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Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin

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Abstract

Renal dysfunction is a frequent finding in patients with acute heart failure (AHF) and an important prognostic factor for adverse outcomes. Worsening of renal function occurs in 30–50 % of patients hospitalised for AHF, and is associated with increased mortality, prolonged hospital stay and increased risk of readmission. Likely mechanisms involved in the decrease in renal function include impaired haemodynamics and activation of neurohormonal factors, such as the renin–angiotensin–aldosterone system, the sympathetic nervous system and the arginine–vasopressin system. Additionally, many drugs currently used to treat AHF have a detrimental effect on renal function. Therefore, pharmacotherapy for AHF should carefully take into account any potential complications related to renal function. Serelaxin, currently in clinical development for the treatment of AHF is a recombinant form of human relaxin-2, identical in structure to the naturally occurring human relaxin-2 peptide hormone that mediates cardiac and renal adaptations during pregnancy. Data from both pre-clinical and clinical studies indicate a potentially beneficial effect of serelaxin on kidney function. In this review, we discuss the mechanisms and impact of impairment of renal function in AHF, and the potential benefits of new therapies, such as serelaxin, in this context.

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References

  1. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J (2007) High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 13(6):422–430

    Article  PubMed  Google Scholar 

  2. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Crespo LM, Drozdz J, Fruhwald F, Gullestad L, Logeart D, Fabbri G, Urso R, Metra M, Parissis J, Persson H, Ponikowski P, Rauchhaus M, Voors AA, Nielsen OW, Zannad F, Tavazzi L (2013) EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 15(7):808–817

    Article  PubMed  Google Scholar 

  3. Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, Krumholz HM (2006) Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 47(10):1987–1996

    Article  PubMed  Google Scholar 

  4. Hillege HL, Girbes AR, de Kam PJ, Boomsma F, de Zeeuw D, Charlesworth A, Hampton JR, van Veldhuisen DJ (2000) Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 102(2):203–210

    Article  CAS  PubMed  Google Scholar 

  5. Smilde TD, Hillege HL, Navis G, Boomsma F, de Zeeuw D, van Veldhuisen DJ (2004) Impaired renal function in patients with ischemic and nonischemic chronic heart failure: association with neurohormonal activation and survival. Am Heart J 148(1):165–172

    Article  CAS  PubMed  Google Scholar 

  6. Swindle J, Chan W, Johnson KW, Becker L, Blauer-Peterson C, Riedel A (2013) Renal impairment in acute heart failure: insights from a managed care database. Circulation 128:A12097

    Google Scholar 

  7. Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, Gottlieb SS, Loh E, Massie BM, Rich MW, Stevenson LW, Young JB, Krumholz HM (2004) Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 43(1):61–67

    Article  PubMed  Google Scholar 

  8. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, Yancy CW, Califf RM, Stevenson LW, Hill JA (2008) Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol 51(13):1268–1274

    Article  PubMed  Google Scholar 

  9. Blair JE, Pang PS, Schrier RW, Metra M, Traver B, Cook T, Campia U, Ambrosy A, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Konstam MA, Gheorghiade M (2011) Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial. Eur Heart J 32(20):2563–2572

    Article  PubMed  Google Scholar 

  10. Gheorghiade M, Pang PS (2009) Acute heart failure syndromes. J Am Coll Cardiol 53(7):557–573

    Article  Google Scholar 

  11. Carubelli V, Metra M, Lombardi C, Bettari L, Bugatti S, Lazzarini V, Dei CL (2012) Renal dysfunction in acute heart failure: epidemiology, mechanisms and assessment. Heart Fail Rev 17(2):271–282

    Article  CAS  PubMed  Google Scholar 

  12. Dupont M, Shrestha K, Singh D, Finucan M, Tang WH (2013) Lack of concordance in defining worsening renal function by rise in creatinine vs rise in cystatin C. Congest Heart Fail 19(4):E17–E21

    Article  PubMed Central  PubMed  Google Scholar 

  13. Klein L, Massie BM, Leimberger JD, O’Connor CM, Pina IL, Adams KF Jr, Califf RM, Gheorghiade M (2008) Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF). Circ Heart Fail 1(1):25–33

