Primary Liver Transplant Recipients Research Articles

A novel nomogram for prognosis stratification in salvage liver transplantation: a national-wide study with propensity score matching analysis in China.

Salvage liver transplantation (SLT) has been reported to be an efficient treatment option for patients with recurrent hepatocellular carcinoma (HCC) after liver resection (LR). However, for recipients who underwent liver transplantation (LT) due to recurrent HCC after LR in China, the selection criteria are not well established. In this study, data from the China Liver Transplant Registry (CLTR) of 4,244 LT performed from January 2015 to December 2019 were examined, including 3,498 primary liver transplantation (PLT) and 746 SLT recipients. Propensity score matching (PSM) analysis was used to minimize between-group imbalances. The overall survival (OS) and disease-free survival (DFS) between PLT and SLT in recipients fulfilling the Milan or Hangzhou criteria were compared based on the multivariate analysis, nomograms were plotted to further classify the SLT group into low- and high-risk groups. In this study, the 1-, 3- and 5-year OS and DFS of SLT recipients fulfilling Milan criteria (OS, P=0.01; DFS, P<0.001) or Hangzhou criteria (OS, P=0.03; DFS, P=0.003) were significantly reduced when compared to that of PLT group after PSM analysis. Independent risk factors, including preoperative transarterial chemoembolization (TACE), alpha fetoprotein (AFP) level, tumor maximum size and tumor total diameter were selected to draw a prognostic nomogram. The low-risk SLT recipients (1-year, 95.34%; 3-year, 84.26%; 5-year, 77.20%) showed a comparable OS with PLT recipients fulfilling Hangzhou criteria (P=0.107). An optimal nomogram model for prognosis stratification and clinical decision guidance of SLT was established. The low-risk SLT recipients based on the nomograms showed comparable survival with those fulfilling Hangzhou criteria in PLT group.

Outcome of liver transplantation with grafts from brain-dead donors treated with dual hypothermic oxygenated machine perfusion, with particular reference to elderly donors

Prompted by the utilization of extended criteria donors, dual hypothermic oxygenated machine perfusion (D‐HOPE) was introduced in liver transplantation to improve preservation. When donors after neurological determination of death (DBD) are used, D‐HOPE effect on graft outcomes is unclear. To assess D‐HOPE value in this setting and to identify ideal scenarios for its use, data on primary adult liver transplant recipients from January 2014 to April 2021 were analyzed using inverse probability of treatment weighting, comparing outcomes of D‐HOPE‐treated grafts (n = 121) with those preserved by static cold storage (n = 723). End‐ischemic D‐HOPE was systematically applied since November 2017 based on donor and recipient characteristics and transplant logistics. D‐HOPE use was associated with a significant reduction of early allograft failure (OR: 0.24; 0.83; p = .024), grade ≥3 complications (OR: 0.57; p = .046), comprehensive complication index (−7.20 points; p = .003), and improved patient and graft survival. These results were confirmed in the subset of elderly donors (>75‐year‐old). Although D‐HOPE did not reduce the incidence of biliary complications, its use was associated with a reduced severity of ischemic cholangiopathy. In conclusion, D‐HOPE improves postoperative outcomes and reduces early allograft loss in extended criteria DBD grafts.

Intraoperative risk factors of acute kidney injury after liver transplantation.

Acute kidney injury (AKI) is one of the most common complications of liver transplantation (LT). We examined the impact of intraoperative management on risk for AKI following LT. In this retrospective observational study, we linked data from the electronic health record with standardized transplant outcomes. Our primary outcome was stage 2 or 3 AKI as defined by Kidney Disease Improving Global Outcomes guidelines within the first 7 days of LT. We used logistic regression models to test the hypothesis that the addition of intraoperative variables, including inotropic/vasopressor administration, transfusion requirements, and hemodynamic markers improves our ability to predict AKI following LT. We also examined the impact of postoperative AKI on mortality. Of the 598 adult primary LT recipients included in our study, 43% (n = 255) were diagnosed with AKI within the first 7 postoperative days. Several preoperative and intraoperative variables including (1) electrolyte/acid‐base balance disorder (International Classification of Diseases, Ninth Revision codes 253.6 or 276.x and International Classification of Diseases, Tenth Revision codes E22.2 or E87.x, where x is any digit; adjusted odds ratio [aOR], 1.917, 95% confidence interval [CI], 1.280–2.869; p = 0.002); (2) preoperative anemia (aOR, 2.612; 95% CI, 1.405–4.854; p = 0.002); (3) low serum albumin (aOR, 0.576; 95% CI, 0.410–0.808; p = 0.001), increased potassium value during reperfusion (aOR, 1.513; 95% CI, 1.103–2.077; p = 0.01), and lactate during reperfusion (aOR, 1.081; 95% CI, 1.003–1.166; p = 0.04) were associated with posttransplant AKI. New dialysis requirement within the first 7 days postoperatively predicted the posttransplant mortality. Our study identified significant association between several potentially modifiable variables with posttransplant AKI. The addition of intraoperative data did not improve overall model discrimination.

