Risk factors and criteria predicting early graft loss after adult-to-adult living donor liver transplantation

Background

Because deceased liver donors are scarce, adult-to-adult living donor liver transplantation (LDLT) is considered a suitable alterative. However, LDLT grafts are usually partial, resulting in a higher risk of early graft loss (EGL). The aim of the present study was to identify the risk factors and criteria predicting EGL after LDLT.

Methods

We retrospectively analyzed 178 consecutive adults who underwent LDLT. The recipients were divided into two groups as follows: group I, wherein patients showed graft survival longer than 3 mo after LDLT (n = 164), and group II, wherein graft loss occurred within 3 mo after transplantation (n = 14).

Results

Univariate analysis showed various risk factors; however, only the preoperative model for end-stage liver disease score, the presence of obvious pretransplant portal hypertension, and intraoperative blood loss were identified as independent predictors of EGL by multivariate analysis. After LDLT, significant differences were observed between the groups in the fold change in total bilirubin levels over postoperative day (POD) 1 (TBIL-f1) and in the international normalized ratio over POD 1 (INR-f1). The combination of TBIL-f1 and INR-f1 on POD 10 was found to be a strong EGL predictor. Furthermore, a minimum indocyanine green (ICG) clearance rate constant K (m-K_ICG) <0.100/min after POD 3 was found to be the strongest predictor of EGL (sensitivity, 100%; specificity, 97.2%).

Conclusions

The postoperative m-K_ICG and combination of TBIL-f1 and INR-f1 on POD 10 were useful predictors of EGL; moreover, m-K_ICG was superior and is expected to be especially useful for ensuring timely retransplantation.     

The Eurotransplant Donor Risk Index in Liver Transplantation: ET‐DRI

Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan–Meier and Cox regression models. From 5723 patients follow‐up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET‐DRI). Concordance‐index calculation shows this ET‐DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET‐DRI for risk indication and possibly for allocation purposes within the Eurotrans‐plant region.     

The difficulty in defining extended donor criteria for liver grafts: the Eurotransplant experience

Donor criteria for liver grafts have been expanded because of organ shortage. Currently, no exact definitions for extended donor grafts have been established. The aim of this study was to analyze the impact of donor‐specific risk factors, independent of recipient characteristics. In collaboration with Eurotransplant and European Liver Transplant Register, solely donor‐specific parameters were correlated with 1‐year survival following liver transplantation. Analyses of 4701 donors between 2000 and 2005 resulted in the development of a nomogram to estimate graft survival for available grafts. Predictions by nomogram were compared to those by Donor Risk Index (DRI). In the multivariate analysis, cold ischemic time (CIT), highest sodium, cause of donor death, γ‐glutamyl transferase (γ‐GT), and donor sex (female) were statistically significant factors for 3 months; CIT, γ‐GT, and cause of donor death for 12‐month survival. The median DRI of this study population was 1.45 (Q1: 1.17; Q3: 1.67). The agreement between the nomogram and DRI was weak (kappa = 0.23). Several donor‐specific risk factors were identified for early survival after liver transplantation. The provided nomogram will support quick organ quality assessment. Nevertheless, this study showed the difficulties of determining an exact definition of extended criteria donors.     

Association between donor age and risk of graft failure after liver transplantation: an analysis of the Eurotransplant database

Grafts from elderly donors are increasingly used for liver transplantation. As of yet there is no published systematic data to guide the use of specific age cutoffs the effect of elderly donors on patient outcomes must be clarified. This study analyzed the Eurotransplant database (01/01/2000–31/07/2014; N = 26 294) out of whom 8341 liver transplantations were filtered to identify for this analysis. 2162 of the grafts came from donors >60 including 203 from octogenarians ≥80 years. Primary outcome was the risk of graft failure according to donor age using a confounder adjusted Cox‐Regression model with frailty terms (or random effects). The proportion of elderly grafts increased during the study period [i.e., octogenarians 0.1% (n = 1) in 2000 to 3.4% (n = 45) in 2013]. Kaplan–Meier and Cox‐analyses revealed a reduced survival and a higher risk for graft failure with increasing donor age. Although the age effect was allowed to vary non‐linearly, a linear association hazard ratio (HR = 1.1 for a 10 year increase in donor age) was evident. The linearity of the association suggests that there is no particular age at which the effect increases more rapidly, providing no evidence for a cutoff age. In clinical practice, the combination of high donor age with HU‐transplantations, hepatitis C, high MELD‐scores and long cold ischemic time should be avoided.     

