Association of Circulating Inflammatory Cytokines IL-6, TNF-α, and Fibroblast Growth Factor 2 with Disease Progression and Clinical Outcomes in Acute Kidney Injury
Abstract
Acute kidney injury (AKI) presents challenges for early risk stratification due to its rapid progression and variable outcomes. This study investigated the predictive value of serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and fibroblast growth factor 2 (FGF-2) for disease progression and clinical outcomes in 104 AKI patients.
Serum biomarkers were measured at diagnosis. Disease progression (worsening of AKI stage) and 28-day major adverse kidney events (MAKE) were assessed.
IL-6 and TNF-α positively correlated with progression and MAKE, while FGF-2 showed negative correlations. Multivariate logistic regression identified IL-6 (aOR=1.034) and TNF-α (aOR=1.082) as independent predictors of progression, but not FGF-2. Cox regression showed TNF-α independently predicted earlier MAKE (aHR=1.031), whereas FGF-2 predicted delayed MAKE (aHR=0.832). IL-6 did not independently affect time to MAKE. The combined biomarker model achieved an AUC of 0.962 for predicting MAKE. Day-of-diagnosis measurement of IL-6, TNF-α, and FGF-2 is significantly associated with AKI progression and adverse outcomes, independent of traditional risk factors.
Evaluating the balance between inflammation and repair may improve risk stratification. The combination of elevated IL-6 and TNF-α with decreased FGF-2 could identify a high-risk phenotype.
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2. Okafor HU, Mbanefo N, Nnakenyi I. Prevalence of acute kidney injury in children with severe malaria using serum neutrophil gelatinase-associated lipocalin. West Afr J Med. 2024;41(8):853-9.
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7. Zhang M, Yang Y, Zhu L, Sun Y, Li X, Chen Y, et al. Plasma proenkephalin and neutrophil gelatinase-associated lipocalin predict mortality in ICU patients with acute kidney injury. BMC Nephrol. 2024;25(8):181.
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9. Sodhi K, Chanchalani G, Tyagi N. Current role of biomarkers in initiation and weaning of kidney replacement therapy in acute kidney injury. World J Nephrol. 2025;14(1):99802.
10. Martin-Sanchez D, Guerrero-Mauvecin J, Fontecha-Barriuso M, et al. Bone marrow-derived RIPK3 mediates kidney inflammation in acute kidney injury. J Am Soc Nephrol. 2022;33(2):357-73.
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12. Chen Y, Zhou X, Wu Y. miR-26a-5p/IL-6 axis alleviates sepsis-induced acute kidney injury by inhibiting renal inflammation. Ren Fail. 2022;44(1):551-61.
13. Komaru Y, Oguchi M, Sadahiro T. Urinary NGAL and plasma IL-6 in discontinuation of continuous venovenous hemodiafiltration in severe acute kidney injury. Ann Intensive Care. 2023;13(1):42.
14. Fischer MA, Howard-Quijano K, Zong NC. Perioperative changes in plasma nitrite and IL-6 levels predict postoperative atrial fibrillation and acute kidney injury after cardiac surgery. Antioxidants (Basel). 2024;13(8):971.
15. Nuer S, Aili Z, Guyha N. Predicting acute kidney injury in children with sepsis using red blood cell distribution and biomarkers (PCT, IL-6, CRP, and cystatin C). J Med Biochem. 2025;44(7):1523-32.
16. González-Lafuente L, Mercado-García E, Vázquez-Sánchez S. Interleukin-6 as a prognostic marker in acute kidney injury and its klotho-dependent regulation. Nefrologia (Engl Ed). 2024;44(6):818-29.
17. Zheng D, Ruan X, Wu Q, Li H, Zhang Y, Wang J, et al. Yishen Jiangzhuo decoction attenuates cisplatin-induced acute kidney injury via inhibition of inflammation, oxidative stress and apoptosis through TNF signaling pathway. Exp Ther Med. 2024;28(2):331.
18. Zhao J, Duan Q, Dong C, Li X, Wang Y, Zhang H, et al. Cul4a attenuates LPS-induced acute kidney injury via blocking NF-κB signaling pathway in sepsis. J Med Biochem. 2022;41(1):62-70.
19. Livingston MJ, Shu S, Fan Y, Chen L, Wang H, LiZ, et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy. 2023;19(1).