    Article  CAS  PubMed  Google Scholar 

  14. Damman K, Tang WH, Testani JM, McMurray JJ (2014) Terminology and definition of changes renal function in heart failure. Eur Heart J 35(48):3413–3416

    Article  PubMed  Google Scholar 

  15. Damman K, Valente MA, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege HL (2014) Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J 35(7):455–469

    Article  PubMed  Google Scholar 

  16. Kociol RD, Greiner MA, Hammill BG, Phatak H, Fonarow GC, Curtis LH, Hernandez AF (2010) Long-term outcomes of medicare beneficiaries with worsening renal function during hospitalization for heart failure. Am J Cardiol 105(12):1786–1793

    Article  PubMed  Google Scholar 

  17. Testani JM, McCauley BD, Chen J, Shumski M, Shannon RP (2010) Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions. Cardiology 116(3):206–212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Metra M, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu MI, Grinfeld L, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K, Prescott MF, Edwards C, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin T, Teerlink JR (2013) 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 61(2):196–206

    Article  CAS  PubMed  Google Scholar 

  19. Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie BM, O’Connor CM, Rich MW, Stevenson LW, Wang Y, Young JB, Krumholz HM (2004) Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 147(2):331–338

    Article  PubMed  Google Scholar 

  20. Llorens P, Miro O, Herrero P, Martin-Sanchez FJ, Jacob J, Valero A, Alonso H, Perez-Dura MJ, Noval A, Gil-Roman JJ, Zapater P, Llanos L, Gil V, Perello R (2014) Clinical effects and safety of different strategies for administering intravenous diuretics in acutely decompensated heart failure: a randomised clinical trial. Emerg Med J 31(9):706–713

    Article  PubMed  Google Scholar 

  21. Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, van Veldhuisen DJ, Shi H, Messig M, Vincent J, Girerd N, Bakris G, Pitt B, Zannad F (2014) Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail 7(1):51–58

    Article  CAS  PubMed  Google Scholar 

  22. Metra M, Davison B, Bettari L, Sun H, Edwards C, Lazzarini V, Piovanelli B, Carubelli V, Bugatti S, Lombardi C, Cotter G, Dei CL (2012) Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circ Heart Fail 5(1):54–62

    Article  PubMed  Google Scholar 

  23. Voors AA, Davison BA, Teerlink JR, Felker GM, Cotter G, Filippatos G, Greenberg BH, Pang PS, Levin B, Hua TA, Severin T, Ponikowski P, Metra M (2014) Diuretic response in patients with acute decompensated heart failure: characteristics and clinical outcome—an analysis from RELAX-AHF. Eur J Heart Fail 16(11):1230–1240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R (2008) Cardiorenal syndrome. J Am Coll Cardiol 52(19):1527–1539

    Article  PubMed  Google Scholar 

  25. McCullough PA, Haapio M, Mankad S, Zamperetti N, Massie B, Bellomo R, Berl T, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bobek I, Cruz DN, Daliento L, Davenport A, Hillege H, House AA, Katz N, Maisel A, Mebazaa A, Palazzuoli A, Ponikowski P, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zanco P, Ronco C, Berl T (2010) Prevention of cardio-renal syndromes: workgroup statements from the 7th ADQI consensus conference. Nephrol Dial Transplant 25(6):1777–1784

    Article  PubMed  Google Scholar 

  26. Cleland JG, Carubelli V, Castiello T, Yassin A, Pellicori P, Antony R (2012) Renal dysfunction in acute and chronic heart failure: prevalence, incidence and prognosis. Heart Fail Rev 17(2):133–149

    Article  CAS  PubMed  Google Scholar 

  27. House AA, Anand I, Bellomo R, Cruz D, Bobek I, Anker SD, Aspromonte N, Bagshaw S, Berl T, Daliento L, Davenport A, Haapio M, Hillege H, McCullough P, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P, Ronco C (2010) Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI consensus conference. Nephrol Dial Transplant 25(5):1416–1420

