Biomedical subjects

Kim M Olthoff

Publications and source records attributed to Kim M Olthoff.

At least 19 recordsLinked to original sources

PubMed2025

Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways.

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2×10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7×10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Journal Article↗

PubMed2025

Expanded Chromatin Accessibility Mapping Explains Genetic Variation Associated with Complex Traits in Liver.

Genome-wide association studies (GWAS) have identified thousands of loci associated with a variety of common, complex human traits. Recent efforts have focused on characterizing chromatin accessibility to discover regulatory elements that modify the expression of nearby genes, suggesting that trait associations are mediated through changes in gene regulation. Genetic variants associated with differences in chromatin accessibility, known as chromatin accessibility quantitative trait loci (caQTLs), are established contributors to gene expression differences, providing mechanistic hypotheses for signals identified by GWAS. Using the assay for transposase-accessible chromatin with sequencing (ATAC-seq), we assessed chromatin accessibility in 189 diverse human liver samples, identifying over two million accessible chromatin regions enriched for gene regulatory features and, in 175 of these samples, over 14,000 caQTLs. Focusing subsequently on liver-relevant complex traits, we obtained publicly available blood lipids GWAS data and identified 157 loci where caQTLs, expression quantitative trait loci (eQTLs), and GWAS signals colocalized. This generated specific molecular hypotheses about regulatory elements, affected genes, and, in some cases, implicated transcription factors. Finally, we enumerated the set of blood lipid trait signals that lack an obvious proposed mechanism beyond catalogs of liver caQTLs and eQTLs. After integrating 10 multi-omic QTL regulatory mechanism datasets whilst considering limitations in statistical power, we found that approximately 20% of blood lipid GWAS signals lacked a statistical link to a proposed mechanism. Our results demonstrate the value of integrating multiple genomic datasets to improve understanding of GWAS signals, while emphasizing the need for additional experimental approaches to fully characterize complex trait associations.

Journal Article↗

PubMed2006

Selective neutralization of the chemokine TCA3 reduces the increased injury of partial versus whole liver transplants induced by cold preservation.

BACKGROUND: Given the shortage of liver donors and the development of techniques for partial liver transplantation, we compared chemokine expression and inflammatory cell infiltration of partial versus whole grafts in a mouse syngeneic liver transplant model. METHODS: Orthotopic liver transplantation, using whole or partial murine liver grafts, was performed following cold preservation in ViaSpan solution for periods of one to eight hours. RESULTS: Partial grafts showed more severe cold ischemia/reperfusion injury and greater inflammatory cell infiltration than whole grafts, and was accompanied by the marked intrahepatic upregulation of multiple chemokines. Quantitative analysis showed that compared with expression in whole grafts harvested after the same period of cold ischemia, partial grafts had eightfold more T-cell activation gene (TCA)-3 (CCL1) chemokine messenger RNA (mRNA) expression (P<0.01) and sixfold more inducible protein (IP)-10 chemokine (CCL10) mRNA expression (P<0.01), as well as increased expression of the chemokine receptors CCR8 (receptor for TCA3) and CXCR3 (receptor for IP-10; P<0.01). Blockade of TCA3 by neutralizing monoclonal antibody significantly decreased intragraft IP-10 expression (P<0.05) but not tumor necrosis factor-alpha or interleukin-6 expression in partial grafts, and significantly decreased cold ischemia/reperfusion injury (P<0.05) and associated neutrophil and T-cell infiltration (P<0.01). CONCLUSIONS: These data demonstrate that the chemokine TCA3/CCL1 is important to the pathogenesis of ischemic injury of experimental partial liver grafts, and that its therapeutic targeting within such grafts can overcome the deleterious effects of prolonged cold preservation and restore liver function to the level achieved using whole liver grafts.

Animals↗

PubMed2006

Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria.

Erythropoietic protoporphyria is a disorder of heme synthesis in which deficient ferrochelatase activity leads to excess production and biliary excretion of protoporphyrin. The main clinical features, photosensitivity and hepatobiliary disease that may progress to liver failure, are caused by the toxicity of protoporphyrin. Liver transplantation has been used to treat liver failure in erythropoietic protoporphyria, but excess production of protoporphyrin by the bone marrow continues causing recurrence of liver disease in the majority of patients. This is the first report of successful sequential liver and bone marrow transplantation in a patient with liver failure as a result of erythropoietic protoporphyria. This combination corrected the severe phenotype, resolving the severe photosensitivity and halting erythropoietic protoporphyria associated liver graft injury. Splenectomy seemed to facilitate the successful bone marrow transplant.

