Urine Neutrophil Gelatinase-Associated Lipocalin and Kidney Injury Molecule-1 to Detect Pediatric Cisplatin-Associated Acute Kidney Injury

Abstract

Background: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin.

Methods: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher).

Results: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0-232.7] versus 14.9 [5.4-29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083-9077] versus 1049 [358-3326] pg/mg creatinine; P<0.01). These markers modestly discriminated for AKI (area under receiver operating characteristic curve [AUC-ROC] range: NGAL, 0.56-0.72; KIM-1, 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROC range, 0.54-0.75) versus early infusions (AUC-ROC range, 0.48-0.65).

Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and associations with late kidney outcomes.

Keywords: acute kidney injury; acute kidney injury and ICU nephrology; chemotherapy; cisplatin nephrotoxicity; cohort studies; diagnostic testing; kidney injury molecule-1; neutrophil gelatinase-associated lipocalin; pediatric hematology/oncology; pediatric nephrology; urine biomarkers.

Graphical abstract

Figure 1.

Flow diagram of study participants showing number of patients enrolled and analysed and urine collection protocol performance. The study flow diagram outlines the number of patients enrolled in the study, those with available data for analyses, and those with urine successfully collected and measured. At the early visit and late visit, urine specimens for the pre-infusion time point were collected on the day of cisplatin infusion, but before cisplatin administration; post-infusion samples were collected 1 day after cisplatin infusion (in the morning). Samples collected near hospital discharge at the early visit were collected a median (interquartile range) of 3 (2–4) days post-cisplatin infusion, whereas discharge samples at the late visit were collected 2 (2–4) days post-infusion. ^aReasons for specimen noncollection at individual time points at the early visit and the late visit included insufficient quantity, participant refusal, sample misplaced, and protocol error. ^bMissing measurements are due to insufficient quantity of specimen available to measure urine creatinine.

Figure 2.

Biomarker excretion patterns surrounding cisplatin infusion at early and late cisplatin visits by serum creatinine-AKI status showing patients with AKI had higher urine biomarker levels. Graph shows box-and-whisker plots (the lower end of the boxes represents the 25th percentile, and the upper end of the boxes represents the 75th percentile; the middle line is the median; the upper whisker outlines the upper adjacent value, and the lower whisker outlines the lower adjacent value) of urine AKI biomarkers measured at three time points surrounding the cisplatin infusion at the early visit (left) and the late visit (right). Time points shown on the x axis: pre-infusion (Pre), before cisplatin infusion start on day of infusion (day 1); morning post-infusion (Post; day 2); and discharge, just before hospital discharge (day 2–5). The number of participants analyzed for each time point are indicated in boxes under each bar. Outliers were excluded. The Skillings–Mack test P value for comparing biomarker levels across the three time points within AKI or non-AKI groups are indicated in boxes at the top of each panel. No urine neutrophil gelatinase-associated lipocalin (NGAL) results were below the lower limit of detection. The number of urine kidney injury molecule-1 (KIM-1) values below the reportable range were as follows. For the early visit: pre, n=21; post, n=36; discharge, n=11. For the late visit: pre, n=8; post, n=29; discharge, n=9. (A) Urine NGAL at the early visit. (B) Urine NGAL at the late visit. (C) Urine KIM-1 at the early visit. (D) Urine KIM-1 at the late visit. *P<0.05, **P<0.01; indicates significant difference between AKI and non-AKI groups for that time point by Mann–Whitney U test. Creat, creatinine.

Figure 3.

Biomarker excretion patterns surrounding cisplatin infusion at early and late cisplatin visits by SCr-AKI severity stage showing patients with severe SCr-AKI had higher biomarker concentrations. Graph shows box-and-whisker plots (the lower end of the boxes represents the 25th percentile, and the upper end of the boxes represents the 75th percentile; the middle line is the median; the upper whisker outlines the upper adjacent value, and the lower whisker outlines the lower adjacent value) of urine AKI biomarkers measured at three time points surrounding the cisplatin infusion at the early visit (left) and late visit (right). Time points shown on the x axis: pre-infusion (Pre), before cisplatin infusion start on day of infusion (day 1); morning post-infusion (Post; day 2); and discharge, just before hospital discharge (day 2–5). The number of participants analyzed for each time point is indicated in boxes under each bar. Outliers were excluded. The Skillings–Mack test P value for comparing biomarker levels across the three time points within each AKI stage are indicated in boxes at the top of each panel. (A) Urine NGAL at the early visit. (B) Urine NGAL at the late visit. (C) Urine KIM-1 at the early visit. (D) Urine KIM-1 at the late visit. *P<0.05, **P<0.01; indicates significant difference between serum creatinine–defined AKI (SCr-AKI) stages for that time point by Kruskal–Wallis test. Creat, creatinine.