Criteria Donor Livers Research Articles

Hypothermic Machine Preservation and Transplantation of “Orphan” Extended Criteria Donor Livers.

Introduction: Hypothermic machine perfusion (HMP) remains investigational in clinical liver transplantation despite widespread utilization in renal transplantation with improved results. Our group has reported the only clinical liver HMP series worldwide with promising results. The aim of this study was to investigate liver HMP in Extended Criteria Donor (ECD) Livers turned down by all other centers in the originating UNOS region (“orphan livers”). Methods: All included HMP livers were “orphan livers” and met at least one of the following ECD Criteria 1) Donor age>65; 2) >25% Macrosteatosis; 3) HCV+ and at least 15% macrosteatosis; 4) donor ischemic injury with AST or ALT>1,000 at time of offer. Thirty one livers were included in the study and underwent HMP for 3-7hrs using centrifugal perfusion with Vasosol® solution and were allografts for solitary, primary transplants in patients with a MELD score<35. These cases were matched to historical Cold Storage (CS) controls based on donor and recipient age, cold ischemic time, donor risk index and MELD score. Results: There were no technical or mechanical failures of HMP. Perfusate electrolytes and parameters were stable in almost all cases. Perfusate levels of AST correlated with the recipient’s peak serum AST on linear regression. There were 2 cases of Primary nonfunction in the CS group and one in the HMP group. Early allograft dysfunction (EAD) rates were 30% in CS controls vs 19% in the HMP group. Time to normalization of serum markers of liver and renal function were lower in the HMP group with serum creatinine on POD 5 being significantly lower in the HMP group. At 12 months, there were five deaths in the HMP group and 6 in the CS group (p=NS). Biliary complications were significantly lower in the HMP group compared to the CS group (4 vs 13, p=0.016) with almost twice as many ERCPs required in the CS group. Mean hospital stay was significantly shorter in the HMP group (13.65±10.9 days vs. 20.14±11.12 days in the CS group, p=0.012). HMP of orphan extended criteria donor livers provided safe and reliable preservation with significantly less biliary complications and overall length of stay in HMP patients. Further multicenter experience with HMP is necessary to further elucidate clinical benefits of HMP in Liver Transplantation.

The Benefits of Hypothermic Machine Perfusion Are Enhanced With Vasosol and α-Tocopherol in Rodent Donation After Cardiac Death Livers

The use of hypothermic machine perfusion (HMP) has recently been used to show an improvement in both standard and extended criteria donor liver grafts but creating a more dynamic preservation environment that can be supplemented with a variety of additives to aid in cold temperature metabolism and vasodilatation. Increasing the benefits of HMP, we explore the use of α-tocopherol in reducing inflammatory markers and apoptotic pathways to reduce the incidence of preservation injury. We explored the use of a donation after cardiac death (DCD) rodent model to test the additive benefits of α-tocopherol in HMP. The addition of α-tocopherol reduced the level of alanine aminotransferase (ALT) over the course of reperfusion as well, reduced the levels of inflammatory cytokines within a 90 minute reperfusion biopsy. Further benefit was seen with α-tocopherol through the reduction of the level of caspase 3/7 in the circulation, shown to be a result of the reduction of the levels of Cytochrome C mRNA. Liver perfusion with Vasosol® and HMP could benefit further from the addition of α-tocopherol to existing formulations of Vasosol®.

Expanding the donor pool in liver transplantation: Extended criteria donors.

Liver transplantation has emerged as a lifesaving operation for patients fortunate enough to receive a donated organ. Today, the 1-year unadjusted survival rate for a liver transplant recipient is 88.2%. 1 For the 5805 adult liver transplant recipients in 2011 alone, this number represents a remarkable outcome achieved through the efforts of transplant and organ procurement teams as well as research advances in transplant immunology and organ preservation. Although the tremendous benefit for recipients cannot be understated, a shortage of organs remains the most significant hurdle in liver transplantation, as demonstrated by the 2456 wait-list deaths in 2011 and the additional 482 patients who were removed from the wait list because they were too sick to undergo transplantation. 1 Furthermore, this disparity between supply and demand varies with a patient’s geography, and it has been demonstrated to alter practice patterns by the greater reliance on living donor liver transplantation in those areas most affected by the organ shortage. 2,3 With the continual growth of the liver transplant wait list, additional avenues for expansion of the donor pool have been pursued. This has been manifested in a greater reliance on extended criteria donor (ECD) liver allografts with a subsequent demonstration of reduced wait-list mortality through their use. 4,5 The use of ECD allografts is a balance between the benefit to the patient in need of liver transplantation (often in a more expedited fashion) and the higher-than-normal risk associated with each type of ECD liver. This review is focused on the various types of ECD liver allografts (Table 1) with the understanding that the art of matching an ECD donor liver to the appropriate recipient requires experience, careful planning, and judgment and is a topic beyond the scope of this review.