20. Liu W, Lin M, Dai Y, et al. Hypoxia activates FGF-23-ERK/MAPK signaling pathway in ischemia-reperfusion-induced acute kidney injury. Kidney Blood Press Res. 2024;49(1):933-945.
21. Tan X, Tao Q, Li G. Fibroblast growth factor 2 attenuates renal ischemia-reperfusion injury via inhibition of endoplasmic reticulum stress. Front Cell Dev Biol. 2020;8(7):147.
22. Livingston MJ, Zhang M, Kwon SH. Autophagy activates EGR1 via MAPK/ERK to induce FGF2 in renal tubular cells for fibroblast activation and fibrosis during maladaptive kidney repair. Autophagy. 2024;20(5):1032-53.
23. Zaragoza JJ, Gómez-Fregoso JA, Hernández-Barajas EM, et al. Acute kidney injury with hypernatremia and major adverse kidney events. Clin Kidney J. 2025;18(2):sfae419.
24. Park UJ, Kim JW. Yuanhuacine modulates lipopolysaccharide-induced interleukin-6 through regulation of the JAK1/STAT3 pathway and prevents tubular damage in acute kidney injury. Exp Ther Med. 2025;30(3):168.
25. de Oliveira Gomes CG, de Andrade MVM, Guedes LR, et al. Evaluation of biomarkers HMGB1 and IL-6 as predictors of mortality in cirrhotic patients with acute kidney injury. Mediators Inflamm. 2020;2020:2867241.
26. Wang J, Xiong M, Fan Y. Mecp2 protects kidney from ischemia-reperfusion injury through transcriptional repressing IL-6/STAT3 signaling. Theranostics. 2022;12(8):3896-3910.
27. Imoto K, Tanaka M, Goya T. Acute kidney injury is an unfavorable prognostic factor in acute liver failure and is associated with tumor necrosis factor-alpha. Medicine (Baltimore). 2023;102(45):e35931.
28. Tianzhi L, Zhang Y, Liu X. Fortunellin attenuates sepsis-induced acute kidney injury by inhibiting inflammation and ferroptosis via the TLR4/NF-κB pathway. Histol Histopathol. 2025;40(7):1083-93.
29. Guo Y, Wang Y, Wang B. Ultrasound-responsive renal-targeted nanoparticles deliver TAK-242 to inhibit NF-κB/NLRP3 signaling and attenuate sepsis-associated acute kidney injury. Biomaterials. 2026;329(14):123922.
30. El-Gedamy MS, Elnagar SS, Shabana EE. Association of tumor necrosis factor alpha gene polymorphism (TNF-α 308 G/A) with enhanced severity of metal-induced chronic kidney disease via upregulation of transmembrane protein expression. Biol Trace Elem Res. 2025;203(12):6426-35.
31. Elmorsy EA, Khodeir MM, Kamal MM Activation of nicotinamide phosphoribosyltransferase protects against unilateral renal ischemia-reperfusion injury via the NAD+/SIRT1/PGC-1α signaling pathway and modulation of NFκB/TNF-α/IL-6. Eur J Pharm Sci. 2025;214(8):107302.
32. An MM, Liu CX, Gong P. Effects of continuous renal replacement therapy on inflammation-related anemia, iron metabolism and prognosis in sepsis patients with acute kidney injury. World J Emerg Med. 2023;14(3):186-192.
33. Hu X, Ma Z, Li S. Fibroblast growth factor 2 is produced by renal tubular cells to act as a paracrine factor in maladaptive kidney repair after cisplatin nephrotoxicity. Lab Invest. 2023;103(3):100009.
34. Geng Y, Gao Y, Qi D. A hydrogel tissue adhesive incorporating basic fibroblast growth factor-loaded liposomes accelerates cutaneous wound healing by enhancing cell proliferation, collagen synthesis and angiogenesis. Acta Biomater. 2025;205(8):242-59.
35. Burcin MAT, Tuba TD, Gulali A. Solid pseudopapillary carcinoma of the pancreas presenting with acute kidney injury and metastatic disease in an elderly male: a case report. Curr Cancer Res. 2025;1(1):25-30.
2. Okafor HU, Mbanefo N, Nnakenyi I. Prevalence of acute kidney injury in children with severe malaria using serum neutrophil gelatinase-associated lipocalin. West Afr J Med. 2024;41(8):853-9.
