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As the number of donation after circulatory death (DCD) liver transplants (LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy (IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes.All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Arizona, and Mayo Clinic Rochester from January 1999 to March 2020 were included (N = 770). Outcomes were compared between 4 distinct radiologic patterns of IC: diffuse necrosis, multifocal progressive, confluence dominant, and minor form.In total, 88 (11.4%) patients developed IC, of which 42 (5.5%) were listed for retransplantation of liver (ReLT). Patients with diffuse necrosis and multifocal progressive patterns suffered from frequent hospital admissions for cholangitis in the first year following DCD LT (median 3 and 2), were largely stent dependent (100% and 85.7%), and almost universally required ReLT. Patients with confluence dominant disease were managed with multiple stents and frequently recovered, ultimately becoming stent free without need for ReLT. Patients with the minor form IC did well with limited need for stent placement or repeat procedures and did not require ReLT. Graft survival was different between the 4 distinct IC patterns (P 0.001).The present analysis provides a detailed analysis on the natural history and clinical course of IC. Patients developing IC can be classified into 4 distinct patterns with distinct clinical courses.

The age of a liver transplant (LT) candidate is one of many variables used in the transplant selection process. Most research about the age at transplant has used prespecified age ranges or categories in assessing associations with transplant outcomes. However, there is a lack of knowledge about the age at transplant and survival. This study aimed to examine associations of age at transplant as a continuous variable, in conjunction with other patient and disease-related factors, with patient and graft survival after LT.We used the Standard Transplant Analysis and Research data to identify LT recipients between January 2002 and June 2018. Cox regression models with a restricted cubic spline term for age examined associations with graft and patient survival after LT. We assessed the interactions of age with recipients' sex, race/ethnicity, region, indication for transplant, body mass index, model for end-stage liver disease score, diabetes, functional status at transplant, and donor risk index.Age at the time of LT showed a nonlinear association with both graft and patient survival. Each demographic, clinical, transplant-related, and donor-related factor influenced these relationships differently.Our results suggest that some older LT candidates may be better than some younger candidates and that clinicians should not exclusively use age to determine who receives LT.

Although the utilization of donation after circulatory death donors (DCDs) for liver transplantation (LT) has increased steadily, much controversy remains, and no common acceptance criteria exist with regard to donor and recipient risk factors and prediction models. A consensus conference was organized by International Liver Transplantation Society on January 31, 2020, in Venice, Italy, to review the current clinical practice worldwide regarding DCD-LT and to develop internationally accepted guidelines. The format of the conference was based on the grade system. International experts in this field were allocated to 6 working groups and prepared evidence-based recommendations to answer-specific questions considering the currently available literature. Working group members and conference attendees served as jury to edit and confirm the final recommendations presented at the end of the conference by each working group separately. This report presents the final statements and recommendations provided by working group 2, covering the entire spectrum of donor and recipient risk factors and prediction models in DCD-LT.

BACKGROUND There is limited information concerning whether social determinants of health affect postliver transplant (LT) outcomes. This study aims to understand to what extent the health of LT recipients' counties of residence influence long-term LT outcomes. METHODS We used the United Network for Organ Sharing data to identify adult LT recipients transplanted between January 2010 and June 2018. Patient-level data were matched to county-level County Health Ranking (CHR) data using transplant recipient zip code, and nationwide CHRs were created. Mixed-effects Cox proportional hazards models were used to examine associations between CHRs and graft and patient survival post-LT. RESULTS Health outcomes rank was significantly associated with posttransplant graft and patient survival, with worst tertile counties showing a 13% increased hazard of both graft failure and patient mortality compared to the best tertile counties. CONCLUSIONS Although county health is associated with LT outcomes, it also appears that LT recipient selection is effective at mitigating major disparities based on county of residence and helps yield equitable outcomes in this respect.

Background Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. Methods Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. Results Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. Conclusions Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.

