Pediatric liver transplant recipients have demonstrated excellent long-term survival. The purpose of this analysis is to investigate factors associated with 20-year survival to identify areas for improvement in patient care.

Kaplan-Meier with log-rank test as well as univariate and multivariate logistic regression methods were used to retrospectively analyze 4,312 liver transplant recipients under the age of 18 between September 30, 1987 and March 9, 1998. Our primary endpoint was 20-year survival among one-year survival.

Logistic regression analysis identified recipient age as a significant risk factor, with recipients below 5 years old having a higher 20-year survival rate (p < 0.001). A preoperative primary diagnosis of a metabolic dysfunction was found to be protective compared to other diagnoses (OR 1.64, CI 1.20-2.25). African-American ethnicity (OR 0.71, CI 0.58-0.87) was also found to be a risk factor for mortality. Technical variant allografts (neither living donor nor cadaveric) were not associated with increased or decreased rates of 20-year survival.

Our analysis suggests that long-term survival is inversely correlated with recipient age following pediatric liver transplant. If validated with further studies, this conclusion may have profound implications on the timing of pediatric liver transplantation.

International travel for transplantation remains a global issue as countries continue to struggle in establishing self-sufficiency. In the United States, the United Network for Organ Sharing (UNOS) requires citizenship classification at time of waitlisting to remain transparent and understand to whom our organs are allocated. This study provides an assessment of patients who travel internationally for liver transplantation and their outcomes using the current citizenship classification used by UNOS.

Adult liver UNOS data from 2003 to 2019 were used. Patients were identified as citizens, noncitizen, nonresidents (NCNR), or noncitizen residents (NC-R) according to citizenship status. Descriptive statistics compared demographics among the waitlisted patients and demographics and donor characteristics among transplant recipients. A competing risks model was used to examine waitlist outcomes. The Kaplan-Meier method and Cox proportional hazards were used for posttransplant outcomes.

There were significant demographic differences according to citizenship group among waitlisted (n = 125 652) and transplanted (n = 71 536) patients. Compared with US citizens, NCNR was associated with a 9% increase in transplant (subdistribution hazard ratio [SHR], 1.09; 95% confidence interval [CI], 1.00-1.18; P = 0.04), and NC-R was associated with a 24% decrease in transplant (SHR, 0.76; 95% CI, 0.72-0.79; P < 0.0001) and a 23% increase in death or removal for being too sick (SHR, 1.23; 95% CI, 1.14-1.33; P < 0.0001). US citizens had significantly inferior graft and patient survival (P < 0.001).

Though the purpose of the citizenship classification system is transparency, the results of this study highlight significant disparities in the access to and outcomes following liver transplantation according to citizenship status.

Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation.

Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups.

Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01).

The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

The ethnicity and socioeconomic status of the host may affect the progression of hepatitis C virus (HCV). We aimed to compare survival and fibrosis progression in Hispanic white (HW) and non-Hispanic white (NHW) recipients of liver transplantation (LT) with HCV. All HW and NHW patients with HCV who underwent transplantation between January 2000 and December 2007 at 2 centers were retrospectively assessed. The primary outcomes were the time to death, death or graft loss due to HCV, and significant fibrosis [at least stage 2 of 4]. Five hundred eleven patients were studied (159 HW patients and 352 NHW patients), and the baseline demographics were similar for the 2 groups. NHW patients were more likely to be male, to have attended college, and to have private insurance, and they had a higher median household income (MHI). The unadjusted rates of survival (log-rank P = 0.93), death or graft loss due to HCV (P = 0.89), and significant fibrosis (P = 0.95) were similar between groups. In a multivariate analysis controlling for center, age [hazard ratio (HR) per 10 years = 1.43, P = 0.01], donor age (HR per 10 years = 1.25, P < 0.001), and rejection (HR = 1.47, P = 0.048) predicted death, whereas HW ethnicity (HR = 1.06, P = 0.77) was not significant. Independent predictors of significant fibrosis were HW ethnicity (HR = 2.42, P = 0.046), MHI (HR per $10,000 = 1.11, P = 0.01), donor age (HR per 10 years = 1.13, P = 0.02), cold ischemia time (HR = 1.06, P = 0.03), and the interaction between ethnicity and MHI (HR = 0.82, P = 0.03). In conclusion, there is no difference in post-LT survival or graft loss due to HCV between HW patients and NHW patients. Socioeconomic factors may influence disease severity; this is suggested by our findings of more significant fibrosis in HW patients with a low MHI.