Expanded Criteria Donor Allografts And Effects Of Center Volume On Liver Transplantation

Introduction: In order to expand the donor pool, the use of expanded criteria donor (ECD) liver allografts has increased. We aimed to determine if there was a difference in center volume and survival of ECD liver allografts in a risk adjusted model. Methods: Data from the Scientific Registry of Transplant Recipients was examined for all deceased donor liver transplants (LT) performed from 2002 to 2008. Transplant centers were assigned volume cut off points by thirds for each individual year: upper 1/3 (HV), middle 1/3 (MV), lower 1/3 (LV).

Digital imaging of extended criteria donor livers to facilitate placement and utilization

The disparity between organ supply and demand has necessitated more aggressive use of livers from extended criteria donors. Organ sharing between donor service areas and transplant centers in other regions is common. Confidence in the graft quality is greatly improved with a digital image taken in conjunction with the recovery surgeon's report and biopsy data. Three cases in which digital images of various levels of quality allowed the recipient's surgery to proceed, minimized the cold ischemia time, and yielded excellent outcomes are described. Another case in which a picture was not available and the liver was discarded after importation is also presented for comparison.

The Utility of Extended Criteria Donor Organs in Severely Ill Liver Transplant Recipients

Organ shortage in liver transplantation has led the transplant community to expand the donor organ pool and reduce waiting list mortality by using so-called marginal donor or extended criteria donor (ECD) livers. The exact impact of these criteria on graft function and recipient survival are still under investigation. Most reports, however, show a clear correlation between organ quality and the posttransplant outcome. The role of ECD liver transplantation for severely ill recipients with high model for end stage liver disease (MELD) scores needs further clarification since transplant surgeons tend to allocate these grafts to more stable patients with lower MELD scores. Especially in the setting of ECD liver transplantation, strategies to improve graft quality and mitigate preservation and reperfusion injury may prove beneficial and play an important role in the future.

Artificial Circulation of the Liver: Machine Perfusion as a Preservation Method in Liver Transplantation

Due to the sharp increase in liver transplant candidates and the subsequent shortage of suitable donor livers, an extension of the current donor criteria is necessary. Simple cold storage, the current standard in organ preservation has proven to be insufficient to preserve extended criteria donor livers. Therefore a renewed interest grew toward alternative methods for liver preservation, such as hypothermic machine perfusion and normothermic machine perfusion. These "new" preservation methods were primarily assessed in rat models, and only a few clinically relevant large animal models have been described so far. This review will elaborate on these alternative preservation methods.

Critical use of extended criteria donor liver grafts in adult-to-adult whole liver transplantation: A single-center experience

This study presents our experience with the use of extended criteria donor (ECD) liver grafts. One hundred fifteen liver transplants were divided into 2 groups: standard (S) and nonstandard (NS). Fifty-eight patients in group S received a liver procured from an ideal donor, whereas 57 patients in group NS received an organ from an ECD. On the basis of the number of risk factors, patients were divided into 3 subgroups: the S group with 58 receiving a standard graft, the NS1 group with 44 receiving a graft with 1 or 2 risk factors, and the NS2 group with 13 receiving a graft with 3 to 4 risk factors. Patient survival was not different at 6, 12, and 24 months (P > 0.05), whereas graft survival was different (P = 0.0079). Both patient survival and graft survival were influenced by the cumulative number of risk factors. The univariate analysis of the donor risk factors detected hemodynamic factors as predictive of graft failure (P = 0.024) and death (P = 0.018). In the multivariate analysis, which was adjusted for recipient age and donor and recipient gender, hemodynamic risk factors and Model for End-Stage Liver. Disease score in the recipient were the only variables independently associated with graft failure (P = 0.006, P = 0.012, negatively). Finally, we observed a reduction of dropout from the list to 9% from 14.1% (P = 0.04) and of mortality on the list to 32.55% from 41.01% (P = 0.11). Critical use of ECD liver grafts allowed recipients in the waiting list to have a greater chance of being transplanted.

