The clinical utility window for acute kidney injury biomarkers in the critically ill

Abstract

Introduction: Acute Kidney Injury (AKI) biomarker utility depends on sample timing after the onset of renal injury. We compared biomarker performance on arrival in the emergency department (ED) with subsequent performance in the intensive care unit (ICU).

Methods: Urinary and plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL), and urinary Cystatin C (CysC), alkaline phosphatase, γ-Glutamyl Transpeptidase (GGT), α- and π-Glutathione S-Transferase (GST), and albumin were measured on ED presentation, and at 0, 4, 8, and 16 hours, and days 2, 4 and 7 in the ICU in patients after cardiac arrest, sustained or profound hypotension or ruptured abdominal aortic aneurysm. AKI was defined as plasma creatinine increase ≥ 26.5 μmol/l within 48 hours or ≥ 50% within 7 days.

Results: In total, 45 of 77 patients developed AKI. Most AKI patients had elevated urinary NGAL, and plasma NGAL and CysC in the period 6 to 24 hours post presentation. Biomarker performance in the ICU was similar or better than when measured earlier in the ED. Plasma NGAL diagnosed AKI at all sampling times, urinary NGAL, plasma and urinary CysC up to 48 hours, GGT 4 to 12 hours, and π-GST 8 to 12 hours post insult. Thirty-one patients died or required dialysis. Peak 24-hour urinary NGAL and albumin independently predicted 30-day mortality and dialysis; odds ratios 2.87 (1.32 to 6.26), and 2.72 (1.14 to 6.48), respectively. Urinary NGAL improved risk prediction by 11% (IDI event of 0.06 (0.002 to 0.19) and IDI non-event of 0.04 (0.002 to 0.12)).

Conclusion: Early measurement in the ED has utility, but not better AKI diagnostic performance than later ICU measurement. Plasma NGAL diagnosed AKI at all time points. Urinary NGAL best predicted mortality or dialysis compared to other biomarkers.

Trial registration: Australian and New Zealand Clinical Trials Registry ACTRN12610001012066. Registered 12 February 2010.

Figure 1

Patient flow and numbers.

Figure 2

Temporal profiles of acute kidney injury (AKI) biomarker concentrations in patients with and without AKI. For each biomarker the graph on the right has individual profiles of AKI patients (blue lines) and non-AKI patients (grey lines). The graph on the left represents median values of AKI patients (blue squares), and non-AKI patients (white circles). Vertical bars cover the interquartile range. The dashed horizontal lines are pre-specified cut points of biomarkers. P-values are for comparison of biomarker concentrations between those with and without AKI were performed using repeated-measures analysis of variance after log-transformation. (A) Plasma creatinine; (B) plasma cystatin C; (C) plasma neutrophil gelatinase-associated lipocalin (NGAL); (D) urinary NGAL; (E) urinary cystatin C; (F) urinary gamma-glutamyltranspeptidase (GGT); (G) urinary α-glutathione-S-transferase (GST); (H) urinary π-GST; (I) urinary alkaline phosphatase (AP); (J) urinary albumin.

Figure 3

Time dependence of biomarker performance in diagnosis of acute kidney injury (AKI). White circles represent the area under the receiver operating characteristic curve (AUC) with 95% confidence interval (shaded areas). An AUC with a confidence interval not overlapping 0.5 was considered diagnostic. (A) Plasma creatinine; (B) plasma cystatin C; (C) plasma neutrophil gelatinase-associated lipocalin (NGAL); (D) urinary NGAL; (E) urinary cystatin C; (F) urinary gamma-glutamyltranspeptidase (GGT); (G) urinary α-glutathione-S-transferase (GST); (H) urinary π-GST; (I) urinary alkaline phosphatase (AP); (J) urinary albumin.

Figure 4

Risk assessment plots showing the additional value of individual biomarkers compared with the reference model for prediction of the composite of mortality or dialysis. The reference model included the modified acute physiological and chronic health evaluation (APACHE) II score (without creatinine score), and AKI₂₄ (present or absent). The new models comprised the reference model plus peak (A) urinary neutrophil gelatinase-associated lipocalin (NGAL), (B) urinary albumin (C) plasma cystatin C, or (D) urinary π-glutathione-S-transferase (GST) within 24 h. Event curves (squares) are sensitivity versus calculated risk. Non-event curves (circles) are 1-specificity versus calculated risk.