Type 5 cardiorenal syndrome resuscitation and intensive care: A systematic review

Introduction. Type 5 Cardiorenal Syndrome (CRS-5) involves combined cardiac and renal dysfunction that occurs as part of a systemic process, mainly sepsis. Effective diagnosis and treatment of this condition in intensive care units presents continued challenges. Objective: To synthesize current evidence on the pathogenesis, diagnostic biomarkers, and therapeutic strategies for CRS-5 in critically ill adults.

Materials and methods. This systematic review was conducted in accordance with the PRISMA guidelines. A search was performed in the PubMed, Embase, and Scopus databases from 2016 to 2025. Included were studies describing the CRS-5 phenotype, the diagnostic accuracy of biomarkers (NGAL – Neutrophil Gelatinase-Associated Lipocalin, KIM-1 – Kidney Injury Molecule 1, CCL14 – Chemokine (C-C motif) ligand 14), hemodynamic parameters (Central Venous Pressure, VExUS – Venous Excess UltraSound), and treatment outcomes in adult patients in the intensive care unit. A total of 25 publications were included in the final analysis of the 40 selected studies.

Results. NGAL demonstrated high sensitivity (88%) but low specificity (47%) in sepsis. KIM-1 showed the highest diagnostic accuracy for acute kidney injury (AKI) with an Area Under Curve (AUC) of 0.93. CCL14 emerged as a promising predictor of persistent severe AKI (AUC 0.79). A 1 mmHg increase in central venous pressure was associated with a 6% higher risk of AKI (Odds Ratio 1.06). The VExUS score was significant in cardiac surgery (Hazard Ratio 3.69) but not universally applicable across all intensive care unit populations. Therapeutically, levosimendan increased GFR by 22% in heart failure patients but was ineffective in established AKI. Ultrafiltration, despite effective fluid removal, did not improve survival.

Conclusion. CRS-5 is an inflammatory-hemodynamic phenotype of critical illness. Integrating biomarkers of cellular stress (NGAL), structural damage (KIM-1), and indicators of venous stasis (central venous pressure, VExUS) into clinical algorithms holds the greatest potential for early risk stratification and the personalization of intensive care.

1. Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine C, Tang WHW, McCullough PA. Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association. Circulation. 2019;139(16):e840–e878. doi: 10.1161/CIR.0000000000000664

2. 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. Cardio-renal syndromes: report from the consensus conference of the Acute Dialysis Quality Initiative. Eur Heart J. 2010;31(6):703–711. doi: 10.1093/eurheartj/ehp507

3. Bagshaw SM, Langenberg C, Haase M, Wan L, May CN, Bellomo R. Urinary biomarkers in septic acute kidney injury. Intensive Care Med. 2007;33(7):1285–1296. doi: 10.1007/s00134007-0656-5

4. Chen JJ, Lee TH, Lee CC, Chang CH. Using lipocalin as a prognostic biomarker in acute kidney injury. Expert Rev Mol Diagn. 2021;21(6):537–551. doi: 10.1080/14737159.2021.1917384

5. Pan HC, Yang SY, Chiou TT, Shiao CC, Wu CH, Huang CT, Wang TJ, Chen JY, Liao HW, Chen SY, Huang TM, Yang YF, Lin HY, Chan MJ, Sun CY, Chen YT, Chen YC, Wu VC. Comparative accuracy of biomarkers for the prediction of hospital-acquired acute kidney injury: a systematic review and meta-analysis. Crit Care. 2022;26(1):349. doi: 10.1186/s13054022-04223-6

6. Shi K, Jiang W, Song L, Li X, Zhang C, Li L, Feng Y, Yang J, Wang T, Wang H, Zhou L, Yu J, Zheng R. Persistent acute kidney injury biomarkers: A systematic review and meta-analysis. Clin Chim Acta. 2025;564:119907. doi: 10.1016/j.cca.2024.119907

7. Beaubien-Souligny W, Rola P, Haycock K, Bouchard J, Lamarche Y, Spiegel R, Denault AY. Quantifying systemic congestion with Point-Of-Care ultrasound: development of the venous excess ultrasound grading system. Ultrasound J. 2020;12(1):16. doi: 10.1186/s13089-020-00163-w

8. Longino A, Martin K, Leyba K, Siegel G, Gill E, Douglas IS, Burke J. Correlation between the VExUS score and right atrial pressure: a pilot prospective observational study. Crit Care. 2023;27(1):205. doi: 10.1186/s13054-023-04471-0

9. Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogné W, Mullens W. Spironolactone to increase natriuresis in congestive heart failure with cardiorenal syndrome. Acta Cardiol. 2018;73(3):1–9. doi: 10.1080/00015385.2018.1455947

10. Grodin JL, Carter S, Bart BA, Goldsmith SR, Drazner MH, Tang WHW. Direct comparison of ultrafiltration to pharmacological decongestion in heart failure: a per-protocol analysis of CARRESS-HF. Eur J Heart Fail. 2018 Jul;20(7):1148–1156. doi: 10.1002/ejhf.1158

11. Premuzic V, Basic-Jukic N, Jelakovic B, Kes P. Continuous Veno-Venous Hemofiltration Improves Survival of Patients With Congestive Heart Failure and Cardiorenal Syndrome Compared to Slow Continuous Ultrafiltration. Ther Apher Dial. 2017;21(4):279–286. doi: 10.1111/1744-9987.12579

12. Rao VS, Ivey-Miranda JB, Cox ZL, Moreno-Villagomez J, Ramos-Mastache D, Neville D, Balkcom N, Asher JL, Bellumkonda L, Bigvava T, Shaburishvili T, Bartunek J, Wilson FP, Finkelstein F, Maulion C, Turner JM, Testani JM. Serial direct sodium removal in patients with heart failure and diuretic resistance. Eur J Heart Fail. 2024;26(5):1215–1228. doi: 10.1002/ejhf.3196

