The Prognostic Synergy of Classic Cytokines (IL-6, IL-1β, TNF-α, TGF-β) and Emerging Biomarkers (Galectin-3, FGF-23) in Predicting Renal and Cardiovascular Outcomes in Patients with Stage 3-4 Chronic Kidney Disease
Cytokine & Partner Biomarkers in CKD Prognosis
Abstract
Background: Chronic Kidney Disease (CKD) progression is driven by intertwined pathways of inflammation, fibrosis, and disordered mineral metabolism. While cytokines like IL-6 and TNF-α are established inflammatory markers, their prognostic value may be enhanced by combining them with emerging partners like Galectin-3 (Gal-3, fibrosis/pro-inflammatory amplifier) and Fibroblast Growth Factor-23 (FGF-23, mineral bone disorder). We investigated the individual and combined prognostic power of this novel panel for renal and cardiovascular (CV) outcomes.
Methods: In this prospective, single-center cohort study, 218 patients with CKD stages 3-4 were enrolled. Baseline serum levels of IL-6, IL-1β, TNF-α, TGF-β, Gal-3, and FGF-23 were measured. Patients were followed for 36 months for a primary composite endpoint: ≥40% decline in eGFR, progression to kidney failure requiring replacement therapy (KFRT), or a major adverse CV event (MACE). Cox proportional-hazards models, Kaplan-Meier analysis, and receiver operating characteristic (ROC) curves were employed.
Results: Over 36 months, 68 patients (31.2%) reached the composite endpoint. Elevated levels of all biomarkers, except IL-1β, were individually associated with the endpoint in univariate analysis. In multivariate Cox regression, only IL-6 (HR: 1.82, 95% CI: 1.30-2.55), Gal-3 (HR: 2.15, 95% CI: 1.45-3.18), and FGF-23 (HR: 1.95, 95% CI: 1.35-2.82) remained independent predictors after adjustment for age, diabetes, eGFR, and albuminuria. A "Triple-Biomarker Risk Score" (TBRS), combining tertiles of IL-6, Gal-3, and FGF-23, showed a powerful graded association with risk. Patients in the high-TBRS group had a 9-fold higher risk (HR: 9.10, 95% CI: 3.82-21.68) compared to the low-score group. The area under the ROC curve (AUC) for the TBRS (0.84) was significantly superior to that of eGFR alone (0.72, p<0.01).
Conclusion: The combination of a classic inflammatory cytokine (IL-6), a fibrotic/pro-inflammatory lectin (Gal-3), and a phosphaturic hormone (FGF-23) provides a superior prognostic signature in moderate CKD. This panel reflects key pathological axes—inflammation, fibrosis, and mineral dysregulation—and significantly improves risk stratification for both renal and cardiovascular outcomes.
References
2. Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012;379(9811):165-80.
3. Mihai S, Codrici E, Popescu ID, et al. Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome. J Immunol Res. 2018;2018:2180373.
4. Zhang WR, Parikh CR. Biomarkers of Acute and Chronic Kidney Disease. Annu Rev Physiol. 2019;81:309-33.
5. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif. 2015;39(1-3):84-92.
6. Amdur RL, Feldman HI, Gupta J, et al. Inflammation and Progression of CKD: The CRIC Study. Clin J Am Soc Nephrol. 2016;11(9):1546-56.
7. Henderson NC, Mackinnon AC, Farnworth SL, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci U S A. 2006;103(13):5060-5.
8. de Boer RA, Voors AA, Muntendam P, et al. Galectin-3: a novel mediator of heart failure development and progression. Eur J Heart Fail. 2009;11(9):811-7.
9. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584-92.
10. Grabner A, Schramm K, Silswal N, et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Transl Med. 2017;9(418):eaag1714.
11. Coca SG, Nadkarni GN, Huang Y, et al. Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease. J Am Soc Nephrol. 2017;28(9):2786-93.
12. Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49.
13. Levey AS, Inker LA, Matsushita K, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64(6):821-35.
14. Song JW, Lam SM, Fan X, et al. Omics-Driven Systems Interrogation of Metabolic Dysregulation in COVID-19 Pathogenesis. Cell Metab. 2020;32(2):188-202.e5.