Adolescent↗

PubMed2005

Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation.

In patients with recent onset renal insufficiency, the decision to perform combined kidney/liver transplantation (CKLT) vs. orthotopic liver transplantation alone (OLTa) can be difficult. We hypothesized that duration of renal dysfunction may correlate with creatinine elevation after liver transplantation. We retrospectively identified 69 liver transplantation patients with pretransplantation creatinine > or =1.5 mg/dL (53 OLTa, 13 CKLT). Variables analyzed were presence of hepatorenal syndrome, creatinine, Model for End-Stage Liver Disease score, albumin, age, race, gender, cause of liver disease, diabetes mellitus, hypertension, and history of ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, renal replacement therapy (RRT), and transjugular intrahepatic portosystemic shunting. Duration of pretransplantation renal dysfunction was predictive of 6- and 12-month creatinine post-OLTa. Area under the receiver operating characteristic (ROC) curve for prediction of 12-month renal insufficiency by renal dysfunction duration was 0.71; optimal duration cutoff was 3.6 weeks. We applied a multivariable model, derived from OLTa patients, to CKLT subjects with definite or possible hepatorenal syndrome. Predicted 12-month creatinine without renal transplantation was >2.0 mg/dL for each patient. CKLT patients as opposed to OLTa patients had longer duration of renal dysfunction (median, 18.1 vs. 2.7 weeks, P < 0.001), higher creatinine (median 4.0 versus 1.7 mg/dL, P < 0.001), and higher rate of pretransplantation RRT (62% vs. 7%, P < 0.001). Adjusting for baseline characteristics, CKLT patients had lower creatinine than OLTa patients at 6 months (P =0.15) and 12 months (P =0.01) after transplantation. In conclusion, duration, but not cause, of renal dysfunction predicts renal outcome in OLTa recipients. Prospective studies may use duration of renal dysfunction to help identify CKLT candidates.

Cohort Studies↗

PubMed2005

Appendicitis among liver transplant recipients.

Appendicitis among liver transplant recipients has not been described in the current literature. We report 8 recipients who experienced appendicitis three weeks to 181 months after liver transplantation (LT). Initial presenting findings differed from the nonimmunosuppressed population in that a majority of the patients did not have leukocytosis (>10,000 cells/mm3). Four patients experienced perforation, three of whom presented three days after the development of abdominal pain. All patients recovered after surgery without untoward sequela.

Abdominal Pain↗

PubMed2005

Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium.

OBJECTIVE: The objective of this study was to characterize the patient population with respect to patient selection, assess surgical morbidity and graft failures, and analyze the contribution of perioperative clinical factors to recipient outcome in adult living donor liver transplantation (ALDLT). SUMMARY BACKGROUND DATA: Previous reports have been center-specific or from large databases lacking detailed variables. The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) represents the first detailed North American multicenter report of recipient risk and outcome aiming to characterize variables predictive of graft failure. METHODS: Three hundred eighty-five ALDLT recipients transplanted at 9 centers were studied with analysis of over 35 donor, recipient, intraoperative, and postoperative variables. Cox regression models were used to examine the relationship of variables to the risk of graft failure. RESULTS: Ninety-day and 1-year graft survival were 87% and 81%, respectively. Fifty-one (13.2%) grafts failed in the first 90 days. The most common causes of graft failure were vascular thrombosis, primary nonfunction, and sepsis. Biliary complications were common (30% early, 11% late). Older recipient age and length of cold ischemia were significant predictors of graft failure. Center experience greater than 20 ALDLT was associated with a significantly lower risk of graft failure. Recipient Model for End-stage Liver Disease score and graft size were not significant predictors. CONCLUSIONS: This multicenter A2ALL experience provides evidence that ALDLT is a viable option for liver replacement. Older recipient age and prolonged cold ischemia time increase the risk of graft failure. Outcomes improve with increasing center experience.

