The combination of kidney function variables with cell cycle arrest biomarkers identifies distinct subphenotypes of sepsis-associated acute kidney injury: a post-hoc analysis (the PHENAKI study)

Abstract

Background

The severity and course of sepsis-associated acute kidney injury (SA-AKI) are correlated with the mortality rate. Early detection of SA-AKI subphenotypes might facilitate the rapid provision of individualized care.

Patients and methods

In this post-hoc analysis of a multicenter prospective study, we combined conventional kidney function variables with serial measurements of urine (tissue inhibitor of metalloproteinase-2 [TIMP-2])* (insulin-like growth factor-binding protein [IGFBP7]) at 0, 6, 12, and 24 h) and then using an unsupervised hierarchical clustering of principal components (HCPC) approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to a composite outcome of in-hospital death or the initiation of renal replacement therapy (RRT).

Results

We included 184 patients presenting SA-AKI within 6 h of the initiation of catecholamines. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal urine output (UO), a low SCr and a low [TIMP-2]*[IGFBP7] level; subphenotype B (74 patients) was characterized by existing chronic kidney disease (CKD), a higher SCr, a low UO, and an intermediate [TIMP-2]*[IGFBP7] level; and subphenotype C was characterized by very low UO, a very high [TIMP-2]*[IGFBP7] level, and an intermediate SCr level. With subphenotype A as the reference, the adjusted hazard ratio (aHR) [95%CI] for the composite outcome was 3.77 [1.92–7.42] (p < 0.001) for subphenotype B and 4.80 [1.67–13.82] (p = 0.004) for subphenotype C.

Conclusions

Combining conventional kidney function variables with urine measurements of [TIMP-2]*[IGFBP7] might help to identify distinct SA-AKI subphenotypes with different short-term courses and survival rates.

Trial registration:

• The AKI-CHECK study was registered at ClinicalTrials.gov (NCT02812784)

Keywords:

• Acute kidney injury
• septic shock
• biomarkers
• phenotype
• cluster

Acknowledgments

Some of these results were presented as an e-Poster at the ESICM 2023 Congress. An earlier version of the manuscript has been posted as a preprint at https://doi.org/10.21203/rs.3.rs-2894389/v1.

Ethics approval and consent to participate

The study protocol was approved by an independent ethics committee (CPP Nord Ouest II, Amiens, France; reference: 2015-A01392-47). Patients and their surrogates were informed of the study’s objectives and procedures and consented to participation.

Consent for publication

Not applicable.

Author contributions

Conception and design of the study: DTB and JM. Inclusion and acquisition of data: DTB, JM, DD, LVV, GB, CB, KK, and CV. Analysis and interpretation of data: DTB, MD, JM, and YZ. Preparation of the manuscript: DTB and JM. All authors read and approved the final manuscript.

Availability of data and material

The datasets used and/or analyzed in this study are available from the corresponding author on request.

Disclosure statement

The authors declare that they have no competing interests.