Snowdon, Victoria K., Lachlan, Neil J., Hadoke, Patrick W.F., Hoy, Anna M., Semple, Scott, Patel, Dilip, Mungall, Will, Kendall, Timothy J., Thomson, Adrian, Lennen, Ross J., Jansen, Mauritis A., Moran, Carmel M., Pellicoro, Antonella, Ramachandran, Prakash, Shaw, Isaac, Aucott, Rebecca L. , Severin, Thomas, Saini, Rajnish, Pak, Judy, Yates, Denise, Dongre, Neelesh, Duffield, Jeremy S., Webb, David J., Iredale, John P., Hayes, Peter C. and Fallowfield, Jonathan A. (2017) Serelaxin for the Treatment of Renal Dysfunction in Cirrhosis: Preclinical Evaluation and Results of a Randomized Phase 2 Trial. PLoS medicine. ISSN 1549-1676; 1549-1277

Abstract

Renal dysfunction is a frequent complication of liver cirrhosis and is associated with increased mortality. Extreme renal hypoperfusion characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients. Serelaxin (recombinant human relaxin-2) binds to relaxin family peptide receptor-1 (RXFP1) and increases renal perfusion in healthy volunteers. Here we showed that serelaxin increased renal blood flow, parenchymal oxygenation and glomerular filtration rate in rats with cirrhosis and renal dysfunction, through reversal of renovascular endothelial dysfunction and activation of the AKT/eNOS/NO signaling pathway in the kidney. In a Phase 2 randomized open-label parallel-group study, male and female patients with alcohol-related cirrhosis and portal hypertension (n=40) were randomized 1:1 to treatment with serelaxin i.v. infusion (60 min at 80μg/kg/day and then 60 min at 30μg/kg/day) or terlipressin (2mg i.v. bolus) and the regional hemodynamic effects were quantified by phase contrast-magnetic resonance angiography. Infusion of serelaxin for 120 min increased total renal arterial blood flow by 65.4% (95% CI 40, 95; P=0.00002) and reduced renal vascular resistance by 38% (95% CI 27, 48; P=0.0003) from baseline. Furthermore, serelaxin was safe and well tolerated with no adverse effect on systemic blood pressure or hepatic perfusion. Selective renal vasodilation using serelaxin may represent a potential new treatment approach for renal dysfunction in human cirrhosis.

Item Type:	Article
Date Deposited:	13 Mar 2017 00:45
Last Modified:	13 Mar 2017 00:45
URI:	https://oak.novartis.com/id/eprint/30205