Urinary Tubular Protein-Based Biomarkers in the Rodent Model of Cisplatin Nephrotoxicity: A Comparative Analysis of Serum Creatinine,Renal Histology,and Urinary KIM-1,NGAL,and NAG in the Initiation,Maintenance,and Recovery Phases of Acute Kidney Injury

Abstract

Background

Several biomarkers are becoming available for the early detection of acute kidney injury (AKI), but few have been directly compared.

Objective

To compare urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl glucosaminidase (NAG) against serum creatinine and renal histological score in the initiation, maintenance, and recovery phases of cisplatin (CP)-induced AKI.

Methods

Sprague-Dawley rats (300–350 g) were injected once through their tail veins with CP (CP group) at 5.5 mg/kg or with same volume of normal saline vehicle (Control group). Rats were euthanized at 2, 4, 6, 12, and 24 hours, and on days 2, 3, 6, and 10 (n = 12 in the CP group and n = 6 in the Control group at each time point), and urine, blood, and kidney samples were analyzed.

Results

A significant increase in serum creatinine was noted by day 3 in the CP group versus Control group [1.46 (0.12) vs 0.28 (0.03) mg/dL; mean (SE); P < 0.05]. The renal histology scores for brush border loss and tubular necrosis were significantly higher at 12 and 24 hours, respectively, in the CP group. Urinary kidney injury molecule-1 levels were significantly higher at 24 hours in the CP group than in the Control group [48.26 (13.13) vs 8.21 (3.31) pg/mg creatinine; P < 0.05] and remained elevated through day 10. Both urine NAG and NGAL levels were significantly higher by day 2 in the CP than in the Control group [NAG, 8.19 (0.82) vs 3.48 (0.40) pg/mg creatinine, P G 0.05; NGAL, 2911.80 (368.10) vs 1412.60 (250.20) pg/mg creatinine, P < 0.05]. Urinary NAG remained elevated for 6 days and NGAL for 3 days.

Conclusions

Our study suggests a temporal hierarchy in the ability of certain urinary protein-based biomarkers to detect AKI after a well-defined tubular injury. Comparative analyses of urinary biomarkers are warranted in clinical settings such as patients receiving CP to discern the time course and pattern of expression.