There is limited information concerning whether social determinants of health affect postliver transplant (LT) outcomes. This study aims to understand to what extent the health of LT recipients' counties of residence influence long-term LT outcomes.We used the United Network for Organ Sharing data to identify adult LT recipients transplanted between January 2010 and June 2018. Patient-level data were matched to county-level County Health Ranking (CHR) data using transplant recipient zip code, and nationwide CHRs were created. Mixed-effects Cox proportional hazards models were used to examine associations between CHRs and graft and patient survival post-LT.Health outcomes rank was significantly associated with posttransplant graft and patient survival, with worst tertile counties showing a 13% increased hazard of both graft failure and patient mortality compared to the best tertile counties.Although county health is associated with LT outcomes, it also appears that LT recipient selection is effective at mitigating major disparities based on county of residence and helps yield equitable outcomes in this respect.

Background Portopulmonary hypertension (POPH) is the presence of pulmonary arterial (PA) hypertension in patients with portal hypertension and is associated with significant morbidity and mortality. In a cohort of POPH patients, we describe the clinical outcomes of POPH patients who underwent liver transplantation (LT). Methods Retrospectively collected data from a prospectively assembled cohort of all consecutive POPH adults evaluated in three transplant centers from 1996 to 2019. Results From a cohort of 228 POPH patients, 50 patients underwent LT. Significant hemodynamic improvement after PA-targeted therapy was observed, with 58% receiving only monotherapy pre-transplant. After LT, 21 (42%) patients were able to discontinue and remained off PA-targeted therapy. The 1, 3, and 5 year unadjusted survival rates after LT were 72%, 63% and 60%, respectively. An elevated pulmonary vascular resistance (PVR) before LT was associated with worse survival rate (HR 1.91, 95% CI 1.07-3.74, p=0.04). No survival difference was observed in those granted MELD exception or transplants performed before or after the year 2010. Conclusion Significant number of POPH patients discontinued PA-targeted therapy after LT. Higher PVR before LT was associated with worse survival, as was monotherapy use. Despite effective PA-targeted therapies, POPH survival outcomes after LT in our cohort were modest and may reflect the need for more aggressive therapy.

In the United States, 5% of adult liver transplant recipients receive a graft donation after circulatory determination of death (DCDD). Concerns for ischemic cholangiopathy (IC), a disease of diffuse intrahepatic stricturing limits broader DCDD use. Single-center reports demonstrate large variation in outcomes.Retrospective deidentified data collected between 2005 and 2013 were entered electronically by 10 centers via a Research Electronic Data Capture database. Our primary outcome was development of intrahepatic biliary strictures consistent with IC.Within 6 months post-DCDD transplant, 162 (21.8%) patients developed a biliary stricture, of which 88 (11.8%) exhibited intrahepatic structuring consistent with IC. Unadjusted 6-month IC rate among the 10 centers varied significantly (P = 0.006) from 6.3% to 25.9%. The only factor associated with increased risk of IC within 6 months was Roux-en-Y hepaticojejunostomy (vs duct-to-duct) (odds ratio, 3.06; 95% confidence interval, 1.52-6.16; P = 0.002). Graft failure by 6 months was more than 3 times higher for DCDD recipients with IC (odds ratio for IC, 3.36; 95% confidence interval, 1.95-5.79).This first report of the large combined experience with DCDD from the Improving DCDD Outcomes in Liver Transplant consortium demonstrates significant differences in IC among centers, the importance of biliary strictures as a risk factor for graft failure, and does not validate other risk factors for IC found in smaller studies.

BACKGROUND: The OPTN implemented Share35 on 6/18/2013 to broaden deceased-donor liver sharing within regional boundaries. We investigated whether increased sharing under Share35 impacted geographic disparity in deceased-donor liver transplantation (DDLT) across Donation Service Areas (DSAs). METHODS: Using SRTR 6/2009-6/2017, we identified 86,083 adult LT candidates and retrospectively estimated MELD-adjusted DDLT rates using nested multilevel Poisson regression with random intercepts for DSA and transplant program. From the variance in DDLT rates across 49 DSAs and 102 programs, we derived the DSA-level median incidence rate ratio (MIRR) of DDLT rates. MIRR is a robust metric of heterogeneity across each hierarchical level; larger MIRR indicates greater disparity. RESULTS: MIRR was 2.18 pre-Share35 and 2.16 post-Share35. Thus, two candidates with the same MELD in two different DSAs were expected to have a 2.2-fold difference in DDLT rate driven by geography alone. After accounting for program-level heterogeneity, MIRR was attenuated to 2.10 pre-Share35 and 1.96 post-Share35. For candidates with MELD 15-34, MIRR decreased from 2.51 pre- to 2.27 post-Share35, and for candidates with MELD 35-40, MIRR increased from 1.46 pre- to 1.51 post-Share35, independent of program-level heterogeneity in DDLT. DSA-level heterogeneity in DDLT rates was greater than program-level heterogeneity pre- and post-Share35. CONCLUSIONS: Geographic disparity substantially impacted DDLT rates before and after Share35, independent of program-level heterogeneity and particularly for candidates with MELD 35-40. Despite broader sharing, geography remains a major determinant of access to deceased-donor liver transplantation.

