Cohort Of Liver Transplant Recipients Research Articles

Toll-Like Receptor 4 Polymorphisms and the Risk of Gram-Negative Bacterial Infections After Liver Transplantation

Toll-like receptor 4 (TLR4) is the main immune molecule that recognizes lipopolysaccharide from gram-negative bacteria. Single-nucleotide polymorphisms (SNPs) in the TLR4 gene that impair lipopolysaccharide recognition may influence gram-negative bacterial infections after liver transplantation. TLR4 D299G and T399I SNPs were assessed in a cohort of 706 liver transplant recipients and were associated with the clinical characteristics and outcome of gram-negative bacterial infections. Cox proportional hazard model was performed to determine covariates associated with outcomes after gram-negative bacterial infections. Of 706 patients, there were 108 with microbiologically confirmed gram-negative bacterial infections, 135 with clinically suspected but not confirmed infections, and 463 patients without gram-negative bacterial infections. The proportions of TLR4 D299G (5/108 [4.6%] vs. 32/463 [6.9%]; P=0.39) and T399I SNPs (19/108 [17.6%] vs. 68/463 [14.7%]; P=0.45) did not differ between those with or without microbiologically confirmed gram-negative bacterial infections. Female gender (odds ratio 2.30, 95% confidence interval [CI]1.50-3.53; P<0.001) and ulcerative colitis (odds ratio 2.18, 95% CI 1.08-4.38; P=0.03) were associated with gram-negative bacterial infections. Among 108 patients with gram-negative bacterial infections, alcoholic liver disease (relative risk [RR] 4.87, 95% CI 1.54-15.44; P=0.007), initial septic shock (RR 10.19, 95% CI 2.70-38.37; P=0.001), and nosocomially-acquired infection (RR 4.61, 95% CI 1.51-14.14; P=0.007) were significantly associated with 90-day mortality after gram-negative bacterial infections. In contrast, TLR4 D299G and T399I SNPs were not significantly associated with mortality after gram-negative bacterial infections. In this cohort of liver transplant recipients with long-term follow-up, no significant association was observed between TLR4 D299G and T399I SNPs and the risk and outcome of gram-negative bacterial infections.

Impact of recipients’ socio-economic status on patient and graft survival after liver transplantation: The IsMeTT experience

Aim We aimed to determine whether education level and socioeconomic status in a cohort of liver transplant recipients in the south of Italy were potential predictors of graft and patient survival. Methods This retrospective study included 221 liver transplant recipients at Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione between January 2006 and September 2009. Donor gender and age, cold ischaemic time, extended criteria donors, recipient age, gender, body mass index, primary aetiology, Model for End-Stage Liver Disease score, co-morbidities, patient health score assessed on the basis of clinical follow-up, highest level of education achieved, and socioeconomic status were collected and analysed. Results Kaplan–Meier analysis of survival measured by education level and socioeconomic status showed a higher survival rate in patients with higher education level ( p = 0.04) and socioeconomic status ( p = 0.01). After adjusting for all covariables, results of the multivariate Cox regression analyses showed that only socioeconomic status remained an independent and significant predictor of overall survival (Hazard Ratio = 0.16, p = 0.03). Conclusion Patient survival after liver transplantation was influenced by low income, low educational level, and lack of access to quality health care. Prospective clinical studies are necessary to fully identify the impact of socioeconomic status on long-term health outcomes, and to propose an evidence-based guide to clinical intervention.

