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Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Immunosuppressive drugs (ISD) present a narrow therapeutic window and extremely high inter- and intra-individual pharmacokinetic variability, which complicates their use in solid organ transplant recipients. In order to find a narrow appropriate equilibrium for each patient with the aim of maintaining clinical efficacy and reducing the risk of adverse drug reactions, a complex both clinical and biological monitoring is required, in particular through the use of therapeutic drug monitoring (TDM)., Area Covered: This review provides an overview of the available information on the relationship between exposure to immunosuppressive drugs and their efficacy and/or toxicity in kidney and liver transplantation. The aim of the review is to describe the pharmacodynamic/pharmacokinetic relationship that exists for immunosuppressive drugs, to summarize the studies that assess the value of TDM for these drugs in clinical practice, and to present the target and monitoring strategies aimed at optimizing patient immunosuppression, which could help to take a step forward in the field of solid organ transplant patient care., Expert Opinion: To improve the care of transplant patients, several TDM innovations can be pursued by investigators. Among these, the development of microsampling methods for TDM or the combination of pharmacodynamic biomarkers with ISD exposure measurements appear to be relevant strategies.

We report a successful, albeit complicated pregnancy with a live-born healthy baby at 28 weeks' gestation, after 10 pregnancy failures, in a 39-year-old patient with a history of liver transplantation and chronic kidney disease with hypertension and proteinuria. Multidisciplinary management (obstetrician, nephrologist and hepatology transplant specialist) allowed close monitoring, adaptation of immunosuppressive treatments and strict control of fetal growth. The onset of preeclampsia at 28 weeks' gestation led to a cesarean section, resulting in the birth of a healthy 830 g boy, with subsequent normal development. Following pregnancy, the patient experienced liver transplant rejection, which resolved after adapting immunosuppressive drugs. No deterioration in kidney function was observed in the year following delivery., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

De novo malignancy (DNM) is the primary cause of mortality after liver transplantation (LT) for alcohol-related liver disease (ALD). However, data on risk factors for DNM development after LT are limited, specifically in patients with ALD. Therefore, we retrospectively analyzed all patients transplanted for ALD at our center before October 2016. Patients with a post-LT follow-up of <12 months, DNM within 12 months after LT, patients not on tacrolimus in the 1st year post-LT, and unknown smoking habits were excluded. Tacrolimus drug exposure level (TDEL) was calculated by area under the curve of trough levels in the 1st year post-LT. 174 patients received tacrolimus of which 19 (10.9%) patients developed a DNM between 12 and 60 months post-LT. Multivariate cox regression analysis identified TDEL [HR: 1.710 (1.211-2.414); p = 0.002], age [1.158 (1.076-1.246); p < 0.001], number of pack years pre-LT [HR: 1.021 (1.004-1.038); p = 0.014] and active smoking at LT [HR: 3.056 (1.072-8.715); p = 0.037] as independent risk factors for DNM. Tacrolimus dose minimization in the 1st year after LT and smoking cessation before LT might lower DNM risk in patients transplanted for ALD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vanlerberghe, van Malenstein, Sainz-Barriga, Jochmans, Cassiman, Monbaliu, van der Merwe, Pirenne, Nevens and Verbeek.)

Background: Cardiovascular events are one of the most important causes of morbidity and mortality in the long-term follow-up of liver transplant recipients. Hypertension is a significant cardiovascular risk factor that occurs frequently after pediatric liver transplantation. Chronic use of immunosuppressants - mainly calcineurin inhibitors - plays a major role in the development of post-transplant hypertension and circadian disturbances such as flattening of the nocturnal blood pressure dip. This requires special attention in children given the long timeframe during which immunosuppressive therapy is necessary. Careful and structured blood pressure monitoring and adequate treatment of hypertension are essential to optimize the quality of life and life expectancy of pediatric liver transplant patients. However, evidence-based guidelines for monitoring and management of post-transplant hypertension and its complications are lacking., Methods: We conducted a comprehensive review of the current knowledge and practices concerning post-transplant hypertension. The databases Pubmed, Embase, Web of Science and Google Scholar were scanned with the following keywords: pediatric liver transplantation, immunosuppression, tacrolimus, cardiovascular effects, hypertension, heart function, kidney function, circadian rhythm, mechanism, monitoring, and management., Results: In this review, we describe the incidence and etiology of hypertension in pediatric liver transplant recipients, the underlying mechanisms and characteristics of calcineurin inhibitor-induced hypertension, and the consequences of and risk factors for post-transplant hypertension. We hereby present an overview of the current practices in blood pressure monitoring and antihypertensive treatment as well as an algorithm for the evaluation and management of hypertension post liver transplantation. Finally, we discuss knowledge gaps and suggestions for future research., (© 2023 Wiley Periodicals LLC.)