Considering extended right lobe grafts as major extended donor criteria in liver transplantation is justified

The outcomes of split-liver transplantation are controversial. This study compared outcomes and morbidity after extended right lobe liver transplantation (ERLT) and whole liver transplantation (WLT) in adults. MEDLINE and Web of Science databases were searched systematically and unrestrictedly for studies on ERLT and its impact on graft and patient survival, and postoperative complications. Graft loss and patient mortality odds ratios (OR) and 95% confidence intervals (CI) were assessed by meta-analyses using Mantel–Haenszel tests with a random-effects model. Vascular and biliary complications, primary nonfunction, 3-month, 1-, and 3-year graft and patient survival, and retransplantation after ERLT and WLT were analyzed. The literature search yielded 10 594 articles. After exclusion, 22 studies (n = 75 799 adult transplant patients) were included in the analysis. ERLT was associated with lower 3-month (OR = 1.43, 95% CI = 1.09–1.89, P = 0.01), 1-year (OR = 1.46, 95% CI = 1.08–1.97, P = 0.01), and 3-year (OR = 1.37, 95% CI = 1.01–1.84, P = 0.04) graft survival. WL grafts were less associated with retransplantation (OR = 0.57; 95% CI = 0.41–0.80; P < 0.01), vascular complications (OR = 0.53, 95% CI = 0.38–0.74, P < 0.01) and biliary complications (OR = 0.67; 95% CI = 0.47–0.95; P = 0.03). Considering ERLT as major Extended Donor Criteria is justified because ERL grafts are associated with vasculobiliary complications and the need for retransplantation, and have a negative influence on graft survival.     

Early‐ and long‐term outcomes of liver transplantation with rescue allocation grafts

In France, liver grafts which have been refused by at least five centers are proposed as rescue allocation (RA). The aim of this study is to clarify the feasibility and safety of RA grafts in liver transplantation (LT). Short‐ and long‐term outcomes of patients who received RA grafts (RA group) were compared with those of patients who received standard allocation (SA) grafts (SA group). From a total of 1635 patients, 102 patients received RA grafts. Before matching, the RA group was characterized primarily by less severe liver disease, but the quality of graft was worse. After matching recipients' characteristics of 102 patients who used RA grafts with 306 patients who used SA grafts, recipients' characteristics were well balanced (1:3 matching). Although the rate of primary dysfunction was significantly higher in the RA group, there is no significant difference in the occurrence of major complications, length of hospitalization, and mortality between two groups. Graft survival (GS) and overall survival (OS) in the RA group were not significantly different from the SA group (GS; HR = 1.03 P = .89, OS; HR = 1.03 P = .90). In the French allocation system, the feasibility and safety of RA grafts might be comparable to SA grafts for carefully selected patients.     

Evaluation of graft stiffness using acoustic radiation force impulse imaging after living donor liver transplantation

