Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 6/2013

Open Access 01-12-2013 | REVIEW ARTICLE

Renal Effects of Levosimendan: A Consensus Report

Authors: Mehmet B. Yilmaz, Elena Grossini, José C. Silva Cardoso, István Édes, Francesco Fedele, Piero Pollesello, Matti Kivikko, Veli-Pekka Harjola, Julia Hasslacher, Alexandre Mebazaa, Andrea Morelli, Jos le Noble, Anders Oldner, Ignacio Oulego Erroz, John T. Parissis, Alexander Parkhomenko, Gerhard Poelzl, Sebastian Rehberg, Sven-Erik Ricksten, Luís M. Rodríguez Fernández, Markku Salmenperä, Mervyn Singer, Sascha Treskatsch, Bojan Vrtovec, Gerhard Wikström

Published in: Cardiovascular Drugs and Therapy | Issue 6/2013

Login to get access

Abstract

Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS).
Literature
1.
Metra M, Cotter G, Gheorghiade M, Dei Cas L, Voors AA. The role of the kidney in heart failure. Eur Heart J. 2012;33:2135–42.PubMedCrossRef
2.
Kallel S, Triki Z, Abdenadher M, Frikha I, Jemel A. Karoui a [acute renal failure after cardiac surgery: evaluation of the RIFLE criteria]. Nephrol Ther. 2013;9:108–14.PubMedCrossRef
3.
Oppert M, Engel C, Brunkhorst F-M, Bogatsch H, Reinhart K, Frei U, et al. Acute renal failure in patients with severe sepsis and septic shock–a significant independent risk factor for mortality: results from the German Prevalence Study. Nephrol Dial Transplant. 2008;23:904–9.PubMedCrossRef
4.
Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJV, Yusuf S, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671–8.PubMedCrossRef
5.
Hillege HL, Girbes AR, de Kam PJ, Boomsma F, de Zeeuw D, Charlesworth A, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102:203–10.PubMedCrossRef
6.
Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159:82–7.PubMedCrossRef
7.
Landoni G, Mizzi A, Biondi-Zoccai G, Bruno G, Bignami E, Corno L, et al. Reducing mortality in cardiac surgery with levosimendan: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth. 2010;24:51–7.PubMedCrossRef
8.
Nieminen MS, Pollesello P, Vajda G, Papp Z. Effects of levosimendan on the energy balance: preclinical and clinical evidence. J Cardiovasc Pharmacol. 2009;53:302–10.PubMedCrossRef
9.
Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107:81–6.PubMedCrossRef
10.
Pagel PS, Hettrick DA, Warltier DC. Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol. 1996;119:609–15.PubMedCrossRef
11.
Faivre V, Kaskos H, Callebert J, Losser M-R, Milliez P, Bonnin P, et al. Cardiac and renal effects of levosimendan, arginine vasopressin, and norepinephrine in lipopolysaccharide-treated rabbits. Anesthesiology. 2005;103:514–21.PubMedCrossRef
12.
Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanecek M. Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med. 2001;29:2185–93.PubMedCrossRef
13.
Grossini E, Molinari C, Pollesello P, Bellomo G, Valente G, Mary D, et al. Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs. J Pharmacol Exp Ther. 2012;342:376–88.PubMedCrossRef
14.
Zager RA, Johnson AC, Lund S, Hanson SY, Abrass CK. Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Renal Physiol. 2006;290:F1453–62.PubMedCrossRef
15.
Rehberg S, Ertmer C, Vincent J-L, Spiegel H-U, Kohler G, Erren M, et al. Effects of combined arginine vasopressin and levosimendan on organ function in ovine septic shock. Crit Care Med. 2010;38:2016–23.PubMed
16.
Neary P, Redmond HP. Ischemia-reperfusion injury and the systemic inflammatory response syndrome. In: Grace PA, Mathie RT, editors. Ischemia-reperfusion injury. London: Blackwell Science; 1999. p. 123–36.
17.
Sucu N, Unlu A, Tamer L, Aytacoglu B, Coskun B, Bilgin R, et al. Effects of trimetazidine on tissue damage in kidney after hindlimb ischemia-reperfusion. Pharmacol Res. 2002;46:345–9.PubMedCrossRef
18.
Caimmi PP, Kapetanakis EI, Beggino C, Molinari C, Giustini G, Crosio E, et al. Management of acute cardiac failure by intracoronary administration of levosimendan. J Cardiovasc Pharmacol. 2011;58:246–53.PubMedCrossRef
19.
Kersten JR, Montgomery MW, Pagel PS, Warltier DC. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg. 2000;90:5–11.PubMedCrossRef
20.
