Pretransplant donor-specific anti-HLA antibodies as predictors of early allograft rejection in ABO-compatible liver transplantation.

The significance of preexisting donor-specific HLA antibodies (HLA-DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA-DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA-DSAs and class II HLA-DSAs were determined by single-antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin-eosin and complement component 4d staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA-DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P < 0.01) and class II (hazard ratio = 6.0, P < 0.01). Pretransplant HLA-DSAs were associated with an increased risk of ACR: P < 0.01 for class I (42% versus 18%), P < 0.001 for class II (37% versus 7%), and P < 0.001 for either class I or II (36% versus 3%). Class I or II HLA-DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA-DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single-center subjects. In conclusion, the present study indicates that pretransplant HLA-DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti-human leukocyte antigen antibodies could serve as donor-specific markers of immunoreactivity to the liver graft.

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

INTRODUCTION: The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. METHODS: We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. RESULTS: Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. CONCLUSION: Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen.

Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension.

Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm(-5) . There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow-up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients.

Complications associated with liver transplantation in the obese recipient.

The prevalence of the metabolic syndrome with attendant morbid obesity continues to increase nationwide. A concomitant increase in non-alcoholic steatohepatitis (NASH) and associated end-stage liver disease requiring transplantation is expected to parallel this trend. Between January 1, 1997 and December 31, 2008, our center performed 813 solitary adult deceased-donor liver transplants. Patients were divided into groups based on the World Health Organization International Classification of obesity. Patients within each obesity class were compared to normal weight recipients. Preoperative demographics among all groups were similar. NASH was more common in higher BMI groups. Operative time, blood product usage, ICU length of stay, infectious complications, and biliary complications requiring intervention were all higher in obese recipients. Deep venous thrombosis occurred more commonly in patients with Class III obesity. Patients with Class II obesity had lower patient (HR 1.82, CI 1.09-3.01, p=0.02) and allograft survival (HR 1.62, CI 1.02-2.65, p=0.04). Obesity class did not reach statistical significance on multivariate analysis. Despite increased technical operative challenges and medical complexities associated with increasing recipient BMI, morbid obesity in and of itself should not be an absolute contraindication to liver transplantation as these patients have reasonable long-term outcomes.

Simultaneous liver and kidney transplantation using donation after cardiac death donors: a brief report.

Although the use of donation after cardiac death (DCD) donor organs has been shown to be a viable option for liver and kidney transplant recipients, outcomes after simultaneous liver and kidney (SLK) transplantation using DCD donors are less clear. We performed a retrospective analysis of 37 adult, primary SLK transplants performed at our center between January 1, 1998 and December 31, 2008. Thirty-two patients received donation after brain death (DBD) organs, and 5 patients received DCD organs. SLK recipients in the 2 groups were similar with respect to age, gender, race, body mass index, donor race, and donor body mass index. The calculated Model for End-Stage Liver Disease scores and pretransplant glomerular filtration rates were similar between the groups. DCD donors were younger and had shorter liver cold ischemia times. The median DCD donor warm ischemia time was 19.0 minutes (6.0-25.0 minutes). The recipient surgical times and hospital lengths of stay were comparable between the groups. Delayed graft function was more frequent in DCD renal allografts (80% versus 31%, P = 0.06). The 1-year graft survival rates for liver allografts (100% for the DCD group versus 94% for the DBD group) and kidney allografts (100% for the DCD group versus 94% for the DBD group) were similar. In conclusion, patients undergoing DCD SLK transplantation have comparable 1-year patient and graft survival rates and acceptable perioperative morbidity in comparison with DBD SLK transplant recipients. Although long-term outcomes remain unknown, the utilization of DCD organs for SLK transplantation should be considered a valid approach to safely expanding the donor organ pool.

CT portography with gastric variceal volume measurements in the evaluation of endoscopic therapeutic efficacy of tissue adhesive injection into gastric varices: a pilot study.