Acoustic radiation force impulse (ARFI) imaging is an ultrasound‐based modality to evaluate tissue stiffness using short‐duration acoustic pulses in the region of interest. Virtual touch tissue quantification (VTTQ), which is an implementation of ARFI, allows quantitative assessment of tissue stiffness. Twenty recipients who underwent living donor liver transplantation (LDLT) for chronic liver diseases were enrolled. Graft types included left lobes with the middle hepatic vein and caudate lobes (n = 11), right lobes (n = 7), and right posterior segments (n = 2). They underwent measurement of graft VTTQ during the early post‐LDLT period. The VTTQ value level rose after LDLT, reaching a maximum level on postoperative day 4. There were no significant differences in the VTTQ values between the left and right lobe graft types. Significant correlations were observed between the postoperative maximum value of VTTQ and graft volume‐to‐recipient standard liver volume ratio, portal venous flow to graft volume ratio, and post‐LDLT portal venous pressure. The postoperative maximum serum alanine aminotransferase level and ascites fluid production were also significantly correlated with VTTQ. ARFI may be a useful diagnostic tool for the noninvasive and quantitative evaluation of the severity of graft dysfunction after LDLT.     

The role of living-donor liver transplantation in surgical treatment for hepatocellular carcinoma

Background/Purpose The role of living-donor liver transplantation (LDLT) in the surgical treatment of patients with hepatocellular carcinoma (HCC) has not been established as yet. Methods Preliminary experience gained from 24 patients who underwent LDLT for HCC between March 2002 and November 2004, and the results of the 131 patients who underwent hepatic resection (HR) for HCC between January 1990 and December 2003 were retrospectively analyzed. The exclusion criteria for LDLT for HCC included extrahepatic metastasis and major vascular invasion. Results (1) LDLT: the median age of the patients was 57 years and the Child-Pugh grades (A/B/C) of the patients were 6, 12, and 6, respectively. The tumor size was 3 cm or less in 15 patients, multinodular tumors were present in 23 patients, and 11 patients (45.8%) met the Milan Criteria. The overall 2-year survival rate was 72.3%, without a significant difference as to whether or not patients met the Milan criteria. (2) HR: on multivariate analysis, the Child-Pugh grade, the presence of cirrhosis, and the number of tumor nodules were considered as independent risk factors for unfavorable survival (P < 0.05). The 84 patients who met the Milan criteria and were Child-Pugh grade A had a 5-year survival rate of 71.3%; this was significantly better than those of the other patients (P < 0.005). Among the 57 patients with intrahepatic recurrence, 18 patients who were Child-Pugh grade A, met the Milan criteria, and were treated by re-resection or ablation therapy achieved a significantly better 5-year survival rate, of 73.1%, as compared to 19.7% in the other 39 patients (P < 0.0045). Conclusions HR could be a first-line treatment with a favorable prognosis for patients who have resectable HCC, preserved liver function, and who meet the Milan criteria. Salvage LDLT could be employed in patients with recurrent tumors that cannot be controlled by conventional treatment or in patients in whom liver function has deteriorated to Child-Pugh grade B or C.     

Extended right split liver graft for primary transplantation in children and adults.

Skepticism remains about the use of the extended right (ER) split graft (segments I, IV-VIII) for adult liver transplantation. We analyzed the results of primary liver transplantation performed with an ER graft in adult and in pediatric recipients. At our Institution, between October 1997 and June 2005, 32 primary liver transplantations with an ER graft were performed in 22 adult and 10 pediatric recipients. All the splitting procedures were performed in situ. Actuarial patient and graft survival among the adult recipients of the ER graft were 100% and 100% at 1 year, and 94% and 94% at 5 years. In the pediatric recipients, patient and graft survival were 90% and 79% both at 1 and 5 years. No hepatic artery thrombosis (HAT) occurred in the adult group, while in the pediatric recipients HAT occurred in two cases. A higher biliary morbidity occurred in the ER graft group when compared with the whole size graft 34% versus 13% (P = 0.03). However, this did not affect patient and graft survival. The results of this study may represent a further argument in favor of extensive splitting of all suitable grafts.     

