Tranexamic acid versus placebo to reduce perioperative blood transfusion in patients undergoing liver resection: protocol for the haemorrhage during liver resection tranexamic acid (HeLiX) randomised controlled trial.

INTRODUCTION: Despite use of operative and non-operative interventions to reduce blood loss during liver resection, 20%-40% of patients receive a perioperative blood transfusion. Extensive intraoperative blood loss is a major risk factor for postoperative morbidity and mortality and receipt of blood transfusion is associated with serious risks including an association with long-term cancer recurrence and overall survival. In addition, blood products are scarce and associated with appreciable expense; decreasing blood transfusion requirements would therefore have health system benefits. Tranexamic acid (TXA), an antifibrinolytic, has been shown to reduce the probability of receiving a blood transfusion by one-third for patients undergoing cardiac or orthopaedic surgery. However, its applicability in liver resection has not been widely researched. METHODS AND ANALYSIS: This protocol describes a prospective, blinded, randomised controlled trial being conducted at 10 sites in Canada and 1 in the USA. 1230 eligible and consenting participants will be randomised to one of two parallel groups: experimental (2 g of intravenous TXA) or placebo (saline) administered intraoperatively. The primary endpoint is receipt of blood transfusion within 7 days of surgery. Secondary outcomes include blood loss, postoperative complications, quality of life and 5-year disease-free and overall survival. ETHICS AND DISSEMINATION: This trial has been approved by the research ethics boards at participating centres and Health Canada (parent control number 177992) and is currently enrolling participants. All participants will provide written informed consent. Results will be distributed widely through local and international meetings, presentation, publication and ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT02261415.

Chronic stress physically spares but functionally impairs innate-like invariant T cells.

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.

An Addition of U0126 Protecting Heart Grafts From Prolonged Cold Ischemia-Reperfusion Injury in Heart Transplantation: A New Preservation Strategy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Blood pressure control according to clinical practice guidelines is associated with decreased mortality and cardiovascular events among liver transplant recipients.

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.

Real-World Study of Once-Daily, Extended-Release Tacrolimus Versus Twice-Daily, Immediate-Release Tacrolimus in Kidney Transplantation: Clinical Outcomes and Healthcare Resource Utilization.

INTRODUCTION: Real-world data with extended-release tacrolimus (ER-T) are lacking in the USA. This study examined clinical outcomes and healthcare resource utilization in kidney transplant patients receiving ER-T in clinical practice. METHODS: This was a retrospective, single-center analysis (February-June 2016) using data from Northwestern University's Enterprise Data Warehouse. Adult patients receiving a kidney transplant in the preceding 4 years, treated de novo or converted to ER-T from immediate-release tacrolimus (IR-T) within 10 days post-transplantation, and maintained on ER-T (at least 3 months) were included. Patients were matched for demographic and clinical characteristics with IR-T-treated control patients. Endpoints included clinical outcomes and healthcare resource utilization up to 1 year post-transplantation. RESULTS: A total of 19 ER-T-treated patients were matched with 55 IR-T-treated patients. No ER-T-treated patients experienced biopsy-confirmed acute rejection (BCAR) or graft failure versus 3 (5.5%) and 3 (5.5%) IR-T-treated patients, respectively. Mean estimated glomerular filtration rate (eGFR), the number of all-cause outpatient visits, readmissions, and all-cause hospitalization days were comparable between groups. Tacrolimus trough levels, days to target level (6-10 ng/mL), and number of required dose adjustments were also similar. CONCLUSION: Real-world clinical outcomes and healthcare resource utilization were similar with ER-T and IR-T. Larger studies will need to investigate the trend toward fewer BCAR events, and increased graft survival with ER-T. FUNDING: Astellas Pharma Global Development, Inc. Plain language summary available for this article.

Assessment and management of coronary artery disease in kidney and pancreas transplant candidates.