Usefulness of a program of neoplasia surveillance in liver transplantation. A preliminary report

De novo malignancies are frequent complications after liver transplantation. Aim of the study is to evaluate whether a surveillance program for malignancy may improve patient survival. We have compared the survival after the diagnosis of malignancy (excluding cutaneous and hepatobiliary carcinomas and lymphoproliferative disease) of patients with symptomatic or incidental malignancies with patients with neoplasia diagnosed on screening. Two hundred and eighty patients with a follow-up greater than three months were followed for a median of 77.5 months (total follow-up: 1515 patient-yr). Thirty-three patients developed 41 malignancies. When compared with general population, the entire cohort of liver transplant recipients had a significantly higher risk of malignancy (relative risk: 2.34), gastrointestinal tract (relative risk: 2.52), urological tract (relative risk: 2.94) and head and neck cancer (relative risk: 4.14), and cancer-related death (relative risk: 2.35). All nine patients diagnosed with cancer with active screening are currently alive and free of malignancy after a median follow-up of 25 months. By contrast, 18/24 patients with diagnosis of cancer prompted by symptoms or incidentally diagnosed died as a consequence of the cancer (median survival: 13.5 months). The difference in survival between both groups was significant (p = 0.002). In conclusion, a close surveillance protocol for the diagnosis of malignancy could be life-saving in liver transplant recipients.

F.37. Frequencies of Toll-like Receptor (TLR)-9 Promoter Region Gene Polymorphisms in a Cohort of Liver Transplant Recipients

F.37. Frequencies of Toll-like Receptor (TLR)-9 Promoter Region Gene Polymorphisms in a Cohort of Liver Transplant Recipients

Acute Necrotizing Pancreatitis and Severe Hepatic Failure: Description of Three Cases

Introduction Acute pancreatitis is not uncommon in fulminant hepatic failure (FHF) as confirmed by histology or serology. A few reports exist of symptomatic pancreatitis in the setting of acute viral hepatitis; the diagnosis is usually made intraoperatively or postmortem. We report three cases of liver transplant (OLT) recipients with severe acute liver failure and severe acute pancreatitis as an intraoperative finding. Methods We undertook a retrospective review among a large cohort of liver transplant recipients to define the impact of this problem. Results Between 1999 and 2007, 293. LTs were performed including 15 (5%) who had severe acute liver failure (nine with FHF and six with an emergency retransplantation [ER]). Among this group, three patients were diagnosed intraoperatively with acute necrotizing pancreatitis (ANP): two patients with associated FHF and one with an ER due to ABO incompatibility. None of the patients had symptoms of pancreatitis. In all, ANP was classified as Balthazar CT grade D-E, which determined the outcome. All the patients developed a pseudocyst and abscess, which required surgical drains. Conclusion ANP was diagnosed as an intraoperative finding in patients with FHF. The mechanism of pancreatitis in patients with FHF is unknown. It may be multifactorial (virus, acute liver failure, hypotension, infection, drug-induced lesion,). This association leads to a worse outcome due to the complications.

Orthotopic Liver Transplantation for Hepatocellular Carcinoma: A Thirteen-Year Single-Center Experience

Background When restrictive selection criteria are applied orthotopic liver transplantation (OLT) is the most efficient option for the treatment of hepatocellular carcinoma (HCC) in terms of survival and recurrence rate. Nevertheless, tumor recurrence may occur in 3.5%–21% of recipients, with a consequent negative impact on prognosis. The aim of this study was to analyze the long-term survival and tumor recurrence rate among a cohort of liver transplant recipients with HCC. Methods During the period 1994–2007, 130 HCC patients, including 111 males with a mean overall age of 57.8 ± 7.1 years (range, 38–70), underwent cadaveric donor-OLT. The etiology of liver disease was alcoholic cirrhosis in 66 patients (50.8%) and viral infection in 52 patients (40%). Baseline alpha fetoprotein values were 53.4 ± 280.9 ng/mL (range, 1–2593). Median interval between inclusion date and transplantation was 179.5 days. Results After a median follow-up of 40.8 months, 93 recipients (71.5%) were alive. Tumor recurrence was detected in 11 patients (8.5%). Neoplasm recurrence sites were as follows: liver graft (45.4%), bone (36.4%), lymphoadenopathies (27.3%), adrenal glands (27.3%), and lung (27.3%). Overall survival rates at 1, 3, 5, and 10 years were 85.1%, 78.3%, 70.1%, and 57%, respectively. After examination of the explanted liver, Milan criteria were surpassed in 32 recipients (24.6%). Nevertheless, no differences in survival were observed according to fulfilment or not of Milan criteria (log-rank test, P > .05). Hepatitis C virus (HCV) infection, female gender, and tumor recurrence were associated with a worse survival rate (log-rank test, < .05). Conclusions OLT is an effective option for the treatment of HCC with good long-term survival and low recurrence rates. In this series, survival was not affected by findings of poor prognostic factors in the explanted liver.

