Sepsis-Associated Acute Kidney Injury in Adults: Mechanistic Heterogeneity, Dynamic Risk Stratification, and the Path Toward Precision Care
DOI:
https://doi.org/10.54097/ks3mrg55Keywords:
Acute Kidney Injury, Biomarkers, Precision Medicine, SepsisAbstract
Sepsis-associated acute kidney injury (SA-AKI) is a common, high-risk, and biologically heterogeneous syndrome in critically ill adults. Building on the 2023 Acute Disease Quality Initiative consensus and major reviews published in 2024 and 2025, this narrative update synthesizes evidence through July 15, 2026 and advances three clinically oriented principles. First, incident SA-AKI should be anchored to sepsis onset, whereas progression, persistence, recovery, and post-AKI acute kidney disease should be anchored to each patient's AKI onset. Second, biomarkers and prediction models should be matched to the clinical question and sampling window rather than ranked by area under the curve alone. Third, prognostic enrichment, which identifies patients at high absolute risk, must be distinguished from predictive enrichment, which identifies differential treatment benefit. Contemporary pathobiology extends beyond systemic hypotension and renal ischemia to include macro-microcirculatory uncoupling, venous congestion, endothelial glycocalyx injury, immunothrombosis, mitochondrial dysfunction, metabolic reprogramming, regulated cell death, and maladaptive repair. Urinary extracellular-vesicle complement receptor 1, multi-omics panels, cell-cycle-arrest and endothelial biomarkers, and explainable machine-learning models are promising, but most remain research tools requiring assay standardization, independent validation, strict temporal separation of predictors and outcomes, and prospective clinical-impact evaluation. Supportive care remains the foundation of management. Fluid amount and composition, perfusion targets, medication safety, and kidney replacement therapy should be individualized according to physiology and kidney trajectory; neither routine restrictive fluid strategies after initial resuscitation nor accelerated kidney replacement therapy without emergency indications has improved survival in unselected populations. Progress toward precision care will require reproducible treatment-response phenotypes, prespecified interaction testing, and risk tools linked to feasible interventions that improve patient-centered outcomes.
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[1] Nian, W., Tao, W., & Zhang, H. (2025). Review of research progress in sepsis-associated acute kidney injury. Frontiers in Molecular Biosciences, 12. https://doi.org/10.3389/fmolb. 2025. 1603392.
[2] Zarbock, A., Nadim, M. K., Pickkers, P., et al. (2023). Sepsis-associated acute kidney injury: Consensus report of the 28th Acute Disease Quality Initiative workgroup. Nature Reviews Nephrology, 19, 401–417. https://doi.org/10.1038/s41581-023-00683-3.
[3] Peerapornratana, S., Manrique-Caballero, C. L., Gómez, H., & Kellum, J. A. (2019). Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney International, 96, 1083–1099. https://doi. org/ 10. 1016/j.kint.2019.05.026.
[4] Bellomo, R., Kellum, J. A., Ronco, C., et al. (2017). Acute kidney injury in sepsis. Intensive Care Medicine, 43, 816–828. https://doi.org/10.1007/s00134-017-4755-7.
[5] Kuwabara, S., Goggins, E., & Okusa, M. D. (2022). The pathophysiology of sepsis-associated AKI. Clinical Journal of the American Society of Nephrology, 17, 1050–1069. https:// doi. org/10.2215/CJN.00850122.
[6] Stanaway, I. B., Morrell, E. D., Mabrey, F. L., et al. (2024). Urinary proteomics identifies distinct immunological profiles of sepsis associated acute kidney injury sub-phenotypes. Critical Care, 28, 419. https://doi.org/10.1186/s13054-024-05202-9.
[7] Bhatraju, P. K., Zelnick, L. R., Herting, J., et al. (2019). Identification of acute kidney injury subphenotypes with differing molecular signatures and responses to vasopressin therapy. American Journal of Respiratory and Critical Care Medicine, 199, 863–872. https://doi.org/ 10.1164/ rccm. 201807-1346OC.
