Urinary Proteomics Identifies Distinct Immunological Profiles of Sepsis Associated AKI Sub-phenotypes

Overview

Journal Crit Care

Specialty Critical Care

Date 2024 Dec 19

PMID 39695715

Authors

Ian B Stanaway

Eric D Morrell

F Linzee Mabrey

Neha A Sathe

Zoie Bailey

Sarah Speckmaier

Jordan Lo

Leila R Zelnick

Jonathan Himmelfarb

Carmen Mikacenic

Laura Evans

Mark M Wurfel

Pavan K Bhatraju

Affiliations

Soon will be listed here.

Abstract

Background: Patients with sepsis-induced AKI can be classified into two distinct sub-phenotypes (AKI-SP1, AKI-SP2) that differ in clinical outcomes and response to treatment. The biologic mechanisms underlying these sub-phenotypes remains unknown. Our objective was to understand the underlying biology that differentiates AKI sub-phenotypes and associations with kidney outcomes.

Methods: We prospectively enrolled 173 ICU patients with sepsis from a suspected respiratory infection (87 without AKI and 86 with AKI on enrollment). Among the AKI patients, 66 were classified as AKI-SP1 and 20 as AKI-SP2 using a three-plasma biomarker classifier. Aptamer-based proteomics assessed 5,212 proteins in urine collected on ICU admission. We compared urinary protein abundances between AKI sub-phenotypes, conducted pathway analyses, tested associations with risk of RRT and blood bacteremia, and predicted AKI-SP2 class membership using LASSO.

Measurement And Main Results: In total, 117 urine proteins were higher in AKI-SP2, 195 were higher in AKI-SP1 (FDR < 0.05). Urinary proteins involved in inflammation and chemoattractant of neutrophils and monocytes (CXCL1 and REG3A) and oxidative stress (SOD2) were abundant in AKI-SP2, while proteins involved in collagen deposition (GP6), podocyte derived (SPOCK2), proliferation of mesenchymal cells (IL11RA), anti-inflammatory (IL10RB and TREM2) were abundant in AKI-SP1. Pathways related to immune response, complement activation and chemokine signaling were upregulated in AKI-SP2 and pathways of cell adhesion were upregulated in AKI-SP1. Overlap was present between urinary proteins that differentiated AKI sub-phenotypes and proteins that differentiated risk of RRT during hospitalization. Variable correlation was found between top aptamers and ELISA based protein assays. A LASSO derived urinary proteomic model to classify AKI-SP2 had a mean AUC of 0.86 (95% CI: 0.69-0.99).

Conclusion: Our findings suggest AKI-SP1 is characterized by a reparative, regenerative phenotype and AKI-SP2 is characterized as an immune and inflammatory phenotype associated with blood bacteremia. We identified shared biology between AKI sub-phenotypes and eventual risk of RRT highlighting potential therapeutic targets. Urine proteomics may be used to non-invasively classify SP2 participants.

Citing Articles

Urinary proteomics in sepsis-associated AKI.

Moser J, van der Aart T, Bouma H Crit Care. 2025; 29(1):77.

PMID: 39956897 PMC: 11831842. DOI: 10.1186/s13054-025-05306-w.

References

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L . Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 384(8):693-704. PMC: 7383595. DOI: 10.1056/NEJMoa2021436. View

Joannidis M, Metnitz P . Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin. 2005; 21(2):239-49. DOI: 10.1016/j.ccc.2004.12.005. View

Hoste E, Bagshaw S, Bellomo R, Cely C, Colman R, Cruz D . Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015; 41(8):1411-23. DOI: 10.1007/s00134-015-3934-7. View

Clermont G, Acker C, Angus D, Sirio C, Pinsky M, Johnson J . Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes. Kidney Int. 2002; 62(3):986-96. DOI: 10.1046/j.1523-1755.2002.00509.x. View

Uchino S, Kellum J, Bellomo R, Doig G, Morimatsu H, Morgera S . Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005; 294(7):813-8. DOI: 10.1001/jama.294.7.813. View

Zarjou A, Agarwal A . Sepsis and acute kidney injury. J Am Soc Nephrol. 2011; 22(6):999-1006. DOI: 10.1681/ASN.2010050484. View

