Early allograft dysfunction after living donor liver transplantation-current concepts and future directions.

Early allograft dysfunction (EAD) after liver transplantation is a significant clinical problem that negatively impacts graft and patient outcomes. The rising incidence of EAD and what it means concerning living donor liver transplantation (LDLT) is an area of great interest. However, EAD after LDLT is a complex research topic yet to be reviewed comprehensively. Most of the literature on EAD is based on experience in deceased donor liver transplantation, and limited information is available in the context of LDLT. Thus, in this review, we present an overview of EAD after LDLT and have attempted to present balanced points of view on all its aspects, such as definitions, pathogenesis, risk factors, predictive markers, and management. The review aims to broadly overview the nature and extent of ongoing research evidence on this complex topic and inform practice in the field by identifying key concepts and knowledge gaps and highlighting areas that require further inquiry.

Incorporating Tumor Biology to Predict Hepatocellular Carcinoma Recurrence in Patients Undergoing Living Donor Liver Transplantation Using Expanded Selection Criteria.

Conventional selection criteria for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) are based on tumour size/number only, and do not consider vital surrogates of tumor biology such as alpha-fetoprotein (AFP) and tumor [18 F]fluorodeoxyglucose positron emission tomography ([18 F]FDG PET) avidity. We analyzed survival outcomes, and predictors of HCC recurrence in 405 patients with cirrhosis and HCC (HCC-cirr) who underwent living donor LT (LDLT) using our expanded selection criteria: no extrahepatic disease or major vascular invasion, irrespective of tumor size/number. Fifty-one percent patients had tumours beyond Milan, and 43% beyond the University of California San Francisco [UCSF] criteria. The 5-year overall survival (OS) and recurrence-free survival (RFS) were 64% and 70%, respectively. Three preoperatively available factors predicted recurrence: pre-LT AFP ≥100 ng/mL (P = 0.005; hazard ratio [HR], 2.190), tumor burden beyond the UCSF criteria (P = 0.001; HR, 2.640), and [18 F]FDG PET avidity (P = 0.004; HR, 2.442). A prognostic model based on the number and combination of the aforementioned preoperative risk factors was developed using a competing-risk RFS model. Three risk groups were identified: low (none or a single risk factor present, 9.3% recurrence), moderate (AFP ≥100 ng/mL and [18 F]FDG PET avidity, or beyond UCSF tumor and [18 F]FDG PET avidity, 25% recurrence), and high (AFP ≥100 ng/mL and beyond UCSF, or presence of all 3 risk factors, 46% recurrence). Acceptable long-term outcomes were achieved using our expanded selection criteria. Our prognostic model to predict recurrence based on preoperative biological and morphological factors could guide pretransplant management (downstaging versus upfront LDLT) with the aim of reducing post-LDLT recurrence.

Living donor financial assistance programs in liver transplantation: The global perspective.

Living donor liver transplantation (LDLT) has increased availability of liver transplantation, particularly in countries with limited access to deceased organ donors. It is unclear how individual countries address the financial impact of donation for potential living donors. Herein, living liver donor financial supports were examined, focusing on countries performing ≥10 LDLT per year in the World Health Organization Transplant Observatory. Categories included health insurance coverage, reimbursement of lost wages, employment protection, and other incentives designed to promote living liver donation. Overall, 26 countries have some form of asssistance in removing disincentives to ease the financial burden of living donation, ranging from childcare, accommodations, meals, and travel reimbursement, to coverage of medical complications post-donation. Most countries provide donation-related medical coverage. Fourteen provide reimbursement of lost wages and/or paid time off. Several unique programs were designed to incentivize living donation, including free entry to museums and observatories, parking and airline discounts, and exemptions on mortgages and medical deductibles. This study highlights the broad range of programs designed to support living liver donation in high-volume LDLT countries. The data collected in this study can provide a framework for other nations to propose and implement ethical reimbursement and incentivization for living liver donors.