Background & Aims: There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US., Methods: From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates., Results: The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant., Conclusions: Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC., Impact and Implications: The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease among liver transplant recipients is common and associated with an increased mortality risk. Several risk factors and causes for the development of chronic kidney disease have been identified. They can be divided into perioperative factors, such as unresolved acute kidney injury; donor-related factors, such as the use of extended criteria liver allografts; and recipient-related factors, such as the use of calcineurin inhibitors and the presence of metabolic syndrome, diabetes, and obesity. There is a bimodal progression, more prominent during the initial post-transplant months, followed by a gradual but progressive decline over the subsequent years. Management strategies to prevent and treat chronic kidney disease in the general population can be reasonably applied to the liver transplant population and include addressing comorbidities such as hypertension and diabetes. Strategies to minimize or withdraw calcineurin inhibitors from the immunosuppressive regimen can slow progression of kidney dysfunction. Patients with advanced chronic kidney disease should be considered for kidney transplantation due to its survival advantage. Allocation policy in the United States confers safety-net allocation priority for liver transplant recipients who develop advanced chronic kidney disease within the first year of liver transplantation., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: After liver transplantation (LT), tacrolimus and ciclosporin treatment can lead to, partially concentration-dependent, chronic kidney disease. Monitoring ciclosporin with two-hour levels reduced overexposure and led to better renal function than trough-monitoring (C0). For tacrolimus, a 4-hour level (C4) can give a reasonable approximation of total drug exposure. We evaluated whether monitoring tacrolimus in stable patients after LT by C4 was superior to C0 regarding renal function, rejection and metabolic parameters., Methods: This open label randomized controlled trial compared C4 monitoring of tacrolimus BID (Prograft) to trough (C0) monitoring in stable LT recipients. The target range for C4 of 7.8-16 ng/ml was calculated to be comparable with target C0 of 4-8 ng/ml. Primary endpoint was the effect on renal function and secondary endpoints were the occurrence of treated biopsy-proven acute rejection, blood pressure and metabolic parameters, during 3 months of follow-up., Results: Fifty patients were randomized to C0 (n = 25) or C4 (n = 25) monitoring. There was no difference in renal function between the C0 and the C4 group (p = .98 and p = .13 for CG and MDRD at 3 months). Also, the amount of proteinuria was similar (p = .59). None of the patients suffered from graft loss or was treated for rejection. Metabolic parameters did not differ between the two groups., Conclusion: Tacrolimus 4-hour monitoring in stable LT patients is not superior to trough monitoring, regarding the effect on renal function, but is safe for use to facilitate tacrolimus monitoring in an afternoon outpatient clinic., (© 2022 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background and Aims: To report 5-year outcomes of the CERTITUDE study., Methods: An observational study in patients with liver transplantation (LTx) compared the long-term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6-month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow-up., Results: Of the 143 enrolled patients, 119 completed the 5-year follow-up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, -15.53 ml/min/1.73 m 2 and EVR, -14.56 ml/min/1.73 m 2 ). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy-proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group., Conclusions: The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketorolac, are effective analgesic medications, but concerns for nephrotoxicity have limited their role for pain control following pediatric liver transplantation (LT). Calcineurin inhibitors (CNIs) and NSAIDs share a similar mechanism of nephrotoxicity, and concomitant administration is traditionally discouraged. A retrospective review of pediatric LT recipients was conducted between 1/1/2015 and 12/31/2019 at a single center. Patients were stratified based on receipt of ketorolac. The primary outcome was the incidence of acute kidney injury (AKI). Secondary outcomes included serum creatinine, urine output, estimated glomerular filtration rate, bleeding incidence, oral morphine milligram equivalents, and hospital length of stay (LOS). The incidence of AKI was similar between the two groups with 25.8% of patients in the ketorolac group versus 29.2% of patients in the nonketorolac group (p = .475) meeting criteria in the first 10 days post-transplant. Opioid requirements were less in the ketorolac group (p < .001), who also demonstrated shorter LOS compared with nonketorolac patients (p = .033). Concurrent CNI and ketorolac use did not result in an increased incidence of AKI in the early post-LT period and resulted in significantly lower opioid requirements along with a decreased hospital LOS., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

It is a well-recognized fact that implementing new guidelines in clinical practice may be difficult; therefore the Italian Society for Organ and Tissue Transplantation (SITO) set out to define practical immunosuppression tools for the management of liver transplantation patients. In 2017, an Italian Working Group of liver transplant experts and hepatologists issued a set of consensus statements along with evidence-based recommendations on the use of everolimus after liver transplantation. This article presents the evidence- and consensus-based algorithms developed within the Italian Working Group, which are aimed towards guiding clinicians in the selection of immunosuppressive regimens for the management of adult liver transplant recipients in real-life practice. The liver transplant recipient population, typically managed in clinical practice, was divided into the following categories: (1) standard patients; (2) critically ill patients; (3) patients with a specific etiology; (4) patients with hepatocellular carcinoma; (5) and patients with de novo malignancies. The algorithms are divided into two parts, according to the time from transplantation (0-3 months and > 3 months) and are discussed here along with relevant supporting literature, when available. Ultimately, it is hoped that the evidence- and consensus-based algorithms developed within the Italian Working Group, and presented here, contribute to simplify, personalize, and optimize immunosuppression of liver transplantation recipients in clinical practice.