: Patients with end-stage renal disease (ESRD) undergoing evaluation for kidney and/or pancreas transplantation represent a population with unique cardiovascular (CV) profiles and unique therapeutic needs. Coronary artery disease (CAD) is common in patients with ESRD, mediated by both the overrepresentation and higher prognostic value of traditional CV risk factors amongst this population, as well as altered cardiovascular responses to failing renal function, likely mediated by dysregulation of the renin-angiotensin-aldosterone system (RAAS) and abnormal calcium and phosphate metabolism. Within the ESRD population, obstructive CAD correlates highly with adverse coronary events, including during the peri-transplant period, and successful revascularization may attenuate some of that increased risk. Accordingly, peri-transplant coronary risk assessment is critical to ensuring optimal outcomes for these patients. The following provides a review of CAD in patients being evaluated for kidney and/or pancreas transplantation, as well as evidence-based recommendations for appropriate peri-transplant evaluation and management.

Cardiovascular Disease Outcomes Related to Early Stage Renal Impairment After Liver Transplantation.

BACKGROUND: In the general population, even mild renal disease is associated with increased cardiovascular (CV) complications. Whether this is true in liver transplant recipients (LTR) is unknown. METHODS: This was a retrospective cohort study of 671 LTR (2002-2012) from a large urban tertiary care center and 37 322 LTR using Vizient hospitalization data linked to the United Network for Organ Sharing. The 4-variable Modification of Diet in Renal Disease equation estimated glomerular filtration rate (eGFR). Outcomes were 1-year CV complications (death/hospitalization from myocardial infarction, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, or stroke) and mortality. Latent mixture modeling identified trajectories in eGFR in the first liver transplantation (LT) year in the 671 patients. RESULTS: Mean (SD) eGFR was 72.1 (45.7) mL/min per 1.73 m. Six distinct eGFR trajectories were identified in the local cohort (n = 671): qualitatively normal-slow decrease (4% of cohort), normal-rapid decrease (4%), mild-stable (18%), mild-slow decrease (35%), moderate-stable (30%), and severe-stable (9%). In multivariable analyses adjusted for confounders and baseline eGFR, the greatest odds of 1-year CV complications were in the normal-rapid decrease group (odds ratio, 10.6; 95% confidence interval, 3.0-36.9). Among the national cohort, each 5-unit lower eGFR at LT was associated with a 2% and 5% higher hazard of all-cause and CV-mortality, respectively (P < 0.0001), independent of multiple confounders. CONCLUSIONS: Even mild renal disease at the time of LT is a risk factor for posttransplant all-cause and CV mortality. More rapid declines in eGFR soon after LT correlate with risk of adverse CV outcomes, highlighting the need to study whether early renal preservation interventions also reduce CV complications.

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε+Vα7.2+CD161++ or CD3ε+MR1 tetramer+ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

A point-based prediction model for cardiovascular risk in orthotopic liver transplantation: The CAR-OLT score.

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).

The impact of coronary artery disease on outcomes after liver transplantation.

AIMS: The aim of this study is to assess the impact of obstructive coronary artery disease (CAD) on outcomes after liver transplantation. BACKGROUND: Patients considered for liver transplantation are at an increased risk for CAD. Obstructive CAD is a contraindication for liver transplantation at most centres. However, the association between severity of CAD and liver transplantation outcomes remains poorly characterized. METHODS: We retrospectively reviewed 386 consecutive liver transplantations performed between January 2001 and December 2005 at Northwestern Memorial Hospital (NMH). A comparative analysis was conducted for a national cohort (n = 23 820) from the United Network for Organ Sharing database. Outcome measures included patient and graft survival, rates of acute myocardial infarction and heart failure. RESULTS: Patient survival remained similar irrespective of CAD severity or cardiovascular risk index (CRI) in the NMH cohort. The CRI closely correlated with the presence of CAD in the NMH cohort [CRI 0, odds ratio (OR) 0.125, 95% confidence interval (95% CI) 0.02-0.61, P = 0.01; CRI 1, OR 1 reference; CRI ≥2, OR 2.28, 95% CI 1.09-4.75, P = 0.02]. In the national cohort using Cox regression, high (≥2) CRI (reference 0, hazard ratio 1.376, 95% CI 1.271-1.488, P < 0.0001) predicted patient mortality and exceeded established risk factors, including Hepatitis C virus (HCV) (hazard ratio 1.321, 95% CI 1.242-1.403, P < 0.0001), hepatocellular carcinoma (HCC) (hazard ratio 1.27, 95% CI 1.181-1.370, P < 0.0001) and diabetes (hazard ratio 1.241, 95% CI 1.160-1.326, P < 0.0001). CONCLUSION: Liver transplantation in patients with CAD is not associated with prohibitive risk for cardiac events and patient mortality. Appropriately treated CAD should therefore not represent a contraindication to liver transplantation.