[8] Wiersema, R., Jukarainen, S., Vaara, S. T., et al. (2020). Two subphenotypes of septic acute kidney injury are associated with different 90-day mortality and renal recovery. Critical Care, 24, 150. https://doi.org/10.1186/s13054-020-02866-x.
[9] Chaudhary, K., Vaid, A., Duffy, Á., et al. (2020). Utilization of deep learning for subphenotype identification in sepsis-associated acute kidney injury. Clinical Journal of the American Society of Nephrology, 15, 1557–1565. https://doi. org/ 10.2215/CJN.09330819.
[10] Fu, M., Zhao, J., Xu, W., et al. (2026). Targeting the TLR4/NF-κB/TNF-α/MMP axis with dexamethasone attenuates glycocalyx degradation and restores microcirculatory perfusion in septic kidneys. Scientific Reports, 16, 18448. https:// doi.org/10.1038/s41598-026-49713-7.
[11] Zhang, Q., Yang, B., Li, X., et al. (2025). Biomarkers of cell cycle arrest, microcirculation dysfunction, and inflammation in the prediction of SA-AKI. Scientific Reports, 15, 8023. https://doi.org/10.1038/s41598-025-92315-y.
[12] Liu, X., Chen, Q., Chen, X., et al. (2026). TREM1-NLRP3-driven pyroptosis in sepsis-associated acute kidney injury (AKI) with parallel autophagy changes. Scientific Reports, 16, 14239. https://doi.org/10.1038/s41598-026-40893-w.
[13] Kumar, A. J., Epler, K., Wang, J., et al. (2025). Kidney mitochondrial DNA contributes to systemic IL-6 release in sepsis-associated acute kidney injury. JCI Insight, 10(13), e177004. https://doi.org/10.1172/jci.insight.177004.
[14] Li, J., Bai, J., Cui, S., et al. (2025). Spatial proteomics reveals multiple mechanisms of mitochondrial damage in renal tubules during sepsis-induced acute kidney injury. Archives of Biochemistry and Biophysics, 772, 110566. https://doi.org/10. 1016/ j.abb.2025.110566.
[15] Dou, Q., Tong, H., Chen, J., et al. (2025). IER3 drives the transition from sepsis-associated AKI to CKD by suppressing the mitochondrial translocation of PRDX5. Cellular and Molecular Life Sciences, 82, 439. https://doi.org/ 10.1007/ s00018-025-05963-8.
[16] Kidney Disease: Improving Global Outcomes Acute Kidney Injury Work Group. (2012). KDIGO clinical practice guideline for acute kidney injury. Kidney International Supplements, 2, 1–138.
[17] Ostermann, M., Zarbock, A., Goldstein, S., et al. (2020). Recommendations on acute kidney injury biomarkers from the Acute Disease Quality Initiative Consensus Conference: A consensus statement. JAMA Network Open, 3(10), e2019209. https://doi.org/10.1001/jamanetworkopen.2020.19209.
[18] Molinari, L., Del Rio-Pertuz, G., Smith, A., et al. (2022). Utility of biomarkers for sepsis-associated acute kidney injury staging. JAMA Network Open, 5(5), e2212709. https://doi. org/ 10. 1001/jamanetworkopen.2022.12709.
[19] Kidney Disease: Improving Global Outcomes (KDIGO). (2026). KDIGO 2026 clinical practice guideline for acute kidney injury and acute kidney disease: public-review draft. https://kdigo.org/wp-content/uploads/2026/03/KDIGO-2026-AKI-AKD-Guideline-Public-Review-Draft-March-2026.pdf.
[20] Hollinger, A., Wittebole, X., François, B., et al. (2018). Proenkephalin A 119-159 (Penkid) is an early biomarker of septic acute kidney injury: the Kidney in Sepsis and Septic Shock (Kid-SSS) study. Kidney International Reports, 3, 1424–1433. https://doi.org/10.1016/j.ekir.2018.08.006.
