Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.
<h4>Background</h4>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 kid...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-02-01
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| Series: | PLoS Medicine |
| Online Access: | https://doi.org/10.1371/journal.pmed.1002248 |
| _version_ | 1797755758229585920 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Victoria K Snowdon |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov NCT01640964. |
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| format | Article |
| id | doaj.art-ab7417500a97421588c9af8b777a3c6d |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-03-12T17:51:48Z |
| publishDate | 2017-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj.art-ab7417500a97421588c9af8b777a3c6d2023-08-03T05:30:22ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762017-02-01142e100224810.1371/journal.pmed.1002248Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.Victoria K SnowdonNeil J LachlanAnna M HoyPatrick W F HadokeScott I SempleDilip PatelWill MungallTimothy J KendallAdrian ThomsonRoss J LennenMaurits A JansenCarmel M MoranAntonella PellicoroPrakash RamachandranIsaac ShawRebecca L AucottThomas SeverinRajnish SainiJudy PakDenise YatesNeelesh DongreJeremy S DuffieldDavid J WebbJohn P IredalePeter C HayesJonathan A Fallowfield<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov NCT01640964.https://doi.org/10.1371/journal.pmed.1002248 |
| spellingShingle | 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 Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. PLoS Medicine |
| title | Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. |
| title_full | Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. |
| title_fullStr | Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. |
| title_full_unstemmed | Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. |
| title_short | Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial. |
| title_sort | serelaxin as a potential treatment for renal dysfunction in cirrhosis preclinical evaluation and results of a randomized phase 2 trial |
| url | https://doi.org/10.1371/journal.pmed.1002248 |
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