Background & Aims Organ scarcity has resulted in increased utilization of donation after cardiac death (DCD) donors. Prior analysis of patient survival following DCD liver transplantation has been ...restricted to single institution cohorts and a limited national experience. We compared the current national experience with DCD and DBD livers to better understand survival after transplantation. Methods We compared 1113 DCD and 42,254 DBD recipients from the Scientific Registry of Transplant Recipients database between 1996 and 2007. Patient survival was analyzed using the Kaplan–Meier methodology and Cox regression. Results DCD recipients experienced worse patient survival compared to DBD recipients ( p < 0.001). One and 3 year survival was 82% and 71% for DCD compared to 86% and 77% for DBD recipients. Moreover, DCD recipients required re-transplantation more frequently (DCD 14.7% vs. DBD 6.8%, p < 0.001), and re-transplantation survival was markedly inferior to survival after primary transplant irrespective of graft type. Amplification of mortality risk was observed when DCD was combined with cold ischemia time >12 h (HR = 1.81), shared organs (HR = 1.69), recipient hepatocellular carcinoma (HR = 1.80), recipient age >60 years (HR = 1.92), and recipient renal insufficiency (HR = 1.82). Conclusions DCD recipients experience significantly worse patient survival after transplantation. This increased risk of mortality is comparable in magnitude to, but often exacerbated by other well-established risk predictors. Utilization decisions should carefully consider DCD graft risks in combination with these other factors.
The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how stress impacts innate-like T cells is unclear. We report that long-term stress ...surprisingly abrogates both T helper 1 (TH1)- and TH2-type responses orchestrated by invariant natural killer T (iNKT) cells. This is not due to iNKT cell death because these cells are unusually refractory to stress-inflicted apoptosis. Activated iNKT cells in stressed mice exhibit a “split” inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23, and IL-27 spikes. iNKT cell dysregulation is mediated by cell-autonomous glucocorticoid receptor signaling and corrected upon habituation to predictable stressors. Importantly, under stress, iNKT cells fail to potentiate cytotoxicity against lymphoma or to reduce the burden of metastatic melanoma. Finally, stress physically spares mouse mucosa-associated invariant T (MAIT) cells but hinders their TH1-/TH2-type responses. The above findings are corroborated in human peripheral blood and hepatic iNKT/MAIT cell cultures. Our work uncovers a mechanism of stress-induced immunosuppression.
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•iT cells are unusually refractory to stress- and glucocorticoid-induced apoptosis•Chronic stress curbs both TH1- and TH2-type responses orchestrated by iT cells•Stress incapacitates iNKT cells via intrinsic glucocorticoid receptor signaling•Stress-elicited glucocorticoids impair the antitumor activity of iNKT cells
Invariant T cells are emergency responders to infection and cancer. Rudak et al. report that psychological stress unusually spares these innate-like T lymphocytes but alters or impairs their cytokine production and cytotoxic and/or antimetastatic capacities through a cell-autonomous, glucocorticoid receptor-dependent mechanism. This may explain certain aspects of stress-induced immunosuppression.
Data for liver transplant recipients (LTRs) regarding the benefit of care concordant with clinical practice guidelines for management of blood pressure (BP) are sparse. This paper reports on ...clinician adherence with BP clinical practice guideline recommendations and whether BP control is associated with mortality and cardiovascular events (CVEs) among LTRs. We conducted a longitudinal cohort study of adult LTRs who survived to hospital discharge at a large tertiary care network between 2010 and 2016. The primary exposure was a BP of <140/<90 mm Hg within year 1 of LT. Among 602 LTRs (mean age 56.7 years, 64% men), 92% had hypertension and 38% had new onset hypertension. Less than 30% of LTRs achieved a BP of <140/<90 mm Hg over a mean of 43.2 months. In multivariable models, adjusted for key confounders, BP control post‐LT compared with lack of control was associated with a significantly lower hazard of mortality (hazard ratio HR 0.48, 95% confidence interval CI 0.39, 0.87) and of CVEs (HR 0.65, 95% CI 0.43, 0.97). The association between BP control of <140/<90 mm Hg with improved survival and decreased CVEs in LTRs suggests that efforts to improve clinician adherence to BP clinical practice recommendations should be intensified.
In a single‐center retrospective cohort study of liver transplant recipients, the authors demonstrate that systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg, concordant with contemporaneous clinical practice guidelines for the management of blood pressure, is associated with a 35% reduction in cardiovascular events and 52% lower mortality after liver transplantation. An editorial from Serper and Asrani is on page 629.
Background
Historically, pre-operative biliary stenting has been associated with higher infectious complication rates following pancreatoduodenectomy. However, alleviation of biliary obstruction is ...necessary for consideration of pre-operative chemotherapy, which may improve disease-free survival, or for mitigation of symptoms while awaiting surgery. Our aim is to compare contemporary post-operative complication risk among patients with pre-operative endoscopic retrograde cholangiopancreatography (ERCP) stenting compared to those without.
Methods
Patients who underwent a pancreatoduodenectomy for pancreatic cancer with biliary obstruction within the ACS-NSQIP registry from 2014 to 2017 were identified. The primary outcome was to compare the risk of 30-day complication (composite outcome) between patients with and without pre-operative ERCP stenting. Propensity score matching was used to ensure balanced baseline characteristics and log-binomial regression models were used to estimate risk ratios for overall perioperative complication between groups.
Results
From 6073 patients with obstructive jaundice undergoing pancreatoduodenectomy for pancreatic cancer, 92% (5564) were eligible for the study. After performing a propensity score matching on 20 baseline characteristics, 952 patients without stenting were matched to up to four patients who received pre-operative ERCP stenting (
n
= 3467) for a matched cohort of 4419. A total of 1901 (55%) patients with pre-operative ERCP stenting experienced a post-operative complication compared to 501 (53%) patients without stenting (risk ratio 1.04, 95% CI 0.97–1.11,
p
= 0.23).