Post–Liver Transplant Early Allograft Dysfunction Modifies the Effect of Pre–Liver Transplant Renal Dysfunction on Post–Liver Transplant Survival

Data on 2,856 primary LT recipients transplanted between 1998 and 2018 were retrospectively reviewed. Patients who died within the first post-LT week, multi-organ transplant, and previous LT recipients were excluded. EAD was defined as 1) total bilirubin ≥10 mg/dl on POD 7, 2) international normalized ratio ≥1.6 on POD 7, and/or 3) alanine aminotransferase or aspartate aminotransferase ≥2000IU/mL in the first postoperative week. Pre-LT renal dysfunction was defined as serum creatinine >1.5mg/dl or on renal replacement therapy at LT. Patients were divided into 4 groups according to pre-LT renal dysfunction and post-LT EAD development. Recipients who had both pre-LT renal dysfunction and post-LT EAD had the worst unadjusted 1, 3, and 5-year post-LT patient and graft survival while patients who had neither renal dysfunction nor EAD had the best survival (P<0.001). Patients with either EAD or renal dysfunction had intermediate survival. After adjusting for multiple factors, the risk of death was significantly higher only in those with both pre-LT renal dysfunction and post-LT EAD (aHR 2.32, CI: 1.68-3.21, P<0.001) while those with renal dysfunction and no EAD had a comparable risk of death to those with normal kidney function at LT (aHR 1.24; CI: 0.96-1.58, P=0.094). Results remained unchanged when pre-LT renal dysfunction was redefined using different glomerular filtration rate cut-offs. Pre-LT renal dysfunction negatively impacts post-LT survival only in patients who develop EAD. Livers at higher risk of post-LT EAD should be used with caution in recipients with pre-LT renal dysfunction.