Published reports describing the national experience with liver grafts from donation after cardiac death (DCD) donors have resulted in reservations with their widespread utilization. The present study aimed to investigate if temporal improvements in outcomes have been observed on a national level and to determine if donor and recipient selection have been modified in a fashion consistent with published data on DCD use in liver transplantation (LT).Patients undergoing DCD LT between 2003 and 2014 were obtained from the United Network of Organ Sharing Standard Transplant Analysis and Research file and divided into 3 equal eras based on the date of DCD LT: era 1 (2003-2006), era 2 (2007-2010), and era 3 (2011-2014).Improvement in graft survival was seen between era 1 and era 2 (P = 0.001) and between era 2 and era 3 (P0.001). Concurrently, an increase in the proportion of patients with hepatocellular carcinoma and a decrease in critically ill patients, retransplant recipients, donor age, warm ischemia time greater than 30 minutes and cold ischemic time also occurred over the same period. On multivariate analysis, significant predictors of graft survival included: recipient age, biologic MELD score, recipient on ventilator, recipient hepatitis C virus + serology, donor age and cold ischemic time. In addition, even after adjustment for all of the aforementioned variables, both era 2 (hazard ratio, 0.81; confidence interval, 0.69-0.94; P = 0.007), and era 3 (hazard ratio, 0.61; confidence interval, 0.5-0.73; P0.001) had a protective effect compared to era 1.The national outcomes for DCD LT have improved over the last 12 years. This change was associated with modifications in both recipient and donor selection. Furthermore, an era effect was observed, even after adjustment for all recipient and donor variables on multivariate analysis.

BACKGROUND The present multicenter study investigated whether equivalent outcomes to primary liver transplant (LT) could be achieved with liver retransplant (reLT) and whether improvements in outcomes have taken place over time, particularly in the direct-acting antiviral era. METHODS All reLT performed at Mayo Clinic Florida, Mayo Clinic Rochester, and Mayo Clinic Arizona were divided into era 1 (2002-2007), era 2 (2008-2012), and era 3 (2013-2017) based on the date of reLT. RESULTS Improvement in graft survival (GS) after reLT was seen over the 3 eras (P < 0.001). In era 1, GS after reLT was inferior to primary LT (P < 0.001), whereas no difference was seen between reLT and primary LT in era 2 (P = 0.68) or era 3 (P = 0.36). A significantly higher proportion of patients achieved sustained viral response (SVR) within the first year after reLT in each subsequent era (era 1: 10.3%, era 2: 22.5%, and era 3: 100%) (P < 0.001). Graft survival was superior in patients undergoing reLT for recurrent hepatitis C virus who achieved SVR after reLT compared with those who did not (P = 0.03). CONCLUSIONS Results similar to primary LT were achieved in era 3. These improvements coincide with the availability of direct-acting antivirals, which resulted in a 100% SVR rate in era 3 and a decrease in the number of patients undergoing reLT for recurrent hepatitis C virus. The historic dogma that reLT results in inferior outcomes should be revisited.