To evaluate race/ethnicity-specific variations in autoimmune hepatitis (AIH) with a focus on Asians and Hispanics, the fastest growing populations in the United States.

AIH is a chronic inflammatory disease in which race/ethnicity-specific variations in clinical epidemiology have been reported. However, earlier studies were small or did not include a comprehensive analysis of Asians and Hispanics, the 2 fastest growing population cohorts in the United States.

A retrospective study analyzing patient data from 1999 to 2010 in a large tertiary-care community hospital to assess AIH epidemiology among a racially diverse population.

One hundred eighty-three patients with AIH were included in the study with 81 patients having "definite" AIH by International Autoimmune Hepatitis Group criteria and 63 were diagnosed with overlap syndromes. Women and whites were the largest cohorts. The average age of diagnosis was similar among all groups. Biopsy-confirmed cirrhosis was present in 34% of AIH patients with Hispanics demonstrating the highest prevalence of cirrhosis (55%). When compared with whites, Asians had higher international normalized ratio (INR) (1.4 U vs. 1.1 U, P<0.01), and Hispanics had lower serum albumin (3.3 g/dL vs. 3.7 g/dL, P<0.001) and platelets (123.8 thousand/mcL vs. 187.5 thousand/mcL, P<0.001) and higher international normalized ratio (1.5 U vs. 1.1 U, P=0.05). Kaplan-Meier survival analysis demonstrated a trend toward worse outcomes among Asians.

Among AIH patients, Hispanics had the highest prevalence of cirrhosis, and Asians had poorer survival outcomes. Race/ethnicity-specific disparities in AIH epidemiology may reflect underlying genetic differences, contributing to variations in disease severity, response to therapy, and overall mortality.

A higher incidence of autoimmune disorders may predispose First Nations (FN) individuals to higher rates and more severe episodes of rejection, graft loss and mortality following liver transplantation for advanced liver disease.

A retrospective review of patient outcomes in a single centre providing long-term follow-up care for FN and non-FN patients transplanted for advanced liver disease was conducted.

A total of 20 FN and 129 non-FN charts were available for review. FN subjects were younger at transplantation (mean [± SD] age 32.4±4.1 years versus 46.3±1.4 years; P=0.00005), less often male (35% versus 58%; P=0.05), more commonly transplanted for autoimmune hepatitis (30% versus 4.7%; P=0.006), less often from urban residences (25% versus 74%; P=0.0001) and less compliant with medical care (20% versus 80%; P=0.007). After a mean follow-up period of 11.0±1.5 years and 8.4±0.5 years in FN and non-FN subjects, respectively, the incidence and severity of rejection, graft and patient survival were similar between cohorts.

Although demographic profiles, nature of the underlying disease and compliance differed, the rates and severity of rejection, graft and patient survival were similar in FN and non-FN patients who underwent liver transplantation for advanced liver disease.

Pathologic evaluation of liver allograft biopsies plays an integral role in the management of patients after liver transplantation. This review summarizes the clinical context and classical histology of different types of allograft rejection and also the common entities that enter the differential diagnosis of allograft rejection, and provides practical approaches to liver allograft biopsy interpretation. In addition, some of the new developments in the field of liver transplant pathology are updated. The purpose of this review is to provide guidance for pathologists interpreting liver allograft biopsies, particularly those interested in developing expertise in the field of liver transplant pathology.

Renal transplantation is the therapy of choice for children with end-stage renal disease (ESRD). Ethnicity affects the transplant survival rates substantially, but there has been no European academic evaluation of the effects of immigration on the pediatric renal transplantation outcome. The aim of this study was to compare the outcomes of renal transplantation between the children of immigrant families and the children of native families at the pediatric nephrology unit of the Medical University of Vienna, Austria. We conducted a retrospective study on all children who underwent renal transplantation at our center between January 1997 and June 2005. The patients were separated into two groups according to their immigration backgrounds. During the time frame of our study, 59 children underwent a total of 63 transplantations. Of these children, 42 were from native Austrian and 17 were from first-generation immigrant families. We analyzed the demographic data and outcome parameters for each of the 59 patients. We found no difference in patient and graft survival rates or long-term function between native and immigrant children. The two groups were also comparable in the rates of acute rejection episodes, 24-h blood pressure, and growth velocity. Living donor source had a positive influence on graft function (p=0.06), 24-h blood pressure (p=0.05), and growth velocity (p=0.02) only in the immigrant group. Our retrospective analysis shows no influence of the migration status on the patient or graft outcome, but we did find that immigrant children benefitted more than native children from living donation as opposed to deceased donation. To explain this fact, biological, heath-economical, psychosocial, and cultural background aspects must be investigated.

Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.

Biochemical cholestasis after liver transplantation is common and often has no clinical significance if biliary anastomosis strictures and leaks have been excluded. There is no agreed upon definition for severe cholestasis, but it is associated with a worse mortality. There has been little evaluation on risk factors, but these include cryoprecipitate and platelet transfusion intraoperatively, nonidentical blood group, suboptimal graft appearance, inpatient status before transplant, and bacteremia within the first month. Associated causes considered as early (<6 months) include ischemia-reperfusion injury, primary nonfunction, small-for-size graft syndrome, infection, drugs and acute cellular rejection. Late causes include hepatic artery thrombosis, chronic rejection, biliary complications, recurrent viral and cholestatic disease, and posttransplant lymphoproliferative disorder.

The impact of ethnicity on the natural history of autoimmune hepatitis (AIH) has not been well characterized. The aim of this study was to assess the natural history of AIH in blacks in comparison with others (nonblacks). This was a 10-year (June 1996 to June 2006) retrospective analysis of patients with AIH from a single tertiary care center. The diagnosis of AIH was defined by the criteria established by the International Autoimmune Hepatitis Club. A poor outcome was defined as liver failure at presentation, failure to achieve remission, need for liver transplantation, and/or death. One hundred one patients with AIH were eligible for the study. Black patients were more likely to have cirrhosis (56.7% versus 37.5%, P = 0.061), have liver failure at the initial presentation (37.8% versus 9.3%, P = 0.001), and be referred for liver transplantation (51.3% versus 23.4%, P = 0.004). The overall mortality was also significantly higher in black patients (24.3% versus 6.2%, P = 0.009). Compared with nonblacks, blacks had more advanced hepatic fibrosis (3.6 +/- 2.7 versus 2.1 +/- 2.4, P = 0.013). A Kaplan-Meier analysis showed that the probability of developing a poor outcome was significantly higher in blacks (P = 0.003). Independent predictors of poor outcome were black ethnicity, the presence of cirrhosis, and the fibrosis stage at presentation. Black males were the group most likely to have a poor outcome (85.7%).

Blacks, especially black men with AIH, have more aggressive disease at the initial presentation, are less likely to respond to conventional immunosuppression, and have a worse outcome than nonblacks.

Previous analyses have reported that minority patients undergoing orthotopic liver transplantation (OLT) have poorer survival than Caucasian recipients. The reason for this disparity is unclear. We examined whether racial differences in survival exist at select academic OLT centers. OLT recipients from 4 academic centers were prospectively enrolled in 2 multicenter databases. Data including demographics, liver disease diagnosis, and post-OLT follow-up were obtained for 2823 (135 African, 2448 Caucasian, and 240 other race) adult patients undergoing primary OLT between 1985 and 2000. The survival of patients and grafts after OLT was compared across race. The Kaplan-Meier estimates for 1-year recipient survival were 90.8% [95% confidence interval (CI): 86.0-95.9] for African Americans, 86.5% (95% CI: 85.1-87.9) for Caucasians, and 84.4% (95% CI: 79.8-89.2) for other races. The 5-year recipient survival probability was 69.2% (95% CI: 60.1-79.7) for African Americans, 72.2% (95% CI: 70.1-74.4) for Caucasians, and 67.5% (95% CI: 60.5-75.3) for other races. The 10-year recipient survival probability for African Americans was 54.4% (95% CI: 41.1-72.1), for Caucasians 50.7% (95% CI: 46.4-55.3), and for other races 55.7% (95% CI: 41.5-74.8). There was no difference in patient survival (P = 0.162) or graft survival (P = 0.582) among racial groups. A multivariable proportional hazards model confirmed the absence of an association between race and post-OLT survival after adjustments for age, gender, total bilirubin, creatinine, prothrombin time, and diagnosis.

These data demonstrate that as a proof of principle, minority OLT recipients should not necessarily expect an OLT outcome inferior to that of Caucasians.

In orthotopic liver transplantation (OLT) distinct causes of graft failure (GF) and death with a functioning graft (DFG) exist. Prognostic factors for one failure type may be distinctly different from those predictive of other types, and an accurate portrayal of these relationships may more clearly explain each factor's importance.

A multivariable cause-specific hazard (CSH) rate analysis using Cox stepwise regression was performed among 877 adults who received primary OLT during 1996-2004 with tacrolimus+steroids as immunosuppression.

