Rule Out Acute Kidney Injury in the Emergency Department With a Urinary Dipstick

Abstract

Introduction: The identification of acute injury of the kidney relies on serum creatinine (SCr), a functional marker with poor temporal resolution as well as limited sensitivity and specificity for cellular injury. In contrast, urinary biomarkers of kidney injury have the potential to detect cellular stress and damage in real time.

Methods: To detect the response of the kidney to injury, we have tested a lateral flow dipstick that measures a urinary protein called neutrophil gelatinase-associated lipocalin (NGAL). Analysis of urine was performed in a prospective cohort of 479 patients (final cohort N = 426) entering an emergency department in New York City and subsequently admitted for inpatient care.

Results: Colorimetric development had high interrater reliability (88% concordance rate) and correlated with traditional enzyme-linked immunosorbent assay (ELISA) measurements (ρ = 0.732, P < .0001). Of the 14% of the cohort who met Acute Kidney Injury Network (AKIN) SCr criteria for acute kidney injury (AKI), 67% demonstrated transient (<2 days) and 33% demonstrated sustained (>2 days) elevation of SCr. Comparing the outcomes of patients with sustained versus transient or undetectable changes in SCr revealed that the urinary NGAL (uNGAL) dipstick had high specificity and negative predictive value (NPV) (high- vs. low-intermediate readings, sensitivity = 0.55, specificity = 0.91, positive predictive value = 0.24, NPV = 0.97, χ² = 20.39, P < 0.001).

Conclusion: We show that the introduction of a bedside uNGAL dipstick permits accurate triage by identifying individuals who do not have tubular injury. In an era of shortening length of stay and rapid decisions based on isolated SCr measurements, real-time exclusion of kidney injury by a dipstick will be particularly useful to overcome the retrospective, insensitive, and nonspecific attributes of SCr.

Keywords: AKI; NGAL; biomarker; dipstick; emergency department.

Graphical abstract

Figure 1

Patient enrollment from the emergency department. Eight hundred thirty-four patients were initially approached in the emergency department, but approximately 50% of these patients were not part of the final cohort for the following reasons: 39% declined to participate, whereas an additional 10% were excluded because they did not meet entry criteria or they failed to meet minimum necessary laboratory or clinical data standards. The final cohort included 426 patients. Cr, creatinine; ESRD, end-stage renal disease.

Figure 2

Development of analytical tools: clinical algorithm for characterization of creatinine kinetics and measurement of urinary neutrophil gelatinase-associated lipocalin (uNGAL) by dipstick. (a) Comparison of serum creatinine (SCr) kinetics and clinical outcomes. Yellow depicts days when the level of SCr met the Acute Kidney Injury Network (AKIN) criteria. Green depicts days when SCr levels did not meet the AKIN criteria. White depicts days when SCr was not measured. Urine was collected at presentation (day 0, d0), and, therefore, SCr trends between days 0 and 2 were critical to determine AKIN scoring (see Methods for AKI Stratification). The automated algorithm adjudicated these categories: no AKI (light gray), transient AKI resolving within 48 hours of detection (blue) (e.g., if met criteria on day 0, then normalized by day 2; and, if met criteria on day 1, then normalized by day 3), and sustained AKI persisting beyond 48 hours of detection (red) (e.g., if met criteria on day 0, then either did not normalize or only normalized ≥day 3; if met criteria on day 1, then either did not normalize or only normalized ≥day 4). Unknown diagnoses are represented in dark gray. tAKI, transient AKI; sAKI, sustained AKI; unknown=insufficient data to make categorization. (b) Anti-NGAL recognizes the glycosylated NGAL gene product (∼22 kDa) and the glycosylated dimer (∼44 kDa). Note nonglycosylated recombinant human NGAL (∼20KDa). (c) The same NGAL antibody was used for the lateral-flow dipstick. Human urine was spiked with increasing amounts of recombinant human NGAL. Note the increasing density of the test line. (d) Representative uNGAL dipsticks; correlation with ELISA measurements. (e) A summary of the dipstick and ELISA measurements in the final cohort. The mean ELISA uNGAL values correlated with low, intermediate, and high dipstick values (∗<0.001, n = 424).

Figure 3

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) measured by dipstick correlates with sustained elevations in creatinine. (a) High uNGAL readings in the emergency department correlate with sustained serum creatinine elevation after admission (P = 0.004, n = 426). (b) The relationship was even more evident once confounders (baseline estimated glomerular filtration rate < 30 or positive urinary tract infection or unknown urinary tract infection status) were excluded (P = 0.008, n = 285). Light gray = low uNGAL, dark gray = intermediate uNGAL, and black = high uNGAL. AKI, acute kidney injury; DPI, dots per inch; sAKI, sustained acute kidney injury; tAKI, transient acute kidney injury; unknown, insufficient data to make categorization.

Figure 4

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) dipstick measurements correlate with AKIN severity and predict the combined endpoint of in-hospital mortality and renal replacement therapy. (a) High uNGAL readings in the emergency department correlate with AKIN severity score (P = 0.002). Black = high uNGAL, dark gray = intermediate uNGAL; light gray = low uNGAL. (b) Patients with high uNGAL dipstick readings were significantly more likely to experience the composite outcome of death and/or renal replacement therapy during the index admission (high vs. low odds ratio = 4.32 [range 1.19–15.65], P = 0.026). AKIN, Acute Kidney Injury Network; DPI, dots per inch.