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 biomarker-positive 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 (NCT00510835).

Keywords: acute kidney injury; cell-cycle arrest biomarkers; dialysis; sepsis; survival.

Figure 1.

Study cohort. AKI = acute kidney injury; ProCESS = Protocol-based Care for Early Septic Shock; sCr = serum creatinine; [TIMP-2] · [IGFBP7] = the product of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor–binding protein 7; UO = urine output.

Figure 2.

Risk assessment flow diagram combining [TIMP-2] · [IGFBP7] (the product of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor–binding protein 7) at Hour 0 and Hour 6. The red boxes indicate the positivity of [TIMP-2] · [IGFBP7] (biomarker values greater than the cutoff), whereas the green ones represent the condition with biomarker-negative results. For each combination, we reported the proportion of patients who achieved the primary endpoint. Subgroup −/− = [TIMP-2] · [IGFBP7] negative at both Hour 0 and Hour 6; Subgroup −/+ = [TIMP-2] · [IGFBP7] negative at Hour 0 and [TIMP-2] · [IGFBP7] positive at Hour 6; Subgroup +/− = [TIMP-2] · [IGFBP7] positive at Hour 0 and [TIMP-2] · [IGFBP7] negative at Hour 6; Subgroup +/+ = [TIMP-2] · [IGFBP7] positive at both Hour 0 and Hour 6.

Figure 3.

Kaplan-Meier analysis at 1 year by [TIMP-2] · [IGFBP7] (the product of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor–binding protein 7) concentrations between Hour 0 and Hour 6. Subgroup −/− = [TIMP-2] · [IGFBP7] negative at both Hour 0 and Hour 6; Subgroup −/+ = [TIMP-2] · [IGFBP7] negative at Hour 0 and [TIMP-2] · [IGFBP7] positive at Hour 6; Subgroup +/− = [TIMP-2] · [IGFBP7] positive at Hour 0 and [TIMP-2] · [IGFBP7] negative at Hour 6; Subgroup +/+ = [TIMP-2] · [IGFBP7] positive at both Hour 0 and Hour 6.

Figure 4.

Risk assessment flow diagram for [TIMP-2] · [IGFBP7] (the product of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor–binding protein 7) at (A) Hour 0 and at (B) Hour 6 in combination with serum creatinine and urine output in predicting the risk of the primary endpoint. The red boxes indicate the positivity of the criteria (when serum creatinine and urine output meet Kidney Disease: Improving Global Outcomes criteria for acute kidney injury (AKI) stage 1, or when [TIMP-2] · [IGFBP7] values are greater than the cutoff). The green boxes represent the condition of normal serum creatinine, urine output (no clinical AKI), and biomarker negativity. For each combination, we reported the proportion of patients who achieved the primary endpoint.