BACKGROUND: N-butyl-2-cyanoacrylate (NBCA) injection is used for treating gastric varices (GV). Determining the degree of obliteration of GV is not readily evident at endoscopy. AIMS: The aim of this study was to evaluate CT portography with gastric variceal volume calculations to assess endoscopic therapeutic efficacy of NBCA injection. METHODS: The study design is a retrospective series pilot study. The setting is a single, tertiary care academic medical center. Ten patients underwent esophagogastroduodenoscopy (EGD) with NBCA injection of GV and had biphasic CT scans performed before and after injection therapy. Based on portal venous images, 3D reconstruction and semi-automated volume calculations of GV were performed. Pre and post injection GV volume calculations were compared. RESULTS: The mean pre-procedure GV volume was 89.84 cm3. Eight patients had significant improvement in GV volume from pre-treatment versus post-treatment (95.65 cm3 vs. 49.65 cm3, P-value 0.04). Pre-procedure GV volume was not significantly different in patients treated for active hemorrhage versus no hemorrhage (101.66 cm3 vs. 72.11 cm3, P-value 0.33). Two patients had a subsequent GV hemorrhage after NBCA injection. The mean residual GV volume in these patients versus those that did not re-bleed was significantly more (127.77 cm3 vs. 38.00 cm3, P-value 0.005). CONCLUSIONS: CT portography with measurement of GV volume is a potentially useful tool in determining the therapeutic efficacy NBCA injection of GV. Patients with higher residual GV volumes are at increased risk of hemorrhage and may benefit from repeat injection to reach ideal GV volumes.

Infected bilomas in liver transplant recipients: clinical features, optimal management, and risk factors for mortality.

BACKGROUND: Infected hepatic fluid collections (bilomas) are a major infectious complication of liver transplantation. Limited data exist on management and outcome of biloma. METHODS: We report a cohort study of 57 liver transplant recipients with posttransplantation bilomas undertaken to identify the clinical features of biloma, management strategies, and outcome. RESULTS: Fever (44%) and abdominal pain (40%) were the most common presenting symptoms, but one-third of patients were asymptomatic; 79% had elevated hepatic enzyme levels. Patients without hepatic artery thrombosis (HAT) had the highest rates of resolution with percutaneous drainage and anti-infective therapy (64%). Retransplantation was necessary in 64% of patients with HAT and biloma. Independent predictors of resolution with nonsurgical therapy were absence of HAT (odds ratio [OR] 7.69; P=.01) and absence of Candida (OR, 9.09; P=.02) or enterococcal infection (OR, 7.69; P=.03). Patients with bilomas had significantly greater mortality (Cox proportional hazard ratio [HR], 2.38; P=.008, by log rank test) and graft loss (HR, 4.31; P<.0001). Predictors of mortality by multivariable analysis included renal insufficiency (OR, 12.51; P=.02) or infection with Candida species (OR, 4.93; P=.03) or gram-negative bacilli (OR, 9.12; P=.01). CONCLUSION: Posttransplantation biloma should be suspected in patients with fever or abdominal pain or abnormalities of hepatic enzymes, and it can be confirmed by computerized tomography and radiographically guided aspiration. Bilomas are most likely to be successfully treated nonsurgically in patients without HAT and without Candida or enterococcus infection.

Donation after cardiac death: the University of Wisconsin experience.

OBJECTIVES: The objective of this analysis was to compare the results of transplantation of livers, pancreases, kidneys, and lungs from donation after cardiac death (DCD) donors to organs transplanted from donation after brain death (DBD) donors. METHODS: From January 1984 through July 2000, outcomes of 382 DCD kidneys were compared to 1,089 kidneys (SPK) transplants and 36 liver transplants from DCD donors were compared to 455 SPK and 510 liver transplants from DBD donors. Likewise, 31 simultaneous pancreas-kidneys transplants from DBD donors. RESULTS: The rate of delayed graft function (DGF) was higher in kidneys transplanted from DCD donors (27.5% versus 21.3%, p=0.01). Likewise, discharge creatinines were higher in recipients of DCD kidneys (1.9 mg/dL versus 1.7 mg/dL, p=0.001). There was no difference in 10-year graft survival between DCD and DBD recipients (45.0% versus 48.0%, p=0.054). No difference in 5-year pancreatic and renal allograft survival was seen after SPK from DCD or DBD donors. After liver transplantation, biliary strictures were higher in recipients of DCD livers (13.9% versus 8.0%, p=0.03). Likewise, 3-year patient and graft survivals were lower for recipients of DCD livers (65.8% versus 84.9%, p=0.01; and 58.6% versus 76.9%, p=0.006). CONCLUSIONS: This large experience with transplantation from DCD donors demonstrates that similar patient and graft survivals can be expected when compared to recipients of organs from DBD donors.

Microwave ablation of giant hepatic cavernous hemangiomas.

