virus (HCV) non‐viremic recipients with HCV viremic donors

In the context of organ shortage, the opioid epidemic, and effective direct‐acting antiviral (DAA) therapy for hepatitis C virus (HCV), more HCV‐infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor‐derived HCV in previously non‐viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor‐derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing. Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non‐viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12 weeks posttreatment with DAA‐based regimens, with a median time from transplant to treatment initiation of 43 days (IQR 20–59). There have been no instances of graft loss or death, with median follow‐up of 380 days (IQR 263–434) posttransplant. Transplantation of HCV‐viremic livers into non‐viremic recipients results in acceptable short‐term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation.     

Late intra‐patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report

Intra‐patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single‐center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000‐2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4‐6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one‐third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.     

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label,single‐arm,one‐way crossover study

There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.     

Long‐Term Outcomes of Living‐Donor Liver Transplantation for Primary Biliary Cirrhosis: A Japanese Multicenter Study

The factors that influence long‐term outcomes after living‐donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC) are not well known. Compared with deceased‐donor transplantation, LDLT has an increased likelihood of a related donor and a decreased number of human leukocyte antigen (HLA) mismatches. To clarify the effects of donor relatedness and HLA mismatch on the outcomes after LDLT, we retrospectively analyzed 444 Japanese patients. Donors were blood relatives for 332 patients, spouses for 105, and “other” for 7. The number of HLA A‐B‐DR mismatches was none to two in 141, three in 123, and four to six in 106 patients. The 15‐year survival rate was 52.6%, and PBC recurred in 65 patients. Recipient aged 61 years or older, HLA mismatches of four or more (maximum of six), graft:recipient weight ratio less than 0.8, and husband donor were adverse indicators of patient survival. IgM 554 mg/dL or greater, donor–recipient sex mismatch, and initial immunosuppression with cyclosporine were significant risks for PBC recurrence, which did not affect patient survival. In subgroup analysis, conversion to cyclosporine from tacrolimus within 1 year diminished recurrence. Prospective studies are needed to determine the influence of pregnancy‐associated sensitization and to establish an optimal immunosuppressive regimen in LDLT patients.     

Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1‐week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one‐way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%‐110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.     

Pediatric Liver Transplant Recipients Who Undergo Transfer to the Adult Healthcare Service Have Good Long‐Term Outcomes

Liver transplantation has transformed survival for children with liver disease necessitating the transfer of a growing number of patients to the adult healthcare service. The impact of transfer on outcomes remains unclear. The aim of this single‐center study of 137 consecutive pediatric liver transplant recipients was to examine the effect of transfer on patient and graft survival. The median time from transplant to transfer was 10.4 years and the median age of the patients at transfer was 18.6 years. After transfer, there were 5 re‐transplants and 12 deaths in 14 patients. The estimated posttransfer 10‐year patient and graft survival was 89.9% and 86.2%, respectively. Overall, 4 patients demonstrated graft loss as a consequence of chronic rejection. Graft loss was associated with older age at first transplant (p = 0.008). When compared to young adult patients transplanted in the adult center, the transferred patients did not have inferior graft survival from the point of transfer (HR 0.28; 95% CI 0.10–0.77, p = 0.014). This suggests that transfer did not impact significantly on graft longevity. In conclusion, pediatric liver transplant recipients who undergo transfer to the adult service have good long‐term outcomes.     

Donor Graft MicroRNAs: A Newly Identified Player in the Development of New‐onset Diabetes After Liver Transplantation

New‐onset diabetes after liver transplantation (NODALT) is a frequent complication with an unfavorable outcome. We previously demonstrated a crucial link between donor graft genetics and the risk of NODALT. We selected 15 matched pairs of NODALT and non‐NODALT liver recipients using propensity score matching analysis. The donor liver tissues were tested for the expression of 10 microRNAs (miRNAs) regulating human hepatic glucose homeostasis. The biological functions of potential target genes were predicted using gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Both miR‐103 and miR‐181a were significantly highly expressed in the NODALT group as compared to the non‐NODALT group. The predicted target genes (e.g. Irs2, Pik3r1, Akt2, and Gsk3b) were involved in glucose import and the insulin signaling pathway. We also observed dysregulation of miRNAs (e.g. let‐7, miR‐26b, miR‐145, and miR‐183) in cultured human hepatocytes treated with tacrolimus or high glucose, the two independent risk factors of NODALT identified in this cohort. The hepatic miRNA profiles altered by tacrolimus or hyperglycemia were associated with insulin resistance and glucose homeostatic imbalance as revealed by enrichment analysis. The disease susceptibility miRNA expressive pattern could be imported directly from the donor and consolidated by the transplant factors.     

Donor‐Specific HLA Antibodies in Living Versus Deceased Donor Liver Transplant Recipients

With less ischemia, improved donor selection and controlled procedures, living donor liver transplantation (LDLT) might lead to less HLA donor‐specific antibody (DSA) formation or fewer adverse outcomes than deceased donor liver transplantation (DDLT). Using the multicenter A2ALL (Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study) biorepository, we compared the incidence and outcomes of preformed and de novo DSAs between LDLT and DDLT. In total, 129 LDLT and 66 DDLT recipients were identified as having serial samples. The prevalence of preformed and de novo DSAs was not different between DDLT and LDLT recipients (p = 0.93). There was no association between patient survival and the timing (preformed vs. de novo), class (I vs. II) and relative levels of DSA between the groups; however, preformed DSA was associated with higher graft failure only in DDLT recipients (p = 0.01). De novo DSA was associated with graft failure regardless of liver transplant type (p = 0.005) but with rejection only in DDLT (p = 0.0001). On multivariate analysis, DSA was an independent risk factor for graft failure regardless of liver transplant type (p = 0.017, preformed; p = 0.002, de novo). In conclusion, although similar in prevalence, DSA may have more impact in DDLT than LDLT recipients. Although our findings need further validation, future research should more robustly test the effect of donor type and strategies to mitigate the impact of DSA.     

The first case of ischemia‐free organ transplantation in humans: A proof of concept

Ischemia and reperfusion injury (IRI) is an inevitable event in conventional organ transplant procedure and is associated with significant mortality and morbidity post‐transplantation. We hypothesize that IRI is avoidable if the blood supply for the organ is not stopped, thus resulting in optimal transplant outcomes. Here we described the first case of a novel procedure called ischemia‐free organ transplantation (IFOT) for patients with end‐stage liver disease. The liver graft with severe macrovesicular steatosis was donated from a 25‐year‐old man. The recipient was a 51‐year‐old man with decompensated liver cirrhosis and hepatocellular carcinoma. The graft was procured, preserved, and implanted under continuous normothermic machine perfusion. The recipient did not suffer post‐reperfusion syndrome or vasoplegia after revascularization of the allograft. The liver function test and histological study revealed minimal hepatocyte, biliary epithelium and vascular endothelium injury during preservation and post‐transplantation. The inflammatory cytokine levels were much lower in IFOT than those in conventional procedure. Key pathways involved in IRI were not activated after allograft revascularization. No rejection, or vascular or biliary complications occurred. The patient was discharged on day 18 post‐transplantation. This marks the first case of IFOT in humans, offering opportunities to optimize transplant outcomes and maximize donor organ utilization.     

High Intrapatient Variability of Tacrolimus Concentrations Predicts Accelerated Progression of Chronic Histologic Lesions in Renal Recipients

High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6–12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low‐IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09–5.60, p = 0.031; and OR 2.40, 95% CI 1.03–5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2‐year follow‐up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.