3. Guo S, Chen Y, Huo Y. Comparison of early and delayed strategy for renal replacement therapy initiation for severe acute kidney injury with heart failure: a retrospective cohort study. Transl Androl Urol. 2023;12(5):715-26.
4. Gambino C, Piano S, Stenico M. Diagnostic and prognostic performance of urinary neutrophil gelatinase-associated lipocalin in patients with cirrhosis and acute kidney injury. Hepatology. 2023;77(5):1630-8.
5. Khoo B, Friedrich JO, Lebovic G. Kidney recovery after iodinated contrast administration in patients with acute kidney injury receiving renal replacement therapy. J Crit Care. 2025;87(8):155015.
6. Loeffler J, Hassan M, Qaqish F, et al. Predictors of renal replacement therapy requirement in cirrhotic patients with acute kidney injury. Dig Dis Sci. 2025;70(4):1540-6.
7. Zhang M, Yang Y, Zhu L, Sun Y, Li X, Chen Y, et al. Plasma proenkephalin and neutrophil gelatinase-associated lipocalin predict mortality in ICU patients with acute kidney injury. BMC Nephrol. 2024;25(8):181.
8. Calças Marques R, Reis M, Pimenta G. Severe acute kidney injury in hospitalized cancer patients: epidemiology and predictive model of renal replacement therapy and in-hospital mortality. Cancers (Basel). 2024;16(3):561.
9. Sodhi K, Chanchalani G, Tyagi N. Current role of biomarkers in initiation and weaning of kidney replacement therapy in acute kidney injury. World J Nephrol. 2025;14(1):99802.
10. Martin-Sanchez D, Guerrero-Mauvecin J, Fontecha-Barriuso M, et al. Bone marrow-derived RIPK3 mediates kidney inflammation in acute kidney injury. J Am Soc Nephrol. 2022;33(2):357-73.
11. Liu Y, Li C, Yang X. Neutrophil gelatinase-associated lipocalin and interleukin-18 in prediction of acute kidney injury in sepsis patients. Int J Gen Med. 2024;17(8):6335-41.
12. Chen Y, Zhou X, Wu Y. miR-26a-5p/IL-6 axis alleviates sepsis-induced acute kidney injury by inhibiting renal inflammation. Ren Fail. 2022;44(1):551-61.
13. Komaru Y, Oguchi M, Sadahiro T. Urinary NGAL and plasma IL-6 in discontinuation of continuous venovenous hemodiafiltration in severe acute kidney injury. Ann Intensive Care. 2023;13(1):42.
14. Fischer MA, Howard-Quijano K, Zong NC. Perioperative changes in plasma nitrite and IL-6 levels predict postoperative atrial fibrillation and acute kidney injury after cardiac surgery. Antioxidants (Basel). 2024;13(8):971.
15. Nuer S, Aili Z, Guyha N. Predicting acute kidney injury in children with sepsis using red blood cell distribution and biomarkers (PCT, IL-6, CRP, and cystatin C). J Med Biochem. 2025;44(7):1523-32.
16. González-Lafuente L, Mercado-García E, Vázquez-Sánchez S. Interleukin-6 as a prognostic marker in acute kidney injury and its klotho-dependent regulation. Nefrologia (Engl Ed). 2024;44(6):818-29.
17. Zheng D, Ruan X, Wu Q, Li H, Zhang Y, Wang J, et al. Yishen Jiangzhuo decoction attenuates cisplatin-induced acute kidney injury via inhibition of inflammation, oxidative stress and apoptosis through TNF signaling pathway. Exp Ther Med. 2024;28(2):331.
18. Zhao J, Duan Q, Dong C, Li X, Wang Y, Zhang H, et al. Cul4a attenuates LPS-induced acute kidney injury via blocking NF-κB signaling pathway in sepsis. J Med Biochem. 2022;41(1):62-70.
19. Livingston MJ, Shu S, Fan Y, Chen L, Wang H, LiZ, et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy. 2023;19(1).
20. Liu W, Lin M, Dai Y, et al. Hypoxia activates FGF-23-ERK/MAPK signaling pathway in ischemia-reperfusion-induced acute kidney injury. Kidney Blood Press Res. 2024;49(1):933-945.