BACKGROUND: As the population in the United States continues to age, an increase in the number of potential donation after circulatory death (DCD) donors with advanced chronological age can be expected. The aim of this study was to analyze a multi-institutional experience in liver transplantation using DCD donors 50 years or older. METHODS: All DCD liver transplant (LT) performed at Mayo Clinic Florida, Mayo Clinic Rochester, and Mayo Clinic Arizona from 2002 to 2016 were included. Recipients of DCD LT were divided into 2 groups: those with donors 50 years or older (N = 155) and those with donors younger than 50 years(N = 316). RESULTS: Graft survival was similar between the DCD donors 50 years or older group and DCD donors younger than 50 group(P = 0.99). Graft survival at 1, 3, and 5 years was 87.0%, 75.6%, and 71.8% in the DCD donors 50 years or older group and 85.8%, 76.0%, and 70.4% in the DCD donors younger than 50 group. The rate of total biliary complications (32.3% vs 23.7%; P = 0.049) and of anastomotic strictures (16.1% vs 8.2%; P = 0.01) were higher in the DCD donors 50 years or older compared with the DCD donors younger than 50 group. No statistical significant difference in the rate of ischemic cholangiopathy (11.6% vs 7.6%; P = 0.15) was seen between the 2 groups. Due to homogeneous practice patterns at the involved institutions, additional Cox regression analysis using national data obtained from Scientific Registry of Transplant Recipients was used to evaluate predictors of graft failure in DCD donors 50 years or older. Significant predictors of graft failure included: a calculated Model for End-Stage Liver Disease score of 30 or higher (P < 0.001), mechanical ventilation at the time of transplant (P < 0.001), medical condition (in intensive care unit) (P = 0.002), and cold ischemia time (P < 0.001). CONCLUSIONS: The present study demonstrates that acceptable graft and patient survival can be achieved with the usage of DCD LT with donors 50 years or older. Optimizing recipient selection criteria and minimizing cold ischemia time may further improve outcomes.

Background. Kidney paired donation (KPD) has emerged as a viable option for renal transplant candidates with incompatible living donors. The aim of this study was to assess the ‘‘performance’’ of a three-site KPD program that allowed screening of multiple donors per recipient. Methods. We reviewed retrospectively the activity of our KPD program involving three centers under the same institutional umbrella. The primary goal was to achieve a transplant that was both ABO compatible and had a negative or low-positive flow cytometric crossmatch (+XM). Results. During the 40-month study period, 114 kidney transplant candidates were enrolledV57% resulting from a + XM and 39% resulting from ABO incompatible (ABOi) donors. Important outcomes were as follows: (1) 81 (71%) candidates received a transplant and 33 (29%) were still waiting; (2) 368 donors were evaluated, including 10 nondirected donors; (3) 82% (37/45) of ABOi candidates underwent transplantation; (4) 56% (36/65) of +XM candidates underwent transplantation (however, all but four of these had a cPRA less than 95%); (5) at the end of the study period, 97% (28/29) of +XM candidates still waiting had a cPRA greater than 95%. Conclusions. These data suggest evaluating large numbers of donors increases the chances of KPD. Patients with a cPRA greater than 95% are unlikely to receive a negative or low-positive +XM, suggesting the need for desensitization protocols in KPD.

Alloantibody can be a major barrier to successful organ transplantation; however, therapy to control antibody production or to alter its impact on the allograft remains limited. The goal of this review is to examine the regulatory steps that are involved in the generation of alloreactive B cells, with a specific emphasis on how known mechanisms relate to clinical situations in transplant recipients. Thus, we will examine the process of activation of mature, naïve B cells and how this relates to de novo antibody production. The role of long-lived plasma cells in persistent antibody production and the factors regulating their longevity will be explored. The regulation of memory B cells and their possible roles in alloimmunity also will be assessed. Finally, we will review current therapeutic approaches aimed at controlling alloantibody and assess their efficacy. By examining the pathways to antibody production mechanistically, we hope to identify important gaps in our current knowledge and gain insight into possible new therapeutic approaches to overcoming antibody in transplant patients.

Background. Chronic kidney disease (CKD) is associated with increased cardiovascular events. The relationships between the markers of inflammation and endothelial dysfunction were investigated both before and after living donor kidney transplantation. Methods. Twenty-seven renal transplant patients were studied. Eleven patients (six male, five female) were on cyclosporine A, whereas 16 patients (nine male, seven female) were treated with tacrolimus based regimes. Twenty-seven subjects (12 males, 15 females) were studied as controls. Plasma adiponectin, high sensitive C reactive protein (hsCRP), Asymetric dimethyl arginine (ADMA) levels were studied before transplantation and on days 1, 3, 7, 14, and 28. The brachial artery flow mediated dilatation (FMD) was studied before transplantation and on the 28th day. Results. Serum hsCRP and ADMA levels decreased significantly from the first posttransplantation day on each measurement (P