Switching from calcineurin-inhibitors (CNI) to everolimus >6-12-months after liver transplantation (LT) seems inefficient in improving renal function, but whether everolimus halts further renal-function decline compared to low-dose CNI remains unclear. In a retrospective single-center study of everolimus after LT (2008-2016) with routine measured glomerular filtration rates (mGFR; 51 Cr-EDTA- or iohexol clearance), we compared by propensity-score matching everolimus therapy to low-dose CNI therapy. The study comprised 36 patients with everolimus introduced on average 22 months post-LT (range 2-105 months, median follow-up 3.4 years), and 36 matched controls. Everolimus introduction was associated with a mean improvement in mGFR of 7 mL/min up to 1 year ( p  = .003), restricted to patients switched <1-year post-transplant and at tacrolimus trough levels >5 ng/mL. The differences between the everolimus group and controls in delta-mGFR from baseline to 1 year (7.3 vs 4.3 mL/min, p  = .25) or 1-year to last follow-up (-0.8 vs -0.2 mL/min/year, p  = .71) were non-significant. Proportions with mGFR decline >3 mL/min/year were similar between groups (11% and 14%, p  = 1.00). Everolimus was stopped in three patients (8%), and acute rejection occurred in 17%. In conclusion, despite an early improvement in renal function after everolimus introduction, we found no evidence that everolimus halts the long-term mGFR decline compared to continued low-dose CNI therapy. Due to retrospective design, small sample size and heterogenous characteristics, definite conclusions require prospective studies.

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation., (© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: To investigate the impact of delayed calcineurin inhibitor (CNI) initiation in liver transplant recipients (LTR) with peri-operative renal insufficiency receiving basiliximab induction, we compared renal outcomes of LTR stratified by the degree of achieved post-operative renal recovery (RR) prior to CNI initiation., Methods: All adult LTR transplanted between 01/2007 and 12/2015 who received basiliximab were included. Patients who received multi-organ transplantations, were repeat transplant recipients, or expired prior to post-operative day (POD) 90 were excluded. The primary outcome of our retrospective analysis was renal function at POD 90., Results: A total of 210 patients were included in our final analysis. Most patients were Caucasian males undergoing liver transplantation for liver disease secondary to hepatitis C virus. Baseline characteristics were similar among the evaluable population. Estimated GFR was significantly higher among patients with the greatest degree of post-operative renal recovery at POD 90; however, this difference did not persist at POD 180. There was no significant difference in incidence or severity of biopsy-proven acute rejection (BPAR) at any measured time point., Conclusions: Delayed CNI initiation following liver transplantation in patients with post-operative renal insufficiency who receive basiliximab induction does not adversely affect the incidence of BPAR or long-term renal outcomes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Randomized, open-label, comparative, single-center, Phase 4, 24-week study comparing pharmacokinetics (PK), safety, and efficacy of once-daily, prolonged-release tacrolimus (PR-T) with twice-daily, immediate-release tacrolimus (IR-T) in adult de novo living-donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR-T or IR-T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration-time curve over 24 hour (AUC 0-24 ). Predefined similarity interval for confidence intervals of ratios: 80%-125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C 24 ), patient/graft survival, biopsy-confirmed acute rejection (BCAR), treatment-emergent adverse events (TEAEs). One-hundred patients were included (PR-T, n = 50; IR-T, n = 50). Compared with IR-T, 40% and 66% higher mean PR-T daily doses resulted in similar AUC 0-24 between formulations on Day 6 (PR-T:IR-T ratio of means 96.8%), and numerically higher AUC 0-24 with PR-T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC 0-24 and C 24 , and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR-T vs IR-T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR-T was efficacious; no new safety signals were detected., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In a 24-month, multicenter, single-arm, prospective study, 56 pediatric liver transplant patients with or without basiliximab induction were converted at 1-6 months post-transplant from standard calcineurin inhibitor (CN) therapy (± mycophenolic acid), to everolimus with reduced exposure to CNI (tacrolimus n=50, cyclosporine n=6). Steroid therapy was optional. Recruitment was stopped prematurely due to high rates of PTLD, treatment-related serious infections leading to hospitalization and premature study drug discontinuation. Subsequently, patients aged <7 years reverted to local standard-of-care immunosuppression. Mean tacrolimus concentration was above or near the upper end of the maintenance target range (2-5 ng/mL) until after month 6 post-enrollment. The primary variable, mean (SD) change in eGFR from baseline to month 12 (last observation carried forward), was +6.2 (19.5) mL/min/1.73 m 2 . Two patients experienced treated biopsy-proven acute rejection. No graft losses or deaths occurred. PTLD occurred in five patients (8.9%) (3/25 [12.0%] patients <2 years, 2/31 aged 2-18 years [6.5%]). Adverse events, serious adverse events, and discontinuation due to adverse events were reported in 100.0%, 76.8%, and 44.6% of patients, respectively. In conclusion, everolimus with reduced CNI improved renal function while maintaining antirejection potency in pediatric liver transplant patients but safety outcomes suggest that patients were overimmunosuppressed., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nonadherence to immunosuppressant medications is a leading cause of poor long-term outcomes in transplant recipients. The Medication Level Variability Index (MLVI) provides a vehicle for transplant outcome risk-stratification through continuous assessment of adherence. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study evaluated whether MLVI predicts late acute rejection (LAR). Four hundred pediatric (1-17-year-old) liver transplant recipients were enrolled and followed for 2 years. The a-priori hypothesis was that a higher MLVI predicts LAR. Predefined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescents to pre-adolescents. In the primary analysis sample of 379 participants, a higher prerejection MLVI predicted LAR (mean prerejection MLVI with LAR: 2.4 [3.6 standard deviation] versus without LAR, 1.6 [1.1]; p = 0.026). Fifty-three percent of the adolescents with MLVI>2 in year 1 had LAR by the end of year 2, as compared with 6% of those with year 1 MLVI≤2. A higher MLVI was significantly associated with all secondary outcomes. MLVI, a marker of medication adherence that uses clinically derived information, predicts LAR in pediatric liver transplant recipients., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses., Methods: This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant., Results: Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC 0-24 ) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC 0-24 (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC 0-24 and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations., Conclusions: Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials.gov number: NCT00189826)., (© 2017 The Authors. Clinical Transplantation Published by John Wiley & Sons Ltd.)