Soeding PF, Crack PJ, Wright CE, Angus JA, Royse CF. Levosimendan preserves the contractile responsiveness of hypoxic human myocardium via mitochondrial K(ATP) channel and potential pERK 1/2 activation. Eur J Pharmacol. 2011;655:59–66.PubMedCrossRef
21.
Avgeropoulou C, Andreadou I, Markantonis-Kyroudis S, Demopoulou M, Missovoulos P, Androulakis A, et al. The Ca2+−sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine. Eur J Heart Fail. 2005;7:882–7.PubMedCrossRef
22.
Uberti F, Caimmi PP, Molinari C, Mary D, Vacca G, Grossini E. Levosimendan modulates programmed forms of cell death through K(ATP) channels and nitric oxide. J Cardiovasc Pharmacol. 2011;57:246–58.PubMedCrossRef
23.
Yakut N, Yasa H, Bahriye Lafci B, Ortac R, Tulukoglu E, Aksun M, et al. The influence of levosimendan and iloprost on renal ischemia-reperfusion: an experimental study. Interact Cardiovasc Thorac Surg. 2008;7:235–9.PubMedCrossRef
24.
Louhelainen M, Merasto S, Finckenberg P, Vahtola E, Kaheinen P, Leskinen H, et al. Effects of calcium sensitizer OR-1986 on a cardiovascular mortality and myocardial remodelling in hypertensive Dahl/Rapp rats. J Physiol Pharmacol. 2009;60:41–7.PubMed
25.
Follath F, Cleland JGF, Just H, Papp JGY, Scholz H, Peuhkurinen K, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360:196–202.PubMedCrossRef
26.
Silva-Cardoso J, Ferrreira J, Oliveira-Soares A, Martins-de-Campos J, Fonseca C, Lousada N, et al. Effectiveness and safety of levosimendan in clinical practice. Rev Port Cardiol. 2009;28:143–53.PubMed
27.
Zemljic G, Bunc M, Yazdanbakhsh AP, Vrtovec B. Levosimendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. J Card Fail. 2007;13:417–21.PubMedCrossRef
28.
Yilmaz MB, Yalta K, Yontar C, Karadas F, Erdem A, Turgut OO, et al. Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine. Cardiovasc Drugs Ther. 2007;21:431–5.PubMedCrossRef
29.
Yilmaz MB, Yontar C, Erdem A, Karadas F, Yalta K, Turgut OO, et al. Comparative effects of levosimendan and dobutamine on right ventricular function in patients with biventricular heart failure. Heart Vessels. 2009;24:16–21.PubMedCrossRef
30.
Zorlu A, Yucel H, Yontar OC, Karahan O, Tandogan I, Katrancioglu N, et al. Effect of levosimendan in patients with severe systolic heart failure and worsening renal function. Arq Bras Cardiol. 2012;98:537–43.PubMedCrossRef
31.
Caira C, Brasolin B, Maestrini V, Scardala R, Orvieto G, Mancone M, et al. 475 Effects of Levosimendan on renal function and renal hemodynamic parameters in patients with acute heart failure. Eur J Heart Fail Suppl. 2007;6:103.CrossRef
32.
Packer M, Colucci W, Fisher L, Massie WM, Teerlink JR, Young J, et al. For the REVIVE heart failure study group. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013;1:103–11.CrossRef
33.
Bragadottir G, Redfors B, Ricksten SE. Effects of levosimendan on renal blood flow, glomerular filtration rate, renal oxygen consumption and oxygenation after cardiac surgery: a randomized controlled study. Crit Care Med, In press.
34.
Eriksson HI, Jalonen JR, Heikkinen LO, Kivikko M, Laine M, Leino KA, et al. Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann Thorac Surg. 2009;87:448–54.PubMedCrossRef
35.
Ristikankare A, Poyhia R, Eriksson H, Valtonen M, Leino K, Salmenpera M. Effects of levosimendan on renal function in patients undergoing coronary artery surgery. J Cardiothorac Vasc Anesth. 2012;26:591–5.PubMedCrossRef
36.
Al-Shawaf E, Ayed A, Vislocky I, Radomir B, Dehrab N, Tarazi R. Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery. J Cardiothorac Vasc Anesth. 2006;20:353–7.PubMedCrossRef
37.
Alvarez J, Taboada M, Rodriguez J, Caruezo V, Bouzada M, Campana O, et al. [Hemodynamic effects of levosimendan following cardiac surgery]. Rev Esp Anestesiol Reanim. 2005;52:389–94.PubMed
38.
Barisin S, Husedzinovic I, Sonicki Z, Bradic N, Barisin A, Tonkovic D. Levosimendan in off-pump coronary artery bypass: a four-times masked controlled study. J Cardiovasc Pharmacol. 2004;44:703–8.PubMedCrossRef
39.
Levin RL, Degrange MA, Porcile R, Salvagio F, Blanco N, Botbol AL, et al. [The calcium sensitizer levosimendan gives superior results to dobutamine in postoperative low cardiac output syndrome]. Rev Esp Cardiol. 2008;61:471–9.PubMedCrossRef
40.
Morelli A, De Castro S, Teboul J-L, Singer M, Rocco M, Conti G, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31:638–44.PubMedCrossRef
