Prognostic Value of Cystatin C in Pulmonary Embolism

Aim        To study a possibility of using serum concentrations of cystatin C (CYS) in early diagnosis and prediction of acute kidney injury (AKI) and associated in-hospital mortality and 30-day risk of death in pulmonary embolism (PE).

Materials and methods        This study included 98 patients with suspected PE, of whom 63 had a confirmed diagnosis and formed the study group; the rest were excluded. CYS was measured on admission. The difference (CYSdiff) between the measured CYS and the estimated CYS corresponding to the glomerular filtration rate (GFR) of 75 ml/min/1.73 m² was calculated using the reversed 2012 CKD-EPI Cystatin C formula. The estimated GFR was calculated as the difference between the CYS-based GFR (2012 CKD-EPI Cystatin C) and the creatinine-based GFR (2009 CKD-EPI). The 30-day mortality risk was assessed according to the ESC/ERS Guidelines for the diagnosis and treatment of acute PE in effect at the time of hospitalization.

Results    AKI was diagnosed in 13 (21%) of 63 patients with PE aged 67±12 years, of whom 36 (57%) were men. In 7 (54%) cases, AKI was associated with chronic kidney disease (CKD), and in 6 (46%) cases, AKI developed for the first time. The measurement of the CYS concentration ensured early diagnosis and prediction of AKI with AUC=0.70 (95% confidence interval (CI) 0.57-0.81; p=0.009), optimal cutoff point (OP) >2.55 μg/ml (sensitivity 70%, specificity 62%), and AKI associated with CKD with AUC=0.78 (95% CI 0.65-0.88; p=0.001), OP >2.55 μg/ml (sensitivity 86%, specificity 62%). Similar predictive value for AKI was determined for CYSdiff: AUC = 0.70 (95% CI 0.57-0.81; p=0.009), OP >1.62 μg/ml with a sensitivity of 69% and specificity of 68%. Five patients (9%) died in hospital. The death rate was higher in AKI (χ2 = 5.8; p=0.018). CYS and CYSdiff levels did not predict in-hospital mortality (p >0.05 for both). The predictive value of eGFRdiff was unsatisfactory for either AKI or mortality (p >0.05 for both). It was found that CYS (AUC=0.76; 95% CI 0.63-0.85; p<0.001; OP>2.17 μg/ml) with a sensitivity of 70%, specificity of 70%, and CYSdiff (AUC=0.77; 95% CI 0.64–0.86; p<0.001; OP>1.22 μg/ml) with a sensitivity of 70%, and specificity of 70%, but not eGFRdiff were associated with a high 30-day risk of death (p=0.804).

Conclusion            The study results confirm the effectiveness of CYS assessment in the early diagnosis and prediction of AKI, including cases associated with CKD. Prediction accuracy can be improved using CYSdiff. CYS levels do not predict in-hospital mortality but are associated with a high 30-day risk of death in patients with PE.

1. Wendelboe A, Weitz JI. Global Health Burden of Venous Thromboembolism. Arteriosclerosis, Thrombosis, and Vascular Biology. 2024;44(5):1007–11. DOI: 10.1161/ATVBAHA.124.320151

2. Sidney S, Lee C, Liu J, Khan SS, Lloyd-Jones DM, Rana JS. Age-Adjusted Mortality Rates and Age and Risk–Associated Contributions to Change in Heart Disease and Stroke Mortality, 2011-2019 and 2019-2020. JAMA Network Open. 2022;5(3):e223872. DOI: 10.1001/jamanetworkopen.2022.3872

3. Murgier M, Bertoletti L, Darmon M, Zeni F, Valle R, Del Toro J et al. Frequency and prognostic impact of acute kidney injury in patients with acute pulmonary embolism. Data from the RIETE registry. International Journal of Cardiology. 2019;291:121–6. DOI: 10.1016/j.ijcard.2019.04.083