Prowle J, Bellomo R . Sepsis-associated acute kidney injury: macrohemodynamic and microhemodynamic alterations in the renal circulation. Semin Nephrol. 2015; 35(1):64-74. DOI: 10.1016/j.semnephrol.2015.01.007. View

Cantaluppi V, Medica D, Quercia A, Dellepiane S, Figliolini F, Virzi G . Perfluorocarbon solutions limit tubular epithelial cell injury and promote CD133+ kidney progenitor differentiation: potential use in renal assist devices for sepsis-associated acute kidney injury and multiple organ failure. Nephrol Dial Transplant. 2017; 33(7):1110-1121. DOI: 10.1093/ndt/gfx328. View

Pickkers P, Mehta R, Murray P, Joannidis M, Molitoris B, Kellum J . Effect of Human Recombinant Alkaline Phosphatase on 7-Day Creatinine Clearance in Patients With Sepsis-Associated Acute Kidney Injury: A Randomized Clinical Trial. JAMA. 2018; 320(19):1998-2009. PMC: 6248164. DOI: 10.1001/jama.2018.14283. View

Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Verney C, Pons B . Timing of Renal Support and Outcome of Septic Shock and Acute Respiratory Distress Syndrome. A Post Hoc Analysis of the AKIKI Randomized Clinical Trial. Am J Respir Crit Care Med. 2018; 198(1):58-66. DOI: 10.1164/rccm.201706-1255OC. View

10.

Barbar S, Clere-Jehl R, Bourredjem A, Hernu R, Montini F, Bruyere R . Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018; 379(15):1431-1442. DOI: 10.1056/NEJMoa1803213. View

11.

Bellomo R, Ronco C, Kellum J, Mehta R, 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. Crit Care. 2004; 8(4):R204-12. PMC: 522841. DOI: 10.1186/cc2872. View

11.

DiRocco D, Bisi J, Roberts P, Strum J, Wong K, Sharpless N . CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. Am J Physiol Renal Physiol. 2013; 306(4):F379-88. PMC: 3920026. DOI: 10.1152/ajprenal.00475.2013. View

12.

Yu G, Liu Q, Dong X, Tang K, Li B, Liu C . Inhibition of inflammation using diacerein markedly improved renal function in endotoxemic acute kidney injured mice. Cell Mol Biol Lett. 2018; 23:38. PMC: 6097202. DOI: 10.1186/s11658-018-0107-z. View

13.

Bellomo R, Kellum J, Ronco C . Acute kidney injury. Lancet. 2012; 380(9843):756-66. DOI: 10.1016/S0140-6736(11)61454-2. View

13.

Luo C, Luo F, Zhang L, Xu Y, Cai G, Fu B . Knockout of interleukin-17A protects against sepsis-associated acute kidney injury. Ann Intensive Care. 2016; 6(1):56. PMC: 4917508. DOI: 10.1186/s13613-016-0157-1. View

14.

Stanski N, Wong H . Prognostic and predictive enrichment in sepsis. Nat Rev Nephrol. 2019; 16(1):20-31. PMC: 7097452. DOI: 10.1038/s41581-019-0199-3. View

14.

Bhatraju P, Zelnick L, Herting J, Katz R, Mikacenic C, Kosamo S . Identification of Acute Kidney Injury Subphenotypes with Differing Molecular Signatures and Responses to Vasopressin Therapy. Am J Respir Crit Care Med. 2018; 199(7):863-872. PMC: 6444649. DOI: 10.1164/rccm.201807-1346OC. View

15.

Wiersema R, Jukarainen S, Vaara S, Poukkanen M, Lakkisto P, Wong H . Two subphenotypes of septic acute kidney injury are associated with different 90-day mortality and renal recovery. Crit Care. 2020; 24(1):150. PMC: 7161019. DOI: 10.1186/s13054-020-02866-x. View

16.

Bhatraju P, Cohen M, Nagao R, Morrell E, Kosamo S, Chai X . Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes. BMC Nephrol. 2020; 21(1):284. PMC: 7368773. DOI: 10.1186/s12882-020-01935-1. View