Donor outcome and liver regeneration after right-lobe graft donation

Sufficiently detailed information on donor safety and the liver regeneration process following right-lobe living donation has been unavailable, so we evaluated donor outcome and liver regeneration in 13 males and 14 females (39.0 +/- 14.8 years old) who provided 27 right-lobe grafts without the middle hepatic vein. Preoperative total liver volume (TLV), graft volume, and postoperative changes in residual liver volume (RLV) were measured by volumetric computed tomography. Histological steatosis of the liver was graded as none, minimal (< or =10%), and mild (11-30%). The median follow-up period was 337 days. Estimated graft volume and actual graft weight were linearly correlated (Y = 177.85 + 0.795X, R(2) = 0.812, P < 0.0001). Graft-to-recipient weight ratio was 1.08 +/- 0.19%. Four donors had postoperative complications, but they resolved in response to conservative treatment. Postoperative hospital stay was 15.2 +/- 5.5 days. Peak liver enzyme values were significantly higher in donors with mild steatosis (n = 7) than without steatosis (n = 16) (P < 0.05). Donor RLV was 40.8 +/- 6.6% of original TLV at surgery, 79.8 +/- 12.0% by 6 months, and 97.2 +/- 10.8% by 12 months. At 3 months the liver of the older donors (> or =50 years) had grown significantly more slowly than in younger donors (70.4 +/- 9.2% vs. 79.3 +/- 9.6%, P = 0.0391). In conclusion, right hepatectomy without middle hepatic vein of living donors is a safe procedure with acceptable morbidity, and the residual liver regenerated to its preoperative size by 1 year. However, meticulous care should be taken in donors with liver steatosis and aged donors.     

The joint impact of donor and recipient parameters on the outcome of heart transplantation in Germany after graft allocation

Organ shortage in heart transplantation (HTx) results in increased use of grafts from donors with substantial risk factors. It is discussed controversially which donor characteristics may be detrimental. Therefore, we evaluated the joint impact of donor‐ and patient‐related risk factors in HTx on patient survival by multiple analysis in a nationwide multicentre study after donor selection was carried out. The research database consists of data concerning hearts donated and transplanted in Germany between 2006 and 2008 as provided by Deutsche Stiftung Organtransplantation and the BQS Institute. Multiple Cox regression (significance level 5%, hazard ratio [95% CI]) was conducted (n = 774, recipient age ≥ 18 years). Survival was significantly decreased by donor age (1.021 [1.008–1.035] per year), nontraumatic cause of death (1.481 [1.079–2.034]), troponin >0.1 ng/ml (2.075 [1.473–2.921]), ischaemia time (1.197 [1.041–1.373] per hour), recipient age (1.017 [1.002–1.031] per year) and in recipients with pulmonary vascular resistance ≥320 dyn*s*cm^?5 (1.761 [1.115–2.781]), with ventilator dependency (3.174 [2.211–6.340]) or complex previous heart surgery (1.763 [1.270–2.449]). After donor selection had been conducted, multiple Cox regression revealed donor age, nontraumatic cause of death, troponin and ischaemia time as well as recipient age, pulmonary hypertension, ventilator dependency and previous complex heart surgery as limiting risk factors concerning patient survival.     

Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation

Kupffer cell depletion by gadolinium chloride (GdCl₃) in rat livers has previously been proven to minimize hepatic ischemia/reperfusion injury after experimental liver transplantation (LTX). In the current study, we evaluated the effects of donor pretreatment with GdCl₃ on hepatic ischemia/reperfusion injury, macro- and microcirculation, and endotoxin clearance of the liver in a porcine model of experimental LTX. Two groups of 12 pigs were treated either with intravenous NaCl (0.9%; control) or GdCl₃ (20 mg/kg). Twenty-four hours after pretreatment, hepatic macrocirculation was quantified by Doppler flowmetry and liver parenchymous microcirculation by implanted thermodiffusion electrodes. The liver grafts were transplanted after 4–6 h of cold ischemia in University of Wisconsin (UW) solution. At 1 and 24 h after LTX, the perfusion values were re-evaluated and histology, biochemical (aspartate aminotransferase, AST) and functional parameters (partial thromboplastin time, prothrombin time, and bilirubin) were analyzed. Furthermore, endotoxin clearance of the liver was evaluated at all time points. In GdCl₃-treated animals 80% of the Kupffer cells were destroyed, and 24 h after LTX ischemia/reperfusion injury in treated grafts was significantly lower in comparison to controls, as shown by histology, AST levels (741±490 U/l in controls vs 379±159 U/l in treated grafts, P<0.05), survival (67% vs 92%), and enhanced macro- (total transhepatic blood flow [THBF]=112±22 ml/min per 100 g in controls vs 157±45 ml/min per 100 g in treated grafts, P0.05) and microcirculation (thermodiffusion [TD]=73±9 ml/min per 100 g in controls vs 90±16 ml/min per 100 g in treated grafts, P0.05). Despite destruction of the macrophage system in the liver, the transhepatic endotoxin gradient of treated livers was enhanced before and 1 h after transplantation (58% in controls vs 85% in treated grafts, P<0.05). Destruction of Kupffer cells of donors by pretreatment with GdCl₃ in pigs is effective in preventing liver graft dys- and nonfunction after LTX. Pretreatment with GdCl₃ does not diminish but increase hepatic endotoxin clearance.     