Older donor age (P=0.004) implied greater primary dysfunction GF, while primary sclerosing cholangitis (PSC; P=0.0002) implied greater vascular thrombosis GF. Recurrent nonmalignant liver disease GF was higher among hepatitis C virus patients (P<0.00001), and younger recipient age (P=0.005) implied greater death from recurrent (metastatic) hepatocellular carcinoma. African-American race (P<0.00001), PSC (P=0.003), and younger recipient age (P=0.005) were independently associated with greater GF due to chronic rejection. Older donor age (P=0.003) implied greater infection DFG, while older recipient age (P=0.003) and pretransplant diabetes (P=0.03) were independently associated with greater cardiovascular/cerebrovascular DFG. Finally, most of these cause-specific predictors were not significant in an overall Cox model for graft survival.

The CSH approach should be more widely used in investigations of prognostic factors. The result of older donor age implying greater primary dysfunction GF and infection DFG but having no association with other failure types demonstrates that its impact is specific to the graft's early posttransplant functional status. In addition, while recipient age was an important prognosticator, its direction of association reverses depending upon the outcome being analyzed.

The article focuses on diagnosis and management of allograft failure in four main categories: (1) ischemic-reperfusion injury (primary nonfunction), (2) technical complications (hepatic artery and portal vein thrombosis), (3) chronic rejection, and (4) recurrent disease. It also discusses the complex problems involved in retransplantation for allograft failure.

Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.

Black transplant recipients have decreased graft survival and increased rejection rates compared with whites. Because increased rejection rates may lead to more immunosuppression in black recipients, ethnic differences may exist for outcomes of posttransplant infectious complications. All episodes of infection between December 1996 and October 1998 on the transplant services at the University of Virginia Health Sciences Center were prospectively evaluated. Parameters recorded included self-designated ethnicity, demographics, APACHE II scores, laboratory and microbiologic data, immunosuppression, episodes of rejection, and outcome measures. Evaluation of 303 episodes of infection demonstrated an increased mortality rate for white compared with black recipients (19% vs. 3%, P = 0.0006) despite having a similar severity of illness (APACHE II score). Among renal transplant recipients, episodes of infection occurring in black recipients (n = 46) were also associated with a decreased mortality rate versus whites (n = 89) (0% vs. 15%, P = 0.006) and shorter mean length of stay (12 +/- 2 vs. 25 +/- 4 days, P = 0.002) despite similar severity of illness and rejection rates. For posttransplant infections in liver transplant recipients, blacks (n = 23) demonstrated a trend toward decreased mortality (9% vs. 26%, P = 0.07) but equal lengths of stay despite similar APACHE II scores, rejection rates, and age. White liver transplant recipients had an increased incidence of viral infections (15% vs. 0%, P = 0.03). All other infecting organisms were similar. The unexpected finding of a significantly decreased rate of mortality associated with posttransplant infections in black recipients remains largely unexplained but may be related to subtle differences in immune response between racial or ethnic groups.

Seronegative hepatitis is a common cause of acute liver failure (ALF) requiring liver transplantation. The primary aim of this study was to examine outcomes following transplantation in this group and to identify factors associated with early (<2 months) mortality. Patients studied were 110 consecutive cases of seronegative ALF transplanted at the Queen Elizabeth Hospital, Birmingham, between January 1992 and January 2004. Univariate analysis of 44 pretransplantation recipient, donor, and operative variables was performed initially to identify factors associated with early posttransplantation mortality. Variables identified as significant or approaching significance were analyzed using stepwise multiple logistic regression analysis. Survival following transplantation for seronegative hepatitis was 83%, 81%, and 73% at 2, 12, and 60 months, respectively. The majority (71%) of deaths occurred within the 1st 2 months and sepsis / multiorgan dysfunction was the most common cause of early death. Univariate analysis revealed 9 variables predicting early death. Subsequent multivariate analysis identified high donor body mass index (BMI; a possible surrogate marker for hepatic steatosis) as the most important predictor of early death (P = .009; odds ratio, 1.2; 95% confidence interval, 1.0-1.3). Recipient age >50 (P = .015; odds ratio, 4.2; 95% confidence interval, 1.3-14.1) and non-Caucasian recipient ethnicity (P = .015; odds ratio, 4.9; 95% confidence interval, 1.2-19.2) were other variables associated with early death on multivariate analysis. This study specifically examined factors that determine the early outcome of transplanted seronegative ALF patients. In conclusion, we found that donor and recipient factors identify patients who have a high chance of early death after transplantation.