Impact of renal impairment on cardiovascular disease mortality after liver transplantation for nonalcoholic steatohepatitis cirrhosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is an independent risk factor for cardiovascular disease (CVD) morbidity after liver transplantation, but its impact on CVD mortality is unknown. We sought to assess the impact of NASH on CVD mortality after liver transplantation and to predict which NASH recipients are at highest risk of a CVD-related death following a liver transplant. METHODS: Using the Organ Procurement and Transplantation Network database, we examined associations between NASH and post-liver transplant CVD mortality, defined as primary cause of death from thromboembolism, arrhythmia, heart failure, myocardial infarction or stroke. A physician panel reviewed cause of death. RESULTS: Of 48 360 liver transplants (2/2002-12/2011), 5057 (10.5%) were performed for NASH cirrhosis. NASH recipients were more likely to be older, female, obese, diabetic and have history of renal failure or prior CVD vs. non-NASH (P < 0.001 for all). Although there was no difference in overall all-cause mortality (log-rank P = 0.96), both early (30-day) and long-term CVD-specific mortality was increased among NASH recipients (Odds ratio = 1.30, 95% Confidence interval (CI): 1.02-1.66; Hazard ratio = 1.42, 95% CI: 1.07-1.41 respectively). These associations were no longer significant after adjustment for pre-transplant diabetes, renal impairment or CVD. A risk score comprising age ≥55, male sex, diabetes and renal impairment was developed for prediction of post-liver transplant CVD mortality (c-statistic 0.60). CONCLUSION: NASH recipients have an increased risk of CVD mortality after liver transplantation explained by a high prevalence of comorbid cardiometabolic risk factors that in aggregate identify those at highest risk of post-transplant CVD mortality.

Clinical outcomes and quality of life in recipients of livers donated after cardiac death.

Donation after cardiac death (DCD) has expanded in the last decade in the US; however, DCD liver utilization has flattened in recent years due to poor outcomes. We examined clinical and quality of life (QOL) outcomes of DCD recipients by conducting a retrospective and cross-sectional review of patients from 2003 to 2010. We compared clinical outcomes of DCD recipients (n = 60) to those of donation after brain death (DBD) liver recipients (n = 669) during the same time period. DCD recipients had significantly lower rates of 5-year graft survival (P < 0.001) and a trend toward lower rates of 5-year patient survival (P = 0.064) when compared to the DBD cohort. In order to examine QOL outcomes in our cohorts, we administered the Short Form Liver Disease Quality of Life questionnaire to 30 DCD and 60 DBD recipients. The DCD recipients reported lower generic and liver-specific QOL. We further stratified the DCD cohort by the presence of ischemic cholangiopathy (IC). Patients with IC reported lower QOL when compared to DBD recipients and those DCD recipients without IC (P < 0.05). While the results are consistent with clinical experience, this is the first report of QOL in DCD recipients using standardized measures. These data can be used to guide future comparative effectiveness studies.

Hispanic/Latino Disparities in Living Donor Kidney Transplantation: Role of a Culturally Competent Transplant Program.

