Relaxin as a therapeutic haemodynamic modulator in liver disease

Introduction: Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis with a high mortality rate and limited treatment options. Central to its pathogenesis is severe, but potentially reversible, renal vasoconstriction leading to functional renal failure. Current pharmacological treatment using splanchnic vasoconstrictors is suboptimal and prognosis without liver transplantation is dismal. The peptide hormone relaxin (RLN) mediates haemodynamic adaptations to pregnancy including increased renal blood flow (RBF) and glomerular filtration rate (GFR). I hypothesised that exogenous RLN could be used therapeutically to improve RBF and renal function in the context of experimental cirrhosis and HRS. Methods: To address this I generated pathologically distinct rat models of liver cirrhosis with features of human HRS including renal vasoconstriction and renal failure. Compensated cirrhosis was induced in male rats by 16 weeks of i.p. carbon tetrachloride (CCl4) and decompensated cirrhosis by bile duct ligation (BDL). I studied the effects of acute i.v. or sustained (72 hr) s.c. infusion of RLN compared with vehicle on systemic haemodynamics, RBF, GFR and kidney histology. I used blood oxygen dependent-magnetic resonance imaging (BOLD-MRI) to detect changes in kidney parenchymal oxygenation and Doppler ultrasound to monitor changes in RBF (velocity time integral, VTI) and renal arterial resistance (resistive index, RI). Hepatic and renal expression of the relaxin receptor RXFP1 was determined by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Vascular functional responses in isolated renal arteries were assessed by wire myography. Relaxin mediated changes in key vaso-regulatory signalling pathways in the kidney and renal vessels were analysed by qPCR, IHC and ELISA. Results: I showed using in vitro myography that the pathophysiological mechanism that underlies renal vasoconstriction in experimental cirrhosis models is an impairment of endothelium-dependent vasodilatation. Selective targeting of renal vasoconstriction using relaxin improved renal blood flow, tissue oxygenation, and normalized glomerular filtration rate in both compensated and decompensated rat cirrhosis. Furthermore, relaxin treatment restored endothelium-dependent vasodilation in isolated renal vessels from CCl4 cirrhotic rats. Relaxin-induced effects on renal blood flow and glomerular filtration rate were mediated though activation of the AKT/eNOS/nitric oxide signalling pathway in kidney, though systemic nitric oxide levels were unaffected. Crucially for human translation, relaxin did not reduce mean arterial blood pressure even in advanced cirrhosis. Conclusion: My findings identify relaxin as the first potential targeted treatment reversing the vascular dysfunction which causes HRS and directly improving renal function in HRS. Clinical translation in carefully selected populations is warranted

How surgical Trainee Research Collaboratives achieve success: A mixed methods study to develop trainee engagement strategies

ObjectivesThis study aimed to understand the role of Surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials (RCTs) and identify strategies to enhance trainee engagement in trials.DesignThis is a mixed methods study. We used observation of TRC meetings, semi-structured interviews, and an online survey to explore trainees’ motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants, and research nurses.SettingThis study was conducted within a secondary care setting in the UK.ParticipantsThe survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialities and UK regions were purposefully sampled for interviews.ResultsWe observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units (CTUs) and research nurses. A 6-minute digital story on YouTube disseminated these strategies.ConclusionTrainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial

<div><p>Background</p><p>Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.</p><p>Methods and findings</p><p>To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow.</p><p>Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; <i>p <</i> 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study’s main limitations were the relatively small sample size and stable, well-compensated population.</p><p>Conclusions</p><p>Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01640964" target="_blank">NCT01640964</a></p></div

Drug Toxicity Deaths after Release from Incarceration in Ontario, 2006-2013: Review of Coroner’s Cases

<div><p>Background</p><p>There is an increased risk of death due to drug toxicity after release from incarceration. The purpose of this study was to describe the timing, rate and circumstances of drug toxicity deaths following release from incarceration. This information can be used to help design potential preventive interventions.</p><p>Methods and Findings</p><p>We reviewed coroner’s files to identify deaths in adults in Ontario between 2006 and 2013 caused by drug toxicity (n = 6,978) and these records were matched with provincial correctional records to identify individuals who died within one year of being released from incarceration (n = 702). Twenty percent (n = 137) of the 702 deaths occurred within one week of release. The majority (77%, n = 538) of deaths after release involved one or more opioids. Of the deaths involving opioids, intervention by another person may have been possible in 318 cases.</p><p>Conclusions</p><p>Between 2006 and 2013 in Ontario, one in ten drug toxicity deaths in adults occurred within one year of release from provincial incarceration. These findings may help to inform the implemention and assessment of interventions aimed at reducing drug toxicity deaths following release from incarceration.</p></div

Medical oncologists' perspectives of the Veterans Affairs National Precision Oncology Program.

BackgroundTo support the rising need for testing and to standardize tumor DNA sequencing practices within the U.S. Department of Veterans Affairs (VA)'s Veterans Health Administration (VHA), the National Precision Oncology Program (NPOP) was launched in 2016. We sought to assess oncologists' practices, concerns, and perceptions regarding Next-Generation Sequencing (NGS) and the NPOP.Materials and methodsUsing a purposive total sampling approach, oncologists who had previously ordered NGS for at least one tumor sample through the NPOP were invited to participate in semi-structured interviews. Questions assessed the following: expectations for the NPOP, procedural requirements, applicability of testing results, and the summative utility of the NPOP. Interviews were assessed using an open coding approach. Thematic analysis was conducted to evaluate the completed codebook. Themes were defined deductively by reviewing the direct responses to interview questions as well as inductively by identifying emerging patterns of data.ResultsOf the 105 medical oncologists who were invited to participate, 20 (19%) were interviewed from 19 different VA medical centers in 14 states. Five recurrent themes were observed: (1) Educational Efforts Regarding Tumor DNA Sequencing Should be Undertaken, (2) Pathology Departments Share a Critical Role in Facilitating Test Completion, (3) Tumor DNA Sequencing via NGS Serves as the Most Comprehensive Testing Modality within Precision Oncology, (4) The Availability of the NPOP Has Expanded Options for Select Patients, and (5) The Completion of Tumor DNA Sequencing through the NPOP Could Help Improve Research Efforts within VHA Oncology Practices.ConclusionMedical oncologists believe that the availability of tumor DNA sequencing through the NPOP could potentially lead to an improvement in outcomes for veterans with metastatic solid tumors. Efforts should be directed toward improving oncologists' understanding of sequencing, strengthening collaborative relationships between oncologists and pathologists, and assessing the role of comprehensive NGS panels within the battery of precision tests

Number of deaths by week since release in the year after release from provincial incarceration, 2006–2013.

<p>Number of deaths by week since release in the year after release from provincial incarceration, 2006–2013.</p

Characteristics of persons who died due to drug intoxication in the year after release from incarceration in Ontario, 2006–2013, n = 702.

<p>Characteristics of persons who died due to drug intoxication in the year after release from incarceration in Ontario, 2006–2013, n = 702.</p