Outcomes After Liver Transplantation in Young Infants

Liver transplantation in infants younger than 90 days is increasingly common. These infants typically arrive for transplantation in fragile medical condition. It is commonly assumed that they may experience high complication rates, difficult postoperative courses, and poor graft and patient survival. We sought to understand whether graft and patient survival rates in these young infants were lower than in older children, these patients experienced more complications than older children, and health care resource utilization was higher in this population. Data queried from the Study of Pediatric Liver Transplantation (SPLIT) database were limited to infants ages 0 to 90 days who had received their primary liver transplant between February 1996 and May 2004. Patients older than 90 days registered in the SPLIT database were used for comparison. Thirty-eight patients, ages 0 to 90 days, were included in the analysis. Their severity of illness was reflected by a median calculated Pediatric Endstage Liver Disease score of 34.8 at transplant. A majority (89.5%) of infants received cadaveric liver grafts, of which 47% were reduced organs. The infants experienced prolonged hospitalizations, spending an average of 50.9 +/- 7.6 days in the hospital after transplant. Long stays in the intensive care unit (average 22.1 +/- 1.5 days) and need for mechanical ventilation (average 16.2 +/- 2.7 days) also occurred. Length of hospitalization, intensive care, and mechanical ventilation were significantly higher than in older children (P < 0.0001). The reoperation rate (60.5%) was high and significantly greater than in older children (P = 0.007), with 10 patients (26.3%) needing 3 or more early reoperations. Reoperations occurred for bleeding, wound complications, biliary complications, and sepsis. There was no difference in vascular or biliary tract complications compared with older children. Bacterial infections were also common (52.6%) and were seen with greater frequency than in older children (P < 0.04). This infant cohort had an overall graft survival of 76.1% and overall patient survival of 87.8% at 1 year, with median follow-up of 12.5 months (range 0.6-84.0 months). Graft and patient survival in infants younger than 90 days was similar to that in older infants and children (P = NS). Young infants experience graft and patient survival similar to that in older cohorts of liver transplant recipients. Posttransplant complication rates, including the reoperation rate, were higher in this younger group, and the duration of hospitalization and intensive support were significantly longer. Future studies to better examine the factors, including age, that may contribute to the need for reoperation in children are warranted. Recognition and further analysis of the cost of care in this age group is also needed.

Absence of Pneumocystis jiroveci pneumonia in liver transplantation recipients receiving short‐term (3‐month) prophylaxis

Pneumocystis jiroveci (formerly known as Pneumocystis carinii) is a fungal pathogen that causes pneumonia (PCP) in liver transplant recipients. Consequently, prophylaxis with trimethoprim-sulfamethoxazole (TMP/SMZ) is typically administered for at least 1 year at most liver transplant programs. At our center we have utilized a short-term (3-month) prophylactic regimen with TMP/SMZ for the past decade and report our experience and speculate on the potential widespread application of this approach. For patients transplanted at our center between January 1997 and January 2007, we recorded all documented PCP infections by review of our liver transplant database and hospital-based electronic medical records system, both of which record all infections and culture results. We recorded no cases of PCP in any of the liver transplant recipients at our center during the study period. We report the absence of PCP in a large cohort of liver transplant recipients receiving a short-term (3-month) prophylaxis with TMP/SMZ. These findings provide a rational basis to consider short-term (3-month) PCP prophylaxis or avoidance of prophylaxis altogether in selected low-risk patients.