Clinical study of causes and outcomes in pediatric liver retransplantation

Objective: To investigate the etiology,clinical features and prognosis of pediatric liver retransplantation. Methods: The data of 1 024 cases of pediatric liver transplantation (<18 years old) from January 2014 to December 2019 operated at Tianjin First Central Hospital were collected,retrospectively. Retransplantation was performed in 26 cases,among which 25 cases received secondary liver transplantation and 1 case received a third liver transplantation. There were 13 male and 12 female patients among the 25 patients. The median age was 12.9(20.5) months(range: 5.8 to 134.8 months), the body weight was 8.0(5.6) kg(range: 5.0 to 30.0 kg) at the time of retransplantation. The pediatric end-stage liver disease(PELD) score was 17.0(21.3) (range: 0 to 45) before retransplantation. The etiology of retransplantation was biliary complications in 7 cases,primary nonfunction of liver graft in 5 cases,antibody-mediated rejection in 4 cases,hepatic artery thrombosis in 3 cases,portal vein thrombosis in 3 cases,concomitant hepatic artery and portal vein thrombosis in 2 cases,thrombogenesis of inferior Vena Cava in 1 case and sinusoidal obstruction syndrome in 1 case. The patients were divided into two groups according to the time interval(30 days) between two liver transplantations,8 patients were classified into early-retransplantation(≤30 days) group and 18 patients were classified into late-retransplantation (>30 days) group. The etiology of liver retransplantation,pre-transplant score,time interval between two transplantations,surgical aspects,major complications and survival rates were compared between the two groups. Continuous variables with normal distribution were compared with t test,while Mann-Whitney U test was applied to compare variables without normal distribution. Categorical variables were compared with chi-square test. The survival curves were created by Kaplan-Meier method and compared by Log Rank test. Results: The median follow-up time was 26.8(30.2) months(range: 1 day to 85.7 months), and the incidence of retransplantation was 1.9%. In the early-retransplantation group,the duration of surgery was (439.8±151.0)minutes,the graft-to-recipient weight ratio was 5.0(1.8)%(range:3.6% to 6.1%),the main cause for retransplantation were primary nonfunction and vascular complications. In the late-retransplantation group,the duration of surgery was (604.4±158.0)minutes,the graft-to-recipient weight ratio was 3.4(2.1)%(range:1.4% to 5.3%),the main cause for retransplantation were biliary complications,antibody mediated rejection and vascular complications.The 3-month,1-year and 2-year recipient survival rates in the early-retransplantation group were all 62.3%,while the recipient survival rates in the late-retransplantation group were 100%,93.8% and 93.8%,respectively. The difference of recipient survival rates was significant between the early-retransplantation group and the late-retransplantation group(P=0.019). The overall 3-month,1-year and 3-year recipient survival rates after the primary liver transplantation were 97.1%,95.4%,94.1%,respectively. Conclusions: The vascular complications,biliary complications,primary nonfunction and antibody-mediated rejection are the main causes of liver retransplantation.The PELD score is higher in patients receiving early retransplantation,while the surgery is relatively more complex in patients receiving late retransplantation,which is reflected by longer duration of surgeries. Patients in the late-retransplantation group showed similar recipient survival rates with primary liver transplantation recipients,and the survival rates are superior to those of patients in the early-retransplantation group. Infection and multiple organ failure are the most common fatal causes after retransplantation.

A comparison of rates and severity of chronic kidney disease in deceased-donor and living-donor liver transplant recipients: times matter

Background/aim The progression of chronic kidney disease (CKD) in recipients of living-donor liver transplant (LDLT) compared to deceased-donor liver transplant (DDLT) has not been studied in the literature. We hypothesize that CKD stage progression in LDLT recipients is reduced compared to that of their DDLT counterparts. Materials and methods A retrospective study was undertaken including 999 adult, single-organ, primary liver transplant recipients (218 LDLT and 781 DDLT) at 2 centers between January 2003 and December 2012, in which CKD progression and regression were evaluated within the first 3 years after transplantation. Results Waiting time from evaluation to transplantation was significantly lower in LDLT patients compared to recipients of DDLT. CKD stage progression from preoperative transplant evaluation to transplantation was significantly greater in DDLT. Deceased-donor liver transplant recipients continued to have higher rates of clinically significant renal disease progression (from stage I–II to stage III–V) across multiple time points over the first 3 years posttransplant. Furthermore, a greater degree of CKD regression was observed in recipients of LDLT.Conclusion It can be concluded that LDLT provides excellent graft and patient survival, significantly reducing the overall incidence of clinically significant CKD stage progression when compared to DDLT. Moreover, there is a significantly higher incidence of CKD stage regression in LDLT compared to DDLT. These observations were maintained in both high and low model for end-stage liver disease(MELD)populations. This observation likely reflects earlier access to transplantation in LDLT as one of the contributing factors to preventing CKD progression.

Controlled DCD Liver Transplantation Is Not Associated With Increased Hyperfibrinolysis and Blood Loss After Graft Reperfusion.

The specific effect of donation after circulatory death (DCD) liver grafts on fibrinolysis, blood loss, and transfusion requirements after graft reperfusion is not well known. The aim of this study was to determine whether transplantation of controlled DCD livers is associated with an elevated risk of hyperfibrinolysis, increased blood loss, and higher transfusion requirements upon graft reperfusion, compared with livers donated after brain death (DBD). A retrospective single-center analysis of all adult recipients of primary liver transplantation between 2000 and 2019 was performed (total cohort n = 628). Propensity score matching was used to balance baseline characteristics for DCD and DBD liver recipients (propensity score matching cohort n = 218). Intraoperative and postoperative hemostatic variables between DCD and DBD liver recipients were subsequently compared. Additionally, in vitro plasma analyses were performed to compare the intraoperative fibrinolytic state upon reperfusion. No significant differences in median (interquartile range) postreperfusion blood loss (1.2 L [0.5-2.2] versus 1.3 L [0.6-2.2]; P = 0.62), red blood cell transfusion (2 units [0-4] versus 1.1 units [0-3]; P = 0.21), or fresh frozen plasma transfusion requirements (0 unit [0-2.2] versus 0 unit [0-0.9]; P = 0.11) were seen in DCD compared with DBD recipients, respectively. Furthermore, plasma fibrinolytic potential was similar in both groups. Transplantation of controlled DCD liver grafts does not result in higher intraoperative blood loss or more transfusion requirements, compared with DBD liver transplantation. In accordance with this, no evidence for increased hyperfibrinolysis upon reperfusion in DCD compared with DBD liver grafts was found.

