J Korean Med Assoc.  2020 Jan;63(1):20-29. 10.5124/jkma.2020.63.1.20.

Cardiorenal syndrome

• Kim MG

• KMID: 2467982
• DOI: http://doi.org/10.5124/jkma.2020.63.1.20

Abstract

To maintain homeostasis of the cardiovascular system, the heart and kidney act bidirectionally. Therefore, acute or chronic dysfunction of one organ can cause dysfunction in the other. This phenomenon is characterized as cardiorenal syndrome (CRS). Concurrent dysfunction of the heart and kidney adversely affects one another and eventually worsens patient outcomes through a vicious cycle. Although a CRS classification system has been proposed, the underlying pathophysiology is multifactorial and clinical access continues to be difficult. Although several therapies, including agents that target the renin-angiotensin-aldosterone system, have been utilized, there is not enough evidence to demonstrate their effectiveness for CRS. Thus, more effort should be made to optimize the diagnosis and treatment strategies for CRS patients. This review will introduce CRS as it is currently understood, discuss the pathophysiology, and examine management strategies.

Keyword

Cardio-renal syndrome; Heart failure; Acute kidney injury; Chronic renal insufficiency

MeSH Terms

Acute Kidney Injury
Cardio-Renal Syndrome*
Cardiovascular System
Classification
Diagnosis
Heart
Heart Failure
Homeostasis
Humans
Kidney
Renal Insufficiency, Chronic
Renin-Angiotensin System

Reference

1. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, Berkowitz RL, Galvao M, Horton DP. ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005; 149:209–216.

2. Bagshaw SM, Cruz DN, Aspromonte N, Daliento L, Ronco F, Sheinfeld G, Anker SD, Anand I, Bellomo R, Berl T, Bobek I, Davenport A, Haapio M, Hillege H, House A, Katz N, Maisel A, Mankad S, McCullough P, Mebazaa A, Palazzuoli A, Ponikowski P, Shaw A, Soni S, Vescovo G, Zamperetti N, Zanco P, Ronco C. Acute Dialysis Quality Initiative Consensus Group. Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant. 2010; 25:1406–1416.

3. Shin JH, Kang KW, Kim JG, Lee SJ. Concurrent renal dysfunction with ischemic heart disease is an important determinant for cardiac and cerebrovascular mortality in patients on chronic digoxin therapy for atrial fibrillation. Kidney Res Clin Pract. 2018; 37:130–137.

4. National Heart, Lung and Blood Institute. Cardio-renal connections in heart failure and cardiovascular disease [Internet]. Bethesda: National Heart, Lung and Blood Institute;2004. cited 2019 Dec 6. Available from: https://www.nhlbi.nih.gov/events/2004/cardio-renal-connections-heart-failure-and-cardiovascular-disease.

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

6. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House AA, 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. Acute Dialysis Quality Initiative (ADQI) consensus group. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J. 2010; 31:703–711.

7. Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TD, Cleland JG, van Veldhuisen DJ, Hillege HL. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail. 2007; 13:599–608.

8. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999; 341:577–585.

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

10. 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; 53:582–588.

11. Mullens W, Abrahams Z, Skouri HN, Francis GS, Taylor DO, Starling RC, Paganini E, Tang WH. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol. 2008; 51:300–306.

12. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med. 2007; 357:797–805.

13. Wu VC, Wu CH, Huang TM, Wang CY, Lai CF, Shiao CC, Chang CH, Lin SL, Chen YY, Chen YM, Chu TS, Chiang WC, Wu KD, Tsai PR, Chen L, Ko WJ. NSARF Group. Long-term risk of coronary events after AKI. J Am Soc Nephrol. 2014; 25:595–605.

14. Garg AX, Clark WF, Haynes RB, House AA. Moderate renal insufficiency and the risk of cardiovascular mortality: results from the NHANES I. Kidney Int. 2002; 61:1486–1494.

15. Cunningham PN, Dyanov HM, Park P, Wang J, Newell KA, Quigg RJ. Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J Immunol. 2002; 168:5817–5823.