21. Tan X, Tao Q, Li G. Fibroblast growth factor 2 attenuates renal ischemia-reperfusion injury via inhibition of endoplasmic reticulum stress. Front Cell Dev Biol. 2020;8(7):147.
22. Livingston MJ, Zhang M, Kwon SH. Autophagy activates EGR1 via MAPK/ERK to induce FGF2 in renal tubular cells for fibroblast activation and fibrosis during maladaptive kidney repair. Autophagy. 2024;20(5):1032-53.
23. Zaragoza JJ, Gómez-Fregoso JA, Hernández-Barajas EM, et al. Acute kidney injury with hypernatremia and major adverse kidney events. Clin Kidney J. 2025;18(2):sfae419.
24. Park UJ, Kim JW. Yuanhuacine modulates lipopolysaccharide-induced interleukin-6 through regulation of the JAK1/STAT3 pathway and prevents tubular damage in acute kidney injury. Exp Ther Med. 2025;30(3):168.
25. de Oliveira Gomes CG, de Andrade MVM, Guedes LR, et al. Evaluation of biomarkers HMGB1 and IL-6 as predictors of mortality in cirrhotic patients with acute kidney injury. Mediators Inflamm. 2020;2020:2867241.
26. Wang J, Xiong M, Fan Y. Mecp2 protects kidney from ischemia-reperfusion injury through transcriptional repressing IL-6/STAT3 signaling. Theranostics. 2022;12(8):3896-3910.
27. Imoto K, Tanaka M, Goya T. Acute kidney injury is an unfavorable prognostic factor in acute liver failure and is associated with tumor necrosis factor-alpha. Medicine (Baltimore). 2023;102(45):e35931.
28. Tianzhi L, Zhang Y, Liu X. Fortunellin attenuates sepsis-induced acute kidney injury by inhibiting inflammation and ferroptosis via the TLR4/NF-κB pathway. Histol Histopathol. 2025;40(7):1083-93.
29. Guo Y, Wang Y, Wang B. Ultrasound-responsive renal-targeted nanoparticles deliver TAK-242 to inhibit NF-κB/NLRP3 signaling and attenuate sepsis-associated acute kidney injury. Biomaterials. 2026;329(14):123922.
30. El-Gedamy MS, Elnagar SS, Shabana EE. Association of tumor necrosis factor alpha gene polymorphism (TNF-α 308 G/A) with enhanced severity of metal-induced chronic kidney disease via upregulation of transmembrane protein expression. Biol Trace Elem Res. 2025;203(12):6426-35.
31. Elmorsy EA, Khodeir MM, Kamal MM Activation of nicotinamide phosphoribosyltransferase protects against unilateral renal ischemia-reperfusion injury via the NAD+/SIRT1/PGC-1α signaling pathway and modulation of NFκB/TNF-α/IL-6. Eur J Pharm Sci. 2025;214(8):107302.
32. An MM, Liu CX, Gong P. Effects of continuous renal replacement therapy on inflammation-related anemia, iron metabolism and prognosis in sepsis patients with acute kidney injury. World J Emerg Med. 2023;14(3):186-192.
33. Hu X, Ma Z, Li S. Fibroblast growth factor 2 is produced by renal tubular cells to act as a paracrine factor in maladaptive kidney repair after cisplatin nephrotoxicity. Lab Invest. 2023;103(3):100009.
34. Geng Y, Gao Y, Qi D. A hydrogel tissue adhesive incorporating basic fibroblast growth factor-loaded liposomes accelerates cutaneous wound healing by enhancing cell proliferation, collagen synthesis and angiogenesis. Acta Biomater. 2025;205(8):242-59.
35. Burcin MAT, Tuba TD, Gulali A. Solid pseudopapillary carcinoma of the pancreas presenting with acute kidney injury and metastatic disease in an elderly male: a case report. Curr Cancer Res. 2025;1(1):25-30.
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| Issue | Articles in Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Acute kidney injury Biomarkers Disease progression Fibroblast growth factor 2 Interleukin-6 Prognosis Tumor necrosis factor-alpha | ||
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How to Cite
1.
Zhang Y, Ao Q, Li M, He X, Cheng Q. Association of Circulating Inflammatory Cytokines IL-6, TNF-α, and Fibroblast Growth Factor 2 with Disease Progression and Clinical Outcomes in Acute Kidney Injury. Iran J Allergy Asthma Immunol. 2026;:1-13.