Comparison of histidine-tryptophan-ketoglutarate solution and University of Wisconsin solution in extended criteria liver donors

Liver, pancreas, and kidney allografts preserved in histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solutions have similar clinical outcomes. This study compares HTK and UW in a large number of standard criteria donor (SCD) and extended criteria donor (ECD) livers at a single center over 5 years. All adult, cadaveric liver and liver-kidney transplants performed between July 1, 2001 and June 30, 2006 were reviewed (n = 698). There were 435 livers (62%) categorized as ECD for severe physiologic stress and 70 (10%) because of old age. Recipient outcomes included perioperative death or graft loss and overall survival. Liver enzymes were analyzed for the first month post-transplant. Biliary complications were assessed through chart review. Overall, 371 donor livers were preserved in HTK (53%), and 327 were preserved in UW (47%). There were no statistically significant differences in any of the primary outcome measures comparing HTK and UW. The HTK group overall had a higher day 1 median aspartate aminotransferase and alanine aminotransferase, but the two groups were similar in function thereafter. HTK was superior to UW in protection against biliary complications. Kaplan-Meier graft survival curves failed to demonstrate a significant difference in SCD or ECD livers. In conclusion, HTK and UW are not clinically distinguishable in this large sample of liver transplants, although HTK may be protective against biliary complications when compared to UW. These findings persisted for both SCD and ECD livers. Given the lower cost per donor for HTK, this preservation solution may be preferable for general use.

Waitlist Mortality Decreases with Increased Use of Extended Criteria Donor Liver Grafts at Adult Liver Transplant Centers

Extended criteria donor (ECD) liver allografts are often allocated to less severely ill liver transplant (LT) candidates who are at a relatively lower risk of pretransplant mortality, but it is not clear that the use of ECD allografts will decrease center waitlist mortality (WLM). Individual patient data from the UNOS OPTN database (2002-2005) were aggregated to obtain center-specific data. Deceased donor allografts with any of the following characteristics were defined as ECDs: from a donor with any of the criteria described by the New York State Department of Health Workgroup; or 12+ h of cold ischemia. Multivariate regression was used to examine the relationship between WLM and ECD, non-ECD and LDLT use after adjusting for candidate severity of illness. A total of 3555 ECD transplants, 11,660 standard criteria donor (SCD) transplants, and 717 LDLTs were performed at 100 centers during this period. The model demonstrated that SCD and ECD LTs were inversely correlated with a center's WLM (beta=-0.242 and -0.221, respectively; p <or= 0.003 for each). LDLTs did not significantly reduce WLM (beta=-0.048, p=0.55). In summary, increasing ECD liver allograft use significantly decreased WLM at US centers. Policies encouraging the increase used of ECDs would further reduce WLM.

BILIARY COMPLICATIONS IN STANDARD AND EXTENDED CRITERIA LIVER ALLOGRAFTS IN WHOLE-ORGAN, CADAVERIC LIVER TRANSPLANTATION.

Purpose Although important liver transplant outcomes, such as primary nonfunction, vascular thrombosis, and graft loss, are well reported for marginal grafts in the transplant literature, there are few reports of biliary complications in extended criteria donor (ECD) livers. This study compares ECD and standard donors (SD) for biliary complications in cadaveric, whole-organ liver transplantation. Methods This study is a retrospective review of all liver transplants between 2001 and 2006, with an extensive review of all endoscopic and percutaneous biliary imaging. Our center uses biliary imaging as first evaluation for elevated liver enzymes, prior to biopsy. Outcomes included need for imaging, leak requiring reoperation, intrahepatic strictures, presence of stones or gravel, and first 30-day liver function tests (AST, ALT, alkaline phosphatase, total bilirubin). Results There were 698 orthotopic transplants, including 593 with choledochocholedochostomy (CDC) and 100 Roux-Y reconstructions (RYHJ) (5 OR deaths). Results are presented in the Table. SD and ECD livers do not differ significantly in requirement for biliary imaging, occurrence of biliary leak, or intrahepatic strictures. ECD livers are more likely to have choledocholithiasis. Thirty-day liver enzymes are statistically equivalent. Conclusion ECD livers have been used extensively at our center to decrease median wait time to less than 30 days, with very few wait list deaths and improved post-transplant survival. Results of this analysis demonstrate no increased risk for biliary complications in patients receiving ECD livers.