We studied pediatric liver transplantation for metabolic disease in a large national cohort to determine whether smaller studies suggesting a survival advantage for these recipients could be corroborated. We also hoped to determine whether higher survival rates in recipients with metabolic disease are associated with lack of structural liver disease, and to evaluate these recipients' risk factors for mortality. Data from the Scientific Registry of Transplant Recipients were used to analyze nationwide results (1990-99) of pediatric liver transplantation for patients with biliary atresia and metabolic disease. Adjusted patient survival rates for children with metabolic disease at 1 and 5 years were 94% and 92%, respectively, - significantly higher than for recipients with biliary atresia (90% and 86%) (p = 0.008). Cox regression models identified recipient black race [relative risk (RR) = 5.1] and simultaneous transplantation of other organs (RR = 3.2) as significant risk factors for mortality in the metabolic group. Adjusted survival rates for metabolic patients with structural and nonstructural liver diseases were similar to each other at both 1 and 5 years. Children with metabolic disease had significantly higher adjusted short- and long-term post-transplant survival rates than those with biliary atresia. Structural disease was not a risk factor for worse outcomes.

Significant diversity in disease severity has been identified for autoimmune disorders among different ethnic groups but there is a lack of data on autoimmune hepatitis (AIH) in populations other than those of European Caucasoid (EC) or Japanese extraction.

To assess the clinical features, response to therapy, and eventual outcome in AIH patients of non-EC ethnicity.

A retrospective review of a regularly updated database of patients with AIH referred to liver outpatient clinics at King's College Hospital, London, since 1983.

Twelve patients were identified (10 female; six African, five Asian, one Arabic; median age at presentation 30 years (range 12-58)) who satisfied international criteria for type 1 (11 cases) or type 2 (one case) AIH. Nine (75%) had cholestatic serum biochemistry and three (25%) had mild biliary changes on liver biopsy without definitive features of primary biliary cirrhosis or cholangiographic evidence of primary sclerosing cholangitis. Four showed a complete biochemical response to standard prednisolone with or without azathioprine therapy, three partial, and five no response. Four have required liver transplantation for intractable disease. By comparison with 180 EC patients with definite AIH attending during the same period, the non-EC patients were younger (p<0.05), presented with cholestatic biochemistry (p=0.014), and morphological biliary features more frequently (p<0.0005) and showed a poorer initial response to standard therapy (p<0.0005).

Clinical expression of AIH in non-EC patients seems to differ in important respects from that in EC or Japanese patients. Management of such patients is challenging and may require alternative or more aggressive treatment strategies.

Chronic rejection is a major cause of graft failure and a frequent reason for retransplantation after pediatric liver transplantation. Identification of risk factors for chronic rejection in pediatric transplant recipients is vital to understanding the pathogenesis of chronic rejection and may help prevent further graft loss.

The study population consisted of 285 children with 385 liver transplants performed at University of Chicago between 1991 and 1999. Logistic regression analysis was used to evaluate risk factors for chronic rejection, including age, sex, race, type of graft (living related vs. cadaveric), native liver disease, acute rejection episodes, cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD).

The chronic rejection rate was significantly lower in recipients of living-related grafts than in recipients of cadaveric grafts (4% vs. 16%, P=0.001). African-American recipients had a significantly higher rate of chronic rejection than did Caucasian recipients (26% vs. 8%, P<0.001). Numbers of acute rejection episodes, transplantation for autoimmune disease, occurrence of PTLD, and CMV infection were also significant risk factors for chronic rejection. However, recipient age, gender, donor-recipient gender mismatch, and donor-recipient ethnicity mismatch were not associated with higher incidence of chronic rejection

We have identified a number of risk factors for chronic rejection in a large group of pediatric liver allograft recipients. We believe that donor-recipient matching for gender or race is not likely to reduce the incidence of chronic rejection. The elucidation of the mechanisms by which living-related liver transplantation affords protection against chronic rejection may provide insight into the immunogenetics of chronic rejection and help prevent further graft loss.

Predisposing factors, long-term occurrence, and histopathological changes associated with recovery or progression to allograft failure from chronic rejection (CR) were studied in adult patients treated primarily with tacrolimus.

CR cases were identified using stringent criteria applied to a retrospective review of computerized clinicopathological data and slides.

