Utility of Biomarkers for Sepsis-Associated Acute Kidney Injury Staging

Abstract

IMPORTANCEThe 23rd Acute Disease Quality Initiative (ADQI-23) consensus conference proposed a framework to integrate biomarkers into the staging of acute kidney injury (AKI). It is unknown whether tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulinlike growth factor binding protein 7 (IGFBP7) could be used for staging. OBJECTIVETo test whether higher levels of urinary [TIMP-2] × [IGFBP7] are associated with lower survival among patients with the same functional stage of AKI. DESIGN, SETTING, AND PARTICIPANTS This cohort study was performed using data from the Protocolized Care for Early Septic Shock (ProCESS) trial, which enrolled critically ill patients with septic shock who presented at academic and community emergency departments and intensive care units in the US from March 2008 to May 2013. Patients with end-stage kidney disease, a reference serum creatinine level of 4 mg/dL or greater (to convert to μmol/L, multiply by 76.25), or missing data on serum creatinine levels or urinary levels of [TIMP-2] × [IGFBP7] were excluded. Data were analyzed from October 2020 to October 2021. EXPOSURES The presence of AKI, assessed using Kidney Disease: Improving Global Outcomes criteria within 24 hours after enrollment and the highest AKI stage as well as urinary [TIMP-2] × [IGFBP7] level at 6 hours after enrollment. A previously reported high-specificity cutoff level for [TIMP-2] × [IGFBP7] of 2.0 (ng/mL) 2 /1000 was used to categorize patients (including those without functional criteria of AKI) according to the new staging system proposed by the ADQI-23 as biomarker negative (urinary [TIMP-2] × [IGFBP7] level Յ2.0 [ng/mL] 2 /1000) or biomarker positive ([TIMP-2] × [IGFBP7] >2.0 [ng/mL] 2 /1000).MAIN OUTCOMES AND MEASURES Survival (assessed using Kaplan-Meier plots and the log-rank test) and mortality (assessed using relative risk [RR] 30 days after enrollment). RESULTSThe analysis included 999 patients with a median age of 61 years (IQR, 50-73 years); 554 (55.5%) were male. Biomarker-positive patients had lower survival and higher mortality at 30 days in the groups with AKI stage 1 (RR, 2.20; 95% CI, 1.02-4.72), stage 2 (RR, 1.53; 95% CI, 1.04-2.27), and stage 3 (RR, 1.61; 95% CI, 1.00-2.60). The associations were specific to patients with AKI. No difference in 30-day survival was found between biomarker-positive and biomarker-negative patients in the absence of functional criteria for AKI (RR, 1.16; 95% CI, 0.45-3.01). CONCLUSIONS AND RELEVANCEThe findings suggest that assessment of the cell-cycle arrest biomarkers TIMP-2 and IGFBP7 may augment AKI staging for patients with functional criteria for AKI.

Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup

“…For example, stage 1S ('subclinical AKI'), could be defined by biomarker-positive evidence of kidney injury that does not meet the KDIGO criteria (that is, AKI stage 1 defined by creatinine and urine output criteria are not achieved). Data from the Protocolized Care for Early Septic Shock (ProCESS) cohort reported in 2022, demonstrate that, for a given stage of KDIGO-defined AKI, higher biomarker values (stages 1B, 2B and 3B) were associated with a higher risk of 30-day mortality than stages 1A, 2A and 3A 105 . However, 30-day survival did not differ between biomarker-positive (stage 1S) and biomarker-negative cases in the absence of KDIGO AKI criteria.…”

Biomarker Enrichment in Sepsis-Associated Acute Kidney Injury: Finding High-Risk Patients in the Intensive Care Unit

“…The original ProCESS trial failed to show a difference in patient outcomes with regard to its primary endpoint of 90-day mortality although there were some differences in fluid balance and AKI event rates across the 3 arms. In a post hoc analyses of a subset of ProCESS patients, the authors sought to assess how TIMP2*IGFBP7 biomarker levels changed before and after the initial 6-h resuscitation protocol and examined how these TIMP2*IGFBP7 changes were associated with patient outcomes (AKI and mortality) [20].…”

“…Where, as above, a TIMP2*IGFBP7 level above 0.30 constituted a biomarker-positive AKI state. In those with stage 1 only, 15% of patients were biomarker positive; this increased to 27% and 34.4% in stages 2 and 3 AKI, respectively [20].…”

“…assess how TIMP2*IGFBP7 biomarker levels changed before and after the initial 6-h resuscitation protocol and examined how these TIMP2*IGFBP7 changes were associated with patient outcomes (AKI and mortality) [20].…”

“…The clinical prognostic value of identifying the unique AKI phenotypes (and endotypes) is emerging and not yet fully established. However, early data do suggest that tubular damage markers are associated with worse outcomes and can be highly correlated to the other molecular signatures of severe AKI [11, 20, 21] (Fig. 1).…”