13. Lannemyr L, Ricksten SE, Rundqvist B, Andersson B, Bartfay SE, Ljungman C, Dahlberg P, Bergh N, Hjalmarsson C, Gilljam T, Bollano E, Karason K. Differential Effects of Levosimendan and Dobutamine on Glomerular Filtration Rate in Patients with Heart Failure and Renal Impairment: A Randomized Double-Blind Controlled Trial. J Am Heart Assoc. 2018;7(16):e008455. doi: 10.1161/JAHA.117.008455

14. Tholen M, Ricksten SE, Lannemyr L. Effects of levosimendan on renal blood flow and glomerular filtration in patients with acute kidney injury after cardiac surgery: a double blind, randomized placebo-controlled study. Crit Care. 2021;25(1):207. doi: 10.1186/s13054-021-03578-6

15. Musikatavorn K, Plitawanon P, Lumlertgul S, Narajeenron K, Rojanasarntikul D, Tarapan T, Saoraya J. Randomized Controlled Trial of Ultrasound-guided Fluid Resuscitation of SepsisInduced Hypoperfusion and Septic Shock. West J Emerg Med. 2021;22(2):369–378. doi: 10.5811/westjem.2020.11.48571

16. Ghosh S, Padhi R, Sahu S, Meher M, Jain P, Subudhi SK, Vihari J, Samal A, Sahu AK. Application of inferior vena cava guided fluid therapy in the management of septic shock. J Infect Dev Ctries. 2024;18(1):75–81. doi: 10.3855/jidc.18489

17. Chen CY, Zhou Y, Wang P, Qi EY, Gu WJ. Elevated central venous pressure is associated with increased mortality and acute kidney injury in critically ill patients: a meta-analysis. Crit Care. 2020;24(1):80. doi: 10.1186/s13054-020-2770-5

18. Kim S, Kim HJ, Ahn HS, Song JY, Um TH, Cho CR, Jung H, Koo HK, Park JH, Lee SS, Park HK. Is plasma NGAL a predictive biomarker for acute kidney injury in sepsis patients? A systematic review and meta-analysis. J Crit Care. 2016;33:171–176. doi: 10.1016/j.jcrc.2016.02.014.

19. Zhang A, Cai Y, Wang PF, Qu JN, Luo ZC, Chen XD, Huang B, Liu Y, Huang WQ, Wu J, Yin YH. Diagnosis and prognosis of neutrophil gelatinase-associated lipocalin for acute kidney injury with sepsis: a systematic review and meta-analysis. Crit Care. 2016 Feb 16;20:41. doi: 10.1186/s13054-016-1212-x

20. Dai X, Zeng Z, Fu C, Zhang S, Cai Y, Chen Z. Diagnostic value of neutrophil gelatinase-associated lipocalin, cystatin C, and soluble triggering receptor expressed on myeloid cells-1 in critically ill patients with sepsis-associated acute kidney injury. Crit Care. 2015 May 6;19(1):223. doi: 10.1186/s13054-015-0941-6

21. Xie Y, Huang P, Zhang J, Tian R, Jin W, Xie H, Du J, Zhou Z, Wang R. Biomarkers for the diagnosis of sepsis-associated acute kidney injury: systematic review and meta-analysis. Ann Palliat Med. 2021;10(4):4159–4173. doi: 10.21037/apm-20-1855

22. Bessière F, Khenifer S, Dubourg J, Durieu I, Lega JC. Prognostic value of troponins in sepsis: a meta-analysis. Intensive Care Med. 2013;39(7):1181–1189. doi: 10.1007/s00134-013-2902-3

23. Wang F, Wu Y, Tang L, Zhu W, Chen F, Xu T, Bo L, Li J, Deng X. Brain natriuretic peptide for prediction of mortality in patients with sepsis: a systematic review and meta-analysis. Crit Care. 2012;16(3):R74. doi: 10.1186/cc11331

24. Vallabhajosyula S, Sakhuja A, Geske JB, Kumar M, Kashyap R, Kashani K, Jentzer JC. Clinical profile and outcomes of acute cardiorespiratory syndrome type-5 in sepsis: An eight-year cohort study. PLoS One. 2018;13(1):e0190965. doi: 10.1371/journal.pone.0190965

25. Andrei S, Bahr PA, Nguyen M, Bouhemad B, Guinot PG. Prevalence of systemic venous congestion assessed by Venous Excess Ultrasound Grading System (VExUS) and association with acute kidney injury in a general ICU cohort: a prospective multicentric study. Crit Care. 2023;27(1):212. doi: 10.1186/s13054-023-04524-4

26. Sav T, Cecen F, Albayrak ES. The effects of ultrafiltration and diuretic therapies on oxidative stress markers in patients with cardio-renal syndrome. Minerva Urol Nefrol. 2017;69(4):400–407. doi: 10.23736/S0393-2249.16.02663-1

27. Kobayashi M, Bayes-Genis A, Duarte K, McMurray JJV, Ferreira JP, Pocock SJ, Van Veldhuisen DJ, Lupón J, Pitt B, Zannad F, Girerd N. Kidney function trajectories before and after hospitalization for heart failure with reduced ejection fraction. Eur Heart J. 2025 Nov 14;46(43):4583–4593. doi: 10.1093/eur-heartj/ehaf457

28. Sharif S, Flindall H, Basmaji J, Ablordeppey E, Díaz-Gómez JL, Lanspa M, Nikravan S, Piticaru J, Lewis K. Critical Care Ultrasonography for Volume Management: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis of Randomized Trials. Crit Care Explor. 2025 May 14;7(5):e1261. doi: 10.1097/CCE.0000000000001261