Living Donor Liver Transplantation for Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute decompensation of previously diagnosed or undiagnosed liver disease with organ failure(s) with high short-term mortality. This study was conducted to report the outcomes of living donor liver transplantation (LDLT) in ACLF and assess the survival benefit of liver transplantation (LT) in these patients. It was a retrospective study of 218 ACLF patients on the basis of European Association for the Study of the Liver (EASL)-chronic liver failure criteria from January 2014 through November 2017. Patients were considered for LDLT if there was no improvement on standard medical therapy for 5-10 days. Prior to LDLT, active sepsis was excluded/treated, and renal, circulatory, and respiratory failures were improved to the greatest extent possible. The mean age was 42.9 years, and 181 patients were male. Sepsis was the most common acute precipitating event followed by alcohol. Of the patients, 35 (16.1%), 66 (30.3%), and 117 (53.7%) were classified into ACLF grades 1, 2, and 3, respectively. Although 80% of the ACLF 1 group and 72.7% of the ACLF 2 group underwent LDLT, only 35% of the ACLF 3 group could undergo LDLT. The circulatory and respiratory failures at admission were significantly higher in the nontransplant group with poor subsequent response to standard medical therapy, exclusion from LDLT, and poor outcomes. None of the patients on high support for circulatory and respiratory failure underwent LDLT. Posttransplant survival at 1 year was comparable among different grades of ACLF (92.9%, 85.4%, and 75.6%; P = 0.15). Among patients in the ACLF 3 group, survival at 90 days was extremely poor in those who could not undergo LDLT (5.9% versus 78%; P < 0.001). In conclusion, LDLT results in good survival with acceptable post-LT morbidity in patients with ACLF.

Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: A single center experience.

BACKGROUND AND AIMS: Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires retransplantation. This study evaluates the incidence and outcome of the patients with CR at a large living donor liver transplant (LDLT) center. METHODS: Data of patients with CR were retrospectively analyzed in 1232 adult (age >18 years) LDLT on tacrolimus (mainly)-based immunosuppression. Sirolimus/everolimus (mammalian target of rapamycin [mTOR] inhibitors) was added to baseline immunosuppression as rescue therapy in patients with CR. Data are shown as median (interquartile range [IQR]). RESULTS: Twenty-three patients (22 males), aged 42 (IQR 45-56) years, had biopsy-proven chronic rejection at 21 (8-44) months after liver transplantation. The incidence of chronic rejection was 1.9% in this cohort. The patients with CR (n = 23) had a significantly higher incidence of cytomegalovirus (CMV) viremia, acute cellular rejection, and history of anastomotic biliary strictures as compared to patients without CR. Five patients were noncompliant with immunosuppression before the diagnosis of CR. Twelve patients (52%) responded to addition of mTOR inhibitors, whereas 11 did not respond and had poor outcome. CONCLUSION: The incidence of chronic rejection is low in LDLT. Treatment with mTOR inhibitors can reverse graft dysfunction in approximately half of the patients.

Right lobe donor hepatectomy: is it safe? A retrospective study.

Donor safety is utmost important in Living donor liver transplantation (LDLT). Small for size syndrome in some recipients with left lobe donors led to the evolution of right lobe LDLT. The aim of the study was to analyze the safety of large series of right lobe (RL) donor hepatectomies and compare outcomes with left lobe (LL) and left lateral segment (LLS) donations. A consecutive cohort of 726 donors from January 2011 to January 2014 were studied; RL (n = 641, 88.3%), LL (n = 36, 4.9%) or LLS (n = 49, 6.8%) depending on the type of donation. The mean age was 34.6 ± 10 years. The overall complication rate was 22.3%. Most were Clavien grade I and II. Clavien grade IIIa, IIIb, IV and V were noted in 4.2% donors. The incidence of these major complications were comparable among RL (n = 28, 4.2%), LL (n = 1, 2.7%) and LLS (n = 2, 4.08%) (P = 0.89). Bile leak was seen in 20 donors (2.7%) and 13 were managed conservatively with prolonged or additional intra-abdominal drainage. Seven underwent re-exploration for bile leak. In centres experienced in right lobe LDLT, morbidity after RL donation is similar to that of LL donation; and with adequate GRWR, same 1-year recipient outcomes.

Cytomegalovirus infection in living donor liver transplant recipients significantly impacts the early post-transplant outcome: A single center experience.

BACKGROUND: Cytomegalovirus (CMV) is the most common viral infection in liver transplant recipients that influences the outcomes of liver transplantation. However, its impact on early outcomes following living donor liver transplantation (LDLT) is not fully defined in the Indian subcontinent. This study was done to assess the impact of CMV infection on early post-transplant outcomes in LDLT recipients. METHODS: Out of 272 LDLTs performed from January 2012 to April 2013, 151 recipients underwent CMV viral load analysis in plasma within 90 days post LDLT based on clinical suspicion. Patients with CMV infection (n = 55) were compared with those without CMV infection (n = 96). RESULTS: The median time interval of CMV infection from LDLT was 25 days (range 2-90 days). The mean age of study population was 48.92 years. About 116 (76.8%) of the patients were male. Hepatitis C virus (HCV) (39.1%)-related chronic liver disease (CLD) was most common indication for liver transplant. No statistically significant difference was observed in etiology of liver disease (P = .38), Chid-Turcotte-Pugh (CTP) (P = .41), and Model for End-stage Liver Disease (MELD) (P = .12) scores between the groups. Patients with CMV infection had significantly higher incidence of acute cellular rejection (16.1% vs 5.4%, P = .02); longer ICU stay (P = .01); and a higher overall 90-day mortality (24.2% vs 6.7%, P = .001). Bacteremia and fungemia were significantly more common in the CMV infection group. CONCLUSION: Cytomegalovirus infection significantly influences the early post LDLT outcomes and contributes to increased overall mortality.

Epidemiological Analysis of Extended-Spectrum Beta-Lactamase-Producing Bacterial Infections in Adult Live Donor Liver Transplant Patients.

INTRODUCTION: Bacterial infections are a leading cause of morbidity and mortality in patients receiving solid-organ transplants. Extended-spectrum beta-lactamases (ESBL) pathogens are the most important pathogenic bacteria infecting these patients. AIM: This study aims to evaluate for the incidence and characteristics of ESBL-positive organism, to look for the clinical outcomes in ESBL-positive infected cases, and to evaluate and draft the antibiotic policy in posttransplant patients during the first 28 days posttransplant. MATERIALS AND METHODS: This is a retrospective data analysis of liver transplant recipients infected with ESBL culture-positive infections. All the culture sites such as blood, urine, and endotracheal tube aspirates were screened for the first ESBL infection they had and noted. This data were collected till day 28 posttransplant. The antibiotic susceptibility pattern and the most common organism were also noted. RESULTS: A total of 484 patients was screened and 116 patients had ESBL-positive cultures. Out of these, 54 patients had infections and 62 patients were ESBL colonizers. The primary infection site was abdominal fluid (40.7%), with Klebsiella accounting for most of the ESBL infections. Colistin was the most sensitive antibiotic followed by tigecycline. The overall mortality was 11.4% and 31 out of 54 ESBL-infected patients died. CONCLUSIONS: Infections with ESBL-producing organism in liver transplant recipients has a high mortality and very limited therapeutic options.

High MELD score does not adversely affect outcome of living donor liver transplantation: Experience in 1000 recipients.

In countries where deceased organ donation is scarce, there is a big gap between demand and supply of organs and living donor liver transplantation (LDLT) plays an important role in meeting this unmet need. This study was conducted to analyze the effect of pretransplant Model for End-stage Liver Disease (MELD) score on outcomes following LDLT. The outcome of 1000 patients who underwent LDLT from July 2010 to March 2015 was analyzed retrospectively. Patients were grouped into low MELD<25 and high MELD ≥25 score to compare short-term outcomes. Cumulative overall survival rates were calculated using Kaplan-Meier methods. A total of 849 recipients were in low MELD group (Mean MELD=16.90±9.2) and 151 were in high MELD group (Mean MELD=28.77±7.2). No significant difference in etiology of CLD was observed between groups except for a higher prevalence of hepatitis C virus (29.6% vs 19.9%, P=.01) in low MELD patients. No significant difference was observed in 1-year survival (88.5% vs 84.1%, P=.12) between the groups. The multivariate analysis showed that pretransplant MELD score does not predict survival of recipients. Pretransplant high MELD score does not adversely affect outcomes after LDLT. In view of shortage of deceased organs, LDLT can be a good option in high MELD recipients.