Impact of Cytomegalovirus in Organ Transplant Recipients in the Era of Antiviral Prophylaxis

Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

Hepatitis C is a risk factor for death after liver retransplantation

Retransplantation for liver allograft failure associated with hepatitis C virus (HCV) has been increasing due to nearly universal posttransplant HCV recurrence and has been demonstrated to be associated with poor outcomes. We report on the risk factors for death after retransplantation among liver recipients with HCV. A retrospective cohort of liver transplant recipients who underwent retransplantation between January 1997 and December 2002 was identified in the Scientific Registry of Transplant Recipients database. Cox regression was used to assess the relative effect of HCV diagnosis on mortality risk after retransplantation and was adjusted for multiple covariates. Of 1,718 liver retransplantations during the study period, 464 (27%) were associated with a diagnosis of HCV infection. Based on Cox regression, retransplant recipients with HCV had a 30% higher covariate-adjusted mortality risk than those without HCV diagnosis (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.54; P = 0.002). Other covariates associated with significant relative risk of death after retransplantation included older recipient age, presence in an intensive care unit (ICU), serum creatinine, and donor age. Additional regression analysis revealed that the increase in mortality risk associated with HCV was concentrated between 3 and 24 months postretransplantation, among patients age 18 to 39 at retransplant, and in patients retransplanted during the years 2000 to 2002. In conclusion, HCV liver recipients account for a considerable proportion of all retransplantations performed. Surprisingly, younger age predicted a higher mortality for recipients with HCV undergoing liver retransplantation. This may reflect a willingness to retransplant younger patients with an increased severity of illness or a more virulent HCV infection in this population. Although HCV was predictive of an increased risk of death, consideration of other characteristics of HCV patients, including donor and recipient age and need for preoperative ICU care may identify those at significantly higher risk.

Late-Onset Cytomegalovirus Disease in Liver Transplant Recipients Despite Antiviral Prophylaxis1

The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.

Hepatitis C etiology of liver disease is strongly associated with early acute rejection following liver transplantation.

Although recurrent hepatitis C (HCV) occurs universally after liver transplantation (LT), its tempo and severity are variable and unpredictable. Diagnosis and treatment of early acute rejection (EAR) likely affect the course of recurrent HCV disease. We have studied a contemporary cohort of LT recipients to reexamine risk factors for EAR. We hypothesized that HCV etiology may represent a significant risk factor for EAR for many reasons. First, recurrent disease commonly causes biochemical abnormalities prompting allograft biopsy. Second, overlapping histologic features of acute rejection and recurrent HCV ambiguity may result in diagnostic ambiguity. Finally, the biology of hepatitis may precipitate an antidonor response in addition to an antiviral response. Records of 285 adult recipients undergoing primary LT for cirrhosis between January 1, 1999, and December 31, 2002, were retrospectively reviewed. EAR was defined as a biopsy-proven or an empirically treated episode within 6 months of LT. Cox proportional hazards analysis identified donor, recipient, transplant, and posttransplant characteristics associated with EAR; Kaplan-Meier analysis was used to assess rejection by etiology. HCV cirrhosis was the etiology for 51% of all LT recipients. There were 135 episodes of EAR (127 biopsy proven) in 117 recipients for an overall incidence of 41%. Patient groups with HCV and cholestatic / autoimmune disease groups exhibited the highest incidence of rejection at 49%. Recipient gender, ethnicity, etiology, LT year, and posttransplant immunosuppression levels were risk factors for EAR in univariate analysis; HCV etiology and female gender remained robust risk factors in multivariate analysis. Interferon-based therapy did not impact the incidence or timing of EAR. In conclusion, HCV etiology is strongly associated with EAR. HCV allograft reinfection may create an immunologic environment predisposed to EAR. Alternatively, the association of HCV and EAR may result from an increased frequency of allograft biopsy and may be further exacerbated by inability to accurately diagnose EAR in the setting of recurrent HCV.

