Cardiorenal syndrome: issues of pathogenesis and diagnosis

The combined disorders in a human’s body related to functioning of such vital organs as heart and kidney with development and progress of concomitant hemodynamic disorders is called as cardiorenal syndrome. In early studies, insufficient cardiac pump function with subsequent renal dysfunction was considered as the main pathophysiologic component of cardiorenal syndrome. At the current stage of studying this syndrome, there is a greater understanding of the mechanisms of its development, however, there are also insufficiently studied aspects, since multiple systems of the human body can influence its occurrence and course.

This review aims to analyze scientific publications covering the studied etiological factors, pathophysiological mechanisms, and pathogenesis of type 2 cardiorenal syndrome, as well as current issues in diagnosis and treatment of chronic kidney disease associated with chronic heart failure.

The objective of the review is to analyze current data on pathogenetic mechanisms, diagnostic approaches and treatment strategies for type 2 cardiorenal syndrome, focusing on novel biomarkers and therapeutic methods.

The literature review was conducted according to:

1. Systematic analysis of publications in international databases (PubMed, Scopus, Web of Science).
2. Priority to clinical guidelines and meta-analyses.
3. Critical evaluation of evidence base.
4. Emphasis on studies with clear diagnostic criteria of type 2 cardiorenal syndrome.
5. Inclusion of both fundamental and clinical research

The analysis covers publications from 2018-2023, including some seminal earlier works that have fundamental importance for understanding of pathogenesis. Special attention was given to studies conducted for the period of 2020-2023 and reflecting modern diagnostic and therapeutic advances.

1. Cardio-Renal Connections in Heart Failure and Cardiovascular, 2019. [Electroniic resource] National Heart, Lung, and Blood Institute. [date of access 2024 October 13]. Available from: https://www.nhlbi.nih.gov/events/2004/cardio-renal-connections-heart-failure-and-cardiovascular-diseasej

2. Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, et al. Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement from the American Heart Association. Circulation. 2019;139:840-878. DOI: https://doi.org/10.1161/CIR.0000000000000664

3. Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, Gottlieb SS, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol. 2004;43:61-67. DOI: https://doi.org/10.1016/j.jacc.2003.07.031

4. House AA, Anand I, Bellomo R. Definition and classification of Cardio-Renal Syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrology Dialysis Transplantation. 2010;25 (5):1416-1420. DOI: https://doi.org/10.1093/ndt/gfq136

5. Ronco C, Bellomo R, McCullough P. Cardiorenal Syndrome: Pathophysiology and Recent Advances in Treatment. Nature Reviews Nephrology. 2023;19(5):311-325.

6. Sudzhaeva OA. Diagnostics of kidney damage in cardiac and cardiac surgical patients: current state of the problem. General Medicine. 2021;1(76):56-65. (In Russ.).

7. Spencer LJ, Degu A, Kalkidan HA, Solomon MA, Cristiana A, Nooshin A, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990– 2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. DOI: https://doi.org/10.1016/S0140-6736(18)32279-7

8. De Vecchis R, Baldi C. Cardiorenal syndrome type 2: from diagnosis to optimal management. Ther Clin Risk Manag. 2014;10:949-961. DOI: https://doi.org/10.2147/TCRM.S63255

9. Braam B, Cupples WA, Joles JA, Gaillard C. Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure. Heart Fail Rev. 2012;17(2):161-175. DOI: https://doi.org/10.1007/s10741-011-9246-2

10. Iyngkaran P, Schneider H, Devarajan P, Anavekar N, Krum H, Ronco C. Cardio-renal syndrome: new perspective in diagnostics. Semin Nephrol. 2012;32(1):3-17. DOI: https://doi.org/10.1016/j.semnephrol.2011.11.002

11. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355(3):260-269. DOI: https://doi.org/10.1056/nejmoa051530

12. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, et al. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol. 2008;51(13):1268-1274. DOI: https://doi.org/10.1016/j.jacc.2007.08.072