    Article  PubMed  Google Scholar 

  28. Bidani AK, Griffin KA, Epstein M (2012) Hypertension and chronic kidney disease progression: why the suboptimal outcomes? Am J Med 125(11):1057–1062

    Article  PubMed Central  PubMed  Google Scholar 

  29. Tumlin JA, Costanzo MR, Chawla LS, Herzog CA, Kellum JA, McCullough PA, Ronco C (2013) Cardiorenal syndrome type 4: insights on clinical presentation and pathophysiology from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 182:158–173

    Article  PubMed  Google Scholar 

  30. Biolo A, Fisch M, Balog J, Chao T, Schulze PC, Ooi H, Siwik D, Colucci WS (2010) Episodes of acute heart failure syndrome are associated with increased levels of troponin and extracellular matrix markers. Circ Heart Fail 3(1):44–50

    Article  CAS  PubMed  Google Scholar 

  31. Tsutsui H, Kinugawa S, Matsushima S (2011) Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol 301(6):H2181–H2190

    Article  CAS  PubMed  Google Scholar 

  32. Guazzi M, Gatto P, Giusti G, Pizzamiglio F, Previtali I, Vignati C, Arena R (2013) Pathophysiology of cardiorenal syndrome in decompensated heart failure: role of lung–right heart–kidney interaction. Int J Cardiol 169(6):379–384

    Article  CAS  PubMed  Google Scholar 

  33. Damman K, Navis G, Smilde TD, Voors AA, van der Bij W, van Veldhuisen DJ, Hillege HL (2007) Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 9(9):872–878

    Article  PubMed  Google Scholar 

  34. Metra M, Cotter G, Gheorghiade M, Dei CL, Voors AA (2012) The role of the kidney in heart failure. Eur Heart J 33(17):2135–2142

    Article  CAS  PubMed  Google Scholar 

  35. Uthoff H, Breidthardt T, Klima T, Aschwanden M, Arenja N, Socrates T, Heinisch C, Noveanu M, Frischknecht B, Baumann U, Jaeger KA, Mueller C (2011) Central venous pressure and impaired renal function in patients with acute heart failure. Eur J Heart Fail 13(4):432–439

    Article  PubMed  Google Scholar 

  36. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL (2009) Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 53(7):582–588

    Article  PubMed  Google Scholar 

  37. Gheorghiade M, De LL, Fonarow GC, Filippatos G, Metra M, Francis GS (2005) Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol 96(6A):11G–17G

    Article  PubMed  Google Scholar 

  38. Dini FL, Demmer RT, Simioniuc A, Morrone D, Donati F, Guarini G, Orsini E, Caravelli P, Marzilli M, Colombo PC (2012) Right ventricular dysfunction is associated with chronic kidney disease and predicts survival in patients with chronic systolic heart failure. Eur J Heart Fail 14(3):287–294

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, Young JB, Tang WH (2009) Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 53(7):589–596

    Article  PubMed Central  PubMed  Google Scholar 

  40. Shamseddin MK, Parfrey PS (2009) Mechanisms of the cardiorenal syndromes. Nat Rev Nephrol 5(11):641–649

    Article  Google Scholar 

  41. Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ (2013) The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 99(11):759–766

    Article  CAS  PubMed  Google Scholar 

  42. Lymperopoulos A (2013) Physiology and pharmacology of the cardiovascular adrenergic system. Front Physiol 4:240

    Article  PubMed Central  PubMed  Google Scholar 

  43. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH (1981) Relation of the renin–angiotensin–aldosterone system to clinical state in congestive heart failure. Circulation 63(3):645–651

    Article  CAS  PubMed  Google Scholar 

  44. Shah BN, Greaves K (2010) The cardiorenal syndrome: a review. Int J Nephrol 2011:920195

    CAS  PubMed Central  PubMed  Google Scholar 

  45. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A (2012) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33(14):1787–1847