4. Menzorov M.V., Filimonova V.V., Erlikh A.D., Barbarash O.L., Berns S.A., Shmidt E.A. et al. Incidence and prognostic value of acute kidney injury in pulmonary embolism: data from the SIRENA registry. Russian Journal of Cardiology. 2022;27(S1):7–16. DOI: 10.15829/1560-4071-2022-4864

5. Kellum JA, Lameire N, Aspelin P, Barsoum RS, Burdmann EA, Goldstein SL et al. Kidney disease : Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney International Supplements. 2012;2(1):1–138. DOI: 10.1038/kisup.2012.1

6. Association of Nephrologists. Clinical Guidelines. Acute Kidney In-jury (AKI). 2020. Av. at: https://rusnephrology.org/wp-content/uploads/2020/12/AKI_final.pdf.

7. Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstädt H et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016;315(20):2190–9. DOI: 10.1001/jama.2016.5828

8. Ostermann M, Legrand M, Meersch M, Srisawat N, Zarbock A, Kellum JA. Biomarkers in acute kidney injury. Annals of Intensive Care. 2024;14(1):145. DOI: 10.1186/s13613-024-01360-9

9. Ostermann M, Zarbock A, Goldstein S, Kashani K, Macedo E, Murugan R et al. Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement. JAMA Network Open. 2020;3(10):e2019209. DOI: 10.1001/jamanetworkopen.2020.19209

10. Kostrubiec M, Łabyk A, Pedowska-Włoszek J, Dzikowska-Diduch O, Wojciechowski A, Garlińska M et al. Neutrophil gelatinase-associated lipocalin, cystatin C and eGFR indicate acute kidney injury and predict prognosis of patients with acute pulmonary embolism. Heart. 2012;98(16):1221–8. DOI: 10.1136/heartjnl-2012-301884

11. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. European Heart Journal. 2014;35(43):3033–69, 3069a–3069k. DOI: 10.1093/eurheartj/ehu283

12. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing G-J, Harjola V-P et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). European Heart Journal. 2019;41(4):543–603. DOI: 10.1093/eurheartj/ehz405

13. Smirnov A.V., Dobronravov V.A., Rumyantsev A.Sh., Shilov E.M., Vatazin A.V., Kayukov I.G. et al. National guidelines acute kidney injury: basic principles of diagnosis, prevention and therapy. Part I. Nephrology. 2016;20(1):79–104. DOI: 10.24884/1561-6274-2016-20-1-8-15

14. Smirnov A.V., Shilov E.M., Dobronravov V.A., Kayukov I.G., Bobkova I.N., Shvetsov M.Yu. et al. National recommendations. Chro nic kidney disease: basic principles of screening, diagnosis, prevention and treatment approaches. Nephrology. 2012;16(1):89–115. DOI: 10.24884/1561-6274-2012-16-1-89-115

15. Levey AS, Stevens LA. Estimating GFR Using the CKD Epidemiology Collaboration (CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence Estimates, and Better Risk Predictions. American Journal of Kidney Diseases. 2010;55(4):622–7. DOI: 10.1053/j.ajkd.2010.02.337

16. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T et al. Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. New England Journal of Medicine. 2012;367(1):20–9. DOI: 10.1056/NEJMoa1114248

17. Zhang L-W, Luo M-Q, Zeng J-L, You Z-B, Chen L-C, Chen J-H et al. The Association of Intraindividual Difference Between Cystatin- and Creatinine-Based Estimated GFR and Contrast-Associated Acute Kidney Injury. Clinical Interventions in Aging. 2024;19:411–20. DOI: 10.2147/CIA.S447042

18. Kashani K, Rosner MH, Ostermann M. Creatinine: From physiology to clinical application. European Journal of Internal Medicine. 2020;72:9–14. DOI: 10.1016/j.ejim.2019.10.025

19. Menzorov M.V., Shutov A.M., Makeeva E.R., Serov V.A., Mikhailova E.V., Parfenova E.A. Difficulties in diagnosing acute kidney injury in patients with ST-segment elevation myocardial infarction. Therapeutic Archive. 2014;86(4):25–9.