MYCOPHENOLATE MOFETYL (MMF) THERAPY USED IN A PRIMARY IMMUNOSUPPRESSIVE REGIMEN FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION (OLT)

A191 Aims: MMF is a new immunosuppressive (IS) drug for use following OLT which may decrease acute rejection and lead to a reduction in calcineurin inhibitors (CNI) in case of nephrotoxicity. Few studies have evaluated its early use in a primary IS regimen on a large cohort of liver transplant recipients. The aims of this study were: a) to evaluate the impact of MMF on patient survival, frequency of acute and chronic allograft rejection, rate of post-transplant infectious events; and b) to quantify CNI reduction in case of nephrotoxicity. Methods: Patients with MMF in a primary IS regimen (group A) were compared to those without initial MMF (group B). Prognostic analysis used χ2, Kruskal-Wallis, T test and log-rank tests, and the Kaplan Meier method. Results: From 1995 to 2003, 169 adult recipients (173 OLT) were followed for 34 months (109 males, 60 females; age: 48 years). An IS regimen with MMF-CNI-corticosteroids was prescribed in group A (95 consecutive patients, mean follow-up 30.5±10 months), and an azathioprine-CNI-corticosteroid regimen was used in group B (74 patients, mean follow-up 44.4±16 months). Within group B, MMF was never used in 48 patients and secondarily introduced in 26 patients in order to reduce CNI (nephrotoxicity in 20% of cases). Post-transplant survival was significantly higher in group A than in group B at 1 year (90.1±3,1% vs 78.4±4.8%, p=0.02) and 2 years (87±3.8% vs 77±4.9%, p=0..05). Acute and chronic rejection rates were significantly lower in group A than in group B (18.9% vs 43.2%, p= 0.0005 and 0% vs 3.9%, p=0.05). The retransplantation rate did not differ in the two groups (1.1% vs 4.1%). The global rate of early bacterial and CMV-induced events did not differ in the two groups (group A: 34% and 35% versus group B: 31% et 29%). In group A, a decrease in the dose of MMF dose was required in 35% of cases and total arrest in 23% of cases. Frequencies of renal dysfunction and severe renal dysfunction (clearance of creatinine <80 ml/min or <30 ml/min) did not differ in the 2 groups at one year (51.7% vs 48.3% and 0% vs 0%), 2 years (37.7% vs 62.3% and 0% vs 1.9%) or 3 years (72.7% vs 83.7%, and 9.1% vs 6.4%). In group B, secondary use of MMF (mean 36 months post-OLT) in 20 transplant recipients with renal dysfunction led to a reduction in CNI (cyclosporine 0.6 mgkg-1d-1 vs 2.6 mgkg-1d-1, p=0.002, tacrolimus 0.02 mgkg-1d-1 vs 0.08, p=0.009) and a stabilization of renal function with an increase in creatinine clearance of 8 ml/min in 1 year compared to patients from group B without MMF. Conclusions: MMF is an efficient and safe immunosuppressant following OLT which reduces rejection and improves 1- and 2-year survival without significantly increased infectious hazard. Moreover, it enables reduction of CNI and maintenance of renal function in cases of nephrotoxicity.

