Discovery and Validation of a Biomarker Model (PRESERVE) Predictive of Renal Outcomes After Liver Transplantation.

BACKGROUND AND AIMS: A high proportion of patients develop chronic kidney disease (CKD) after liver transplantation (LT). We aimed to develop clinical/protein models to predict future glomerular filtration rate (GFR) deterioration in this population. APPROACH AND RESULTS: In independent multicenter discovery (CTOT14) and single-center validation (BUMC) cohorts, we analyzed kidney injury proteins in serum/plasma samples at month 3 after LT in recipients with preserved GFR who demonstrated subsequent GFR deterioration versus preservation by year 1 and year 5 in the BUMC cohort. In CTOT14, we also examined correlations between serial protein levels and GFR over the first year. A month 3 predictive model was constructed from clinical and protein level variables using the CTOT14 cohort (n = 60). Levels of ß-2 microglobulin and CD40 antigen and presence of hepatitis C virus (HCV) infection predicted early (year 1) GFR deterioration (area under the curve [AUC], 0.814). We observed excellent validation of this model (AUC, 0.801) in the BUMC cohort (n = 50) who had both early and late (year 5) GFR deterioration. At an optimal threshold, the model had the following performance characteristics in CTOT14 and BUMC, respectively: accuracy (0.75, 0.8), sensitivity (0.71, 0.67), specificity (0.78, 0.88), positive predictive value (0.74, 0.75), and negative predictive value (0.76, 0.82). In the serial CTOT14 analysis, several proteins, including ß-2 microglobulin and CD40, correlated with GFR changes over the first year. CONCLUSIONS: We have validated a clinical/protein model (PRESERVE) that early after LT can predict future renal deterioration versus preservation with high accuracy. This model may help select recipients at higher risk for subsequent CKD for early, proactive renal sparing strategies.

MELD-GRAIL-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.

BACKGROUND AND AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of wait-list (WL) mortality is adjudicated by the Model for End Stage Liver Disease-Sodium (MELD-Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. APPROACH AND RESULTS: We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD-Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27-40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared with MELD-Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. CONCLUSION: Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may affect outcomes for 12%-17% awaiting transplant and affect organ allocation.

External Validation of a Pretransplant Biomarker Model (REVERSE) Predictive of Renal Recovery After Liver Transplantation.

In patients with end-stage liver disease, the ability to predict recovery of renal function following liver transplantation (LT) remains elusive. However, several important clinical decisions depend on whether renal dysfunction is recoverable after LT. We used a cohort of patients undergoing LT to independently validate a published pre-LT model predictive of post-transplant renal recovery (Renal Recovery Assessment at Liver Transplant [REVERSE]: high osteopontin [OPN] and tissue inhibitor of metalloproteinases-1 [TIMP-1] levels, age < 57, no diabetes). Serum samples pre-LT and 4-12 weeks post-LT (n = 117) were analyzed for kidney injury proteins from three groups of recipients: (1) estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m2 prior to and after LT (irreversible acute kidney injury [AKI]), (2) eGFR < 30 mL/minute/1.73 m2 prior to LT and >50 mL/minute/1.73 m2 after LT (reversible AKI [rAKI]) (3) eGFR > 50 mL/minute/1.73 m2 prior to and after LT (no AKI). In patients with elevated pre-LT serum levels of OPN and TIMP-1, recovery of renal function correlated with decreases in the level of both proteins. At 4 weeks post-LT (n = 77 subset), the largest decline in OPN and TIMP-1 was seen in the rAKI group. Validation of the REVERSE model in this independent data set had high area under the curve (0.78) in predicting full post-LT renal recovery (sensitivity 0.86, specificity 0.6, positive predictive value 0.81, negative predictive value 0.69). Our eGFR findings were confirmed using measured GFR. Conclusion: The REVERSE model, derived from an initial training set combining plasma biomarkers and clinical characteristics, demonstrated excellent external validation performance characteristics in an independent patient cohort using serum samples. Among patients with kidney injury pre-LT, the predictive ability of this model may prove beneficial in clinical decision-making both prior to and following transplantation.

