Date Published: February 28, 2017
Publisher: Public Library of Science
Author(s): Victoria K. Snowdon, Neil J. Lachlan, Anna M. Hoy, Patrick W. F. Hadoke, Scott I. Semple, Dilip Patel, Will Mungall, Timothy J. Kendall, Adrian Thomson, Ross J. Lennen, Maurits A. Jansen, Carmel M. Moran, Antonella Pellicoro, Prakash Ramachandran, Isaac Shaw, Rebecca L. Aucott, Thomas Severin, Rajnish Saini, Judy Pak, Denise Yates, Neelesh Dongre, Jeremy S. Duffield, David J. Webb, John P. Iredale, Peter C. Hayes, Jonathan A. Fallowfield, Maarten W. Taal
Abstract: BackgroundChronic 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.Methods and findingsTo 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.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%; p < 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.ConclusionsOur 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.Trial registrationClinicalTrials.gov NCT01640964
Partial Text: Acute kidney injury (AKI) is a major challenge for healthcare providers and clinicians worldwide, affecting an estimated 13 million people and contributing to 1.7 million deaths every year . AKI occurs in approximately 20% of patients with liver cirrhosis who are admitted into hospital, and the associated morbidity and mortality remain unacceptably high . Hepatorenal syndrome (HRS), the most severe form of AKI in cirrhosis, develops in more than 50% of patients with cirrhosis who die . HRS is a functional, and potentially reversible, type of renal failure characterized by intense renal vasoconstriction and hypoperfusion and is associated with a dismal prognosis . It occurs in response to portal hypertension (PHT) and the associated splanchnic arterial vasodilatation and impairment of cardiac function that lead to a reduction in effective circulating volume, with compensatory activation of neurohormonal systems and an intrarenal imbalance between vasoconstrictor and vasodilator systems causing increased renal vascular resistance (RVR) [5,6]. Pooling of blood in the splanchnic circulation also alters gut permeability and enhances bacterial translocation, with the release of endotoxin and increase in pro-inflammatory cytokines leading to amplification of circulatory dysfunction . Imaging studies have shown a significant (~40%) reduction in renal blood flow (RBF) and redistribution of intrarenal blood flow in patients with compensated cirrhosis compared to healthy volunteers [8,9]. As cirrhosis advances, systemic hemodynamics are increasingly disturbed, RBF becomes progressively compromised, and patients are susceptible to episodes of AKI (including HRS) in response to precipitating factors, particularly bacterial infections .
We have shown for the first time, to the best of our knowledge, that serelaxin attenuated renal vasoconstriction (RVR), improved RBF and endothelial dysfunction, and reversed impaired kidney function in experimental rat models of cirrhosis, PHT, and renal dysfunction (Fig 3). Crucially, we went on to demonstrate the translational relevance of these findings by showing in patients with cirrhosis and PHT that serelaxin reduced RVR and caused a substantial increase in RBF (Fig 7).