After 1973 days median follow-up, 35 (3.3%) of 1049 primary liver allograft recipients first developed CR between 16 and 2532 (median 242) days. The most significant risk factors for CR were the number (P<0.001) and histological severity (P<0.005) of acute rejection episodes and donor age >40 years (P<0.03). Other demographic and matching parameters were not associated with CR in this cohort. Ten patients died with, but not of, CR. Eight required retransplantation because of CR at a median of 268 days. Ten resolved either histologically or by normalization of liver injury tests over a median of 548 days. CR persisted for 340 to 2116 days in the remaining seven patients. More extensive bile duct loss (P<0.01), smallarterial loss (P<0.03), foam cell clusters (P<0.01) and higher total bilirubin (P<0.02) and aspartate aminotransferase (P<0.03) were associated with allograft failure from CR.

Early chronic liver allograft rejection is potentially reversible and a combination of histological, clinical, and laboratory data can be used to stage CR. Unique immunological and regenerative properties of liver allografts, which lead to a low incidence and reversibility of early CR, can provide insights into transplantation biology.

In contrast to all other vascularized organ allografts, chronic rejection (CR) of the liver is potentially reversible. We therefore studied demographic, perioperative, biochemical, and histologic features associated with reversibility or progression to graft failure. Using very stringent clinical and histological criteria, we identified a subgroup of 23 of 916 patients receiving primary liver allografts with CR from the Liver Transplantation Database. Of these, 13 experienced graft failure as a result of CR, and 10 patients recovered to normal histology or liver injury test results. Male-to-female sex mismatch (p = 0.07), younger recipient age (p = 0.09), younger donor age (p = 0.06), white-to-white race match (p = 0.09), primary diagnosis of biliary atresia (p = 0.02), and cold ischemia time of more than 12 hours (p = 0.02) were associated with graft failure. Patients who eventually recovered from CR were more likely to have acute rejection within the first 2 weeks (70% vs 23%; p = 0.04), had a higher number of acute rejection episodes (p = 0.08), and were more likely to have been treated with OKT3 (90% vs 46%, p = 0.07). Although overlap existed in the histopathologic findings between the patients whose grafts failed and those who recovered, those patients who developed bile duct loss in more than 50% of the portal tracts (p < 0.01), severe (bridging) perivenular fibrosis (p = 0.05), and the presence of foam cell clusters (p = 0.06) were more likely to require retransplantation. In contrast to other solid organ allografts, CR of the liver is not an irreversible process. These findings can be used to understand the evolution of CR and to design a biologically correct and clinically relevant staging system.

Chronic hepatic allograft rejection is characterized by the histological findings of ductopenia and a decreased number of hepatic arteries in portal tracts in the presence of foam cell (obliterative) arteriopathy. Recent studies have extended the histological spectrum of chronic rejection to include the presence of biliary epithelial atrophy or pyknosis involving the majority of small ducts present in the liver biopsy specimen. Overall, the incidence of chronic rejection in adults appears to be decreasing and is currently approximately 4%. However, the incidence of chronic rejection in pediatric liver transplant recipients has been more stable and ranges from 8% to 12% in most studies. Clinical risk factors associated with chronic rejection include: underlying liver disease, HLA donor-recipient matching, positive lymphocytotoxic cross-match, cytomegalovirus infection, recipient age, donor-recipient ethnic origin, male donor into female recipient, number of acute rejection episodes, histological severity of acute rejection episodes, low cyclosporine trough levels, and retransplantation for chronic rejection. Chronic rejection, once diagnosed, frequently leads to graft failure; however, a number of reports indicated 20% to 30% of the patients with this diagnosis may respond to additional immunosuppressive therapy or even resolve spontaneously receiving baseline immunosuppression. Newer immunosuppressive agents, such as tacrolimus and mycophenolate, may successfully reverse chronic rejection, particularly when it is diagnosed in its early histological stages.

Intrahepatic cholestasis following liver transplantation commonly occurs after liver transplantation and may be caused by infections, drugs such as cyclosporine and sulfonamides, and acute or chronic rejection. Less common causes such as fibrosing cholestatic hepatitis or recurrent primary biliary cirrhosis or primary sclerosing cholangitis may also be encountered. Biliary strictures may also be present. Although some disorders may be managed medically, others often require repeat liver transplantation. Prompt recognition and specific treatment can improve the outcome for liver transplant recipients.