41.
Morelli A, Ertmer C, Pietropaoli P, Westphal M. Reducing the risk of major elective non-cardiac surgery: is there a role for levosimendan in the preoperative optimization of cardiac function? Curr Drug Targets. 2009;10:863–71.PubMedCrossRef
42.
Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. 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. 2009;53:582–8.PubMedCrossRef
43.
Parissis JT, Paraskevaidis I, Bistola V, Farmakis D, Panou F, Kourea K, et al. Effects of levosimendan on right ventricular function in patients with advanced heart failure. Am J Cardiol. 2006;98:1489–92.PubMedCrossRef
44.
Poelzl G, Zwick RH, Grander W, Metzler B, Jonetzko P, Frick M, et al. Safety and effectiveness of levosimendan in patients with predominant right heart failure. Herz. 2008;33:368–73.PubMedCrossRef
45.
Russ MA, Prondzinsky R, Carter JM, Schlitt A, Ebelt H, Schmidt H, et al. Right ventricular function in myocardial infarction complicated by cardiogenic shock: improvement with levosimendan. Crit Care Med. 2009;37:3017–23.PubMedCrossRef
46.
Lorenz JN, Schnermann J, Brosius FC, Briggs JP, Furspan PB. Intracellular ATP can regulate afferent arteriolar tone via ATP-sensitive K+channels in the rabbit. J Clin Invest. 1992;90:733–40.PubMedCrossRef
47.
Redfors B, Bragadottir G, Sellgren J, Sward K, Ricksten SE. Dopamine increases renal oxygenation: a clinical study in post-cardiac surgery patients. Acta Anaesthesiol Scand. 2010;54:183–90.PubMedCrossRef
48.
Appel RG, Wang J, Simonson MS, Dunn MJ. A mechanism by which atrial natriuretic factor mediates its glomerular actions. Am J Physiol. 1986;251:1036–42.
49.
Morgan CJ, Gill PJ, Lam S, Joffe AR. Peri-operative interventions, but not inflammatory mediators, increase risk of acute kidney injury after cardiac surgery: a prospective cohort study. Intensive Care Med. 2013;39:934–41.PubMedCrossRef
50.
Gecit I, Kavak S, Yuksel MB, Basel H, Bektas H, Gumrukcuoglu HA et al. Effect of short-term treatment with levosimendan on oxidative stress in renal tissues of rats. Toxicol Ind Health. 2012.
51.
Chew MS, Hawthorne WJ, Bendall J, Whereat S, Huang S, Ting I, et al. No beneficial effects of levosimendan in acute porcine endotoxaemia. Acta Anaesthesiol Scand. 2011;55:851–61.PubMedCrossRef
52.
Hasslacher J, Bijuklic K, Bertocchi C, Kountchev J, Bellmann R, Dunzendorfer S, et al. Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: a prospective observational study. Crit Care. 2011;15:R166.PubMedCrossRef
Metadata
Title
Renal Effects of Levosimendan: A Consensus Report
Authors
Mehmet B. Yilmaz
Elena Grossini
José C. Silva Cardoso
István Édes
Francesco Fedele
Piero Pollesello
Matti Kivikko
Veli-Pekka Harjola
Julia Hasslacher
Alexandre Mebazaa
Andrea Morelli
Jos le Noble
Anders Oldner
Ignacio Oulego Erroz
John T. Parissis
Alexander Parkhomenko
Gerhard Poelzl
Sebastian Rehberg
Sven-Erik Ricksten
Luís M. Rodríguez Fernández
Markku Salmenperä
Mervyn Singer
Sascha Treskatsch
Bojan Vrtovec
Gerhard Wikström
Publication date
01-12-2013
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 6/2013
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-013-6485-6

Other articles of this Issue 6/2013

Cardiovascular Drugs and Therapy 6/2013 Go to the issue

ORIGINAL ARTICLE

Rationale and Design of a Randomized, Double-Blind, Placebo Controlled Multicenter Trial to Study Efficacy, Security, and Long Term Effects of Intermittent Repeated Levosimendan Administration in Patients with Advanced Heart Failure: LAICA study

REVIEW ARTICLE

Exercise-induced Myalgia may Limit the Cardiovascular Benefits of Statins

EDITORIAL

Pro-Inflammatory Role of Platelets in Hypertension-Mediated End-Organ Damage

ORIGINAL ARTICLE

Docosahexaenoic Acid Supplementation Alters Key Properties of Cardiac Mitochondria and Modestly Attenuates Development of Left Ventricular Dysfunction in Pressure Overload-Induced Heart Failure

ORIGINAL ARTICLE

Mechanistic Studies of AVE3085 Against Homocysteine in Endothelial Protection

ORIGINAL ARTICLE

Acute Intravenous Infusion of an Adenosine Regulating Agent Improves Left Ventricular Function in Dogs with Advanced Heart Failure

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits