Use of Cell Cycle Arrest Biomarkers in Conjunction With Classical Markers of Acute Kidney Injury

Abstract

Objectives: Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death.

Design: Prospective, international, Sapphire study.

Setting: Academic Medical Center.

Patients: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3.

Interventions: None.

Measurements and main results: The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2-3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]•[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]•[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2-3) within 7 days.

Conclusions: Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]•[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.

Figure 1.

Kaplan-Meier curves for Stage 3 acute kidney injury (AKI) or death by AKI status by serum creatinine (SCr) and tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) level relative to the 0.3 (A) and 2.0 (B) cutoffs. Patients are grouped as [TIMP-2]•[IGFBP7] negative and no AKI by SCr (purple), [TIMP-2]•[IGFBP7] negative and AKI by SCr (green), [TIMP-2]•[IGFBP7] positive and no AKI by SCr (blue), [TIMP-2]•[IGFBP7] positive and AKI by SCr (red). The values below the plots indicate number at risk. Long-rank p < 0.001 for both panels.

Figure 2.

Kaplan-Meier curves for Stage 3 acute kidney injury (AKI) or death by AKI status by urine output (UO) and tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) level relative to the 0.3 (A) and 2.0 (B) cutoffs. Patients are grouped as [TIMP-2]•[IGFBP7] negative and no AKI by UO (purple), [TIMP-2]•[IGFBP7] negative and AKI by UO (green), [TIMP-2]•[IGFBP7] positive and no AKI by UO (blue), [TIMP-2]•[IGFBP7] positive and AKI by UO (red). The values below the plots indicate number at risk. Long-rank p < 0.001 for both panels.

Figure 3.

Kaplan-Meier curves for death or dialysis within 9 mo among patients who were alive and dialysis-free at 7 d after enrolment. Patients who did not progress to stage 2–3 AKI within 7 d from enrollment were divided into three categories based on the maximum tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) value within 30 hr of enrollment and the maximum AKI stage within 12 hr of [TIMP-2]•[IGFBP7] as (1) no AKI, (2) stage 1 AKI and [TIMP-2]•[IGFBP7] less than or equal to 2.0, and (3) stage 1 AKI and [TIMP-2]•[IGFBP7] greater than 2.0. Patients who progressed to stage 2–3 AKI within 7 d were included as a single category. Long-rank p = 0.004.