Serological Studies of West Nile Virus in a Liver Transplant Population

Solid organ transplant populations are at increased risk for serious clinical manifestations of West Nile virus (WNV) infection. To monitor liver transplant recipients during the 2003 WNV season in Manitoba and to identify incidence, clinical presentation and serology. Serial blood specimens were obtained from adult patients followed at the liver transplant outpatient clinic between May 2003 and October 2003. Studies for WNV infection included immunoglobulin (Ig) G and IgM enzyme immunoassay (EIA), hemagglutination inhibition (HI), plaque reduction neutralization test and reverse transcriptase-polymerase chain reaction. None of the 79 patients had clinical presentations suggestive of WNV infection. On testing of the final serum specimen obtained, 14 patients (18%) had positive IgG anti-WNV by EIA and six patients (7%) had indeterminate IgG anti-WNV by EIA, although all were negative by IgM EIA. Four (20%) of the EIA-positive samples were reactive by HI, but all of these were negative by WNV plaque reduction neutralization test; this is consistent with the presence of non-West Nile flavivirus antibody in these sera. Blood specimens obtained throughout the season from EIA- and HI-positive individuals were uniformly negative for WNV-RNA by reverse transcriptasepolymerase chain reaction. Age, sex, hematology and biochemistry findings, hepatitis B or C virus status, immunosuppressive regimen (cyclosporin or tacrolimus) and pretransplant diagnosis of liver disease were similar for EIA-positive and EIA-negative patients. For the 10 patients with a positive IgG EIA maintained on cyclosporin, the cyclosporin level was 129.1+/-28.6 microg/L compared with 85.6+/-36.7 microg/L in 26 patients who were EIA-negative (P=0.002). False-positive IgG EIA serology for WNV was common in this cohort of liver transplant recipients, and was associated with elevated serum cyclosporin levels.

Low incidence of cytomegalovirus disease in liver transplant recipients receiving sirolimus primary immunosuppression with 3‐day corticosteroid taper

Cytomegalovirus (CMV) disease is the most common infection following liver transplantation, occurring in approximately 20% of recipients. In liver transplant recipients, CMV is associated with a higher cost following transplantation, subsequent infections, and recurrent hepatitis C. Since we have initiated a prednisone-free immunosuppressive regimen in January 2000, we have noted an extremely low incidence of CMV disease in our cohort of liver transplant recipients. We report our findings here. All 150 patients transplanted between January 2000 and December 2002 with tacrolimus (or cyclosporin A) and sirolimus, and 3-day corticosteroid taper were retrospectively analyzed. Recipients who were CMV IgG negative with a CMV IgG-positive donor ("CMV mismatch") received conventional prophylactic therapy with intravenous and oral ganciclovir. The incidence of CMV disease (defined as positive tissue culture or positive immunohistochemical stain of affected tissue or CMV-DNA >3000 associated with clinical symptoms) was recorded for each patient. The proportion of "CMV mismatches" (donor CMV IgG positive, recipient CMV IgG negative) was 15%. The mean total number of days of ganciclovir prophylaxis (intravenous and/or oral) administered to "CMV mismatch" patients was 45.6 days. The incidence of CMV disease in patients receiving sirolimus primary immunosuppression was 2%. The mean time to diagnosis of CMV disease was 139 days. (1) The incidence of CMV disease is very low using a prednisone-free, sirolimus immunosuppressive regimen. (2) Two possible explanations for this finding include appropriate prophylaxis with ganciclovir and low levels of immunosuppression including the absence of prednisone.

Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience.

To evaluate the incidence of posttransplant lymphoproliferative disease (PTLD) and the risk factors and the impact of this complication on survival outcomes in a large cohort of liver transplant recipients at a single institution. Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, in large part due to the availability and reliance on the use of nonspecifically directed immunosuppression. However, as predicted and subsequently verified in 1968, an increased incidence of certain de novo malignancies has been observed, particularly with regards to lymphoid neoplasms. While many reports have confirmed and clarified the nature of PTLD, the literature is fraught with conflicting experience and outcomes with PTLD. Four thousand consecutive patients who underwent liver transplants between February 1981 and April 1998 were included in this analysis and were followed to November 2001. The effect of recipient age at the time of transplant, recipient gender, diagnosis, baseline immunosuppression, grading of PTLD, and association with Epstein-Barr virus were compared. The causes of death were also examined. Treatment for PTLD varied over the 20-year period, but all included massive reduction or elimination of baseline immunosuppression. The 1-year patient survival for liver transplant patients with PTLD was 85%, while the overall patient survival for the entire cohort was 53%. The actuarial 20-year survival was estimated at 45%. The overall median time to PTLD presentation was 10 months, and children had an incidence of PTLD that was threefold higher than adults. Patient survival was better in children, in patients transplanted in the era of tacrolimus immunosuppression, in patients with polymorphic PTLD, and in those with limited disease. Interestingly, neither the presence or absence of Epstein-Barr virus nor the timing of PTLD presentation appeared to influence overall patient survival. Patients transplanted for alcohol-related liver disease had a similar incidence of PTLD but had a higher risk of mortality. While PTLD continues to pose problems in patients receiving liver transplants, improvements in patient survival have been observed over time. While it is too early to assess the impact of new advances in prophylaxis, diagnosis, and treatment, such approaches are based on an increased knowledge of the pathophysiology of PTLD.