Eurotransplant donor‐risk‐index and recipient factors: influence on long‐term outcome after liver transplantation – A large single‐center experience

The organ shortage has led to increased use of marginal organs. The Eurotransplant Donor‐Risk‐Index (ET‐DRI) was established to estimate outcome after Liver Transplantation (LT). Currently, data on impact of ET‐DRI on long‐term outcome for different indications and recipient conditions are missing. Retrospective, single‐center analysis of long‐term graft survival (GS) of 1767 adult primary LTs according to indication, labMELDcategory (1: ≤18; 2: >18–25; 3: >25–35; 4: >35), and ET‐DRI. Mean ET‐DRI in our cohort was 1.63 (±0.43). One‐, 10, and 15‐yr GS was 83.5%, 63.3%, and 54.8%. Long‐term GS was significantly influenced by ET‐DRI. Accordingly, four ET‐DRI categories were defined and analyzed with respect to underlying disease. Significant impact of these categories was observed for: Alcohol, cholestatic/autoimmune diseases (CD/AIH), and HCV, but not for HCC, HBV, cryptogenic cirrhosis, and acute liver failure. labMELD categories showed no significant influence on graft, but on patient survival. Matching ET‐DRI categories with labMELD revealed significant differences in long‐term GS for labMELDcategories 1, 2, and 3, but not 4. In multivariate analysis, HCV combined with ET‐DRI > 2 and labMELDcategory 3 combined with ET‐DRI > 2 emerged as negative predictors. To achieve excellent long‐term graft survival, higher risk organs (ET‐DRI > 1.4) should be used restrictively for patients with CD/AIH or HCV. Organs with ET‐DRI > 2 should be avoided in patients with a labMELD of >25–35.     

The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft

Small-for-size (SFS) graft syndrome is one of the major causes of graft loss in living donor liver transplantation (LDLT). We examined whether splenectomy is beneficial for overcoming SFS graft syndrome in LDLT. The patients were classified into two groups: the Sp (−) group ( n  = 69), in which splenectomy was not performed, and the Sp (+) group ( n  = 44), in which it was. The incidence of SFS graft syndrome was investigated. Risk factors of SFS graft syndrome were identified by univariate- and multivariate analysis. To clarify whether splenectomy is beneficial for patients with a SFS graft, subgroup analysis was performed for patients who had a graft weight-to-standard liver weight (GW-SLW) ratio of 40% or less ( n  = 50). Thirty-one of 113 patients developed SFS graft syndrome. A multivariate analysis identified that having a male donor was an independent risk factor of SFS graft syndrome. SFS graft syndrome occurred in 11 of 50 patients with a GW-SLW ratio <40%, and Sp (−) was an independent risk factor for the occurrence of SFS graft syndrome in patients ( P  = 0.014). Simultaneous splenectomy is favorable for overcoming SFS graft syndrome in LDLT patients with a GW-SLW of 40% or less.     