A Model for Glomerular Filtration Rate Assessment in Liver Disease (GRAIL) in the Presence of Renal Dysfunction.

Estimation of glomerular filtration rate (eGFR) in patients with liver disease is suboptimal in the presence of renal dysfunction. We developed a model for GFR assessment in liver disease (GRAIL) before and after liver transplantation (LT). GRAIL was derived using objective variables (creatinine, blood urea nitrogen, age, gender, race, and albumin) to estimate GFR based on timing of measurement relative to LT and degree of renal dysfunction (www.bswh.md/grail). The measured GFR (mGFR) by iothalamate clearance (n = 12,122, 1985-2015) at protocol time points before/after LT was used as reference. GRAIL was compared with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD-4, MDRD-6) equations for mGFR < 30 mL/min/1.73 m2 . Prediction of development of chronic kidney disease (mGFR < 20 mL/min/1.73 m2 , initiation of chronic dialysis) and listing or receipt of kidney transplantation within 5 years was examined in internal cohort (n = 785) and external validation (n = 68,217, 2001-2015). GRAIL had less bias and was more accurate and precise as compared with CKD-EPI, MDRD-4, and MDRD-6 at time points before/after LT for low GFR. For mGFR < 30 mL/min/1.73 m2 , the median difference (eGFR-mGFR) was GRAIL: 5.24 (9.65) mL/min/1.73 m2 as compared with CKD-EPI: 8.70 (18.24) mL/min/1.73 m2 , MDRD-4: 8.82 (17.38) mL/min/1.73 m2 , and MDRD-6: 6.53 (14.42) mL/min/1.73 m2 . Before LT, GRAIL correctly classified 75% as having mGFR < 30 mL/min/1.73 m2 versus 36.1% (CKD-EPI), 36.1% (MDRD-4), and 52.8% (MDRD-6) (P < 0.01). An eGFR < 30 mL/min/1.73 m2 by GRAIL predicted development of CKD (26.9% versus 4.6% CKD-EPI, 5.9% MDRD-4, and 10.5% MDRD-6) in center data and needing kidney after LT (48.3% versus 22.0% CKD-EPI versus 23.1% MDRD-4 versus 48.3% MDRD-6, P < 0.01) in national data within 5 years after LT. Conclusion: GRAIL may serve as an alternative model to estimate GFR among patients with liver disease before and after LT at low GFR.

Acute liver allograft antibody-mediated rejection: an inter-institutional study of significant histopathological features.

Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathological characteristics have been described, specific features that could be used (1) to make a generalizable scoring system and (2) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created training and validation cohorts of putative acute AMR and control cases from 3 high-volume liver transplant programs; these cases were evaluated blindly by 4 independent transplant pathologists. Evaluations of hematoxylin and eosin (H&E) sections were performed alone without knowledge of either serum donor-specific human leukocyte antigen alloantibody (DSA) results or complement component 4d (C4d) stains. Routine histopathological features that strongly correlated with severe acute AMR included portal eosinophilia, portal vein endothelial cell hypertrophy, eosinophilic central venulitis, central venulitis severity, and cholestasis. Acute AMR inversely correlated with lymphocytic venulitis and lymphocytic portal inflammation. These and other characteristics were incorporated into models created from the training cohort alone. The final acute antibody-mediated rejection score (aAMR score)--the sum of portal vein endothelial cell hypertrophy, portal eosinophilia, and eosinophilic venulitis divided by the sum of lymphocytic portal inflammation and lymphocytic venulitis--exhibited a strong correlation with severe acute AMR in the training cohort [odds ratio (OR) = 2.86, P < 0.001] and the validation cohort (OR = 2.49, P < 0.001). SPSS tree classification was used to select 2 cutoffs: one that optimized specificity at a score > 1.75 (sensitivity = 34%, specificity = 86%) and another that optimized sensitivity at a score > 1.0 (sensitivity = 81%, specificity = 71%). In conclusion, the routine histopathological features of the aAMR score can be used to screen patients for acute AMR via routine H&E staining of indication liver transplant biopsy samples; however, a definitive diagnosis requires substantiation by DSA testing, diffuse C4d staining, and the exclusion of other insults.