[21] Fiorentino, M., Xu, Z., Smith, A., et al. (2020). Serial measurement of cell-cycle arrest biomarkers [TIMP-2]·[IGFBP7] and risk for progression to death, dialysis, or severe acute kidney injury in patients with septic shock. American Journal of Respiratory and Critical Care Medicine, 202, 1262–1270. https://doi.org/10.1164/rccm.201906-1197 OC.
[22] Bagshaw, S. M., Al-Khafaji, A., Artigas, A., et al. (2021). External validation of urinary C-C motif chemokine ligand 14 (CCL14) for prediction of persistent acute kidney injury. Critical Care, 25, 185. https://doi.org/10.1186/s13054-021-03618-1.
[23] Li, N., Tang, T. T., Gu, M., et al. (2025). Single urinary extracellular vesicle proteomics identifies complement receptor CD35 as a biomarker for sepsis-associated acute kidney injury. Nature Communications, 16, 6960. https://doi. org/ 10.1038/s41467-025-62229-4.
[24] Huang, P., Liu, Y., Li, Y., et al. (2025). Metabolomics- and proteomics-based multi-omics integration reveals early metabolite alterations in sepsis-associated acute kidney injury. BMC Medicine, 23, 79. https://doi.org/10.1186/s12916-025-03920-7.
[25] Xu, W., Zhang, Z., Gu, F., et al. (2026). Integrating metabolomics and machine learning with in silico analysis to identify early biomarkers and molecular interactions in sepsis-associated acute kidney injury. Scientific Reports, 16, 10963. https://doi.org/10.1038/s41598-026-45255-0.
[26] Lv, Y., Yu, M., Mao, Y., et al. (2026). Association of serum S100A8/A9 with sepsis-associated acute kidney injury and 28-day mortality: a hybrid cohort study. Scientific Reports, 16. https://doi.org/10.1038/s41598-026-59502-x.
[27] Jiang, W., Zhang, Y., Weng, J., et al. (2025). Explainable machine learning model for predicting persistent sepsis-associated acute kidney injury: Development and validation study. Journal of Medical Internet Research, 27, e62932. https:// doi.org/10.2196/62932.
[28] Ge, X., Chen, W., Shi, J., et al. (2025). Prediction of moderate-to-severe sepsis-associated acute kidney injury using a dual-timepoint machine learning model: Development, multiregional validation, and clinical deployment study. Journal of Medical Internet Research, 27, e73840. https:// doi. org/10.2196/73840.
[29] Kiernan, E., Zelnick, L. R., Khader, A., et al. (2025). Molecular phenotyping of sepsis and differential response to fluid resuscitation. American Journal of Respiratory and Critical Care Medicine, 211, 1681–1688. https://doi.org/ 10.1164/ rccm. 202412-2377OC.
[30] Evans, L., Rhodes, A., Alhazzani, W., et al. (2021). Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Medicine, 47, 1181–1247. https://doi.org/10.1007/s00134-021-06506-y.
[31] Meyhoff, T. S., Hjortrup, P. B., Wetterslev, J., et al. (2022). Restriction of intravenous fluid in intensive care unit patients with septic shock. The New England Journal of Medicine, 386, 2459–2470. https://doi.org/10.1056/NEJMoa2202707.
[32] Shapiro, N. I., Douglas, I. S., Brower, R. G., et al. (2023). Early restrictive or liberal fluid management for sepsis-induced hypotension. The New England Journal of Medicine, 388, 499–510. https://doi.org/10.1056/NEJMoa2212663.
[33] Hernández, G., Ospina-Tascón, G. A., Damiani, L. P., et al. (2019). Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA, 321, 654–664. https:// doi.org/10.1001/jama.2019.0071.
[34] Asfar, P., Meziani, F., Hamel, J. F., et al. (2014). High versus low blood-pressure target in patients with septic shock. The New England Journal of Medicine, 370, 1583–1593. https:// doi. org/10.1056/NEJMoa1312173.