Immunosuppression impact on long-term cardiovascular complications after liver transplantation

Background: With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed. Objective: The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation. Methods: Eighty-seven sequential patients (CSA: n = 50, mean age 48 years, M/F 32/18; and FK-506: n = 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were ≥18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx. Results: At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P < 0.05), HTN (62% versus 38%, P < 0.05), HLIP (14% versus 5%, P = 0.08), and cardiovascular disease (18% versus 0%, P < 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group. Conclusion: Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease.

Long-term survival after liver transplantation in 4,000 consecutive patients at a single center.

To evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. Four thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. The overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. Significantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation: a report of three cases

Background/Aims: Post-transplant lymphoproliferative disorders (PT-LPD) are a well-known complication of organ transplantation. Their incidence after liver transplantation in adults ranges from 1.8 to 4%. Reduction of immunosuppression led to remission in a few cases. Other treatments include chemotherapy, interferon alpha therapy and/or intravenous-immunoglobulins, or antiviral drugs. However, monoclonal antibodies directed against B-cell specific antigens have rarely been used in those patients. Our aim was to study the feasibility and efficacy of Rituximab, a new, promising human chimeric antibody that recognizes the CD20 antigen, for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation.Methods: Rituximab (IDEC-C2HB8; Roche Laboratories, Neuilly-sur-Seine, France) was administered at a 375 mg/m2 dose on days 1, 8, 15, and 22, in an outpatient setting, in three patients with PT-LPD. The tumor was classified as polymorphic PT-LPD in two cases and PT-LPD with features of large cell lymphoma in one case. All the tumors expressed the CD20 antigen and were EBV-related, and the clonality was confirmed in all three cases. The 4 injections of the anti-CD20 monoclonal antibody were associated with reduced immunosuppression in the three patient.Results: The treatment with Rituximab was well tolerated without any side effects. The two patients with polymorphic PT-LPDs underwent rapid complete remission, whereas the treatment modalities were ineffective in the patient with the large-cell non-Hodgkinlymphoma.Conclusion: These results must be confirmed in a larger cohort of liver transplant recipients suffering from lymphoproliferation. However, they indicate rapid efficiency of Rituximab in association with reduced immunosuppression in these disorders.

Cost-effectiveness of different strategies of cytomegalovirus prophylaxis in orthotopic liver transplant recipients.

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in liver transplant recipients and several different strategies of CMV chemoprophylaxis are in practice. A cost-effective analysis was performed to compare these strategies. A hypothetical cohort of liver transplant recipients was followed up for a year posttransplantation in a Markov model, as they made possible transitions to different states of health with respect to CMV infection and disease. Different strategies of chemoprophylaxis were compared. Cost per patient, yield in terms of gain in quality-adjusted stages, amount of time spent in the state of CMV disease, and CMV-related mortality were the outcome measures compared. Oral ganciclovir administered universally to all transplant recipients was the most favored strategy. Restricting prophylaxis to defined high-risk groups or extending the duration of prophylaxis beyond 3 months did not improve cost-effectiveness. The strategy of short-term, oral ganciclovir-based chemoprophylaxis for CMV in liver transplant recipients is cost-effective by current standards of healthcare interventions.