16. Kumar A, Paladugu B, Mensing J, Kumar A, Parrillo JE. Nitric oxide-dependent and -independent mechanisms are involved in TNF-alpha -induced depression of cardiac myo-cyte contractility. Am J Physiol Regul Integr Comp Physiol. 2007; 292:R1900–R1906.

17. Lelubre C, Vincent JL. Mechanisms and treatment of organ failure in sepsis. Nat Rev Nephrol. 2018; 14:417–427.

18. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017; 43:304–377.

19. Cho W, Hwang TY, Choi YK, Yang JH, Kim MG, Jo SK, Cho WY, Oh SW. Diastolic dysfunction and acute kidney injury in elderly patients with femoral neck fracture. Kidney Res Clin Pract. 2019; 38:33–41.

20. Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, Lerma EV, Mezue K, Molitch M, Mullens W, Ronco C, Tang WHW, McCullough PA. American Heart Association Council on the Kidney in Cardiovascular Disease and Council on Clinical Cardiology. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scienti-fic statement from the American Heart Association. Circulation. 2019; 139:e840–e878.

21. Hitomi H, Kiyomoto H, Nishiyama A. Angiotensin II and oxidative stress. Curr Opin Cardiol. 2007; 22:311–315.

22. Zhong J, Guo D, Chen CB, Wang W, Schuster M, Loibner H, Penninger JM, Scholey JW, Kassiri Z, Oudit GY. Prevention of angiotensin II-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2. Hypertension. 2011; 57:314–322.

23. Searles CD. The nitric oxide pathway and oxidative stress in heart failure. Congest Heart Fail. 2002; 8:142–147.

24. Forstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res. 2017; 120:713–735.

25. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation. 2001; 103:2055–2059.

26. Kelly KJ. Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol. 2003; 14:1549–1558.

27. Cho E, Kim M, Ko YS, Lee HY, Song M, Kim MG, Kim HK, Cho WY, Jo SK. Role of inflammation in the pathogenesis of cardiorenal syndrome in a rat myocardial infarction model. Nephrol Dial Transplant. 2013; 28:2766–2778.

28. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011; 121:4393–4408.

29. Faris R, Flather MD, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure. Cochrane Database Syst Rev. 2006; (1):CD003838.

30. Felker GM, O'Connor CM, Braunwald E. Heart Failure Clini-cal Research Network Investigators. Loop diuretics in acute decompensated heart failure: necessary? Evil? A necessary evil? Circ Heart Fail. 2009; 2:56–62.

31. Gilotra NA, Princewill O, Marino B, Okwuosa IS, Chasler J, Almansa J, Cummings A, Rhodes P, Chambers J, Cuomo K, Russell SD. Efficacy of intravenous furosemide versus a novel, ph-neutral furosemide formulation administered subcutaneously in outpatients with worsening heart failure. JACC Heart Fail. 2018; 6:65–70.

32. Sica DA. Pharmacotherapy in congestive heart failure: drug absorption in the management of congestive heart failure: loop diuretics. Congest Heart Fail. 2003; 9:287–292.

33. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM. NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011; 364:797–805.

34. 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. Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012; 367:2296–2304.

35. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, Jaski BE, Fang JC, Feller ED, Haas GJ, Anderson AS, Schollmeyer MP, Sobotka PA. UNLOAD Trial Investigators. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007; 49:675–683.

36. Felker GM, Mentz RJ, Cole RT, Adams KF, Egnaczyk GF, Fiuzat M, Patel CB, Echols M, Khouri MG, Tauras JM, Gupta D, Monds P, Roberts R, O'Connor CM. Efficacy and safety of tolvaptan in patients hospitalized with acute heart failure. J Am Coll Cardiol. 2017; 69:1399–1406.

37. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C. Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007; 297:1319–1331.

38. Ahmed A, Fonarow GC, Zhang Y, Sanders PW, Allman RM, Arnett DK, Feller MA, Love TE, Aban IB, Levesque R, Ekundayo OJ, Dell'Italia LJ, Bakris GL, Rich MW. Reninangiotensin inhibition in systolic heart failure and chronic kidney disease. Am J Med. 2012; 125:399–410.