Introduction: Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection. Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored. Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.

The cause of post-transplant CNI-NCs is multifactorial and not ascribed solely to CNI toxicity. A total of 90 children (aged <20 years) who underwent LDLT were evaluated to investigate the predictive factors associated with CNI-NCs. Twelve patients (13.3%) developed CNI-NCs after LDLT (age range, 2-15 years). The symptoms of CNI-NCs were seizures, VD, and stupor. The median onset of CNI-NCs was 10 days (range, 5-30 days) post-transplant. In the univariate analysis, higher recipient age at LDLT, donor age and recipient's BW, lower actual GV/SLV and TAC dosage/BW, and higher mean T-Bil and sodium level for 7 days after transplantation were independently significantly associated with TAC-NCs. Multivariate analysis showed that the T-Bil level in the first week after LDLT was the only significant independent predictive factor for TAC-NCs (HR, 1.588; 95% CI, 1.042-2.358; P=.031). In conclusion, CNI-NCs occurred most frequently in children over 5 years and were associated with hyperbilirubinemia for 7 days post-transplant, regardless of TAC levels. The transplant team should refer to a neurologist to define the diagnosis and to collaborate to resolve the neurological problems., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The incidence of acute kidney injury (AKI) after liver transplantation (LTx) ranges from 17% to 94%. AKI is associated with prolonged hospitalization and increased early mortality. In our cohort study, we examined the impact of AKI on long-term patient survival and on the incidence of stage 4-5 chronic kidney disease (CKD)., Methods: We studied 491 LTx recipients at a single center between 1990 and 2012. We identified 278 pts (56.6%) with AKI defined as either an increase in serum creatinine (SCr) ≥26.5 μmol/L within 48 hour or elevation in SCr 1.5× baseline within 7 days (KDIGO criteria)., Results: In a multivariable Cox proportional hazards model, survival was worse in patients with AKI (HR: 1.41, 95% CI 1.03-1.92). Severe (stage 3) AKI was associated with worse patient survival (HR: 2.29, 95% CI 1.46-3.58). The risk of developing stage 4-5 CKD was also higher in patients with AKI (17.5% vs 9.1%) with a HR of 2.39 (95% CI 1.27-4.47). Delaying initiation of calcineurin inhibitors >48H was not associated with a decreased risk of CKD., Conclusions: Our findings suggest that AKI after LTx is associated with poor long-term outcomes, including worse survival and higher incidence of CKD stage 4-5. Strategies to prevent and manage LTx patients with AKI need to be developed., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Data from the 24-month randomized, multicenter, open-label H2304 study in 719 de novo liver transplant recipients were analyzed to evaluate the influence of variables potentially affecting immunological or renal response: recipient age, gender, end-stage disease, hepatitis C virus (HCV) status, and Model for End-stage Liver Disease score and estimated glomerular filtration rate (eGFR) at randomization (day 30). Treated BPAR was similar between everolimus with reduced tacrolimus (EVR + Reduced TAC) vs. conventional tacrolimus-based therapy (TAC Control) in all subpopulations, with a trend to lower risk under everolimus with reduced tacrolimus (EVR + Reduced TAC) in patients < 60 yrs and HCV-negative recipients. Risk of graft loss or death was similar in both treatment groups for all subpopulations. The change in eGFR to month 24 showed a benefit for EVR + Reduced TAC vs. TAC Control in all subpopulations other than those with the lowest baseline eGFR (30 to < 55 mL/min/1.73 m(2)), with a significant difference in favor of EVR + Reduced TAC for younger recipients (< 60 yr), female patients, HCV-negative patients and those with baseline eGFR of 55 to < 70 mL/min/1.73 m(2). Everolimus with reduced tacrolimus maintains efficacy to at least two yr after liver transplantation even in patients with risk factors for rejection, with particular renal benefits in specific patient subpopulations., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Recurrence of primary biliary cirrhosis (PBC) after liver transplantation (LT) is not rare and can occasionally lead to severe graft dysfunction and retransplantation. Ursodeoxycholic acid (UDCA) is a safe and effective treatment for PBC. However, whether preventive administration of UDCA after LT could lower the incidence of PBC recurrence is unknown., Methods: Patients transplanted for PBC in five French and Swiss centers from 1988 to 2010 were included. Most patients from a single center received UDCA (10-15 mg/kg/d) preventively. Recurrence of PBC was histologically defined from biopsies routinely performed at 1, 5, 10, and 15 years of follow-up, and at any time when clinically indicated., Results: A total of 90 patients with a 1-year minimum follow-up were studied retrospectively, including 19 (21%) patients receiving preventive UDCA. The mean follow-up was 12 years. Recurrence was diagnosed in 48 (53%) patients. The recurrence rates at 5, 10, and 15 years were 27%, 47%, and 61%, respectively. In a multivariate proportional hazards model adjusted for potential confounders and risk factors, preventive UDCA was the only factor affecting the risk of recurrence significantly (HR=0.32; 95% CI: 0.11-0.91). The 5, 10, and 15-year rates of recurrence were 11%, 21%, and 40%, respectively, under preventive UDCA, and 32%, 53%, and 70%, respectively, without preventive UDCA. Seven patients with recurrence (15%) progressed to cirrhosis, requiring retransplantation in one. However, neither recurrence nor preventive UDCA had a significant impact on survival., Conclusions: Preventive treatment with UDCA reduces the risk of PBC recurrence after LT., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: 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., (© 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc.)