Preformed class II donor-specific antibodies are associated with an increased risk of early rejection after liver transplantation.

Preformed donor-specific human leukocyte antigen antibodies (DSAs) are considered a contraindication to the transplantation of most solid organs other than the liver. Conflicting data currently exist on the importance of preformed DSAs in rejection and patient survival after liver transplantation (LT). To evaluate preformed DSAs in LT, we retrospectively analyzed prospectively collected samples from all adult recipients of primary LT without another organ from January 1, 2000 to May 31, 2009 with a pre-LT sample available (95.8% of the patients). Fourteen percent of the patients had preformed class I and/or II DSAs with a mean fluorescence intensity (MFI) ≥ 5000. Preformed class I DSAs with an MFI ≥ 5000 remained persistent in only 5% of patients and were not associated with rejection. Preformed class II DSAs with an MFI of 5000 to 10,000 remained persistent in 23% of patients, and this rate increased to 33% for patients whose MFI was ≥10,000 (P < 0.001). Preformed class II DSAs in multivariable Cox proportional hazards modeling were associated with an increased risk of early rejection [hazard ratio (HR) = 1.58; p = 0.004]. In addition, multivariate modeling showed that in comparison with no DSAs (MFI < 1000), preformed class I and/or II DSAs with an MFI ≥ 5000 were independently correlated with the risk of death (HR = 1.51; p = 0.02).

Tumor biology and pre-transplant locoregional treatments determine outcomes in patients with T3 hepatocellular carcinoma undergoing liver transplantation.

Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre-transplant locoregional therapy (LRT) on HCC and our institution's experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty-five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha-fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five-yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre-transplant LRT did not affect post-transplant outcomes in patients meeting Milan criteria but did result in lower three-yr HCC recurrence (7% vs. 75%, p < 0.001) and better three-yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre-transplant LRT are important factors that determine the post-transplant outcomes in patients with HCC who meet R4T3 criteria.

Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression.

BACKGROUND & AIMS: The prevalence of chronic hepatitis C (CH-C) remains high and the complications of infection are common. Our goal was to project the future prevalence of CH-C and its complications. METHODS: We developed a multicohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy. RESULTS: Prevalence of CH-C peaked in 2001 at 3.6 million. Fibrosis progression was inversely related to age at infection, so cirrhosis and its complications were most common after the age of 60 years, regardless of when infection occurred. The proportion of CH-C with cirrhosis is projected to reach 25% in 2010 and 45% in 2030, although the total number with cirrhosis will peak at 1.0 million (30.5% higher than the current level) in 2020 and then decline. Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy. CONCLUSIONS: Prevalence of hepatitis C cirrhosis and its complications will continue to increase through the next decade and will mostly affect those older than 60 years of age. Current treatment patterns will have little effect on these complications, but wider application of antiviral treatment and better responses with new agents could significantly reduce the impact of this disease in coming years.

A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C.

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.

Non-HLA Autoantibodies at 1 Year Negatively Affect 5-Year Native Renal Function in Liver Transplant Recipients.

BACKGROUND: Angiotensin II type-1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) autoantibodies, in addition to allograft injury, can bind native endothelial cells and cause vascular vasoconstriction and fibrosis progression in nontransplanted organs. Therefore, we investigated long-term native renal function in liver transplant (LT) recipients with and without anti-AT1R-Abs and/or anti-ETAR-Abs present in serum. METHODS: Primary LT recipients at our single center from January 2000 to April 2009 had their prospectively collected pre-LT (1269 patients) and year 1 post-LT (795 patients) serum tested retrospectively for anti-AT1R-Abs and/or anti-ETAR-Abs. Anti-AT1R-Abs and anti-ETAR-Abs testing was accomplished with a standardized solid phase assay in which >10 U was considered positive. RESULTS: Pretransplant anti-AT1R-Abs and/or anti-ETAR-Abs did not change the median delta creatinine from pretransplant to 1 year post-transplant. In multivariable analysis controlling for diabetes (DM) and calcineurin inhibitor (CNI) use, anti-AT1R-Abs and/or anti-ETAR-Abs at 1-year remained statistically significantly associated with a decline in GFR (measured by Modification of Diet in Renal Disease-6) from years 1-5 post-LT (P = .04). In diabetic patients the association with a decline in renal function was more pronounced with (-9.29 mL/min) vs without (-2.28 mL/min) anti-AT1R-Abs and/or anti-ETAR-Abs at year 1, respectively (P = .004). CONCLUSION: At 1-year post-LT, the autoantibodies anti-AT1R-Abs and/or anti-ETAR-Abs are associated in multivariable analysis with an increased risk of native renal function decline especially in diabetic patients.

Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease.

Nonalcoholic steatohepatitis (NASH) may account for many cases of cryptogenic cirrhosis. If so, then steatosis might recur after liver transplantation. Two thousand fifty-two patients underwent primary liver transplantation for chronic liver disease between 1986 and 2004. Serial liver biopsy samples were assessed for steatosis and fibrosis. Two hundred fifty-seven patients (12%) had a pretransplant diagnosis of cryptogenic cirrhosis (239) or NASH (18). Fatty liver developed in 31% and was more common when the pretransplant diagnosis was NASH (45% at 5 years versus 23% for cryptogenic cirrhosis, P = 0.007). NASH developed in only 4% and occurred exclusively when steatosis had already occurred. Steatosis after liver transplantation was associated with the baseline body weight and body mass index by univariate analyses, but no pretransplant or posttransplant characteristic independently predicted steatosis after liver transplantation because obesity was so common in all groups. Five percent and 10% developed bridging fibrosis or cirrhosis after 5 and 10 years, respectively, and this was more common after NASH (31%) than in those who developed steatosis alone (6%) or had no fat (3%, P = 0.002). One-, 5-, and 10-year survival was the same in patients who underwent transplantation for cryptogenic cirrhosis or NASH (86%, 71%, and 56%) and in patients who underwent transplantation for other indications (86%, 71%, and 53%; not significant), but death was more often due to cardiovascular disease and less likely from recurrent liver disease. In conclusion, fatty liver is common after liver transplantation for cryptogenic cirrhosis or NASH but is twice as common in the latter group; this suggests that some cryptogenic cirrhosis, but perhaps not all, is caused by NASH. Posttransplant NASH is unusual, and steatosis appears to be a prerequisite. Advanced fibrosis is uncommon, and survival is the same as that of patients who undergo transplantation for other causes.

Indications for combined liver and kidney transplantation: propositions after a 23-yr experience.

The frequency of combined liver and kidney transplants (CLKT) persists despite the pronounced scarcity of organs. In this review, we sought to ascertain any factors that would reduce the use of these limited commodities. Seventy-five adult CLKT were performed over a 23-yr period at our center, 29 (39%) of which occurred during the Model for End-stage Liver Disease (MELD) era. Overall, patient survival rates were 82%, 73%, and 62% at one, three, and five yr, respectively. There was no difference in patient survival based either on pre-transplant hemodialysis status or by glomerular filtration rate (GFR) at the time of transplant. Patients undergoing a second CLKT or a liver retransplantation at the time of CLKT had a survival rate of 30% at three months. In the MELD era, patient survival was unchanged (p = NS) despite an older recipient population (p = 0.0029) and a greater number of hepatitis C patients (p = 0.0428). In summary, patients requiring liver retransplantation with concomitant renal failure should be denied CLKT. Renal allografts may also be spared by implementing strict criteria for renal organ allocation (GFR < 30 mL/min at the time of evaluation) and considering the elimination of preemptive kidney transplantation in CLKT.

Improved results of transplantation for hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver Transplantation.