Utilization of Extended Donor Criteria Liver Allograft: Is the Elevated Risk of Failure Independent of the Model for End-Stage Liver Disease Score of the Recipient?

The goal of this analysis was to determine if outcomes from the use of extended criteria donor (ECD) livers were dependent upon the Model for End-Stage Liver Disease (MELD) score of the recipient. The Organ Procurement and Transplantation Network (OPTN) database as of March 4, 2006 was used for the analysis. Data from 12,056 adult liver transplant (LTx) recipients between June 1, 2002 and June 30, 2005 was analyzed. The donor risk index (DRI) was calculated as previously reported. A DRI of > or =1.7 was classified as ECD. Relative risk (RR) estimates were derived from Cox regression models adjusted for DRI, recipient MELD, age, sex, ethnicity, diagnosis, and year of transplant. Data from 2,873 grafts falling in the ECD category (23.8%) and their recipients were analyzed. Recipients with low MELD scores (<15) received the highest proportion of ECD livers (33%). ECD livers were associated with a significant increase in the RR of graft failure within each MELD category. However, this effect held within each of the three MELD categories. The use of ECD grafts expands the organ pool at expense of increased RR of liver failure. Our analysis showed no significant interaction between DRI and MELD score of the recipient. The fact that there is no additional impact of ECD livers in recipients with high MELD scores suggests that this group of patients may benefit from this pool of grafts.

Use of Extended Criteria Livers Decreases Wait Time for Liver Transplantation Without Adversely Impacting Posttransplant Survival

The use of extended criteria donors (ECDs) could minimize shortage of suitable donor livers for transplantation. In 3 years, the aggressive use of ECD livers has reduced the wait list at our center from 257 to 30 patients with a median wait time of 18 days without using living donors. This study compares the graft/patient survival from standard (SD) and ECD for our transplant population between 2001 and 2005. Records of all adult liver transplant recipients over 4 years were reviewed (n = 571). ECD criteria included: age >59 years, BMI >34.9, maximum AST/ALT >500, maximum bilirubin >2.0, peak serum sodium >170, HBV/HCV/HTLV reactive, donation after cardiac death, cold ischemia time >12 hours, ICU stay >5 days, 3 or more pressors simultaneously, extensive alcohol abuse, cancer history (nonskin), active meningitis/bacteremia, or significant donor liver trauma. Outcomes included graft and patient survival at 90 days, 1 year, and 2 years. Sixty-eight percent of recipients (n = 388) received ECD livers. Primary factors accounting for ECD-liver status included: elevated liver function tests (20%), hypernatremia (12.6%), and extensive alcohol abuse (11.4%). Graft survival was (SD, ECD): 90-day 91%, 88%; 1-year 84%, 80%; 2-year 78%, 77%; patient survival was: 90-day 93%, 90%; 1-year 87%, 82%; 2-year 83%, 79%. Kaplan-Meier survival analysis failed to demonstrate an overall difference in graft or patient survival at any time point. Only donor age >60 years was associated with decreased graft and patient survival. Liver grafts from ECD can be used to dramatically reduce wait list time with outcomes comparable to those for SD without resorting to living donor liver transplantation.

OUTCOMES OF ORTHOTOPIC LIVER TRANSPLANTS USING EXTENDED CRITERIA DONOR LIVERS

P570 Aims: Extended criteria donor (ECD) liver utilization has expanded the limited donor pool for patients awaiting orthotopic liver transplant (OLT). Many centers approach ECD livers with caution as the outcomes following their use remains unclear. The goal of this review was to analyze outcomes of OLT using ECD livers compared to a control group of standard criteria donor (SCD) liver allografts. Methods: All OLT recipients at our center between Jan 2002-Oct 2003 were categorized as having received an ECD or SCD liver. ECD allografts were defined as having any one or more of the following: donor age > 60 yrs, biopsy exhibiting >40% macrovesicular and/or >75% microvesicular steatosis, any donor down time (±CPR), use of 2 or more pressors within 12 hrs of procurement, or liver function studies > 5 × upper limit of normal. Parameters that were reviewed included: recipient demographics (age, sex, MELD, mean follow-up, length of stay), graft ischemic times (total and warm), laboratory data, and clinical outcomes (death, biliary complications, rejections). Results: 90 OLTs (42 ECD and 48 SCD) were performed during the study period. No statistical differences were observed in laboratory data including: serum creatinine, transaminases (AST/ALT), total bilirubin, and albumin at discharge, day 30, 90, and 180 for both groups. The two groups were similar with respect to rejection episodes per patient ECD (1.1) vs. SCD (1.3) [p=ns]. Five instances of vascular complications were identified (3 ECD vs. 2 SCD), although only one of those was a hepatic artery thrombosis. Conclusions: Clinical outcomes following OLT using ECD livers are identical to those using SCD livers. No differences were noted insofar as early or mid laboratory values, LOS, biliary or vascular complications. With intelligent recipient selection, the aggressive use of ECD liver allografts can become an important component of any transplant program.Figure

