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. 2024 Dec 18;28(1):419.
doi: 10.1186/s13054-024-05202-9.

Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes

Ian B Stanaway  1   2 , Eric D Morrell  2   3 , F Linzee Mabrey  2   3 , Neha A Sathe  2   3 , Zoie Bailey  2   3 , Sarah Speckmaier  2   3 , Jordan Lo  2   3 , Leila R Zelnick  1   2 , Jonathan Himmelfarb  1 , Carmen Mikacenic  2   4 , Laura Evans  3 , Mark M Wurfel  1   3 , Pavan K Bhatraju  5   6
Affiliations

Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes

Ian B Stanaway et al. Crit Care. .

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.

Keywords: Acute kidney injury; Intensive care unit; Sepsis; Urinary proteomics.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The University of Washington institutional review board approved this study. Consent for publication: No individual personal data is included in the study. The IRB provided waiver of consent to participate in this study. Competing interests: There are no conflicts of interest among the authors of this manuscript.

Figures

Fig. 1
Fig. 1
Comparison of urinary proteomic profile between patients with AKI-SP1 and AKI-SP2. Volcano plot showing 117 urinary proteins with higher abundance in AKI-SP2 and 195 urinary proteins with higher urinary abundance in AKI-SP1 adjusted for age, sex, COVID-19 diagnosis, and body mass index
Fig. 2
Fig. 2
Pathway analysis of urinary proteins between AKI-SP1 and AKI-SP2. 17 pathways were upregulated in AKI-SP2, while 3 pathways were downregulated in AKI-SP2 using WebGestalt based on a FDR ≤ 0.1. To the left of the figure includes each pathway ID and to the right of the figure includes the total number of proteins within the pathway
Fig. 3
Fig. 3
Association of urinary proteins with risk of RRT during hospitalization. Among 86 patients with AKI-SP1 or AKI-SP2, 13 (15%) developed RRT. A greater abundance of urinary proteins to the right of 1 (n = 206) demonstrate a higher odds of receiving dialysis and a greater abundance of urinary proteins to the left of 1 (n = 179) demonstrate a higher odds for not receiving dialysis. Urinary proteins that are also significantly associated with AKI-SP1 are colored purple and urinary proteins significantly associated with AKI-SP2 are colored gold to demonstrate the overlap in biological processes leading to AKI sub-phenotypes and also to risk of dialysis
See this image and copyright information in PMC

Comment in

  • Urinary proteomics in sepsis-associated AKI.
    Moser J, van der Aart TJ, Bouma HR. Moser J, et al. Crit Care. 2025 Feb 16;29(1):77. doi: 10.1186/s13054-025-05306-w. Crit Care. 2025. PMID: 39956897 Free PMC article. No abstract available.

References

    1. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813–8. - PubMed
    1. Joannidis M, Metnitz PGH. Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin. 2005;21:239–49. - PubMed
    1. Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41:1411–23. - PubMed
    1. Clermont G, Acker CG, Angus DC, Sirio CA, Pinsky MR, Johnson JP. Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes. Kidney Int. 2002;62:986–96. - PubMed
    1. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet Lond Engl. 2012;380:756–66. - PubMed

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