Improved outcome after liver transplantation (LTX) for hepatocellular carcinoma (HCC) made LTX a legitimate treatment of the disease. We analyzed trends of LTX for HCC with tumors known before transplantation in 902 patients in a large international registry across 3 periods: 1983-1990, 1991-1996, and 1997-2005. Patient survival improved gradually across eras, with 5-year survival rates of 25.3%, 44.4%, and 67.8%, respectively (P < 0.0001), and the 5-year tumor recurrence rate declined from 59% to 41.3% and 15%, respectively (P < 0.0001). The number of HCC nodules and tumor size decreased over time, and there were fewer moderately or poorly differentiated tumors. Tumors > 5 cm decreased from 54.5% to 31.7% and 11.7%, respectively (P < 0.0001), and LTX with >or=4 nodules decreased from 38.9% to 23.5% and 15.1%, respectively (P = 0.0044). Poorly differentiated tumors decreased from 37.2% to 31.8% and 20.3%, respectively (P = 0.0005). Tumor microvascular invasion remained at 21.2% to 23.8% despite changes in patient selection over time (P = 0.7124). Stepwise Cox regression analysis (n = 502) showed significant risk for tumor recurrence and patient survival for transplants before 1997 [hazard ratio (HR), 1.82 and 1.88, respectively], tumor size > 6 cm (HR, 2.09 and 1.76), microvascular invasion (HR, 1.75 and 1.69, respectively), and alpha-fetoprotein > 200 (HR, 2.45 and 2.32, respectively). In conclusion, outcome after LTX for HCC has improved continuously over the past 20 years. Improved perioperative care and better patient selection may partially explain the improved outcome after LTX for HCC.

Acute kidney injury following liver transplantation: definition and outcome.

The incidence of acute kidney injury (AKI) has been reported to vary between 17% and 95% post-orthotopic liver transplantation. This variability may be related to the absence of a uniform definition of AKI in this setting. The purpose of this study was to identify the degree of AKI that is associated with long-term adverse outcome. Furthermore, to determine the best definition (for use in future studies) of AKI not requiring dialysis in post-liver transplant patients, we retrospectively reviewed the effect of 3 definitions of AKI post-orthotopic liver transplantation on renal and patient outcome between 1997 and 2005. We compared patients with AKI to a control group without AKI by each definition. AKI was defined in 3 groups as an acute rise in serum creatinine, from the pretransplant baseline, of >0.5 mg/dL, >1.0 mg/dL, or >50% above baseline to a value above 2 mg/dL. In all groups, the glomerular filtration rate was significantly lower at both 1 and 2 years post-transplant. Patient survival was worse in all groups. Graft survival was worse in all groups. The incidence of AKI was highest in the group with a rise in creatinine of >0.5 mg/dL (78%) and lowest in patients with a rise in creatinine of >50% above 2.0 mg/dL (14%). Even mild AKI, defined as a rise in serum creatinine of >0.5 mg/dL, was associated with reduced patient and graft survival. However, in comparison with the other definitions, the definition of AKI with the greatest impact on patient's outcome post-liver transplant was a rise in serum creatinine of >50% above baseline to >2 mg/dL.

Twenty years' follow-up of portal vein conduits in liver transplantation.

Portal vein problems remain a formidable challenge in liver transplantation. In select situations, a portal vein conduit can provide a solution. No long-term results have been reported. This study was designed to assess the impact of portal vein conduits on graft survival after liver transplantation and the safety of portal vein conduits and to establish the long-term results (up to 20 years) of portal vein conduits. Data from 2370 adult liver transplants were prospectively collected into a computerized research database and analyzed. All portal vein conduits were constructed from the donor iliac vein obtained at the liver retrieval. Portal vein conduits were required in 35 (1.5%) first transplants. The long-term (up to 20 years of follow-up) graft survival after liver transplantation using portal vein conduits was excellent and comparable to that of the control group. The graft survival was 65% with the conduit versus 66% without the conduit at 5 years of follow-up, 58% versus 51% at 10 years, and 48% versus 35% at 15 years. There was a higher rate (8.6% versus 1.4%) of portal vein thrombosis after the portal vein conduit, and the majority occurred in the first 3 months after transplantation. For the same time period, there was no statistically significant difference in graft survival or patient survival for the retransplants with and without portal vein conduits. There was no statistically significant difference in graft survival or patient survival for the transplants with portal vein conduits and with portal vein thrombendvenectomy. In conclusion, portal vein conduits can be used safely for liver transplantation with no negative impact on long-term graft survival or patient survival. Despite the higher rate of portal vein thrombosis in the immediate postoperative period, excellent long-term results can be obtained.