UNLABELLED: Hispanic Americans face disparities in access to kidney transplantation, particularly living donor kidney transplantation (LDKT). This study compared characteristics of LDKT recipients before and after implementing the Hispanic Kidney Transplant Program (HKTP) at Northwestern Medicines (NM) and other centers. METHODS: The NM HKTP, initiated in December 2006, delivers culturally and linguistically competent and congruent care. Program-specific data were used to compare the mean ratios of Hispanic to non-Hispanic white LDKTs between pre-HKTP (2001-2006) and post-HKTP (2008-2013), and to compare the characteristics of NM's adult LDKT patients between pre-HKTP and post-HKTP. The same ratio was calculated for transplant centers in regions with a significant Hispanic population (≥25%) and performing in the top tertile of total LDKT volume in the pre-HKTP period. The number of Hispanic and non-Hispanic white patients added to the waiting list were compared between pre-HKTP (2001-2006) and post-HKTP (2008-2013) as a proxy for increased patient referrals and a pathway by which the HKTP may increase LDKTs. RESULTS: The ratio of Hispanic to non-Hispanic white LDKTs significantly increased by 70% after the implementation of NM's HKTP (pre-HKTP mean = 0.20, post-HKTP mean = 0.34; P= 0.001). None of the other transplant centers experienced a similar increase in their ratio of Hispanic to non-Hispanic white LDKTs. The NM waiting list additions grew by 91% among Hispanics, but grew only 4% for non-Hispanic whites. CONCLUSIONS: These data suggest that the development and implementation of a culturally congruent transplant program can positively affect Hispanic LDKT and thereby reduce Hispanics disparities in LDKT rates. Further studies are needed to prospectively evaluate the generalizability of implementing such culturally competent interventions at other transplant programs.

Simulation modeling of the impact of proposed new simultaneous liver and kidney transplantation policies.

BACKGROUND: Increasing use of kidney grafts for simultaneous liver and kidney (SLK) transplants is causing concern about the most effective utilization of scarce kidney graft resources. This study evaluated the impact of implementing the proposed United Network for Organ Sharing SLK transplant policy on outcomes for end-stage liver disease (ESLD) and end-stage renal disease (ESRD) patients awaiting transplant. METHODS: A Markov model was constructed to simulate a hypothetical cohort of ESLD patients over a 30-year time horizon starting from age 50. The model applies the different criteria being considered in the United Network for Organ Sharing policy and tallies outcomes, including numbers of procedures and life years after liver transplant alone (LTA) or SLK transplant. RESULTS: When 1-week pretransplant dialysis duration is required, the numbers of SLK transplants and LTAs would be 648 and 9,065, respectively. If the pretransplant dialysis duration is extended to 12 weeks, there would be 240 SLK transplants and 9,426 LTAs. This change results in a decrease of 6,483 life years among SLK transplant recipients and an increase of 4,971 life years among LTA recipients. However, by increasing the dialysis duration to 12 weeks from 1 week, 408 kidney grafts would be released to the kidney waitlist because of the decline in SLK transplants; this yields 796 additional life years gained among ESRD patients. CONCLUSION: Implementation of the proposed SLK transplant policy could restore access to kidney transplants for patients with ESRD albeit at the detriment of patients with ESLD and renal impairment.

Improving Geographic Equity in Kidney Transplantation Using Alternative Kidney Sharing and Optimization Modeling.

The national demand for kidney transplantation far outweighs the supply of kidney organs. Currently, a patient's ability to receive a kidney transplant varies depending on where he or she seeks transplantation. This reality is in direct conflict with a federal mandate from the Department of Health and Human Services. We analyze current kidney allocation and develop an alternative kidney sharing strategy using a multiperiod linear optimization model, KSHARE. KSHARE aims to improve geographic equity in kidney transplantation while also respecting transplant system constraints and priorities. KSHARE is tested against actual 2000-2009 kidney allocation using Organ Procurement and Transplant Network data. Geographic equity is represented by minimizing the range in kidney transplant rates around local areas of the country. In 2009, less than 25% of standard criteria donor kidneys were allocated beyond the local area of procurement, and Donor Service Area kidney transplantation rates varied from 3.0% to 30.0%, for an overall range of 27.0%. Given optimal sharing of kidneys within 600 miles of procurement for 2000-2009, kidney transplant rates vary from 5.0% to 12.5% around the country for an overall kidney transplant range of 7.5%. Nationally sharing kidneys optimally between local areas only further decreases the transplant rate range by 1.7%. Enhancing the practice of sharing kidneys by the KSHARE model may increase geographic equity in kidney transplantation.