成人右半肝活体肝移植21例分析

目的 探讨成人右半肝活体肝移植供受者处理的关键性技术问题。方法 回顾性分析2007年4月至2009年5月首都医科大学附属北京佑安医院肝胆外科完成21例成人右半肝活体肝移植的资料。 结果 供者术后无死亡,发生并发症23例次,按照Clavien系统分级：Ⅰ级15例次,Ⅱ级8例次。经积极非手术治疗后,所有供者均痊愈。受者术后发生胆道并发症7例,均经外科手术处理痊愈,术后1个月内死亡4例。移植物含肝中静脉4例,不含肝中静脉17例,两组受者1年存活率分别为75%与76%（χ2 = 1.000,P = 0.617）。 结论 右半肝活体肝移植是治疗终末期肝病尤其是各种原因导致的急性肝功能衰竭的重要手段。仔细术前评估,精细手术操作,合理地分配肝中静脉并保证移植物和残肝的功能性体积,术后密切监护、妥善处理并发症是供受者安全的重要保证。     

The Impact of Deceased Donor Kidney Risk Significantly Varies by Recipient Characteristics

As of May 2012, over 92 000 patients were awaiting a solitary kidney transplant in the United States and new waitlist registrations have been rising for over a decade. The decreasing availability of donor organs makes it imperative that organ allocation be as efficient and effective as possible. We performed a retrospective cohort study of adult recipients in the United States (n = 109 392) using Scientific Registry of Transplant Recipients data. The primary aim was to evaluate the interaction of donor risk with recipient characteristics on posttransplant outcomes. Donor quality (based on kidney donor risk index [KDRI]) had significant interactions by race, primary diagnosis and age. The hazard of KDRI on overall graft loss in non‐African Americans was 2.16 (95%CI 2.08‐2.25) versus 1.85 (95%CI 1.75‐1.95) in African Americans (p < 0.0001), 2.16 (95%CI 2.08‐2.24) in nondiabetics versus 1.84 (95%CI 1.74‐1.94) in diabetics (p < 0.0001), and 2.22 (95%CI 2.13‐2.32) in recipients <60 years versus 1.83 (95%CI 1.74‐1.92) in recipients ≥60 (p < 0.0001). The relative hazard for diabetics at KDRI = 0.5 was 1.49 but at KDRI = 2.0 the hazard was significantly attenuated to 1.17; among African Americans the respective risks were 1.50 and 1.17 and among recipients 60 and over, it was between 1.64 and 1.22. These findings are critical considerations for informed decision‐making for transplant candidates.     

Clinical analysis of emergency liver transplantation: the role of living donor liver transplantation

The current liver allocation system requires reevaluation because of the advancements in peri‐transplantation care and surgical techniques. And, the role of living donor liver transplantation (LDLT) in an emergency has not been determined yet. Retrospective review of all patients undergoing emergency liver transplantation (LT) from January 2000 to June 2010 was conducted, and clinical data were analyzed. Of the total 505 LTs, 69 patients (13.7%) underwent an emergency LT. Of these, 54 patients (78.3%) underwent LDLT using a right liver, and 15 patients (21.7%) underwent deceased donor liver transplantation (DDLT). The overall hospital mortality was 21.7% (15/69). The leading cause of death after transplantation was sepsis (60.0%). Multivariate analysis demonstrated that a model for end‐stage liver disease (MELD) >33 [hazard ratio (HR), 16.6; 95% confidence interval (CI), 1.443–191.632; p = 0.024] and existence of pre‐transplantation intubation (HR, 18.2; 95% CI, 1.463–225.483; p = 0.024) were independent factors associated with poor survival after emergency LT. LDLT group and DDLT group showed no difference in hospital mortality (p = 0.854) and graft survival (p = 0.861). Thus, MELD score and respiratory insufficiency could be parameters predicting post‐transplant survival. And, LDLT using the right liver could be an appropriate alternative to DDLT in an emergency.