    Article  PubMed  Google Scholar 

  46. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128(16):e240–e327

    Article  PubMed  Google Scholar 

  47. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, Heizer GM, Komajda M, Massie BM, McMurray JJ, Nieminen MS, Reist CJ, Rouleau JL, Swedberg K, Adams KF Jr, Anker SD, Atar D, Battler A, Botero R, Bohidar NR, Butler J, Clausell N, Corbalan R, Costanzo MR, Dahlstrom U, Deckelbaum LI, Diaz R, Dunlap ME, Ezekowitz JA, Feldman D, Felker GM, Fonarow GC, Gennevois D, Gottlieb SS, Hill JA, Hollander JE, Howlett JG, Hudson MP, Kociol RD, Krum H, Laucevicius A, Levy WC, Mendez GF, Metra M, Mittal S, Oh BH, Pereira NL, Ponikowski P, Tang WH, Tanomsup S, Teerlink JR, Triposkiadis F, Troughton RW, Voors AA, Whellan DJ, Zannad F, Califf RM (2011) Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 365(1):32–43

    Article  PubMed  Google Scholar 

  48. Sackner-Bernstein JD, Skopicki HA, Aaronson KD (2005) Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 111(12):1487–1491

    Article  CAS  PubMed  Google Scholar 

  49. van Deursen V, Hernandez AF, Stebbins A, Hasselblad V, Ezekowitz JA, Califf RM, Gottlieb SS, O’Connor CM, Starling RC, Tang WH, McMurray JJ, Dickstein K, Voors AA (2014) Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF). Circulation 130(12):958–965

    Article  PubMed  Google Scholar 

  50. O’Connor CM, Gattis WA, Uretsky BF, Adams KF Jr, McNulty SE, Grossman SH, McKenna WJ, Zannad F, Swedberg K, Gheorghiade M, Califf RM (1999) Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 138(1 Pt 1):78–86

    Article  PubMed  Google Scholar 

  51. Tacon CL, McCaffrey J, Delaney A (2012) Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med 38(3):359–367

    Article  CAS  PubMed  Google Scholar 

  52. Fedele F, Bruno N, Brasolin B, Caira C, D’Ambrosi A, Mancone M (2014) Levosimendan improves renal function in acute decompensated heart failure: possible underlying mechanisms. Eur J Heart Fail 16(3):281–288

    Article  CAS  PubMed  Google Scholar 

  53. Yilmaz MB, Yalta K, Yontar C, Karadas F, Erdem A, Turgut OO, Yilmaz A, Tandogan I (2007) Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine. Cardiovasc Drugs Ther 21(6):431–435

    Article  CAS  PubMed  Google Scholar 

  54. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E (2012) Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 367(24):2296–2304

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Krishnamoorthy A, Greiner MA, Sharma PP, DeVore AD, Johnson KW, Fonarow GC, Curtis LH, Hernandez AF (2014) Transient and persistent worsening renal function during hospitalization for acute heart failure. Am Heart J 168(6):891–900

    Article  PubMed  Google Scholar 

  56. Palmer JB, Friedman HS, Waltman Johnson K, Navaratnam P, Gottlieb SS (2014) Association of worsening renal function with length of stay and costs in patients hospitalized with acute heart failure. J Card Fail 20(Suppl.):S50–S51

    Article  Google Scholar 

  57. Teichman SL, Unemori E, Dschietzig T, Conrad K, Voors AA, Teerlink JR, Felker GM, Metra M, Cotter G (2009) Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev 14(4):321–329

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ (2002) Activation of orphan receptors by the hormone relaxin. Science 295(5555):671–674

    Article  CAS  PubMed  Google Scholar 

  59. Kohsaka T, Min G, Lukas G, Trupin S, Campbell ET, Sherwood OD (1998) Identification of specific relaxin-binding cells in the human female. Biol Reprod 59(4):991–999

    Article  CAS  PubMed  Google Scholar 

  60. Novak J, Parry LJ, Matthews JE, Kerchner LJ, Indovina K, Hanley-Yanez K, Doty KD, Debrah DO, Shroff SG, Conrad KP (2006) Evidence for local relaxin ligand-receptor expression and function in arteries. FASEB J 20(13):2352–2362