The Impact of Previous Abdominal Surgery in a High-Acuity Liver Transplant Population

BackgroundIt is not uncommon for liver transplant (LT) recipients to have had previous abdominal surgery (PAS) preceding transplant. The impact of PAS on morbidity and mortality in LT patients remains unclear. In this study, we investigated the correlation between PAS and LT outcomes in a high-acuity patient population. Materials and methodsThis is a single-center retrospective review of 936 adult primary LT recipients between 2012 and 2018. Patients were divided based on PAS history. PAS was subdivided into upper abdominal surgery (UAS) and lower abdominal surgery (LAS). UAS was separated into high-impact UAS and low-impact UAS. Finally, we studied patients with PAS ≤90 d versus PAS >90 d. ResultsExtensive adhesiolysis was the only significant perioperative factor between the PAS group (n = 367) and the non-PAS group (n = 569) (P < 0.001). Red blood cell (RBC) transfusion (20U versus 17U, P = 0.044) and abdominal packing (24.2% versus 13.3%, P = 0.008) were significantly higher in the UAS group (n = 186) versus the LAS group (n = 181). Patients with high-impact UAS required greater RBC (P = 0.021) and fresh frozen plasma transfusion (P = 0.005), and arterial conduits (P = 0.016) during LT. Compared with recipients with PAS >90 d (n = 338), recipients with PAS ≤90 d (n = 29) had significantly higher RBC transfusion (P = 0.046), fresh frozen plasma transfusion (P = 0.022), and abdominal packing (P = 0.025). No differences in patient and graft survival was observed. ConclusionsThese findings suggest that, with appropriate care in the perioperative setting, PAS is not a contraindication to successful LT. Careful consideration is warranted when risk stratifying patients with multiple comorbidities who had PAS, especially those with UAS or PAS ≤90 d.

Outcomes of Liver Transplantation Among Older Recipients With Nonalcoholic Steatohepatitis in a Large Multicenter US Cohort: the Re-Evaluating Age Limits in Transplantation Consortium.

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P<0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1year and 82.4% at 3years compared with 88.9% at 1year and 80.4% at 3years for non-NASH patients (log-rank P=0.58 and P=0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

Pediatric retransplantation of the liver: A prognostic scoring tool.

Few prognostic models have been created in children that receive liver retransplantation (rLT). We examined the SRTR database of 731 children that underwent second liver transplant between 2002 and 2018. Proportional hazards models using backward variable selection were used to identify recipient, donor, and surgical characteristics associated with survival. A simple prognostic scoring system or nomogram (ie, each risk factor was weighted on a five-point scale) was constructed based on the fitted model. Recipient age (P<.001), MELD/PELD (P<.001), recipient ventilated (P=.003), donor cause of death (P=.024), graft type (P=.045), first graft loss due to biliary tract complications (P=.048), and survival time of the first graft (P=.006) were significant predictors of retransplant survival. The bias-corrected Harrell's C-index for the multivariable model was 0.63. Survival was significantly different (P<.001) for those at low risk (0-4 points), medium risk (5-7 points), and high risk (8+ points). Survival was equivalent between low risk pediatric second transplant recipients and pediatric primary liver transplant recipients (P=.67) but significantly worse for medium- (P<.001) and high-risk (P<.001) recipients. With simple clinical characteristics, this scoring tool can modestly discriminate between those children at high risk and those children at low risk of poor outcomes after second liver transplant.