Adult↗

PubMed2005

Serum protein electrophoresis abnormalities in adult solid organ transplant patients with post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP. Twenty-three (61%) had MG with nine (24%) showing multiple MG. Background gammaglobulin levels were abnormal in 13 (34%) patients with five (13%) and eight (21%) having polyclonal hypergammaglobulinemia or hypogammaglobulinemia, respectively. Hypogammaglobulinemia was correlated with the presence of MG (p = 0.01) and polymorphic B-cell hyperplasia histology (p = 0.01). No correlation between SPEP findings and overall survival were noted. With median follow-up of 116 wk (range 2-261 wk), 21 (55%) patients are alive with 20 (53%) in complete remission. Response to reduction in immunosuppression was correlated with improved overall survival (262 wk vs. 68 wk, p = 0.003). Persistence of MG after complete response of the PTLD did not predict relapse. There is a high incidence of MG and gammaglobulin abnormalities in patients with PTLD.

Adult↗

PubMed2005

Liver and intestine transplantation: summary analysis, 1994-2003.

With nearly two years of data available since the inception of the MELD and PELD allocation system, this article examines national OPTN/SRTR data to describe trends in waiting list composition, waiting list mortality, transplant rates, and patient and graft outcomes for liver transplantation. Following a 6% reduction in the size of the waiting list after MELD was implemented in 2002, the number of patients on the waiting list grew by 2% from 2002 to 2003, while the number of liver transplants increased by 6%. The overall death rate while on the liver waiting list has decreased from 225 deaths per 1,000 patient years in 1994 to 124 deaths in 2003. As with the waiting list death rates, post-transplant death rates have also decreased over the past decade. Unadjusted one-year patient survival was lower for older donor age groups (88% for donors aged 18-34, 87% for donors aged 35-49, 85% for donors aged 50-64); a similar trend was observed at three and five years following transplantation. Intestine transplantation is performed with slowly increasing frequency and success. Early graft losses and rejection rates have changed little since 1994, but rejection is easier to control and long-term survival is improving.

Adolescent↗

PubMed2004

Early kidney dysfunction post liver transplantation predicts late chronic kidney disease.

BACKGROUND: Acute and chronic renal dysfunction (ARD, CRD) are common complications after liver transplantation and are associated with poor outcome. METHODS: We reviewed the results of 181 liver transplants performed in our institution between January 1, 1998 and December 31, 2000 in which the recipients were alive with good liver function at the end of the follow-up period (mean 2.7 years). Renal dysfunction was defined as a serum creatinine (Cr) greater than or equal to 2 mg/dL in both acute and chronic settings. RESULTS: The incidence of ARD during the first posttransplant week was 39.2% (n=71), whereas late CRD occurred in 6.0% (n=11) of the patients by the end of the follow-up period. Among the variables we examined for association with CRD, five factors were found to be statistically significant in univariate analysis: pretransplant diabetes (PRTDM) (0.000), Cr greater than or equal to 2 during the first postoperative week (0.003), posttransplant diabetes (POTDM) (0.014), age greater than 50 (0.025), and tacrolimus level greater than 15 ng/mL at postoperative day 15 (0.058). In binary logistic regression analysis, PRTDM (odds ratio [OR]=5.7, 95% confidence interval [CI]) and early postoperative ARD (OR=10.2 95% CI) remained consistently significant. Nine of 11 patients with CRD also had a history of ARD during the first postoperative week. These patients progressed to CRD despite the fact that seven of nine had normalized their renal function by day 90 posttransplant. CONCLUSION: We suggest that a combination of events during the first postoperative week after liver transplant serve as a physiologic "stress test" for the kidneys. Patients who fail the test (peak Cr >/=2 mg/dL during the first postoperative week) as well as the patients with diabetes mellitus are at increased risk of CRD. In such cases, conversion to a less nephrotoxic regimen may be beneficial.

Acute Disease↗

PubMed2004

A matched comparison study of medical and psychiatric complications and anesthesia and analgesia requirements in methadone-maintained liver transplant recipients.

