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

1. Selby NM, Fluck RJ, Kolhe NV, Taal MW. International criteria for acute kidney injury: advantages and remaining challenges. PLoS Med. 2016;13(9):e1002122. doi: 10.1371/journal.pmed.1002122 27622526

2. Angeli P, Rodriguez E, Piano S, Ariza X, Morando F, Sola E, et al. Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis. Gut. 2015;64(10):1616–22. doi: 10.1136/gutjnl-2014-307526 25311034

3. Besso J, Pru C, Padron J, Plaz J. Hepatorenal syndrome. In: Gullo A, Lumb D, editors. Intensive and critical care medicine: reflections, recommendations and perspectives. Milan: Springer-Verlag; 2007. pp. 9–27.

4. Martin-Llahi M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology. 2011;140(2):488–96.e4. doi: 10.1053/j.gastro.2010.07.043 20682324

5. Krag A, Bendtsen F, Henriksen JH, Moller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut. 2010;59(1):105–10. doi: 10.1136/gut.2009.180570 19837678

6. Newby DE, Hayes PC. Hyperdynamic circulation in liver cirrhosis: not peripheral vasodilatation but ‘splanchnic steal’. QJM. 2002;95(12):827–30. 12454326

7. Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133(3):818–24. doi: 10.1053/j.gastro.2007.06.065 17854593

8. Kew MC, Brunt PW, Varma RR, Hourigan KJ, Williams HS, Sherlock S. Renal and intrarenal blood-flow in cirrhosis of the liver. Lancet. 1971;2(7723):504–10. 4105661

9. McAvoy NC, Semple S, Richards JM, Robson AJ, Patel D, Jardine AG, et al. Differential visceral blood flow in the hyperdynamic circulation of patients with liver cirrhosis. Aliment Pharmacol Ther. 2016;43(9):947–54. doi: 10.1111/apt.13571 26947424

10. Stadlbauer V, Wright GA, Banaji M, Mukhopadhya A, Mookerjee RP, Moore K, et al. Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology. 2008;134(1):111–9. doi: 10.1053/j.gastro.2007.10.055 18166350

11. Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jimenez W, Arroyo V, et al. MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology. 2005;41(6):1282–9. doi: 10.1002/hep.20687 15834937

12. Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut. 2013;62(1):131–7. doi: 10.1136/gutjnl-2011-301255 22637695

13. Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O’Leary JG, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology. 2016;150(7):1579–89.e2. doi: 10.1053/j.gastro.2016.02.026 26896734

14. Conrad KP. Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension. 2010;56(1):2–9. doi: 10.1161/HYPERTENSIONAHA.109.133926 20497994

15. Novak J, Parry LJ, Matthews JE, Kerchner LJ, Indovina K, Hanley-Yanez K, et al. Evidence for local relaxin ligand-receptor expression and function in arteries. FASEB J. 2006;20(13):2352–62. doi: 10.1096/fj.06-6263com 17077312

16. Debrah DO, Conrad KP, Jeyabalan A, Danielson LA, Shroff SG. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension. 2005;46(4):745–50. doi: 10.1161/01.HYP.0000184230.52059.33 16172427

17. Fallowfield JA, Hayden AL, Snowdon VK, Aucott RL, Stutchfield BM, Mole DJ, et al. Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology. 2014;59(4):1492–504. doi: 10.1002/hep.26627 23873655

18. Smith MC, Danielson LA, Conrad KP, Davison JM. Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers. J Am Soc Nephrol. 2006;17(11):3192–7. doi: 10.1681/ASN.2005090950 17035617

19. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–91. 17695343

20. McIntyre CA, Williams BC, Lindsay RM, McKnight JA, Hadoke PW. Preservation of vascular function in rat mesenteric resistance arteries following cold storage, studied by small vessel myography. Br J Pharmacol. 1998;123(8):1555–60. doi: 10.1038/sj.bjp.0701768 9605561

21. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381(9860):29–39. doi: 10.1016/S0140-6736(12)61855-8 23141816

22. Escorsell A, Bandi JC, Moitinho E, Feu F, Garcia-Pagan JC, Bosch J, et al. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol. 1997;26(3):621–7. 9075670

23. Barthelmes D, Parviainen I, Vainio P, Vanninen R, Takala J, Ikonen A, et al. Assessment of splanchnic blood flow using magnetic resonance imaging. Eur J Gastroenterol Hepatol. 2009;21(6):693–700. doi: 10.1097/MEG.0b013e32831a86e0 19293721

24. Kim SW, Schou UK, Peters CD, de Seigneux S, Kwon TH, Knepper MA, et al. Increased apical targeting of renal epithelial sodium channel subunits and decreased expression of type 2 11beta-hydroxysteroid dehydrogenase in rats with CCl4-induced decompensated liver cirrhosis. J Am Soc Nephrol. 2005;16(11):3196–210. doi: 10.1681/ASN.2004080721 16192424

25. McGuane JT, Debrah JE, Sautina L, Jarajapu YP, Novak J, Rubin JP, et al. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology. 2011;152(7):2786–96. doi: 10.1210/en.2010-1126 21558316

