title: Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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. 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01640964.
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Snowdon
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Lachlan
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hoy
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Patrick W F
authors.identifier: http://orcid.org/0000-0002-1041-1781
authors.initials: PW
authors.lastname: Hadoke
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.|Clinical Research Imaging Centre, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Semple
authors.affiliation: Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Dilip
authors.identifier: http://orcid.org/0000-0003-4892-0386
authors.initials: D
authors.lastname: Patel
authors.affiliation: Biological Services, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Will
authors.initials: W
authors.lastname: Mungall
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Timothy J
authors.identifier: http://orcid.org/0000-0002-4174-2786
authors.initials: TJ
authors.lastname: Kendall
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Adrian
authors.identifier: http://orcid.org/0000-0001-7320-300X
authors.initials: A
authors.lastname: Thomson
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Lennen
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Maurits A
authors.identifier: http://orcid.org/0000-0002-7077-0188
authors.initials: MA
authors.lastname: Jansen
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Moran
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pellicoro
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Prakash
authors.identifier: http://orcid.org/0000-0001-5996-2413
authors.initials: P
authors.lastname: Ramachandran
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Isaac
authors.identifier: http://orcid.org/0000-0002-5628-0318
authors.initials: I
authors.lastname: Shaw
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Aucott
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Severin
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Saini
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, United States of America.
authors.forename: Judy
authors.identifier: http://orcid.org/0000-0001-9653-950X
authors.initials: J
authors.lastname: Pak
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America.
authors.forename: Denise
authors.initials: D
authors.lastname: Yates
authors.affiliation: Novartis Pharma, Basel, Switzerland.
authors.forename: Neelesh
authors.initials: N
authors.lastname: Dongre
authors.affiliation: Division of Nephrology and Lung Biology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.affiliation: British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hayes
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Jonathan A
authors.identifier: http://orcid.org/0000-0002-5741-1471
authors.initials: JA
authors.lastname: Fallowfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D007674:Kidney Diseases / Q000188:drug therapy*; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects; D012065:Relaxin / Q000494:pharmacology* / Q000627:therapeutic use*; D012606:Scotland; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; C577649:serelaxin protein, human; D012065:Relaxin