Conclusion
Pre-operative ERCP stenting was not associated with an increased risk of post-operative complication in patients undergoing pancreatoduodenectomy with obstructive jaundice. Biliary stenting may be safely considered for symptom relief and to potentially facilitate pre-operative chemotherapy for pancreatic cancer.
Ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in organ transplantation. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling ...pathway plays a crucial role in cell physiological and pathological processes including IRI. This study aims to investigate whether inhibition of ERK signaling with U0126 can prevent prolonged cold IRI in heart transplantation.
Rat cardiac cell line H9c2 cells were treated with U0126 before exposure to hypothermic hypoxia/reoxygenation (H/R) conditions. The effect of U0126 on H9c2 cells in response to H/R stress was determined by measuring cell death, reactive oxygen species production, mitochondrial membrane potential, and ERK signaling activation. Mouse syngeneic heterotopic heart transplantation was conducted, where a donor heart was preserved in the University of Wisconsin (UW) solution supplemented with U0126 for 24 hours at 4°C before transplantation. Heart graft function, histopathologic changes, apoptosis, and fibrosis were measured to assess IRI.
Phosphorylated ERK was increased in both in vitro H/R-injured H9c2 cells and in vivo heart grafts with IRI. Pretreatment with U0126 inhibited ERK phosphorylation and prevented H9c2 cells from cell death, reactive oxygen species generation, and mitochondrial membrane potential loss in response to H/R. Preservation of donor hearts with U0126-supplemented solution improved graft function and reduced IRI by reductions in cell apoptosis/death, neutrophil infiltration, and fibrosis of the graft.
Addition of U0126 to UW solution reduces ERK signal activation and attenuates prolonged cold IRI in a heart transplantation model. ERK inhibition with U0126 may be a useful strategy to minimize IRI in organ transplantation.
Liver transplantation (LT) candidates today are increasingly older, have greater medical acuity, and have more cardiovascular comorbidities than ever before. Steadily rising model for end-stage liver ...disease (MELD) scores at the time of transplant, resulting from high organ demand, reflect the escalating risk profiles of LT candidates. In addition to advanced age and the presence of comorbidities, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Patients with cirrhosis requiring LT usually demonstrate increased cardiac output and a compromised ventricular response to stress, a condition termed cirrhotic cardiomyopathy. These cardiac disturbances are likely mediated by decreased beta-agonist transduction, increased circulating inflammatory mediators with cardiodepressant properties, and repolarization changes. Low systemic vascular resistance and bradycardia are also commonly seen in cirrhosis and can be aggravated by beta-blocker use. These physiologic changes all contribute to the potential for cardiovascular complications, particularly with the altered hemodynamic stresses that LT patients face in the immediate post-operative period. Post-transplant reperfusion may result in cardiac death due to a multitude of causes, including arrhythmia, acute heart failure, and myocardial infarction. Recognizing the hemodynamic challenges encountered by LT patients in the perioperative period and how these responses can be exacerbated by underlying cardiac pathology is critical in developing recommendations for the pre-operative risk assessment and management of these patients. The following provides a review of the cardiovascular challenges in LT candidates, as well as evidence-based recommendations for their evaluation and management.
To conduct a meta-analysis to enhance understanding of the risks of biliary complications, particularly ischemic cholangiopathy (IC), after donation after cardiac death (DCD) compared with donation ...after brain death (DBD) liver transplantation.
Biliary complications after liver transplantation have profound health and economic implications which merit further investigation.
The MEDLINE (1950–2009), EMBASE, and Cochrane Library databases were searched and supplemented by review of conference proceedings and publication bibliographies. All original single institution studies reporting outcomes for DCD and DBD liver transplant recipients were considered. Odds ratios (OR) and 95% confidence intervals (CI) based on random effects models were calculated.
Eleven publications, all retrospective cohort studies, involving 489 DCD and 4455 DBD recipients, were included. Donation after cardiac death recipients had a 2.4 times increased odds of biliary complications (95% CI= 1.8–3.4) and a 10.8 times increased odds of IC (95% CI = 4.8–24.2).Ischemic cholangiopathy was present in 16% of DCD compared with 3% of DBD recipients. Donation after cardiac death recipients also experienced higher odds of 1-year patient mortality (OR = 1.6, 95% CI = 1.04–2.5) and graft failure (OR = 2.1, 95% CI = 1.5–2.8).
Donation after cardiac death liver transplantation is marred by inferior outcomes including higher rates of biliary complications and IC as well as increased mortality and graft failure. Despite current federal mandates to increase DCD donation, these serious complications translate into poor outcomes for individuals and increased healthcare costs. These risks should be considered in decisions regarding the utilization of these grafts.
Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk‐assessment tool that ...allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point‐based prediction model (risk score) for CVD complications after OLT, the Cardiovascular Risk in Orthotopic Liver Transplantation risk score, among a cohort of 1,024 consecutive patients aged 18‐75 years who underwent first OLT in a tertiary‐care teaching hospital (2002‐2011). The main outcome measures were major 1‐year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias‐corrected 95% confidence intervals for the regression coefficients of the final model. Among 1,024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included preoperative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the point‐based score (C statistic = 0.78, bias‐corrected C statistic = 0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer‐Lemeshow P = 0.33). Conclusion: The point‐based risk score can identify patients at risk for CVD complications after OLT surgery (available at www.carolt.us); this score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. (Hepatology 2017;66:1968–1979)
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