26. Robertson S, Gray GA, Duffin R, McLean SG, Shaw CA, Hadoke PW, et al. Diesel exhaust particulate induces pulmonary and systemic inflammation in rats without impairing endothelial function ex vivo or in vivo. Part Fibre Toxicol. 2012;9:9. doi: 10.1186/1743-8977-9-9 22480168

27. Vairappan B. Endothelial dysfunction in cirrhosis: role of inflammation and oxidative stress. World J Hepatol. 2015;7(3):443–59. doi: 10.4254/wjh.v7.i3.443 25848469

28. Salmeron JM, Ruiz del Arbol L, Gines A, Garcia-Pagan JC, Gines P, Feu F, et al. Renal effects of acute isosorbide-5-mononitrate administration in cirrhosis. Hepatology. 1993;17(5):800–6. 8491447

29. Edwards RM. Comparison of the effects of fenoldopam, SK & F R-87516 and dopamine on renal arterioles in vitro. Eur J Pharmacol. 1986;126(1–2):167–70. 2875883

30. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426–37. doi: 10.1053/j.gastro.2013.02.042 23474284

31. Leo CH, Jelinic M, Ng HH, Marshall SA, Novak J, Tare M, et al. Vascular actions of relaxin: nitric oxide and beyond. Br J Pharmacol. 2016 Sep 2.

32. Garcia-Martinez R, Noiret L, Sen S, Mookerjee R, Jalan R. Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury. Liver Int. 2015;35(2):335–43. doi: 10.1111/liv.12528 24620819

33. Trebicka J, Leifeld L, Hennenberg M, Biecker E, Eckhardt A, Fischer N, et al. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology. 2008;47(4):1264–76. doi: 10.1002/hep.22170 18318439

34. Moore XL, Su Y, Fan Y, Zhang YY, Woodcock EA, Dart AM, et al. Diverse regulation of cardiac expression of relaxin receptor by alpha1- and beta1-adrenoceptors. Cardiovasc Drugs Ther. 2014;28(3):221–8. doi: 10.1007/s10557-014-6525-x 24852484

35. Bax L, Bakker CJ, Klein WM, Blanken N, Beutler JJ, Mali WP. Renal blood flow measurements with use of phase-contrast magnetic resonance imaging: normal values and reproducibility. J Vasc Interv Radiol. 2005;16(6):807–14. doi: 10.1097/01.RVI.0000161144.98350.28 15947044

36. Jelinic M, Leo CH, Post Uiterweer ED, Sandow SL, Gooi JH, Wlodek ME, et al. Localization of relaxin receptors in arteries and veins, and region-specific increases in compliance and bradykinin-mediated relaxation after in vivo serelaxin treatment. FASEB J. 2014;28(1):275–87. doi: 10.1096/fj.13-233429 24036884

37. Dschietzig T, Bartsch C, Baumann G, Stangl K. Relaxin-a pleiotropic hormone and its emerging role for experimental and clinical therapeutics. Pharmacol Ther. 2006;112(1):38–56. doi: 10.1016/j.pharmthera.2006.03.004 16647137

38. Ring-Larsen H. Renal blood flow in cirrhosis: relation to systemic and portal haemodynamics and liver function. Scand J Clin Lab Invest. 1977;37(7):635–42. doi: 10.3109/00365517709100657 594643

39. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005;42(2):439–47. doi: 10.1002/hep.20766 15977202

40. Pereira RM, dos Santos RA, Oliveira EA, Leite VH, Dias FL, Rezende AS, et al. Development of hepatorenal syndrome in bile duct ligated rats. World J Gastroenterol. 2008;14(28):4505–11. doi: 10.3748/wjg.14.4505 18680230

41. O’Brien A, China L, Massey KA, Nicolaou A, Winstanley A, Newson J, et al. Bile duct-ligated mice exhibit multiple phenotypic similarities to acute decompensation patients despite histological differences. Liver Int. 2016;36(6):837–46. doi: 10.1111/liv.12876 26012885

42. Shah N, Dhar D, El Zahraa Mohammed F, Habtesion A, Davies NA, Jover-Cobos M, et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. J Hepatol. 2012;56(5):1047–53. doi: 10.1016/j.jhep.2011.11.024 22266601

43. Fagundes C, Pepin MN, Guevara M, Barreto R, Casals G, Sola E, et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol. 2012;57(2):267–73. doi: 10.1016/j.jhep.2012.03.015 22521351

44. Trawale JM, Paradis V, Rautou PE, Francoz C, Escolano S, Sallee M, et al. The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study. Liver Int. 2010;30(5):725–32. doi: 10.1111/j.1478-3231.2009.02182.x 20040048

45. Kobalava Z, Villevalde S, Kotovskaya Y, Hinrichsen H, Petersen-Sylla M, Zaehringer A, et al. Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel-group study. Br J Clin Pharmacol. 2015;79(6):937–45. doi: 10.1111/bcp.12572 25511105

46. Metra M, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol. 2013;61(2):196–206. doi: 10.1016/j.jacc.2012.11.005 23273292