39. SOLVD Investigators. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991; 325:293–302.

40. Bohm M, Pogue J, Kindermann I, Poss J, Koon T, Yusuf S. Effect of comorbidities on outcomes and angiotensin converting enzyme inhibitor effects in patients with predominantly left ventricular dysfunction and heart failure. Eur J Heart Fail. 2014; 16:325–333.

41. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000; 160:685–693.

42. Brisco MA, Zile MR, Hanberg JS, Wilson FP, Parikh CR, Coca SG, Tang WH, Testani JM. Relevance of changes in serum creatinine during a heart failure trial of decongestive strategies: insights from the DOSE trial. J Card Fail. 2016; 22:753–760.

43. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail. 2011; 4:685–691.

44. Beldhuis IE, Streng KW, Ter Maaten JM, Voors AA, van der Meer P, Rossignol P, McMurray JJ, Damman K. Reninangiotensin system inhibition, worsening renal function, and outcome in heart failure patients with reduced and preserved ejection fraction: a meta-analysis of published study data. Circ Heart Fail. 2017; 10:e003588.

45. Solomon SD, Claggett B, McMurray JJ, Hernandez AF, Fonarow GC. Combined neprilysin and renin-angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis. Eur J Heart Fail. 2016; 18:1238–1243.

46. Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Swedberg K, Zile MR, Packer M, Desai AS, Solomon SD, McMurray JJV. Renal Effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail. 2018; 6:489–498.

47. Haynes R, Judge PK, Staplin N, Herrington WG, Storey BC, Bethel A, Bowman L, Brunskill N, Cockwell P, Hill M, Kalra PA, McMurray JJV, Taal M, Wheeler DC, Landray MJ, Baigent C. Effects of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease. Circulation. 2018; 138:1505–1514.

48. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348:1309–1321.

49. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341:709–717.

50. Barrera-Chimal J, Pérez-Villalva R, Rodríguez-Romo R, Reyna J, Uribe N, Gamba G, Bobadilla NA. Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury. Kidney Int. 2013; 83:93–103.

51. Agarwal R, Rossignol P, Romero A, Garza D, Mayo MR, Warren S, Ma J, White WB, Williams B. Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2019; 394:1540–1550.

52. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, Kolkhof P, Joseph A, Pieper A, Kimmeskamp-Kirschbaum N, Ruilope LM. Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015; 314:884–894.

53. Cohen-Solal A, Kotecha D, van Veldhuisen DJ, Babalis D, Bohm M, Coats AJ, Roughton M, Poole-Wilson P, Tavazzi L, Flather M. SENIORS Investigators. Efficacy and safety of nebivolol in elderly heart failure patients with impaired renal function: insights from the SENIORS trial. Eur J Heart Fail. 2009; 11:872–880.

54. Ghali JK, Wikstrand J, Van Veldhuisen DJ, Fagerberg B, Goldstein S, Hjalmarson A, Johansson P, Kjekshus J, Ohlsson L, Samuelsson O, Waagstein F, Wedel H. MERIT-HF Study Group. The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF). J Card Fail. 2009; 15:310–318.

55. Castagno D, Jhund PS, McMurray JJ, Lewsey JD, Erdmann E, Zannad F, Remme WJ, Lopez-Sendon JL, Lechat P, Follath F, Höglund C, Mareev V, Sadowski Z, Seabra-Gomes RJ, Dargie HJ. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial. Eur J Heart Fail. 2010; 12:607–616.

56. Badve SV, Roberts MA, Hawley CM, Cass A, Garg AX, Krum H, Tonkin A, Perkovic V. Effects of beta-adrenergic antagonists in patients with chronic kidney disease: a systematic review and meta-analysis. J Am Coll Cardiol. 2011; 58:1152–1161.

57. 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, Corbalán 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, Méndez 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. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011; 365:32–43.

58. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128.

59. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–657.