Use of Mycophenolate Mofetil Suspension as Part of Induction Therapy After Living-Donor Liver Transplant

The aim of this study was to evaluate recipient safety, tolerability, and pharmacokinetics of mycophenolate mofetil suspension compared with mycophenolate mofetil capsules as part of induction therapy after living-donor liver transplant. Between July 2017 and April 2019, we retrospectively enrolled 20 adult primary living-donor liver transplant recipients. Recipients were divided into 3 groups: group 1 received mycophenolate mofetil suspension of 3000 mg (n = 6), group 2 received 3000 mg mycophenolate mofetil via opened capsules (n = 8), and group 3 received mycophenolate mofetil suspension of 2000 mg (n = 6). Administration was started on postoperative day 1, with tacrolimus administered on postoperative day 2 or day 3. The values of area under the plasma concentration time curve for 0 to 12 hours were significantly higher in the 3000 mg/day mycophenolate mofetil suspension group than in the 2000 mg/day mycophenolate mofetil suspension group (P = .024) and in the 3000mg/day mycophenolate mofetil capsule group (P = .013). Significant positive correlations were shown between blood concentration at 8 hours after administration and the plasma concentration time curve for 0 to 12 hours (r2 = 0.96; P < .001) in patients in the suspension group. No patients required mycophenolate mofetil reduction because of leukopenia and diarrhea. Only 1 biopsy-proven acute cellular rejection was recognized in the mycophenolate mofetil suspension group (at 2000 mg/day). There were no significant differences in frequency of opportunistic infections among the 3 groups. Mycophenolate mofetil suspension is useful as part of immunosuppressive induction therapy after living-donor liver transplant because its concentration increases greater than that of mycophenolate mofetil capsules and because of the low risk of rejection and adverse events.

Pilot, Open, Randomized, Prospective Trial for Normothermic Machine Perfusion Evaluation in Liver Transplantation From Older Donors.

Ex situ normothermic machine perfusion (NMP) might minimize ischemia/reperfusion injury (IRI) of liver grafts. In this study, 20 primary liver transplantation recipients of older grafts (≥70years) were randomized 1:1 to NMP or cold storage (CS) groups. The primary study endpoint was to evaluate graft and patient survival at 6months posttransplantation. The secondary endpoint was to evaluate liver and bile duct biopsies; IRI by means of peak transaminases within 7 days after surgery; and incidence of biliary complications at month 6. Liver and bile duct biopsies were collected at bench surgery, end of ex situ NMP, and end of transplant surgery. Interleukin (IL) 6, IL10, and tumor necrosis factor α (TNF-α) perfusate concentrations were tested during NMP. All grafts were successfully transplanted. Median (interquartile range) posttransplant aspartate aminotransferase peak was 709 (371-1575) IU/L for NMP and 574 (377-1162) IU/L for CS (P=0.597). There was 1 hepatic artery thrombosis in the NMP group and 1 death in the CS group. In NMP, we observed high TNF-α perfusate levels, and these were inversely correlated with lactate (P<0.001). Electron microscopy showed decreased mitochondrial volume density and steatosis and an increased volume density of autophagic vacuoles at the end of transplantation in NMP versus CS patients (P<0.001). Use of NMP with older liver grafts is associated with histological evidence of reduced IRI, although the clinical benefit remains to be demonstrated.

Early Allograft Dysfunction Is Associated With Higher Risk of Renal Nonrecovery After Liver Transplantation.

Early allograft dysfunction (EAD) identifies allografts with marginal function soon after liver transplantation (LT) and is associated with poor LT outcomes. The impact of EAD on post-LT renal recovery, however, has not been studied. Data on 69 primary LT recipients (41 with and 28 without history of renal dysfunction) who received renal replacement therapy (RRT) for a median (range) of 9 (13-41) days before LT were retrospectively analyzed. Primary outcome was renal nonrecovery defined as RRT requirement 30 days from LT. Early allograft dysfunction developed in 21 (30%) patients, and 22 (32%) patients did not recover renal function. Early allograft dysfunction was more common in the renal nonrecovery group (50% vs 21%, P = 0.016). Multivariate logistic regression analysis demonstrated that EAD (odds ratio, 7.25; 95% confidence interval, 2.0-25.8; P = 0.002) and baseline serum creatinine (odds ratio, 3.37; 95% confidence interval, 1.4-8.1; P = 0.007) were independently associated with renal nonrecovery. History of renal dysfunction, duration of renal dysfunction, and duration of RRT were not related to renal recovery (P > 0.2 for all). Patients who had EAD and renal nonrecovery had the worst 1-, 3-, and 5-year patient survival, whereas those without EAD and recovered renal function had the best outcomes (P < 0.001). Post-LT EAD was independently associated with renal nonrecovery in LT recipients on RRT for a short duration before LT. Furthermore, EAD in the setting of renal nonrecovery resulted in the worst long-term survival. Measures to prevent EAD should be undertaken in LT recipients on RRT at time of LT.