13. Melenovsky V, Cervenka L, Viklicky O, Franekova J, Havlenova T, Behounek M, et al. Kidney Response to Heart Failure: Proteomic Analysis of Cardiorenal Syndrome. Kidney Blood Press Res. 2018;43(5):1437-1450. DOI: https://doi.org/10.1159/000493657

14. Ostraga M, Gierlotka MJ, Stonka G, Nadziakiewicz P, Gasior M. Clinical characteristics, treatment, and prognosis of patients with ischemic and nonischemic acute severe heart failure. Analysis of data from the COMMIT-AHF registry. Pol Arch Intern Med. 2017;127(5):328-335. DOI: https://doi.org/10.20452/pamw.3996

15. Bishara B, Abu-Saleh N, Awad H, Goltsman I, Ramadan R, Khamaysi I, et al. Pneumoperitoneum aggravates renal function in cases of decompensated but not compensated experimental congestive heart failure: role of nitric oxide. J Urol. 2011;186(1):310-317. DOI: https://doi.org/10.1016/j.juro.2011.03.040

16. Mohmand H, Goldfarb S. Renal dysfunction associated with intra-abdominal hypertension and the abdominal compartment syndrome. J Am Soc Nephrol. 2011;22(4):615-621. DOI: https://doi.org/10.1681/asn.2010121222

17. Lazzarini V, Bettari L, Bugatti S, Carubelli V, Lombardi C, et al. Can we prevent or treat renal dysfunction in acute heart failure? Heart Fail Rev. 2012;17(2):291-303. DOI: https://doi.org/10.1007/s10741-011-9253-3

18. Medvedeva EA, Shilyaeva NV, Iskhakov EN, Schukin YuV. Cardiorenal syndrome in chronic heart failure: pathogenesis, diagnostics, prognosis and opportunities for treatment. Russian Journal of Cardiology. 2017;(1):136-141. (In Russ.).

19. Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, et al. Spironolactone to increase natriuresis in congestive heart failure with cardiorenal syndrome. Acta Cardiol. 2019;74(2):100-107. DOI: https://doi.org/10.1080/00015385.2018.1455947

20. Reznik EV, Nikitin IG. Cardiorenal syndrome in patients with chronic heart failure as a stage of the cardiorenal continuum (Part I): definition, classification, pathogenesis, diagnosis, epidemiology. The Russian Archives of Internal Medicine. 2019;1(45):5-22. (In Russ.).

21. Raina R, Nair N, Chakraborty R, Nemer L, Dasgupta R, Varian K An Update on the Pathophysiology and Treatment of Cardiorenal Syndrome. Cardiology Research. 2020;11(2):76-88. DOI: https://doi.org/10.14740/cr955

22. Pullen AB, Jadapalli JK, Rhourri-Frih B, et al. Re-evaluating the causes and consequences of non-resolving inflammation in chronic cardiovascular disease. Heart Fail Rev. 2020; 25:381-391. DOI: https://doi.org/10.1007/s10741-019-09817-x

23. Kumar U, Wettersten N, Garimella PS. Cardiorenal Syndrome: Pathophysiology. Cardiol Clin. 2019;37(3):251-265. DOI: https://doi.org/10.1016/j.ccl.2019.04.001

24. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024 Apr;105(4S):S117-S314.

25. Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B, Michelson EL, et al. CHARM Investigators and Committees. Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet. 2009;15:543-550. DOI: https://doi.org/10.1016/s0140-6736(09)61378-7

26. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20(8):1813-1821. DOI: https://doi.org/10.1681/asn.2008121270

27. Astor BC, Hallan SI, Miller ER, Yeung E, Coresh J. Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population. Am J Epidemiol. 2008;167(10):1226-1234. DOI: https://doi.org/10.1093/aje/kwn033

28. Dutta A, Saha S, Bahl A, Mittal A, Basak T. A comprehensive review of acute cardio-renal syndrome: need for novel biomarkers. Front Pharmacol. 2023 May 23;14:1152055. DOI: https://doi.org/10.3389/fphar.2023.1152055