Aim: To determine whether low-dose tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is a safe approach to decrease the incidence of chronic kidney disease (CKD) in liver transplantation (LT) recipients., Methods: We analyzed the medical records of 689 patients who underwent LT between March 1999 and December 2012 in a single Chinese center. Immunosuppression was initiated with a calcineurin inhibitor (TAC or CSA) and prednisone with or without MMF. CKD is defined by the glomerular filtration rate (GFR), estimated by an abbreviated Modification of Diet in Renal Disease formula, < 60 mL/min per 1.73 m(2) for at least 3 consecutive months after LT. Individuals with TAC trough concentrations ≤ 8 ng/mL at 3 mo after LT were defined as the low-dose group. The incidence of CKD within 5 years was compared between the TAC group and the CSA group, as well as between four subgroups (low-dose and high-dose TAC groups with or without MMF)., Results: No difference regarding the occurrence of pre-LT renal dysfunction or that of post-LT rejection was found between the TAC and CSA groups or between the four subgroups. With a definition of GFR < 60 mL/min per 1.73 m(2), the overall incidence of CKD was significantly higher in the CSA group than in the TAC group. The incidence of CKD in the low-dose TAC + MMF group (7.7%) was significantly lower than that observed in the low-dose TAC group (15.9%), high-dose TAC group (24.6%) and high-dose TAC + MMF group (18.5%). The cumulative 1-, 3- and 5-year incidence rates of CKD were 12.7%, 14.5% and 16.7%, respectively. The cumulative 5-year survival rates were 61.7% and 82.2% in patients with or without CKD, respectively., Conclusion: In LT patients, the choice of immunosuppressive therapy appears to affect renal function and patient survival.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years., (© 2014 The Authors. American Journal of Transplantation Published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.)

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long-term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long-term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow-up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post-transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus-based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus-based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials., (© 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Despite the increase in long-term survival, liver transplant recipients still exhibit higher morbidity and mortality than the general population. This is in part attributed to the lifelong administration of immunosuppression and its associated side effects. Several studies reported in the last decades have evaluated the impact of immunosuppression minimization in liver transplant recipients, but results have been inconsistent due to the heterogeneity of study designs and insufficient sample sizes. On the other hand, complete immunosuppression withdrawal has proven to be feasible in approximately 20% of carefully selected liver transplant recipients, especially in older patients and those with longer duration after transplantation. The long-term risks and clinical benefits of this strategy, however, also need to be clarified. As a consequence, and despite the general perception that a large proportion of liver recipients are over-immunosuppressed, it is currently not possible to derive evidence-based guidelines on how to manage long-term immunosuppression to improve clinical outcomes. Large clinical trials of drug minimization and/or withdrawal focused on clinically-relevant long-term outcomes are required. Development of personalized medicine tools and a deeper understanding of the pathogenesis of idiopathic inflammatory graft lesions will be pre-requisites to achieve these goals., (Copyright © 2013. Published by Elsevier B.V.)

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that are involved in regulation transplant rejection and tolerance induction. Thus, CTLA-4 and PDCD1 may be good candidate genes to evaluate in liver transplant rejection. In this retrospective study, we investigated whether four functional single nucleotide polymorphisms (SNP) of the CTLA-4 gene and PDCD1 gene were associated with susceptibility to liver transplant rejection. The SNPs -1772T>C (rs733618), -1661A>G (rs4553808) of the CTLA-4 gene, and the SNPs 7146G>A (rs11568821), 7209C>T (rs41386349) of the PDCD1 gene were genotyped by polymerase chain reaction allele specific restriction enzyme analysis (PCR-ASRA) in 100 liver recipients with acute rejection, 104 liver transplant recipients without acute rejection and 100 healthy control individuals. For the selected SNPs we did not detect any significant difference in genotypic and allelic frequencies between liver transplant recipients with and without acute rejection. In conclusion, our results suggest that the tested SNPs may not be associated with susceptibility to acute liver transplant rejection in a Caucasian population., (Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the prophylaxis of chronic kidney disease (CKD) after liver transplantation (LT) with low-dose calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF)., Methods: From March 1999 to December 2009, a total of 572 patients (478 males and 94 females) underwent LT enrolled in the study. Initial immunosuppression was by triple-drug regimens that included a CNI, MMF, and prednisone. The initial dose of CNI was 0.05-0.10 mg/kg per day for tacrolimus (TAC) and 5-10 mg/kg per d for cyclosporine A (CSA) respectively, and was gradually reduced based on a stable graft function. The serum trough level of CNI was 6-8 ng/mL for TAC and 120-150 ng/mL for CSA 3-mo post-operation, 4-6 ng/mL for TAC and 80-120 ng/mL for CSA 1-year after transplantation was expected with stable liver function. MMF was personalized between 1.0-1.5 g/d. Glomerular filtration rate (GFR) was estimated by an abbreviated Modification of Diet in Renal Disease formula. Risk factors of CKD were examined by univariate and multivariate logistic regression., Results: With a definition of GFR < 60 mL/min per 1.73 m(2), the incidence of CKD was 17.3% 5-year after LT. There were 68.3% (293 of 429 cases) patients managed to control their TAC trough concentrations within 8 ng/mL and 58.0% (83 of 143 cases) patients' CSA trough concentrations within 150 ng/mL. Of the 450 recipients followed-up over 1 year, 55.5% (183 of 330 cases) of which were treated with TAC had a trough concentration ≤ 6 ng/mL while 65.8% (79 of 120 cases) of which were treated with CSA had a concentration ≤ 120 ng/mL. The incidence of CKD in the groups of lower CNI trough concentrations was significantly lower than the groups with CNI concentrations above the ideal range. Patients with CKD had much higher CNI trough concentrations than that of patients without CKD. MMF was adopted in 359 patients (62.8%). Patients administrated with MMF had a relatively low CNI trough concentrations but with no significant difference. The graft function remained stable during follow-up. No difference was found between different groups of CNI trough concentrations. Pre-LT renal dysfunction, ages, acute kidney injury, high blood trough concentrations of CNI in 3 mo (TAC > 8 ng/mL, CSA > 150 ng/mL) and hypertension after operation were associated with CKD progression, while male gender and adoption of MMF were protection factors., Conclusion: Low dose of CNI combined with MMF managed to prevent CKD after LT with stable graft function.