Approximately 85% of patients receiving methadone maintenance therapy (MMT) for opiate dependence in the United States are infected with hepatitis C virus (HCV). MMT is significantly underrepresented in most liver transplant programs, but the number of patients receiving MMT is increasing and few data are available to guide treatment. We evaluated MMT in our program (27 pretransplant and 10 posttransplant cases) for medical and psychiatric complications and anesthesia and analgesia requirements. After transplant, 10 patients receiving MMT were compared with a matched control group of 19 patients who were not receiving MMT and not dependent on opiates. Fewer patients receiving MMT retained a spot on the transplant waiting list (65%) than patients not receiving MMT (80%); 30% of patients receiving MMT pretransplant used heroin, cocaine, or marijuana, and more than 25% were lost to follow-up. Liver disease according to mean Child-Turcotte-Pugh (CTP) score and transplant waiting times was similar between the 2 groups. Patients receiving MMT required significantly more intraoperative anesthesia and postoperative analgesia (mean fentanyl 3,175 microg/d, SD = 2,832; intravenous morphine 67.86 mg/d, SD = 38.84, respectively) compared with patients not receiving MMT (mean fentanyl 1,324 microg/d, SD = 1,122; intravenous morphine 12.17 mg/d, SD = 10.24, respectively). More patients receiving MMT had severe recurrent HCV infection (60%) and worse survival (60%) versus patients not receiving MMT (21% and 78.9%, respectively). Follow-up times did not differ between groups (MMT: mean 4.19 years, median 1.15 years, SD = 7.6; non-MMT: mean 2.68 years, median 2.19 years, SD = 1.73). Finally, patients receiving MMT required an average methadone dose increase of 60% from pretransplant to posttransplant. Postoperative analgesia guidelines are described. Posttransplant, 20% of patients receiving MMT used alcohol or illicit drugs. Data do not support withholding the provision of liver transplantation to patients receiving MMT, but larger, well-controlled studies are warranted.

Adult↗

PubMed2004

Liver transplantation for hepatocellular carcinoma validation of present selection criteria in predicting outcome.

Appropriate patient selection is crucial in ensuring acceptable outcomes from orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) has elected to prioritize HCC patients for OLT based on criteria of tumor burden. However, it is unclear whether these criteria correlate with outcome, or with the pathobiological features associated with tumor recurrence. Therefore, we analyzed 109 consecutive patients undergoing OLT for HCC at our center, to determine the utility of present selection criteria in predicting outcome. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified tumor node metastases (pTNM) classification system. Multifocality was defined as >4 tumor nodules on explant. Survival analysis was performed using Kaplan-Meier and Cox proportional hazards regression methods. At a median follow-up of 18.9 months, the overall mortality was 19% with 15 patients (14%) dying of recurrent HCC. Kaplan-Meier 1, 3 and 5-year survival rates were 89.5%, 68%, and 65%, respectively. Recurrence-free rates of 1, 3, and 5 years were 89%, 75%, and 65%, respectively. On univariate analysis, the factors found to be significantly associated with recurrence of HCC were explant features of macrovascular invasion, tumor size (per centimeter increase), pTNM stage (per 1-stage increase), and pre-transplant serum alphafetoprotein (AFP) >300 ng/mL. In defining a threshold level, we found that explant tumor diameter > or =3 cm, and those tumors classified as at least pT3 on pathological examination, were significantly associated with recurrence (P =.01 and.03, respectively). Tumor size on explant was found to be strongly correlated with multifocality (P =.017) and vascular invasion (P =.02). Patients exceeding pathological UNOS criteria were 3.1 times more likely to have recurrence of HCC (P =.03). In conclusion, we found that tumor size appears to be a surrogate marker for negative pathobiological predictors of outcome, i.e., vascular invasion and multifocality. Present UNOS selection criteria for HCC based on tumor burden appear to provide adequate discriminatory power in predicting outcome of OLT.

Adult↗

PubMed2004

Summary report of a national conference: Evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA.