    Article  CAS  PubMed  Google Scholar 

  61. Díez J (2014) Serelaxin: a novel therapy for acute heart failure with a range of hemodynamic and non-hemodynamic actions. Am J Cardiovasc Drugs 14:275–285

    Article  PubMed Central  PubMed  Google Scholar 

  62. Jelinic M, Leo CH, Post Uiterweer ED, Sandow SL, Gooi JH, Wlodek ME, Conrad KP, Parkington H, Tare M, Parry LJ (2014) 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 28(1):275–287

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. McGuane JT, Debrah JE, Sautina L, Jarajapu YP, Novak J, Rubin JP, Grant MB, Segal M, Conrad KP (2011) Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology 152(7):2786–2796

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ (2010) Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol 7(1):48–58

    Article  CAS  PubMed  Google Scholar 

  65. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M (2010) Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep 7(2):75–82

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Danielson LA, Kercher LJ, Conrad KP (2000) Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol Regul Integr Comp Physiol 279(4):R1298–R1304

    CAS  PubMed  Google Scholar 

  67. Boehnert MU, Hilbig H, Armbruster FP (2005) Relaxin as an additional protective substance in preserving and reperfusion solution for liver transplantation, shown in a model of isolated perfused rat liver. Ann N Y Acad Sci 1041:434–440

    Article  CAS  PubMed  Google Scholar 

  68. Boehnert MU, Armbruster FP, Hilbig H (2009) Relaxin as a protective substance in the preserving solution for liver transplantation: spectrophotometric in vivo imaging of local oxygen supply in an isolated perfused rat liver model. Ann N Y Acad Sci 1160:320–321

    Article  CAS  PubMed  Google Scholar 

  69. Collino M, Rogazzo M, Pini A, Benetti E, Rosa AC, Chiazza F, Fantozzi R, Bani D, Masini E (2013) Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury. J Cell Mol Med 17(11):1494–1505

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Samuel CS, Zhao C, Bathgate RA, Du XJ, Summers RJ, Amento EP, Walker LL, McBurnie M, Zhao L, Tregear GW (2005) The relaxin gene-knockout mouse: a model of progressive fibrosis. Ann N Y Acad Sci 1041:173–181

    Article  CAS  PubMed  Google Scholar 

  71. Samuel CS, Cendrawan S, Gao XM, Ming Z, Zhao C, Kiriazis H, Xu Q, Tregear GW, Bathgate RA, Du XJ (2011) Relaxin remodels fibrotic healing following myocardial infarction. Lab Invest 91(5):675–690

    Article  CAS  PubMed  Google Scholar 

  72. Sasser JM, Molnar M, Baylis C (2011) Relaxin ameliorates hypertension and increases nitric oxide metabolite excretion in angiotensin II but not N(omega)-nitro-l-arginine methyl ester hypertensive rats. Hypertension 58(2):197–204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Segal MS, Sautina L, Li S, Diao Y, Agoulnik AI, Kielczewski J, McGuane JT, Grant MB, Conrad KP (2012) Relaxin increases human endothelial progenitor cell NO and migration and vasculogenesis in mice. Blood 119(2):629–636

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Danielson LA, Sherwood OD, Conrad KP (1999) Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 103(4):525–533

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Danielson LA, Welford A, Harris A (2006) Relaxin improves renal function and histology in aging Munich Wistar rats. J Am Soc Nephrol 17(5):1325–1333

    Article  CAS  PubMed  Google Scholar 

  76. Smith MC, Danielson LA, Conrad KP, Davison JM (2006) Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers. J Am Soc Nephrol 17(11):3192–3197

    Article  CAS  PubMed  Google Scholar 

  77. Voors AA, Dahlke M, Meyer S, Stepinska J, Gottlieb SS, Jones A, Zhang Y, Laurent D, Slart RH, Navis GJ (2014) Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study. Circ Heart Fail 7:994–1002