The influence of ethnic origin on organ donation and renal allograft survival after renal transplantation has been controversial. Several large studies have reported inferior renal allograft survival in black recipients, whereas others have reported equal survival. However, the issue of race as it relates to organ donation, patient referral, and patient selection in orthotopic liver transplantation has not been investigated. We retrospectively reviewed our results of organ donation, patient referral and selection, and orthotopic liver transplantation since 1989. Because of a concerted educational effort by this organ procurement organization, the percentage of black donors has increased from 6.1% in 1988 to 21.9% in 1996. Since the inception of the Liver Transplant Program in 1989, 844 patients have been referred to our transplant center for organ transplant evaluation. Disproportionately fewer black patients (119; 14.1%) were referred for liver transplantation than white patients (725; 85.9%) based on the prevalence of end-stage liver disease in these populations. The acceptance rate for listing for transplantation was similar between the two groups. The percentage of patient referrals who actually underwent transplantation was similar across racial lines (43% black v 42% white patients). However, it appeared that black patients were referred for liver transplantation at a later stage and were more critically ill at the time of referral. Nevertheless, the patient and graft survival were similar between black and white patients. The 1- and 3-year survival rates in white recipients was 88% and 81%, respectively, versus 96% and 84% in black recipients. Within this organ procurement organization, black donation has increased over the past 10 years. Unfortunately, there may be a selection bias at the level of referral for liver transplantation. However, once patients are referred to this center for liver transplantation, the rate of transplantation and survival is similar between white and black patients.

Poor graft function early after liver transplantation is an important cause of morbidity and mortality. We defined early allograft dysfunction (EAD) using readily available indices of function and identified donor, graft, and pretransplant recipient factors associated with this outcome.

This study examined 710 adult recipients of a first, single-organ liver transplantation for non-fulminant liver disease at three United States centers. EAD was defined by the presence of at least one of the following between 2 and 7 days after liver transplantation: serum bilirubin >10 mg/dl, prothrombin time (PT) > or =17 sec, and hepatic encephalopathy.

EAD incidence was 23%. Median intensive care unit (ICU) and hospital stays were longer for recipients with EAD than those without (4 days vs. 3 days, P = 0.0001; 24 vs. 15 days, P = 0.0001, respectively). Three-year recipient and graft survival were worse in those with EAD than in those without (68% vs. 83%, P = .0001; 61% vs. 79%, P = 0.0001). A logistic regression model combining donor, graft, and recipient factors predicted EAD better than models examining these factors in isolation. Pretransplant recipient elevations in PT and bilirubin, awaiting a graft in hospital or ICU, donor age > or =50 years, donor hospital stay >3 days, preprocurement acidosis, and cold ischemia time > or =15 hr were independently associated with EAD.

Recipients who develop EAD have longer ICU and hospital stays and greater mortality than those without. Donor, graft, and recipient risk factors all contribute to the development of EAD. Results of these analyses identify factors that, if modified, may alter the risk of EAD.

A pronounced similarity exists between liver allograft rejection and graft-versus-host disease (GVHD) in the damage and eventual destruction of small intrahepatic bile ducts. Although an immunologic reaction has an important role, precisely identifying the target antigens or reason for persistence of the immune response has been difficult. An important difference between GVHD and liver rejection is the development of obliterative arteriopathy only in rejection. The three main histopathologic features of acute rejection are a predominantly mononuclear but mixed portal inflammation, subendothelial inflammation of portal or terminal hepatic veins (or both), and bile duct inflammation and damage. In acute rejection, a controversial issue is determining when therapeutic intervention is needed. The recommended approach is to base treatment on a combination of histopathologic changes and liver injury or dysfunction. Chronic rejection, which usually does not occur before 2 months after transplantation, is characterized by two main histopathologic features: (1) damage and loss of small bile ducts and (2) obliterative arteriopathy. Acute GVHD begins within the first month after transplantation and most commonly involves the skin, gastrointestinal tract, and liver, whereas chronic GVHD usually develops more than 80 to 100 days after liver transplantation and affects 30 to 50% of long-term survivors. Recognition of the early, cellular stages of chronic GVHD is important in preventing irreversible damage.

