Serial Measurement of Cell-Cycle Arrest Biomarkers [TIMP-2] · [IGFBP7] and Risk for Progression to Death, Dialysis, or Severe Acute Kidney Injury in Patients with Septic Shock

Abstract

Rationale: Urinary TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein 7) can predict acute kidney injury (AKI) in patients with sepsis.Objectives: To address critical questions about whether biomarkers can inform the response to treatment and whether they might be used to guide therapy, as most sepsis patients present with AKI. Methods:We measured [TIMP-2] $ [IGFBP7] before and after a 6-hour resuscitation in 688 patients with septic shock enrolled in the ProCESS (Protocol-based Care for Early Septic Shock) trial. Our primary endpoint was stage 3 AKI, renal replacement therapy, or death within 7 days.Measurements and Main Results: The endpoint was reached in 113 patients (16.4%). In patients with negative [TIMP-2] $ [IGFBP7] at baseline, those who became positive (.0.3 U) after resuscitation had three-times higher risk compared with those who remained negative (21.8% vs. 8.5%; P = 0.01; odds ratio [OR], 3.0; 95% confidence interval [CI], 1.31-6.87). Conversely, compared with patients with a positive biomarker at baseline that were still positive at Hour 6, risk was reduced for patients who became negative (23.8% vs. 9.8%; P = 0.01; OR, 2.15; 95% CI, 1.17-3.95). A positive [TIMP-2] $ [IGFBP7] after resuscitation was associated with worse outcomes in both patients with and without AKI at that time point. The clinical response to resuscitation, as judged by the Acute Physiology and Chronic Health Evaluation II score, was weakly predictive of the endpoint (area under the curve, 0.68; 95% CI, 0.62-0.73) and improved with addition of [TIMP-2] $ [IGFBP7] (0.72; 95% CI, 0.66-0.77; P = 0.03). Different resuscitation protocols did not alter biomarker trajectories, nor did they alter outcomes in biomarkerpositive or biomarker-negative patients. However, biomarker trajectories were associated with outcomes. Conclusions: Changes in urinary [TIMP-2] $ [IGFBP7] after initial fluid resuscitation identify patients with sepsis who have differing risk for progression of AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 00510835).

Trajectory of Kidney Function: The Canary in Sepsis

“…1262–1270 ) report the findings from a secondary analysis of the ProCESS (Protocolized Care for Early Septic Shock) study ( 7 ), a multicenter randomized controlled trial (RCT) completed in the United States that recruited patients from the emergency department with septic shock and tested two alternative resuscitation strategies compared with usual care. The current study validates that prespecified cutoffs of the product of two urinary biomarkers, TIMP2 (tissue inhibitor of metalloproteinases 2) and IGFBP7 (insulin-like growth factor binding protein 7), are associated with the development of a composite outcome of stage 3 AKI, renal replacement therapy, or death within 7 days after study enrollment ( 8 ).…”

Targeting acute kidney injury in COVID-19

“…Trial designs that require the interventional agent to be administered before AKI manifests can be more challenging but even here use of biomarkers can be helpful. Patients with sepsis who have a positive urinary [TIMP-2]•[IGFBP7] that remains elevated despite fluid resuscitation are at dramatically increased risk for dying or progressing to Stage 3 AKI within 7 days [ 77 ]. Thus, the design here can be to use a screening biomarker test first and a follow-up 6 h later.…”

Urinary CXCL10 is Associated with Acute Kidney Injury and Sepsis, and Predicts Mortality in Critically Ill Children

“…Considering that septic AKI is a frequent complication in critically ill patients, and associated with higher risk of in-hospital mortality [28,32], the identi cation of early biomarkers of septic AKI is extremely important. Urinary biomarker neutrophil gelatinase-associated lipocalin and cell cycle biomarkers of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 are the frequently investigated and have been proved to predict septic AKI in patients with sepsis [32][33][34]. Our nding emphasizes that uCXCL10, as any other biomarker, must be interpreted in the speci c clinical context.…”