Kidney dysfunction is common after liver transplantation (LT) and is often attributed to calcineurin inhibitors (CNIs). Very few studies have looked at histological causes. The study is a retrospective analysis of histological findings and diagnosis in all patients who underwent a kidney biopsy after LT from 2010 to 2020. Data are shown as mean ± standard deviation or medians (25–75 interquartile range). The study cohort consisted of 26 patients (25 males, 1 female), aged 55 ± 7 years at the time of the kidney biopsy. Kidney biopsies were done at 27.5 (6.7–60.7) months after LT. At the time of the kidney biopsy, the median serum creatinine was 2.10 (1.50–2.86) mg/dl and proteinuria was 3.8 (1.8–5.9) gm/day. Twenty-four (92%) patients were on CNIs. The diagnoses on kidney biopsies were diabetic nephropathy (n = 7), focal segmental glomerulosclerosis (n = 4), CNI nephrotoxicity (n = 3), IgA nephropathy (n = 4), chronic glomerulonephritis (n = 3), hypertensive nephropathy (n = 1), membranous glomerulonephritis (n = 1), acute on chronic interstitial nephritis (n = 1), and C1q nephropathy (n = 1), and the sample was inadequate in one patient. A total of sixteen patients had progression of kidney disease. The kidney function remained stable/improved in 6 (23%) patients, follow-up data were not available for 4 patients. Fourteen (53.8%) patients (including one with CNI nephrotoxicity) required hemodialysis at 13.5 (5.7–29) months after the kidney biopsy. Although the kidney biopsy diagnosed the cause of unexplained renal insufficiency in LT recipients, the majority of patients progressed to end-stage renal disease despite treatment modifications. The use of CNIs was an uncommon cause of renal impairment. [ABSTRACT FROM AUTHOR]

Background: Mammalian target of rapamycin (mTOR) inhibitors, such as everolimus and sirolimus, may be efficacious in preserving renal function in liver transplantation (LT) recipients while preventing hepatocellular carcinoma (HCC) recurrence.Materials and Methods: In this study, we retrospectively evaluated the safety, efficacy, and renoprotective effects of mTOR inhibitors in LT recipients. Among the 84 patients enrolled, mTOR inhibitor was commenced during the first year after LT. Renal function was measured by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation.Results: Regarding the type of mTOR inhibitor, everolimus was used in 71 patients and sirolimus in 13 patients. Concomitant tacrolimus was used in 63 patients (75.0%). For total enrolled patients, kidney function did not significantly change during 12 months after initiation of mTOR inhibitors, although tacrolimus-withdrawn patients (n = 21) showed better kidney function compared to tacrolimus-minimized patients (n = 63) after conversion. However, a significant improvement in kidney function was observed in the eGFR

Background: Mammalian target of rapamycin (mTOR) inhibitors, such as everolimus and sirolimus, may be efficacious in preserving renal function in liver transplantation (LT) recipients while preventing hepatocellular carcinoma (HCC) recurrence. Materials and Methods: In this study, we retrospectively evaluated the safety, efficacy, and renoprotective effects of mTOR inhibitors in LT recipients. Among the 84 patients enrolled, mTOR inhibitor was commenced during the first year after LT. Renal function was measured by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation. Results: Regarding the type of mTOR inhibitor, everolimus was used in 71 patients and sirolimus in 13 patients. Concomitant tacrolimus was used in 63 patients (75.0%). For total enrolled patients, kidney function did not significantly change during 12 months after initiation of mTOR inhibitors, although tacrolimus-withdrawn patients (n = 21) showed better kidney function compared to tacrolimus-minimized patients (n = 63) after conversion. However, a significant improvement in kidney function was observed in the eGFR <60 ml/min/1.73 m2 group (n = 19) 12 months after initiation of mTOR inhibitors, for both patient groups with early + mid starters (n = 7, stating within 1 year after LT) and late starters (n = 12, starting over 1 year after LT). mTOR inhibitors were safely administered without serious adverse events that led to drug discontinuation. Conclusion: We demonstrated that patients with renal impairment showed significant improvement in renal function regardless of the timing of mTOR inhibitor start, suggesting that switch to mTOR inhibitors may be beneficial when renal function declines. [ABSTRACT FROM AUTHOR]