Mayo Clinic pathology files from March 1985 to March 1995 contained records of 584 orthotopic liver transplantations in 515 patients. The most common indication for liver transplantation was primary sclerosing cholangitis (PSC), followed by primary biliary cirrhosis (PBC), and cryptogenic cirrhosis. In 59 patients, a total of 69 single or repeated retransplantations became necessary. Vascular complications necessitated retransplantation in 35 cases, followed by irreversible rejection in 16 cases, and primary graft failure in 8 cases. Ninety-nine patients died, 25 of them after one or more retransplantations. Infectious complications caused death in 38 cases, followed by graft-related complications (excluding rejection) in 22 cases, noninfectious systemic diseases such as intracerebral hemorrhage (21 cases), malignancies in 13 cases, and irreversible rejection in 5 cases. In the decade from 1985 to 1995, only 14 patients had irreversible rejection that often was associated with other complications such as ischemic cholangitis. Furthermore, the rate of irreversible rejection decreased dramatically. Thus, although 5 deaths were caused by irreversible rejection, none occurred since March 1991, and of the 16 retransplantations for irreversible rejection, only one needed to be performed during these last 4 years. The disappearance of irreversible rejection, which can be described as the "vanishing vanishing bile duct syndrome," must be considered when new immunosuppressants are tested, because graft loss and death from rejection are no longer suitable criteria.

The hepatic metabolism of lidocaine to monoethyl-glycinexylidide (MEGX) is the basis of a dynamic test of liver function. To understand its potential value in liver transplantation, the latter has been considered in the following three separate stages: pretransplantation assessment of potential candidates, potential liver donors, and the transplant recipient. In pretransplantation patients, data support its role in assessing risk of morbidity and mortality. In assessment of the liver transplant donor, there are differences concerning apparent usefulness, and these must be resolved. In the liver transplant recipient, serial measurements are useful to measure real-time hepatic metabolic activity. Low MEGX values reflect the clinical condition of the patient, and the importance of entirely assessing the patient, not just noting the test result, is paramount. This review has considered the role of the MEGX test in liver transplantation.

Chronic irreversible rejection is a major cause of graft loss and retransplantation after orthotopic liver allotransplantation. To identify risk factors we retrospectively analysed 423 adult consecutive primary liver allograft recipients. The endpoint of the study was graft failure due to chronic rejection leading either to retransplantation or death. Chronic rejection developed in 22 (5.2%) patients. Pretransplant diagnosis of primary biliary cirrhosis or autoimmune hepatitis, recipient age less than 30 years, 1 or more episodes of acute cellular rejection, and transplantation of an organ from cytomegalovirus (CMV). IgG positive donor to an IgG negative recipient were identified as risk factors for chronic rejection. Transplantation of a liver from a male donor into a female recipient was also associated with an increased probability of chronic rejection. By logistic regression analysis, the probability of chronic rejection was predicted by: sex and cytomegalovirus match of donor and recipient, the presence of acute rejection, recipient age, transplantation for autoimmune hepatitis or primary biliary cirrhosis, and recipients receiving no azathioprine during the third month after transplantation. Sensitisation to antigens expressed by bile-duct epithelium as in primary biliary cirrhosis or exposure to donor bile-duct minor histocompatibility antigens, such as the male sex related H-Y antigen, may provide an explanation. More selective allocation of donor organs may allow a reduction in the incidence of ductopaenic rejection and graft loss.

The role of true cold ischemia times (CIT) and rewarming ischemia times (WIT) in determining outcome after liver transplantation was investigated in 230 adult recipients. Using multivariate analysis, WIT (time from the start of implantation until restoration of arterial and portal blood supply) and donor intensive care stay (P = .04 and .0004, respectively) but not CIT (the time from donor portal vein flushing until the graft was removed from University of Wisconsin solution; P > .30) emerged as independent determinants of graft survival. In the small number of patients with a WIT of greater than 180 minutes, there were reductions in graft survival (58% v 80% for WIT greater than 180 minutes) but these just failed to reach significance (P = .055). CIT had no influence on graft survival using cut-offs of 12 or 18 hours. A WIT of greater than 180 minutes was associated with an increased median area under the curve of day 1 through 7 serum bilirubin (1,370 v 915 mumol/L.day; P = .048) and trends towards an increased incidence of primary graft nonfunction or dysfunction (22.2% v 6.2% for WIT of less than 180 minutes; P = .065) and the day 1 through 7 area under the curve of serum aspartate aminotransferase (3,310 v 1,440 IU/L.day; P = .092). A prolonged CIT (greater than 18 hours) led to a prolonged hospital stay (69 v 31 days; P = .03), an increased area under the curve of day 8 through 14 serum bilirubin (2,500 v 995 mumol/L.day; P = .003), and a trend towards an increased incidence of initial poor graft function (33.3% v 6.3% for less than 18 hours; P = .092). The incidence of acute rejection increased (to 64.3% from 53.4%; P = .04) in patients with preservation injury (serum aspartate aminotransferase greater than 1,500 IU/L during the first 2 postoperative days). True CIT and WIT are important determinants of outcome after liver transplantation.