PURPOSE: This study was designed to explore the safety and efficacy of percutaneous microwave (MW) ablation as an alternative treatment for symptomatic giant hepatic hemangiomas. METHODS: Patients (n = 7; 6 females, 1 male; mean age = 44 years) with symptomatic, giant hemangiomas (n = 8) were treated with ultrasound-guided percutaneous MW ablation and followed for a mean of 18 months. Patient pain was recorded both before and after the procedure according to the 10-point visual analog scale. All patients were treated using one or three gas-cooled 17-gauge antennas powered by a 2.4-GHz generator (Neuwave Medical, Madison, WI). Mean ablation time was 11.6 min. Four patients received hydrodissection to protect the abdominal wall, colon, or gallbladder (5 % dextrose in water, mean volume 900 mL). Immediate postablation biphasic CT of the abdomen was performed, and four of seven patients have undergone delayed follow-up imaging. RESULTS: All ablations were technically successful with no major or minor complications. Average pain score decreased from 4.6 to 0.9 (p < 0.05), and six of seven patients report resolution or improvement of symptoms at 18-month average follow-up (range 1-33 months). Immediately postablation, mean tumor diameter decreased 25 % (from 7.3 to 5.5 cm, p < 0.05) and volume decreased 62 % (from 301 to 113 cm(3), p < 0.05). DISCUSSION: In this series, percutaneous MW ablation was safe, well-tolerated, and effective in markedly shrinking large hepatic hemangiomas and improving symptoms in most patients.

Chronic kidney disease stage progression in liver transplant recipients.

BACKGROUND AND OBJECTIVES: There is little information on chronic kidney disease (CKD) stage progression rates and outcomes in liver transplant recipients. Identifying modifiable risk factors may help prevent CKD progression in liver transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective review of 1151 adult, deceased-donor, single-organ primary liver transplants between July 1984 and December 2007 and analyzed kidney outcomes and risk factors for CKD stage progression. Seven hundred twenty-nine patients had an available estimated GFR at 1 year posttransplant to establish a baseline stage. The primary end point was the CKD progression from one stage to a higher stage (lower GFR). RESULTS: Kaplan-Meier estimates of patient survival were 91%, 74%, and 64% at 5, 10, and 15 years, respectively. Estimates of liver allograft survival were 89%, 71%, and 60% at the same time points. At 1 year, 7%, 34%, 56%, 3%, and 1% of patients were in CKD stages 1, 2, 3, 4, and 5. The incidence of stage progression was 28%, 40%, and 53% at 3, 5, and 10 years. The incidence of ESRD was 2.6%, 7.5%, and 18% at 5, 10, and 20 years. Multivariable Cox regression analyses demonstrated that CKD stage at 1 year, pretransplant diabetes and urinary tract infections/hypercholesterolemia in the first year proved to be independent risk factors for stage progression (hazard ratio 1.9, 0.28, 1.39, and 1.46, respectively, P < 0.05). CONCLUSIONS: Future studies will determine whether treatment of risk factors in the first posttransplant year prevent CKD progression in liver transplant recipients.

Liver transplantation for HELLP syndrome.

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a rare complication of pregnancy that is associated with preeclampsia and may result in rupture of the liver. Although there have been case reports of liver transplantation for HELLP syndrome, the outcomes of transplantation for this rare indication have not been reported. Furthermore, the optimal management of complicated HELLP syndrome and indications for liver transplantation are unclear. Our objective was to review the national experience with liver transplantation for HELLP syndrome and to develop a comprehensive algorithm for the management of liver complications of HELLP syndrome, including indications for transplantation. A recent case from our institution is reported and the literature is reviewed. The results of liver transplantation for HELLP syndrome were analyzed from the United Network for Organ Sharing database. Between October 1987 and November 2003 there have been 8 deceased donor liver transplants performed for complications related to HELLP syndrome. As of the most recent follow-up, 6 of the 8 patients are alive, with both deaths occurring within 1 month of transplantation, and 2 patients have required retransplantation. This review supports that good results can be obtained with liver transplantation for patients with complicated HELLP syndrome that have either ongoing, uncontrolled hemorrhage or liver necrosis and failure. Patients with complicated HELLP syndrome are best managed at a center with expertise in liver transplantation.

The prevalence of alcohol-induced liver disease and hepatitis C and their interaction in a tertiary care setting.

BACKGROUND & AIMS: We examined the prevalence and clinical characteristics of alcohol-induced liver disease (ALD) in patients referred to a tertiary care center and examined the interaction between ALD and hepatitis C virus (HCV) in a longitudinal survival model. METHODS: A total of 1611 patients with chronic liver disease referred to a tertiary care center between 1994 and 2001 were analyzed. The survival of ALD, HCV, and the combination of the 2 (ALD + HCV) was compared in cirrhotic and precirrhotic patients by using Kaplan-Meier estimates. A Cox proportional hazards model was used to examine the independent effects of predictors on survival. RESULTS: ALD comprised 31% of the cohort, ALD + HCV comprised 14%, HCV comprised 22%, and the rest comprised 33%. The survival of precirrhotic patients with HCV was significantly better than the survival of those with ALD (hazard ratio, 0.27; P = 0.0006) over long-term and 1-year (hazard ratio, 0.24; P = 0.016) follow-up periods. There was no difference in survival between patients with ALD and ALD + HCV ( P = 0.62). In patients with cirrhosis, survival did not differ by cause; decompensated liver disease (hazard ratio, 1.67; P = 0.004) and continued alcohol abuse (hazard ratio, 2.19; P = 0.002) predicted worse survival in this group. CONCLUSIONS: ALD with HCV remains a prevalent cause of chronic liver disease in patients referred to a U.S. tertiary care center. In patients with ALD, the addition of HCV does not change survival, suggesting alcoholism is the driving force for mortality in patients coming to clinical attention. In patients with cirrhosis, ongoing excessive alcohol use and complications of end-stage liver disease drive mortality, irrespective of the underlying cause of chronic liver disease.

Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease.

BACKGROUND/AIMS: The utility of the model for end stage liver disease (MELD) score in non-transplant patients, particularly in those with less severe chronic liver disease remains uncertain. We studied and compared the predictive abilities of the MELD score and the Child-Turcotte-Pugh (CTP) score for intermediate (1-year) and long-term (5-year) mortality. METHODS: One thousand six hundred and eleven patients with chronic liver disease were studied. Observed and predicted survival curves were plotted to evaluate the predictive ability of the MELD score for survival. Receiver operating characteristic (ROC) curves was used to compare the MELD and CTP score. A multivariable model was constructed to examine predictors of mortality. RESULTS: The MELD score was a good predictor of 1-year mortality in chronic liver disease (c-statistics for all subgroups >/=0.75) and of 3- and 6-month mortality in alcoholic hepatitis (c-statistic >/=0.83). The CTP score had similar predictive abilities as the MELD. Hepatic encephalopathy was a strong independent predictor of death (Hazard ratio-2.8, P<0.0001). CONCLUSIONS: The MELD score is a valid prognostic score for intermediate term mortality in a heterogeneous population with chronic liver disease although the CTP score is equivalent in predicting survival. Inclusion of hepatic encephalopathy adds additional prognostic value to the MELD score.

Infected bilomas in liver transplant recipients, incidence, risk factors and implications for prevention.

Bilomas, infected hepatic fluid collections, are a frequent complication of liver transplantation. We report a case-control cohort study to determine the incidence and microbiologic profile of bilomas and risk factors for biloma formation in 492 patients undergoing liver transplantation from 1994 to 2001. Fifty-seven patients (11.5%) developed one or more bilomas; 95% in the first year post-transplantation. The most common initial infecting pathogens were enterococci (37%), one-half resistant to vancomycin (VRE); coagulase-negative staphylococci (26%); and Candida species (26%). Infection by coagulase-negative staphylococci was strongly associated with the presence of a T-tube (OR 9.60, p=0.02). In stepwise logistic regression multivariable analyses, hepatic artery thrombosis (OR 90.9, p<0.0001), hepatic artery stenosis (OR 13.2, p<0.0001) and Roux-en-Y choledochojejunostomy (OR 5.8, p=0.03) were independent risk factors for biloma formation; ursodeoxycholic acid use was highly protective (OR 0.1, p=0.002). Strategies to prevent biloma formation must focus on measures to prevent hepatic artery thrombosis and colonization of liver transplant patients by multiresistant nosocomial pathogens. T-tube drainage post-transplantation bears reassessment. The protective effect of ursodeoxycholic acid found in this study warrants confirmation in a prospective multicenter, randomized trial.

Liver transplantation at the University of Wisconsin.

Liver transplantation remains the only definitive therapy for patients with decompensated liver disease. Significant advances over the past 20 years in surgical technique, immunosuppressive agents, patient selection, and infection prophylaxis and treatment have led to improved patient and graft survival. The success of liver transplantation coupled with expanding indications has resulted in a marked shortage of donor organs. Our approach at the University of Wisconsin to address the shortage of liver allografts is to maximize organ donation and recovery, include the use of liver allografts from donation after cardiac death, the use of split liver transplant, and the use of living-donor liver transplant when necessary. Split-liver transplantation is an effective technique to expand the number of organs available for transplantation. Continued improvements in organ preservation remain a priority to maximize outcomes, especially when the use of marginal donors or split-liver transplantation is planned. Recipient selection criteria have been expanded to include older recipients as well as previous recipients of multiple allografts. Over time it has become clear that less intensive immunosuppression is required since many patients can be maintained on tacrolimus monotherapy. We remain committed to a continued evaluation of donor and recipient factors in order to maximize outcomes of liver transplantation, as well as a critical appraisal of current and newer immunosuppressive agents and their effects on long-term outcome and recurrent disease.