20. Ostermann M, Shaw AD, Joannidis M. Management of oliguria. Intensive Care Medicine. 2023;49(1):103–6. DOI: 10.1007/s00134-022-06909-5

21. Prowle JR, Croal B, Abbott TEF, Cuthbertson BH, Wijeysundera DN, for the METS study investigators et al. Cystatin C or creatinine for pre-operative assessment of kidney function and risk of post-operative acute kidney injury: a secondary analysis of the METS cohort study. Clinical Kidney Journal. 2024;17(1):sfae004. DOI: 10.1093/ckj/sfae004

22. Smirnov A.V., Rumyantsev A.Sh., Kayukov I.G., Antonova T.V., Galkina O.V., Dobronravov V.A. et al. Acute kidney injury. - M.: MIA; 2015. - 488p. ISBN 978-5-9986-0228-3

23. Zhang Z, Lu B, Sheng X, Jin N. Cystatin C in Prediction of Acute Kidney Injury: A Systemic Review and Meta-analysis. American Journal of Kidney Diseases. 2011;58(3):356–65. DOI: 10.1053/j. ajkd.2011.02.389

24. Peng P, Fu XC, Wang Y, Zheng X, Bian L, Zhati N et al. The value of serum cystatin c in predicting acute kidney injury after cardiac surgery: A systematic review and meta-analysis. PLOS ONE. 2024;19(11):e0310049. DOI: 10.1371/journal.pone.0310049

25. Shutov A.M., Efremova E.V., Menzorov M.V. Renal continuum: classification issues. Ulyanovsk Medico-biological Journal. 2023;1:43–9. DOI: 10.34014/2227-1848-2023-1-43-49

26. Menzorov M.V., Filimonova V.V., Erlikh A.D., Barbarash O.L., Berns S.A., Shmidt E.A. et al. Renal dysfunction in patients with pulmonary embolism: data from the SIRENA register. Russian Journal of Cardiology. 2021;26(S2):26–34. DOI: 10.15829/1560-4071-2021-4422

27. Hu Y, Liu H, Du L, Wan J, Li X. Serum Cystatin C Predicts AKI and the Prognosis of Patients in Coronary Care Unit: a Prospective, Observational Study. Kidney and Blood Pressure Research. 2017;42(6):961–73. DOI: 10.1159/000485341

28. Stevens PE, Ahmed SB, Carrero JJ, Foster B, Francis A, Hall RK et al. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International. 2024;105(4S):S117–314. DOI: 10.1016/j.kint.2023.10.018

29. Kim H, Park JT, Lee J, Jung JY, Lee K-B, Kim Y-H et al. The difference between cystatin C- and creatinine-based eGFR is associated with adverse cardiovascular outcome in patients with chronic kidney disease. Atherosclerosis. 2021;335:53–61. DOI: 10.1016/j.atherosclerosis.2021.08.036

30. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care. 2004;8(4):R204–12. DOI: 10.1186/cc2872

31. Baykal ND, Mermit B, Alp HH, Yıldız H. Evaluation of neutrophil gelatinase-associated lipocalin (NGAL), hypoxia-induced factor-1 alpha (HIF-1α) and apelin 13 levels as new potential biomarkers for pulmonary thromboembolism: A prospective clinical study. Respiratory Medicine. 2024;233:107776. DOI: 10.1016/j.rmed.2024.107776

32. Birkelo BC, Koyner JL, Ostermann M, Bhatraju PK. The Road to Precision Medicine for Acute Kidney Injury. Critical Care Medicine. 2024;52(7):1127–37. DOI: 10.1097/CCM.0000000000006328

33. Ostermann M, Wu V, Sokolov D, Lumlertgul N. Definitions of acute renal dysfunction: an evolving clinical and biomarker paradigm. Current Opinion in Critical Care. 2021;27(6):553–9. DOI: 10.1097/MCC.0000000000000886