A national conference was held to review and assess data gathered since implementation of MELD and PELD and determine future directions. The objectives of the conference were to review the current system of liver allocation with a critical analysis of its strengths and weaknesses. Conference participants used an evidence-based approach to consider whether predicted outcome after transplantation should influence allocation, to discuss the concept of minimal listing score, to revisit current and potential expansion of exception criteria, and to determine whether specific scores should be used for automatic removal of patients on the waiting list. After review of data from the first 18 months since implementation, association and society leaders, and surgeons and hepatologists with wide regional representation were invited to participate in small group discussions focusing on each of the main objectives. At the completion of the meeting, there was agreement that MELD has had a successful initial implementation, meeting the goal of providing a system of allocation that emphasizes the urgency of the candidate while diminishing the reliance on waiting time, and that it has proven to be a powerful tool for auditing the liver allocation system. It was also agreed that the data regarding the accuracy of PELD as a predictor of pretransplant mortality were less conclusive and that PELD should be considered in isolation. Recommendations for the transplant community, based on the analysis of the MELD data, were discussed and are presented in the summary document.

Adult↗

PubMed2004

Survival among pediatric liver transplant recipients: impact of segmental grafts.

Segmental liver transplantation with living donor (LD), reduced cadaveric (Reduced), and split cadaveric (Split) allografts has expanded the availability of size-appropriate organs for pediatric recipients. The relevance of recipient age to the selection of graft type has not been fully explored, but could offer the potential to maximize recipient outcome and donor utilization. We conducted a retrospective cohort study among children 12 years of age or less utilizing the United Network of Organ Sharing (UNOS) database. Cox proportional-hazards analysis was used to explore the association of recipient age and graft type to graft and patient survival. Among children <1 year of age and those 1 to 2 years of age, 3-year LD graft survival was superior to whole cadaveric (CAD) organs, Split grafts, and Reduced grafts (for children <1 year of age: 79.4 vs. 61.5, 66.0, and 61.1%, respectively, P = .0003; and for children 1-2 years of age: 79.2 vs 66.9, 57.1, and 63.9%, respectively, P = .02). However, in children 3 to 12 years of age, after controlling for multiple donor and recipient factors, LD grafts failed to offer a survival advantage (hazard ratio = .61; 95% confidence interval = .37-1.02) compared to CAD organs. In an adjusted analysis examining patient survival, there appeared to be minimal association between recipient age and graft type. Much of the difference in graft survival could be attributed to events in the perioperative period. In conclusion, LD liver transplantation provides improved graft survival in children 2 years of age or less.

Cadaver↗

PubMed2004

Combined orthotopic heart and liver transplantation: the need for exception status listing.

Through May 2004, 33 combined orthotopic heart-liver transplants (OHT/OLT) have been performed nationwide. No published data exist to date regarding outcomes of patients awaiting such transplants, although progression of two organ disease processes may contribute to premature death for waiting patients. Retrospective data were collected on patients listed for combined OHT/OLT from both an individual tertiary care transplant center and the national UNOS registry to delineate listing criteria and evaluate patient outcomes in both the pre- and post-MELD eras. All patients who survived to transplantation or died on the waiting list were included in the analysis. Results show that 29.6% of patients registered nationally and 42% of patients listed institutionally survived to transplantation. Survival to transplantation was associated with less severe liver disease, though patients with MELD scores ranging from 19 to 26 had significantly higher wait list mortality than expected when compared to single-organ liver transplants. Following combined orthotopic heart-liver transplantation, 80% and 70% of patients survive 1 and 3 years, respectively. In conclusion, combined OHT/OLT is a successful therapy, but current organ allocation policies may not ensure expeditious transplantation in critically ill patients with dual vital organ failure. Providing exception status listing to these patients would ensure more expeditious transplantation and potentially contribute to improved survival.

Adult↗

PubMed2004

Patterns of transgene expression and viral clearance from the transplanted liver following ex vivo adenovirus-mediated gene transfer.