    Article  CAS  PubMed  Google Scholar 

  78. Conrad KP, Shroff SG (2011) Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep 13(6):409–420

    Article  CAS  PubMed  Google Scholar 

  79. Dschietzig T, Teichman S, Unemori E, Wood S, Boehmer J, Richter C, Baumann G, Stangl K (2009) Intravenous recombinant human relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial. J Card Fail 15(3):182–190

    Article  CAS  PubMed  Google Scholar 

  80. Ponikowski P, Mitrovic V, Ruda M, Fernandez A, Voors AA, Vishnevsky A, Cotter G, Milo O, Laessing U, Zhang Y, Dahlke M, Zymlinski R, Metra M (2014) A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure. Eur Heart J 35(7):431–441

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Ponikowski P, Unemori E, Voors AA, Adams KF Jr, Dorobantu MI, Grinfeld LR, Jondeau G, Marmor A, Masip J, Pang PS, Werdan K, Teichman SL, Trapani A, Bush CA, Saini R, Schumacher C, Severin TM, Metra M (2013) Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 381(9860):29–39

    Article  CAS  PubMed  Google Scholar 

  82. Metra M, Ponikowski P, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, Hua TA, Severin T, Unemori E, Voors AA, Teerlink JR (2013) Effects of serelaxin in subgroups of patients with acute heart failure: results from RELAX-AHF. Eur Heart J 34(40):3128–3136

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Novartis Pharmaceuticals (2015). http://www.novartis.com/downloads/newsroom/corporate-fact-sheet/2a_Pharmaceuticals_EN.pdf. Accessed 19 Feb 2015

  84. Clinicaltrials.gov. NCT01870778 (2015) Efficacy, safety and tolerability of serelaxin when added to standard therapy in AHF. https://clinicaltrials.gov/ct2/show/NCT01870778. Accessed 19 Feb 2015

  85. Clinicaltrials.gov. NCT02064868 (2014) Effect of serelaxin versus standard of care in acute heart failure (AHF) patients (RELAX-AHF-EU) http://www.clinicaltrials.gov/ct2/show/NCT02064868?term=NCT02064868&rank=1. Accessed 19 Feb 2015

  86. Clinicaltrials.gov. NCT02007720 (2014) Efficacy, Safety and tolerability of sexelaxin when added to standard therapy in AHF. http://www.clinicaltrials.gov/ct2/show/NCT02007720?term=NCT02007720&rank=1. Accessed 19 Feb 2015

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Acknowledgments

We thank Minal Kotecha of CircleScience, an Ashfield Company, part of UDG Healthcare plc, for providing writing assistance, which was funded by Novartis Pharma AG, Basel, Switzerland. The authors did not receive any funding grants to support the development of this manuscript.

Conflict of interest

Roland E Schmieder: Received Speakers Bureau honoraria and is an advisory board member for Novartis. His University Hospital has also received grants from Novartis. Veselin Mitrovic: Employed by Kerckhoff-Klinik Forschungsgesellschaft mbH, has received grant/research support from Bayer and Novartis; honoraria from Bayer, Novartis and GlaxoSmithKline and is a consultant for Cardiorentis and a Board Member for Daichi Sankyo. Christian Hengstenberg: Received speakers bureau honoraria from AstraZeneca, Boehringer, Edwards, Novartis, and Symetis; Advisory Board member for Novartis.

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Authors and Affiliations

  1. Department of Nephrology and Hypertension, University Hospital of the University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany

    Roland E. Schmieder

  2. Kerckhoff-Klinik, Bad Nauheim, Germany

    Veselin Mitrovic

  3. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

    Christian Hengstenberg

  4. DZHK (German Centre for Cardiovascular Research), partnersite Munich Heart Alliance, Munich, Germany

    Christian Hengstenberg

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  1. Roland E. Schmieder
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  2. Veselin Mitrovic
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  3. Christian Hengstenberg
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Correspondence to Roland E. Schmieder.

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Schmieder, R.E., Mitrovic, V. & Hengstenberg, C. Renal impairment and worsening of renal function in acute heart failure: can new therapies help? The potential role of serelaxin. Clin Res Cardiol 104, 621–631 (2015). https://doi.org/10.1007/s00392-015-0839-y

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