Expanded criteria donor grafts for deceased donor liver transplantation under the MELD system: A decision analysis

Expanded criteria donor (ECD) liver grafts have a higher likelihood of primary graft failure (PGF) compared with standard criteria donor (SCD) grafts. Given a choice between an available ECD graft versus waiting for an SCD graft that may not always become available, what should liver transplant candidates do? The study's aim was to estimate 1-year survival comparing immediate ECD liver grafting with waiting for an SCD organ. Using UNOS data, published literature estimates, and expert opinion, we constructed a Markov decision analytic model to estimate survival while waiting for an SCD transplant and survival with immediate ECD transplant. Sensitivity analyses were performed by varying model parameters individually and simultaneously with a second-order Monte Carlo simulation. For all patients with MELD scores >20, survival was higher with immediate ECD transplant despite the additional increased risk for PGF. Survival was better with an immediate ECD transplant unless the probability of PGF exceeded 23%, 72%, and 88% for recipients with MELD scores of 11-20, 21-25, and 26-30 respectively. For patients with MELD scores >30, the survival benefit with the immediate ECD strategy persisted at even higher rates of PGF. In conclusion, our results suggest that, despite the higher risk for PGF, transplantation with an available ECD graft should be preferred over waiting for an SCD organ for patients with advanced MELD scores. At less advanced MELD scores, the survival benefit depends on the risk of PGF associated with the ECD organ.

6 Definitions and outcomes of transplants using expanded criteria donor livers

Non-alcoholic steatohepatitis (NASH) has become one of the most common liver diseases and is still without approved pharmacotherapy. Lifestyle interventions using exercise and diet change remain the current treatment of choice and even a small weight loss (5–7%) can already have a beneficial effect on NASH. However, the underlying molecular mechanisms of exercise and diet interventions remain largely elusive, and it is unclear whether they exert their health effects via similar or different pathways.Ldlr−/−.Leiden mice received a high fat diet (HFD) for 30 weeks to establish a severe state of NASH/fibrosis with simultaneous atherosclerosis development. Groups of mice were then either left untreated (control group) or were treated for 20 weeks with exercise (running wheel), diet change (switch to a low fat chow diet) or the combination thereof. The liver and distant organs including heart, white adipose tissue (WAT) and muscle were histologically examined. Comprehensive transcriptome analysis of liver, WAT and muscle revealed the organ-specific effects of exercise and diet and defined the underlying pathways.Exercise and dietary change significantly reduced body weight, fat mass, adipocyte size and improved myosteatosis and muscle function with additive effects of combination treatment. WAT inflammation was significantly improved by diet change, tended to be reduced with exercise, and combination therapy had no additive effect. Hepatic steatosis and inflammation were almost fully reversed by exercise and diet change, while hepatic fibrosis tended to be improved with exercise and was significantly improved with diet change. Additive effects for the combination therapy were shown for liver steatosis and associated liver lipids, and atherosclerosis, but not for hepatic inflammation and fibrosis. Pathway analysis revealed complementary effects on metabolic pathways and lipid handling processes, thereby substantiating the added value of combined lifestyle treatment.Exercise, diet change and the combination thereof can reverse established NASH/fibrosis in obese Ldlr−/−.Leiden mice. In addition, the lifestyle interventions had beneficial effects on atherosclerosis, WAT inflammation and muscle function. For steatosis and other parameters related to adiposity or lipid metabolism, exercise and dietary change affected more distinct pathways that acted complementary when the interventions were combined resulting in an additive effect for the combination therapy on important endpoints including NASH and atherosclerosis. For inflammation, exercise and diet change shared several underlying pathways resulting in a net similar effect when the interventions were combined.