Twenty years of follow-up of aortohepatic conduits in liver transplantation.

Arterial problems remain a formidable challenge in liver transplantation. In many situations, an aortohepatic conduit can provide a solution. No long-term results (over 5 years) have been reported. This study was designed to assess the impact of aortohepatic conduits on graft survival after liver transplantation and the safety of aortohepatic conduits and to establish the long-term results (up to 20 years) of aortohepatic conduits. Data from 2346 adult liver transplants were prospectively collected into the computerized database and analyzed. In the majority of cases, arterial conduits were constructed from the donor iliac artery obtained at the liver retrieval. Aortohepatic conduits were required in 149 (6.4%) first transplants. The long-term graft survival after liver transplantation using aortohepatic conduits was excellent and comparable to that of the control group. The graft survival was 59% with the conduit versus 67% without the conduit at 5 years of follow-up, 50% versus 52% at 10 years, and 33% versus 35% at 15 years. With up to 20 years of follow-up, there was no statistically significant difference in graft survival, patient survival, hepatic artery complications, or biliary complications. For the same time period, there was no statistically significant difference in graft survival or patient survival for the retransplants with and without aortohepatic conduits. In conclusion, in experienced hands, aortohepatic conduits can be used safely for liver transplantation with no negative impact on long-term graft survival, patient survival, hepatic artery complications, or biliary complications. Excellent long-term results can be obtained.

Late acute rejection after liver transplantation impacts patient survival.

Hepatic allograft rejection still remains an important problem following liver transplantation. Early acute rejection, occurring within three months of transplant, is a common event and usually of lesser significance with respect to prognosis than other non-immune-related post-transplant morbidities. However, little is known about late acute rejection (LAR) including factors affecting its occurrence and long-term outcome. In this study, we analyzed LAR including the incidence, clinical risk factors, patient survival, and graft survival. LAR was defined as acute cellular rejection later than six months after liver transplant. Adult patients who had a minimum of 24 months of graft survival were included in this study. A total of 1604 case records of consecutive adult patients (over age 18 yr) who underwent liver transplant between 1985 and 2003 were reviewed. Of the 1604 patients, 305 (19.0%) developed LAR. Patients with primary diagnoses of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis had higher incidences of LAR, while patients with metabolic disease and retransplant had lower incidence of LAR (p = 0.0024). The LAR group had more female and younger recipients than the no LAR group (p = 0.0026, p = 0.0131, respectively). Patient survival as well as graft survival were significantly lower in the LAR group (p = 0.0083, p = 0.0075, respectively). PTLD was the only significant independent predictor of late rejection. The careful management and treatment of PTLD, especially immunosuppressive management, is important to prevent LAR, which is related to poorer patient survival.