Objective: To evaluate factors related to liver graft survival with a focus on immunosuppressive schemes based on calcineurin inhibitors (tacrolimus or cyclosporine). Methodology: This study was carried out through an open cohort constructed by deterministic and probabilistic matching through three databases of the SUS with assessment of liver graft survival from 2000 to 2015 in Brazil. From this first cohort, a second cohort was constructed by pairing 1: 1 to more precisely assess the effect of the immunosuppressive scheme on graft survival. The Kaplan-Meier method and was used to estimate the probability of survival. Cox's model of proportional risks was used to assess factors related to graft loss. Result: We found 12,687 patients in the Full cohort and 470 patients in the Matched cohort. The overall graft survival rates at 1, 5, 10, and 16 years were 72.6, 63.3, 52.8, and 45.3%, respectively. Patients younger had a longer graft survival than older ones. In the Full cohort, male patients had a higher survival rate than female ones. Therapeutic schemes based on tacrolimus were more prevalent and had a better survival rate when compared to schemes that used cyclosporine. Tacrolimus without association with antiproliferative agents or rapamycin inhibitors was the therapeutic scheme associated with greater survival rate in both cohorts (HR = 0.81, 95% CI = 0.72–0.91), (HR = 0.50, 95% CI = 0.30–0.85). In addition, white-skinned patients had longer survival rate in both cohorts (HR = 0.55, 95% CI = 0.50–0.61 and HR = 0.50, 95% CI = 0.34–0.75). On the other hand, patients who a greater time ratio without using an immunosuppressant had lower graft survival rate (HR = 6.46, 95% CI = 5.05–8.27 and HR = 6.57, 95% CI = 2.66–16.22). Conclusion: This 16-year cohort showed that the older age and the greater time ratio without using an immunosuppressant are risk factors for liver graft loss. White-skinned patients and tacrolimus-based regimens, especially tacrolimus without other immunosuppressants, are factors of better prognosis to the graft. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is an effective and lifesaving treatment for patients with end-stage liver disease and hepatocellular carcinoma. Significant improvement in intermediate and long-term survival has been possible due to advancements in immunosuppressive therapy, perioperative care, and surgical techniques. Despite these advances, metabolic complications, including diabetes mellitus, cardiovascular diseases, malignancies, and renal dysfunction, are challenging issues after LT. Acute kidney injury (AKI) and chronic kidney disease (CKD) after LT are common and result in significant morbidity and mortality. Early diagnosis of kidney injury after LT is challenging, and no technique has yet proven effective in prediction of renal dysfunction. The methods for assessing renal function range from formulas that predict glomerular filtration rate to non-invasive biomarkers. The universal adoption of the model for end-stage liver disease has a direct impact on the incidence of peri-transplant AKI and development of CKD in the long-term. Post-LT renal dysfunction is multifactorial and is usually a result of pre-transplantation comorbidities, occurrence of renal dysfunction on the waiting list, perioperative events, and post-transplant nephrotoxic immunosuppressive medication use. Early identification of patients at risk for renal dysfunction and adoption of preventive measures are crucial in the pre-transplant period. No data are currently available to suggest a surgical technique that reliably demonstrates renal protection. Nephroprotective strategies during LT follow accepted surgical practice guidelines, such as maintenance of intravascular volume and mean arterial pressure. The management of kidney disease following LT is challenging, as by the time the serum creatinine is significantly elevated, few interventions impact the course of progression. Early nephroprotective measures are strongly advised and they mostly center on delaying the administration of calcineurin inhibitors (CNIs) during the initial postoperative period, lowering CNI dosage and combining CNI with mycophenolate mofetil and everolimus. The reasons for renal failure following LT, the techniques used to diagnose it, and the therapies designed to preserve renal function both immediately and late after LT are all critically evaluated in this review. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Background: Direct‐acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon‐based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified. Methods: Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation‐related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real‐time polymerase chain reaction or luciferase assay. Results: Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P ≤ .01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P ≤ .01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT. Conclusion: For patients with HCV GT2a, GT3a, or GT4a infection, mTOR‐based immunosuppressive therapy may be beneficial. CNI‐based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease is a common complication after liver transplantation. In this study, we analyzed the results of kidney biopsy in liver transplantation recipients with renal impairment. Methods: Between 1999 and 2012, 544 liver transplants were performed at our hospital. We retrospectively analyzed the clinical and histological data of 10 liver transplantation recipients referred for kidney biopsy. Results: The biopsies were performed at a median of 24.5 months (range, 3–73 months) after liver transplantation. The serum creatinine level was 1.81±0.5 mg/dL at the time of kidney biopsy. There were no immediate complications. The most common diagnosis was glomerulonephritis (GN), such as immunoglobulin A nephropathy (n=4), mesangial proliferative GN (n=1), focal proliferative GN (n=1), and membranous GN (n=1). Typical calcineurin inhibitor (CNI)-induced nephrotoxicity was detected in three cases (30%). Chronic tissue changes such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy were present in 90%, 80%, and 80% of cases, respectively, and mesangial proliferation was detected in 40% of cases. We began treatment for renal impairment based on the result of kidney biopsy; for example, angiotensin-receptor blockers or steroids were prescribed for GN, and the CNI dose was reduced for CNI nephrotoxicity. As a result, eight of 10 patients showed improvement in glomerular filtration rate, but two progressed to end-stage renal disease. Conclusion: Kidney biopsy is a safe and effective method for determining the cause of renal impairment after liver transplantation. Management of patients based on the result of kidney biopsy may improve renal outcomes.