29. Amsalem Y, Garty M, Schwartz R, Sandach A, Behar S, Caspi A, et al. Prevalence and significance of unrecognized renal insufficiency in patients with heart failure. Eur Heart J. 2008;29(8):1029-1036. DOI: https://doi.org/10.1093/eurheartj/ehn102

30. Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol. 2009;20(3):672-679. DOI: https://doi.org/10.1681/asn.2008070669

31. Melnik AA. Cardiorenal syndrome: diagnostics and treatment. Kidneys. 2017;1(6):2-14. (In Russ.).

32. Makhieva AT, Mambetova AM. Fetuin A – a marker for assessing the risk of developing mineral-bone disorders and the formation of cardiovascular calcification in patients with chronic kidney disease stage 5D. Nephrology. 2022;26(4):105-109. (In Russ.). DOI: https://doi.org/10.36485/1561-6274-2022-26-4-105-109

33. Hatamizadeh P, Fonarow GC, Budoff MJ, Darabian S, Kovesdy CP, Kalantar-Zadeh K. Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol. 2013;9(2):99-111. DOI: https://doi.org/10.1038/nrneph.2012.279

34. Takada T, Kodera Y, Matsubara M, Kawashima Y, Maeda T. Serum monomeric α2-macroglobulin as a clinical biomarker in diabetes. Atherosclerosis. 2013;228:270-276.

35. Annapoorani P, Dhandapany PS, Sadayappan S, Ramasamy S, Rathinavel A. Cardiac isoform of alpha-2 macroglobulin — a new biomarker for myocardial infarcted diabetic patients. Atherosclerosis. 2006;186:173-176.

36. McCallum W, Testani JM. Updates in Cardiorenal Syndrome. Med Clin North Am. 2023 Jul;107(4):763-780. DOI: https://doi.org/10.1016/j.mcna.2023.03.011

37. Zyryanov SK, Ushkalova EA. Comparative pharmacoeconomic analysis of medication for patients after acute decompensated heart failure. Russian Journal of Cardiology. 2020;25(1):65-71. (In Russ.) DOI: https://doi.org/10.15829/1560-4071-2020-1-3690

38. Mareev VYu, Fomin IV, Ageev FT, Begrambekova YuL, Vasyuk YuA, Garganeeva AA, et al. Russian Heart Failure Society, Russian Society of Cardiology. Russian scientific medical society of internal medicine guidelines for heart failure: chronic (CHF) and acute decompensated (ADHF). Diagnosis, prevention and treatment. Kardiologiia. 2018;58(S6):8-158. (In Russ.). DOI: https://doi.org/10.18087/cardio.2475

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40. Jujo K, Saito K, Ishida I. Diuretic Strategies in Cardiorenal Syndrome: A Systematic Review. ESC Heart Failure. 2023;10(2):789-802.

41. Heine GH, Rogacev KS. Pharmacologic treatment of heart failure with reduced ejection fraction in chronic kidney disease. Deutsche medizinische Wochenschrift. 2019;144(24):1714-1720. DOI: https://doi.org/10.1055/a-0887-0792

42. Chitturi C, Novak JE. Diuretics in the Management of Cardiorenal Syndrome. Adv Chronic Kidney Dis. 2018;25(5):425-433. DOI: https://doi.org/10.1053/j.ackd.2018.08.008

43. Brandenburg V, Heine GH. The Cardiorenal Syndrome. Deutsche medizinische Wochenschrift. 2019;144(6):382-386. DOI: https://doi.org/10.1055/a-0661-4456

44. Wettersten N, Maisel AS, Cruz DN. Toward Precision Medicine in the Cardiorenal Syndrome. Adv Chronic Kidney Dis. 2018 Sep;25(5):418-424. DOI: https://doi.org/10.1053/j.ackd.2018.08.017