Efficacy and Safety of Generic Mycophenolate Mofetil (My-rept) 500-Milligram Tablets in Primary Liver Transplant Recipients

BackgroundGeneric immunosuppressants may be cost-effective if clinical outcomes are equivalent to the brand-name medications. Mycophenolate mofetil in the form of My-rept may be cost-effective being a generic immunosuppressant, which is available as a 500-mg tablet as well as a 250-mg capsule (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea). ObjectiveThis study aimed to evaluate the efficacy, safety, cost-effectiveness, and convenience of My-rept 500-mg tablets in liver transplant recipients. SettingThe setting was an outpatient liver transplantation clinic of a tertiary hospital in Korea. MethodA phase 4, single-center, open-label, noncomparative study was undertaken. A total of 50 patients were recruited. Acute transplant rejection, changes in blood chemistry, white blood cell count, assessments of renal function, occurrence of adverse drug reactions, and other characteristics of the patients were recorded for 24 weeks. After study termination, a satisfaction survey was conducted. ResultsAll enrolled patients and their liver grafts had survived for 24 weeks post-transplantation. No episodes of acute rejection were reported. Nine patients (18.8%) presented with adverse drug reactions that had been commonly reported with the use of other mycophenolate mofetil products, and no serious adverse drug reactions were reported. ConclusionIn conclusion, the My-rept 500-mg tablet appears to be feasible and convenient for administration to recipients of a liver transplant.

An objective definition for clinical suspicion of T-cell-mediated rejection after liver transplantation.

A uniform definition of clinical suspicion of T-cell-mediated rejection (TCMR) in liver transplantation (LT) is needed to homogenize clinical decisions, especially within randomized trials. This multicenter study included a total of 470 primary LT recipients. The derivation cohort consisted of 142 patients who had clinically driven liver biopsies at any time after LT. The external validation cohort included 328 patients who underwent protocol biopsies at day 7-10 after LT. The rates of moderate-severe histological TCMR were 33.8% in the derivation cohort and 43.6% in the validation cohort. Independent predictors (ie, risk factors) of moderate-severe TCMR in the derivation cohort were as follows: serum bilirubin >4mg/dL (OR=5.83; P<.001), rising bilirubin within the 4days prior to liver biopsy (OR=4.57; P=.003), and blood eosinophils count >0.1×109 /L (OR=3.81; P=.004). In the validation cohort, the number of risk factors was an independent predictor of moderate-severe TCMR (OR=1.74; P=.001), after controlling for hepatitis C status. The number of risk factors paralleled the rates of moderate-severe TCMR in the derivation and validation cohorts (P<.001 in both comparisons). In conclusion, increased serum bilirubin, rising bilirubin and eosinophilia are validated risk factors for moderate-severe histological TCMR and could be used as objective criteria to select candidates for liver biopsy.

Subclinical Antibody-Mediated Rejection

Subclinical Antibody-Mediated Rejection

Low incidence of acute rejection in hepatitis B virus positive liver transplant recipients and the impact of hepatitis B immunoglobulin

Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects.We compared the incidence, risk factors and outcomes of ACR among 40,593 primary LT recipients with HBV, hepatitis C, steatohepatitis, and immune liver disease (OPTN 2000-2011). We also assessed the in vitro effect of HBIG on alloimmune lymphoproliferation and regulatory T cell generation using mixed lymphocyte reactions.In multivariate analysis, HBV status remained a strong independent predictor of freedom from ACR (OR 0.58, 95% CI: 1.5–2.1). Patient (67.7% vs 72.3%) and graft (60.8% vs 69.1%) survival were significantly lower in patients with ACR versus no ACR for all causes except HBV. HBIG use had no statistical association with ACR. In vitro, HBIG at concentrations equivalent to clinical dosing did not inhibit lymphoproliferation or promote regulatory T cell development.In summary, the incidence and impact of ACR is lower now for HBV LT and does not appear to be secondary to HBIG by our in vitro and in vivo analyses. Rather, it may be due to the innate immunosuppressive properties of chronic HBV infection.