The article presents analysis of scientific literature of the last 20 years about medicamental immunosupression in early age pediatric liver recipients in view of immune response characteristics and immunosuppressive drugs pharmacokinetics in such patients. The modern concept of immunosuppressive therapy protocol choice in pedia- tric liver recipients depending on complications development (nephrotoxicity, arterial hypertension and neuroto- xicity, the high risk of infectious complications, post-transplant proliferative disorders, metabolic and cosmetic side effects) is presented. Different opportunities of early steroid withdrawal, calcineurin inhibitor minimization in pediatric liver allograft recipients are covered.

Aim Simeprevir (SMV) is a protease inhibitor which demonstrates good tolerability and high antiviral response in patients with hepatitis C. The clinical outcomes of triple therapy using simeprevir, pegylated interferon and ribavirin (SMV/PEG IFN/RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT) have not been well reported. In this study, we assessed the outcomes of patients with recurrent hepatitis C (genotype 1) after LDLT who received triple therapy at our hospital. Methods SMV/PEG IFN/RBV was administrated for 12 weeks (triple therapy), followed by another 12 weeks or extended period of PEG IFN/RBV (dual therapy). Virological response, interaction with calcineurin inhibitors and adverse events were retrospectively analyzed. Results Ten patients with recurrent hepatitis C after LDLT completed 12 weeks of triple therapy. Nine patients achieved rapid or early virological response, and one patient was a non-responder. The nine responders received subsequent dual therapy, and the duration of dual therapy was extended (24 to 36 weeks) in five cases. Although one patient was in relapse 8 weeks after completing the standard duration (12 weeks) of dual therapy, eight patients achieved sustained virological response for 12 weeks (SVR12). The SVR12 rate was 80%. Trough levels of calcineurin inhibitor did not show marked changes after introduction of SMV in all cases. There were no major adverse events associated with SMV. Conclusion SMV treatment may be a safe and effective option for recurrent hepatitis C after LDLT. [ABSTRACT FROM AUTHOR]

Aim Renal dysfunction is a common complication of liver transplantation ( LT), related to hepatorenal syndrome with end-stage liver disease or calcineurin-inhibitor nephrotoxicity. Chronic kidney disease ( CKD) is also a common problem in long-term survivors post- LT. This study was done to investigate the association between renal functional status soon after LT and the development of CKD. Methods We retrospectively evaluated 63 patients who were aged 18 years or older, and underwent LT at Tohoku University Hospital. The estimated glomerular filtration rate (e GFR) was calculated by the Modification of Diet in Renal Disease study equation for Japan. Results Before transplantation, 25 patients (39.7%) were diagnosed with CKD (e GFR, <60 mL/min per 1.73 m2). The incidence of CKD was 22.4% (13/58) at 2 years, 23.2% (13/56) at 3 years and 22.7% (12/54) at 5 years. The patients with CKD at 2 years post-transplant were more likely to have a history of glomerulonephritis, and were significantly older at the time of LT, compared to those without CKD. Levels of e GFR of less than 60 mL/min per 1.73 m2 in the first month post-transplant and a volume of intraoperative blood loss of more than 300 mL/kg were predictive factors for the development of CKD at 2 years post-transplant and thereafter. Conclusion We have shown that there is an improvement of renal function in the majority of patients after LT. Regardless of the presence of pre-existing CKD, both renal function status at the first month post-transplant and a volume of intraoperative blood loss were predictive factors for the development of CKD at 2 years post-transplant and thereafter. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) is a rare but serious complication of organ transplantation. This article presents the first literature review on TMA following non-renal solid organ transplantation (SOT). Ischemia–reperfusion, immunosuppressive drugs, acute interfering disease and a relative deficiency of the von Willebrand factor (vWF) cleaving protease (ADAMTS13) appear to play a major role in its pathogenesis. De novo TMA occurs in 4.0% of liver and 2.3% of lung transplant recipients, whereas the incidence remains unknown after intestinal transplantation. The median time of onset is 2, 37 and 8 weeks after liver, lung and intestinal transplantations respectively, with a three month survival of about 70%. In heart transplantation TMA is rare, occurrence is late and prognosis is poor. In TMA early after liver transplantation an elevated vWF/ADAMTS13 ratio may show diagnostic value. Early withdrawal of calcineurin inhibitors (CNI) proves to be lifesaving. Conversion to another CNI and rechallenge after resolution are generally safe, except after heart transplantation. The value of plasma exchange therapy remains controversial. [ABSTRACT FROM AUTHOR]