[35] Gordon, A. C., Mason, A. J., Thirunavukkarasu, N., et al. (2016). Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA, 316, 509–518. https://doi.org/10. 1001/ jama. 2016.10485.
[36] Gaudry, S., Hajage, D., Schortgen, F., et al. (2016). Initiation strategies for renal-replacement therapy in the intensive care unit. The New England Journal of Medicine, 375, 122–133. https://doi.org/10.1056/NEJMoa1603017.
[37] Barbar, S. D., Clere-Jehl, R., Bourredjem, A., et al. (2018). Timing of renal-replacement therapy in patients with acute kidney injury and sepsis. The New England Journal of Medicine, 379, 1431–1442. https://doi.org/10. 1056/ NEJMoa 1803213.
[38] STARRT-AKI Investigators. (2020). Timing of initiation of renal-replacement therapy in acute kidney injury. The New England Journal of Medicine, 383, 240–251. https://doi.org/ 10. 1056/NEJMoa2000741.
[39] Pickkers, P., Mehta, R. L., Murray, P. T., et al. (2018). Effect of human recombinant alkaline phosphatase on 7-day creatinine clearance in patients with sepsis-associated acute kidney injury: A randomized clinical trial. JAMA, 320, 1998–2009. https://doi.org/10.1001/jama.2018.14283.
[40] Pickkers, P., Angus, D. C., Bass, K., et al. (2024). Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL). Intensive Care Medicine, 50, 68–78. https://doi.org/10.1007/s00134-023-07271-w.
[41] Shi, K., Jiang, W., Song, L., et al. (2025). Efficacy of hybrid blood purification for SA-AKI subtypes identified by CCL14: study protocol for a single-centre randomized controlled clinical trial. Trials, 26, 312. https://doi.org/10.1186/s13063-025-09058-4.
[42] Chawla, L. S., Bellomo, R., Bihorac, A., et al. (2017). Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup. Nature Reviews Nephrology, 13, 241–257. https://doi.org/ 10. 1038/ nrneph.2017.2.
[43] Chiang, H. Y., Liang, C. C., Hsiao, Y. L., et al. (2025). Sepsis-associated acute kidney disease incidence, trajectory, and outcomes. Kidney Medicine, 7, 100959. https://doi.org/ 10. 1016/ j. xkme.2024.100959.
[44] Bhatraju, P. K., Zelnick, L. R., Chinchilli, V. M., et al. (2020). Association between early recovery of kidney function after acute kidney injury and long-term clinical outcomes. JAMA Network Open, 3(10), e202682. https://doi.org/ 10.1001/ jamanetwor kopen.2020.2682.
[45] Legrand, M., Bagshaw, S. M., Bhatraju, P. K., et al. (2024). Sepsis-associated acute kidney injury: Recent advances in enrichment strategies, sub-phenotyping and clinical trials. Critical Care, 28, 92. https://doi.org/10.1186/s13054-024-04877-4.
[46] Zarbock, A., Forni, L. G., Ostermann, M., et al. (2024). Designing acute kidney injury clinical trials. Nature Reviews Nephrology, 20, 137–146. https://doi.org/10.1038/s41581-023-00758-1.
[47] Semler, M. W., Self, W. H., Wanderer, J. P., et al. (2018). Balanced crystalloids versus saline in critically ill adults. The New England Journal of Medicine, 378, 829–839. https://doi. org/ 10.1056/NEJMoa1711584.
[48] Brown, R. M., Wang, L., Coston, T. D., et al. (2019). Balanced crystalloids versus saline in sepsis: A secondary analysis of the SMART clinical trial. American Journal of Respiratory and Critical Care Medicine, 200, 1487–1495. https://doi.org/10. 1164/ rccm.201903-0557OC.
[49] Chawla, L. S., Davison, D. L., Brasha-Mitchell, E., et al. (2013). Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Critical Care, 17, R207. https://doi.org/10.1186/cc13015.
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