Background. Mice lacking fms-like tyrosine kinase 3 ligand (Flt3L -/- ) as the result of targeted gene disruption show severe reductions in dendritic cell (DC) subsets. We examined the development of vascular sclerosis and alloimmune reactivity in wild-type C57BL/6 (B6) and Flt3L -/- B6 (H2 b ) recipients of aortic allografts from normal BALB/c (H2 d ) donors. Methods. DC deficiency was confirmed by flow cytometric analysis. Aortic allografts were anastomosed to the infra-renal portion of the recipient's abdominal aorta. No immunosuppressive therapy was administered. Transplant outcome was assessed 60 days postgrafting by histologic and immunohistochemical examination of the grafts. Host reactivity to donor alloantigens was determined by assaying splenic T-cell proliferation and T-cell infiltration within the grafts, immunoglobulin-G subclass alloantibody levels (by flow cytometry), and cytokine production (by enzyme-linked immunosorbent assay or graft immunohistochemistry). Results. Sixty days posttransplant, BALB/c allografts in wild-type B6 recipients showed severe chronic arteriopathy (intimal thickening, α-smooth muscle actin + cell proliferation, fibrosis, and elastic lamina disruption). In contrast, profound deficiency of host myeloid, lymphoid-related, and pre-plasmacytoid DC subsets was accompanied by marked reductions in each feature of chronic rejection. Improvement in graft appearance was associated with antigen-specific suppression of ex vivo anti-donor T-cell proliferative activity and reductions in interferon-γ but with enhancement of interleukin-10 secretion in response to donor alloantigen challenge. Conclusion. Permanent deficiency of host DC subsets resulting from targeted gene disruption markedly inhibits the development of transplant vascular sclerosis, associated with striking reductions in both anti-donor T-cell reactivity and immunoglobulin-G alloantibody production.

There are various approaches to the enhancement of dendritic cell (DC) tolerogenicity for the promotion of cell or organ allograft survival. Both pharmacologic and biologic agents, including several commonly used immunosuppressive drugs, and specific anti-inflammatory cytokines inhibit DC maturation, whereas co-stimulation-blocking agents can also promote the induction of antigen-specific T-cell unresponsiveness by DC. Delivery of genes encoding molecules that subvert T-cell responses by various mechanisms, and targeting of DC migration by selective manipulation of chemokine and chemokine receptor expression, represent additional promising strategies. In this short review, the authors consider those approaches that have been used to promote the tolerogenicity of donor-derived DC in experimental models. Whereas most work to date has focused on myeloid DC, manipulation of other DC subsets may also offer potential for improving the outcome of transplantation and enhancing tolerance induction.

Background. Expression of human complement regulating factor (hCRF) in porcine organs prevents hyperacute rejection of these organs after xenotransplantation to nonhuman primates. Experiments were designed to characterize endothelial and smooth muscle function of arteries from pigs transgenic for hCD46. Methods. Arterial blood from outbred pigs transgenic for hCD46 expression and nontransgenic animals of the same lineage was analyzed for angiotensin-converting enzyme (ACE), C-type natriuretic peptide (CNP), and nitric oxide. Aortic endothelial cells were prepared for measurement of mRNA or activity for nitric oxide synthase (NOS). Rings cut from femoral and pulmonary arteries were suspended in organ chambers for measurement of isometric tension. Results. CNP was significantly greater, ACE was similar, and nitric oxide was significantly less in plasma from transgenic compared with nontransgenic pigs. Neither mRNA nor activity of NOS differed between the groups. Endothelium-dependent relaxations to bradykinin and acetylcholine but not the calcium ionophore were shifted significantly to the left in femoral and pulmonary arteries from hCD46 transgenic pigs compared with nontransgenic pigs. The ACE-inhibitor captopril augmented relaxations similarly in both groups, but N G -monomethyl-L-arginine (L-NMMA) did not inhibit relaxations in rings from transgenic pigs. Conclusions. Data suggest that expression of hCD46 on endothelium of pigs selectively augments endothelium-dependent relaxations to bradykinin by increased release of endothelium-derived factors other than nitric oxide. There does not seem to be any change in activity of ACE or NOS with expression of the human protein. Increased relaxations to bradykinin may be beneficial in lowering vascular resistance when transgenic organs are used for xenotransplantation.