Donor-specific Antibodies, Immunoglobulin-free Light Chains, and BAFF Levels in Relation to Risk of Late-onset PTLD in Liver Recipients.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a neoplastic complication of transplantation, with early cases largely due to immunosuppression and primary Epstein-Barr virus infection. Etiology may differ for later-onset cases, but the contributions of immunosuppression, immune reactivity to the donor organ, and chronic B cell activation are uncertain. METHODS: We conducted a case-control study of late-onset PTLD (diagnosed >1 year posttransplant) in a cohort of liver recipients. We assessed serum samples (obtained >6 months before diagnosis in cases) from N = 60 cases and N = 166 matched controls for donor-specific antibodies (DSAs, evaluable for N = 221 subjects), immunoglobulin kappa and lambda free light chains (FLCs, N = 137), and B cell activating factor (BAFF, N = 226). Conditional or unconditional logistic regression was used to calculate adjusted odds ratios (aORs). RESULTS: Circulating DSAs were less common in PTLD cases than controls (18% vs 30%), although this difference was borderline significant (aOR, 0.51; 95% confidence interval [CI], 0.24-1.10; P = 0.09). Donor-specific antibodies against class II HLA antigens predominated and likewise showed a borderline inverse association with PTLD (aOR, 0.58; 95% CI, 0.27-1.24). The FLC levels were less frequently abnormal in cases than controls, but measurements were available for only a subset and confidence intervals were wide (elevated kappa: aOR, 0.57; 95% CI, 0.15-2.12; P = 0.40; elevated lambda: aOR, 0.68; 95% CI, 0.30-1.50; P = 0.34). B cell-activating factor levels were not associated with PTLD. CONCLUSIONS: Our results suggest that circulating DSAs are associated with decreased risk of late-onset PTLD. Because DSAs may develop in the setting of underimmunosuppression, the inverse association with DSAs supports a role for immunosuppression in the etiology of late-onset PTLD.

Chronic AMR in Liver Transplant: Validation of the 1-Year cAMR Score's Ability to Determine Long-term Outcome.

BACKGROUND: A proposed chronic antibody-mediated rejection (AMR) score has recently predicted 50%10-year death-censored allograft loss in patients with donor-specific alloantibodies (DSA) mean florescence intensity (MFI) greater than 10 000 and requires confirmation in patients with lower MFI (1000-10 000). METHODS: All patients who underwent liver transplantation from January 2000 to April 2009, had DSA (MFI ≥1000) in serum 10 to 14 months postliver transplantation, and had a protocolized liver biopsy were evaluated (n = 230). The previously proposed chronic AMR (cAMR) score was used to risk-stratify putative chronic AMR in DSA+ patients with MFI from 1000 to 10 000. RESULTS: The MFI distribution of DSA+ recipients were as follows: 66% had MFI 1000 to 4999, 14% had MFI 5000 to 10 000, and 20% had MFI greater than 10 000. The cAMR score distribution on 1-year protocol liver biopsy found that 41% had a score less than 13; 27% a score of 13 to 27.5, and 32% a score greater than 27.5. MFI correlated with 1-year cAMR category (<13, 46% vs 21% and >27.5, 29% vs 42% when MFI was 1000-10 000 vs MFI >10 000; P = 0.047). In patients with a cAMR score less than 13, 10-year death-censored allograft survival was 96% to 100% regardless of MFI (P = NS). The risk of allograft loss increased in patients with a cAMR score greater than 13 (P = 0.004) in DSA+ patients with MFI 1000 to 10 000. DSA MFI greater than 10 000 versus MFI 1000 to 10 000 at 1 year was also more likely to persist at 5 years (95% vs 68%; P < 0.0001). CONCLUSIONS: Validation of the previously proposed cAMR score in a separate cohort predicts death-censored long-term allograft failure in DSA+ patients regardless of MFI, and higher MFI at 1 year predicts DSA persistence at 5 years.

Non-HLA Antibodies Impact on C4d Staining, Stellate Cell Activation and Fibrosis in Liver Allografts.

BACKGROUND: Recent data have shown an increased risk for rejection, fibrosis progression, and death in liver transplantation (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1 of 2000 to 4 of 2009 with known HLA DSA status for angiotensin II type-1 receptor and endothelin-1 type A receptor autoantibodies pre-LT, and year 1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death (hazard ratio [HR], 1.66; P = 0.02) especially if the HLA DSA was of the IgG3 subclass (HR, 2.28; P = 0.01). A single de novo non-HLA autoantibody was associated with an increased risk for T cell-mediated rejection or antibody-mediated rejection (68% vs 41%, P = 0.01) and fibrosis progression (HR, 1.84; P = 0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared with HLA DSA (71% vs 3%; P < 0.001). Liver sinusoidal endothelial cell activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-angiotensin II type-1 receptor and anti-endothelin-1 type A receptor autoantibodies are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to liver sinusoidal endothelial cell capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.