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

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-hocanalysis of a multicentre prospective study, we combined conventional kidney function variables (the pre-admission serum creatinine (SCr) and estimated glomerular filtration rate, SCr on inclusion (0 h) and at 24 h, blood urea nitrogen at 0 h, and the weight-corrected urine output (UO) at 0, 6, 12 and 24 h) 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 approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to the renal replacement therapy initiation rate and survival rate in the first seven days. Results: We included 184 patients presenting SA-AKI within six hours of the diagnosis of septic shock. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal UO, a low SCr and a low [TIMP-2]*[IGFBP7] level; subphenotype B (74 patients) was characterized by existing chronic kidney disease, 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. Renal replacement therapy was initiated within the first seven days in four (4%), 27 (36%) and three (27%) patients from the subphenotype A, B and C groups, respectively (p<0.001). After adjustment for confounding factors, the seven-day survival rate [95% confidence interval (CI)] was respectively 88% [80–96], 80% [72–88] and 75% [56–94] in the subphenotypes A, B and C. With subphenotype A as reference, the adjusted hazard-ratio [95%CI] for seven-day mortality was 1.53 [0.76–3.08] (p=0.24) in subphenotype B and 5.90 [2.04–17.07] (p=0.001) in subphenotype C. Conclusions: By combining conventional kidney function variables with urine measurements of a cell-cycle arrest biomarker, we identified three distinct SA-AKI subphenotypes with different short-term courses and survival rates. This approach might help to better stratify patients in the early phases of septic shock but its value must be confirmed in a larger, independent cohort. Trial registration: the AKI-CHECK study was registered at ClinicalTrials.gov (NCT02812784) before the inclusion of the first patient. Running head: Subphenotypes of sepsis-associated acute kidney injury