BACKGROUND/AIMS: In the rat liver transplant model, the liver graft can be transduced ex vivo by adenovirus encoding CTLA-4Ig (AdCTLA-4Ig) to achieve high level of immunosuppression in the liver after transplantation. To characterize the pattern of transgene expression following ex vivo gene transfer to the liver and examine whether immunosuppression would promote adenovirus persistence, we followed the life span of vector DNA and transgene expression in the transplanted liver. METHODS: Rat liver grafts were perfused ex vivo with adenovirus carrying the reporter gene beta-galactosidase (AdlacZ). The period of transgene expression was assessed at predetermined intervals after transplantation into syngeneic, allogeneic or nude (athymic) recipients. Clearance of vector DNA was assessed by PCR analysis of liver DNA after transplantation. RESULTS: Graft transduction with AdCTLA-4Ig or systemic cyclosporine treatment effectively abrogated the alloimmune response but did not result in sustained lacZ expression. The course of viral DNA clearance from the liver was also unaffected by immunosuppression as was the implied nucleolytic cleavage of viral DNA. CONCLUSIONS: In the transplant setting, local expression of CTLA-4Ig or systemic immunosuppression does not solve the problem of viral clearance from the liver. Non-adaptive immune mechanisms may have a significant role in the host response to adenovirus after liver transplantation.

Abatacept↗

PubMed2004

Pattern of ischemia reperfusion injury in a mouse orthotopic liver transplant model.

BACKGROUND: The molecular pathways of ischemic injury after liver transplantation are complex and difficult to dissect because of the presence of many variables. Transgenic and genetically deficient strains of mice provide ideal models for the study of the contribution of a single gene product in biological processes in vivo. Although well described in rats, prolonged preservation has not been studied in a mouse model of orthotopic liver transplantation (mOLT). The aim of this study was to establish a model of cold ischemia and reperfusion injury in mOLT and describe the pattern of the regenerative response to various lengths of cold storage. MATERIALS AND METHODS: mOLT was performed using a syngeneic combination. Grafts were preserved at 4 degrees C in University of Wisconsin (Viaspan) solution for increasing periods of cold preservation. After cold storage, the liver grafts were transplanted and recipient survival was monitored. Hepatocellular injury was determined by histology, and the regenerative response was quantitated by interleukin 6 upregulation and DNA replication. RESULTS: Long-term survival was 100%, 100%, 88%, and 0% for cold preservation of 1, 4, 8, and 16 h, respectively. Grafts with short preservation times (1 and 4 h) demonstrated limited injury and a weak regenerative response, with slight IL-6 early upregulation and minimal cell division. Eight hours of cold ischemia resulted in prominent injury and an intense regenerative response accompanied by significant IL-6 upregulation and DNA synthesis. Sixteen hours of storage resulted in all recipients succumbing to liver failure, with histology showing extensive hepatic necrosis. CONCLUSIONS: This study demonstrated the feasibility of using the mOLT model for the study of molecular mechanisms associated with recovery from cold ischemia and reperfusion injury. Increasing lengths of cold ischemia correlate with progressive tissue damage whereas recovery is associated with a regenerative response that correlates with the severity of injury.

Animals↗

PubMed2004

Survival following liver transplantation from non-heart-beating donors.

OBJECTIVE: To determine whether patient and graft survival following transplantation with non-heart-beating donor (NHBD) hepatic allografts is equivalent to heart-beating-donor (HBD) allografts. SUMMARY BACKGROUND DATA: With the growing disparity between the number of patients awaiting liver transplantation and a limited supply of cadaveric organs, there is renewed interest in the use of hepatic allografts from NHBDs. Limited outcome data addressing this issue exist. METHODS: Retrospective evaluation of graft and patient survival among adult recipients of NHBD hepatic allografts compared with recipients of HBD livers between 1993 and 2001 using the United Network of Organ Sharing database. RESULTS: NHBD (N = 144) graft survival was significantly shorter than HBD grafts (N = 26856). One- and 3-year graft survival was 70.2% and 63.3% for NHBD recipients versus 80.4% and 72.1% (P = 0.003 and P = 0.012) for HBD recipients. Recipients of an NHBD graft had a greater incidence of primary nonfunction (11.8 vs. 6.4%, P = 0.008) and retransplantation (13.9% vs. 8.3%, P = 0.04) compared with HBD recipients. Prolonged cold ischemic time and recipient life support were predictors of early graft failure among recipients of NHBD livers. Although differences in patient survival following NHBD versus HBD transplant did not meet statistical significance, a strong trend was evident that likely has relevant clinical implications. CONCLUSIONS: Graft and patient survival is inferior among recipients of NHBD livers. NHBD donors remain an important source of hepatic grafts; however, judicious use is warranted, including minimization of cold ischemia and use in stable recipients.

Adult↗