Beyond the NIH Multicenter HIV Transplant Trial Experience: Outcomes of HIV+ Liver Transplant Recipients Compared to HCV+ or HIV+/HCV+ Coinfected Recipients in the United States.

The effectiveness of liver transplant (LT) in human immunodeficiency virus (HIV) and HIV/hepatitis C virus (HCV) coinfected recipients in the United States is unknown. We investigated (i) the effect of HIV on US patient and allograft LT outcomes, compared to HCV+ and HIV/HCV uninfected recipients and (ii) whether LT at centers that participated in the National Institutes of Health (NIH) Solid Organ Transplantation in HIV Trial, reflecting experience and a standardized approach to patient selection, impacted outcomes. A retrospective cohort study of primary LT recipients transplanted 27 February 2002 through 31 December 2013, categorized by serostatus: HCV+ (n = 20 829), HIV+ (n = 72), HIV+/HCV+ (n = 160), and HIV-/HCV- uninfected (n = 22 926) as reference. Survival was determined using Cox regression, stratified according to center NIH trial participation. HCV (hazard ratio [HR] 1.46, 95% confidence interval [CI], 1.41-1.52) and HIV/HCV coinfection (HR 2.62, 95% CI, 2.06-3.33) were associated with mortality; HIV monoinfection was not (HR 1.37, 95% CI, .86-2.18). This was unchanged after stratification on NIH trial participation, although mortality was higher in NIH-enrolling (HIV+: HR 1.65, 95% CI, .93-2.92; HIV+/HCV+: HR 3.15, 95% CI, 2.32-4.28) than in non-enrolling centers (HIV+: HR 1.03, 95% CI, .43-2.47, HIV+/HCV+: HR 2.55, 95% CI, 1.64-3.96). Although allograft loss was higher in HIV/HCV coinfected recipients transplanted at enrolling (HR 2.64, 9%% CI, 1.91-3.64) vs nonenrolling centers (HR 2.22, 95% CI, 1.41-3.49), there was no difference in HIV and HCV monoinfected patients. HIV+ LT recipient outcomes were superior to HCV+ or HIV/HCV coinfected recipients. Despite a standardized approach and plausibly more experience with HIV patients, transplantation at NIH study center did not improve outcomes.

Improved Survival in Liver Transplant Recipients Receiving Prolonged-Release Tacrolimus in the European Liver Transplant Registry

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data.

Potential role of the donor in hepatocellular carcinoma recurrence after liver transplantation.

A subset of liver transplantation (LT) recipients who undergo transplantation for hepatocellular carcinoma (HCC) will develop postoperative recurrence. There has yet to be a thorough investigation of donor factors influencing recurrence. Data regarding adult, primary LT recipients with HCC (n = 5002) who underwent transplantation between January 1, 2006 and September 30, 2010 were extracted from the United Network for Organ Sharing database, and the cumulative incidence of post-LT recurrence by donor factors was subsequently estimated. Among the HCC LT recipients, 324 (6.5%) developed recurrence. An analysis of donor characteristics demonstrated a higher cumulative incidence of recurrence within 4 years of transplantation among recipients with donors ≥ 60 years old (11.8% versus 7.3% with donors < 60 years old, P < 0.001) and with donors from a nonlocal share distribution (10.6% versus 7.4% with donors with a local share distribution, P = 0.004). The latter 2 findings held true in a multivariate analysis: the risk of HCC recurrence increased by 70% for recipients of livers from donors ≥ 60 years old [subhazard ratio (SHR) = 1.70, 95% confidence interval (CI) = 1.31-2.20, P < 0.001] and by 42% for recipients of nonlocal share distribution livers (SHR = 1.42, 95% CI = 1.09-1.84, P = 0.009) after adjustments for clinical characteristics. In conclusion, the consideration of certain donor factors may reduce the cumulative incidence of posttransplant HCC recurrence and thus improve long-term survival after LT.