15. Drechsler C, Delgado G, Wanner C, et al. Galectin-3, Renal Function, and Clinical Outcomes: Results from the LURIC and 4D Studies. J Am Heart Assoc. 2015;4(11):e001831.
16. Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol. 2014;25(2):349-60.
17. Ridker PM, Rane M. Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease. Circ Res. 2021;128(11):1728-46.
18. Schuett K, Savvaidis A, Maxeiner S, et al. Clonal Hematopoiesis-Associated Inflammation and Heart Failure with Preserved Ejection Fraction. Circulation. 2021;144(20):1620-2.
19. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-31.
20. Mackinnon AC, Gibbons MA, Farnworth SL, et al. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185(5):537-46.
21. Ho JE, Liu C, Lyass A, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol. 2012;60(14):1249-56.
22. Tang WH, Shrestha K, Shao Z, et al. Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol. 2011;108(3):385-90.
23. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393-408.
24. Hénaut L, Massy ZA. New Insights into the Key Role of Fibroblast Growth Factor 23 in Chronic Kidney Disease. J Nephrol. 2018;31(5):597-607.
25. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305(23):2432-9.
26. Ortiz A, Covic A, Fliser D, et al. Epidemiology, contributors to, and clinical trials of mortality risk in chronic kidney failure. Lancet. 2014;383(9931):1831-43.
27. Kohan DE, Barton M. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. 2014;86(5):896-904.
28. Tuttle KR, Brosius FC 3rd, Cavender MA, et al. SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. Am J Kidney Dis. 2021;77(1):94-109.
29. Vergaro G, Prud'homme M, Fazal L, et al. Inhibition of Galectin-3 Pathway Prevents Isoproterenol-Induced Left Ventricular Dysfunction and Fibrosis. J Pharmacol Exp Ther. 2016;357(3):518-27.
30. Block GA, Wheeler DC, Persky MS, et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol. 2012;23(8):1407-15.
31. Niu J, Wu J, Li X, Xie J. Biomarker Panels for Prediction of Chronic Kidney Disease Progression. Am J Nephrol. 2020;51(6):487-96.
32. Grams ME, Rebholz CM, McMahon B, et al. Identification of Soluble TNFR1 and TNFR2 as Candidate Biomarkers Associated with Risk of ESRD and Mortality in Patients with CKD. Kidney Int Rep. 2019;4(6):804-13.
33. Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016;12(6):325-38.
34. Komada T, Muruve DA. The role of inflammasomes in kidney disease. Nat Rev Nephrol. 2019;15(8):501-20.
35. Collins FS, Tabak LA. Policy: NIH plans to enhance reproducibility. Nature. 2014;505(7485):612-3.
36. Smith ER, Cai MM, McMahon LP, et al. Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab. 2012;97(9):3357-65.
37. Shlipak MG, Tummalapalli SL, Boulware LE, et al. The Case for Early Identification and Intervention of Chronic Kidney Disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2021;99(1):34-47.
38. Kalim S, Wald R, Yan AT, et al. Extended-Release Niacin Therapy and Risk of Mortality and Kidney Function Decline in Advanced Chronic Kidney Disease. Am J Kidney Dis. 2018;71(4):519-28.
39. Altman DG, Vergouwe Y, Royston P, Moons KG. Prognosis and prognostic research: validating a prognostic model. BMJ. 2009;338:b605.
40. Parikh CR, Puthumana J, Shlipak MG, et al. Relationship of Kidney Injury Biomarkers with Long-Term Cardiovascular Outcomes after Cardiac Surgery. J Am Soc Nephrol. 2017;28(12):3699-707.
Copyright (c) 2026 Wenliang Zhai , Shubin Guo
This work is licensed under a Creative Commons Attribution 4.0 International License.
The published articles will be distributed under the Creative Commons Attribution 4.0 International License (CC BY). It is allowed to copy and redistribute the material in any medium or format, and remix, transform, and build upon it for any purpose, even commercially, as long as appropriate credit is given to the original author(s), a link to the license is provided and it is indicated if changes were made. Users are required to provide full bibliographic description of the original publication (authors, article title, journal title, volume, issue, pages), as well as its DOI code. In electronic publishing, users are also required to link the content with both the original article published in Journal of Medical Biochemistry and the licence used.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.