Prediction of nonalcoholic fatty liver in prospective liver donors.

BACKGROUND: Metabolic risk factors should be important in addition to imaging for prediction of steatosis in prospective liver donors. MATERIALS AND METHODS: The study group included all prospective liver donors who had a liver biopsy during workup. Risk factors of metabolic syndrome were analyzed, and body mass index (BMI) ≥25 kg/m2 was used in place of waist circumference. Three BMI cutoffs (25, 28, and 30 kg/m2 ) and two CT-measured liver attenuation index (LAI) cutoffs (<5 and ≤10) were used for steatosis assessment of ≥5%, ≥10%, and ≥20%. RESULTS: Of the 573 prospective donors (307 females), 282 (49.2%) donors had nonalcoholic fatty liver (NAFL). When donors with NAFL were compared with donors having normal histology, multivariate analysis showed BMI, ALT, triglycerides, and LAI as significant predictors of NAFL. BMI ≥25 kg/m2 and LAI <10 were better cutoffs. The presence of ≥2 metabolic risk factors had better sensitivity than CT-LAI for the presence of NAFL and ≥20% steatosis (58% and 54% vs 47% and 22%, respectively, for CT-LAI ≤10). The presence of LAI >10 and <2 metabolic risk factors predicted <10% steatosis with 96% specificity and 92% positive predictive value. CONCLUSION: The presence of ≥2 metabolic risk factors improves sensitivity of CT-LAI for prediction of donor steatosis.

Good outcome of living donor liver transplantation in drug-induced acute liver failure: A single-center experience.

INTRODUCTION: Drug-induced acute liver failure (ALF) is associated with high mortality. There is limited literature on results of living donor liver transplantation (LDLT). MATERIAL AND METHODS: The study was conducted at a tertiary care center in North India. All patients who received LDLT for drug-induced ALF were included. The data are shown as median (IQR). RESULTS: A total of 18 patients (15 females and three males), aged 34 (25-45) years, underwent LDLT for drug-induced liver injury (DILI)-related ALF. Etiology of ALF was antitubercular medications (n=14), orlistat (n=1), flutamide (n=1), and complementary alternative medications (n=2). The baseline parameters were as following: bilirubin 17.7 (16.3-23.8) mg/dL, INR 3.3 (2.5-4.0), jaundice encephalopathy interval 6 (3-17.5) days, arterial ammonia 109 µmol/L (73-215), Model for End-Stage Liver Disease (MELD) 24 (18-33), grade of encephalopathy 2 (1-4), which progressed to grade 3 (3-4) before transplantation. All patients underwent right lobe LDLT; hospital stay was 17 (13-22) days, and ICU stay was 5 (5-7) days. Two patients died in the first month after liver transplantation due to sepsis and multi-organ failure; the rest of the patients are alive and doing well at a follow-up of 50 (4-82 months). CONCLUSION: Good outcomes can be obtained by LDLT for drug-induced ALF.

(D+10) MELD as a novel predictor of patient and graft survival after adult to adult living donor liver transplantation.

We modified the previously described D-MELD score in deceased donor liver transplant, to (D+10)MELD to account for living donors being about 10 years younger than deceased donors, and tested it on living donor liver transplantation (LDLT) recipients. Five hundred consecutive LDLT, between July 2010 and December 2012, were retrospectively analyzed to see the effect of (D+10)MELD on patient and graft survival. Donor age alone did not influence survival. Recipients were divided into six classes based on the (D+10)MELD score: Class 1 (0-399), Class 2 (400-799), Class 3 (800-1199), Class 4 (1200-1599), Class 5 (1600-1999), and Class 6 (>2000). The 1 year patient survival (97.1, 88.8, 87.6, 76.9, and 75% across Class 1-5, P=.03) and graft survival (97.1, 87.9, 82.3, 76.9, and 75%; P=.04) was significantly different among the classes. The study population was divided into two groups at (D+10)MELD cut off at 860. Group 1 had a significantly better 1 year patient (90.4% vs 83.4%; P=.02) and graft survival (88.6% vs 80.2%; P=.01). While donor age alone does not predict recipient outcome, (D+10)MELD score is a strong predictor of recipient and graft survival, and may help in better recipient/donor selection and matching in LDLT.