Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs

Abstract

Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint. These metabolite changes included time and treatment-dependent increases in lactate, taurine, glucose, lactate, alanine, and citrate as well as 9 other known metabolites. As early as 3 days post dose, gentamicin induced increases in urinary albumin, clusterin, neutrophil gelatinase associated protein (NGAL) and total protein concentrations. Urinary albumin, clusterin, and NGAL showed earlier and more robust elevations than traditional kidney safety biomarkers, blood urea nitrogen and serum creatinine. Elevations in urinary kidney injury molecule 1 (KIM-1) were less reliable for detection of gentamicin nephrotoxicity in dogs based on values generated utilizing multiple first-generation, canine-specific KIM-1 immunoassays. The metabolic fingerprint was further evaluated in male and female dogs that received Compound A which induced slightly reversible renal tubular alterations characterized as degeneration/necrosis and concurrent significant increases in urinary taurine amongst other markers. These data support further investigations to demonstrate the value of urinary metabolites, albumin, clusterin, NGAL and taurine as promising markers to enable early detection of DIKI in dogs.

Serial Serum Creatinine and Urinary Acute Kidney Injury Biomarker Measurements in Dogs Envenomated by the European Adder (Vipera Berus).

“…Species differences, sample size, and different mechanisms of renal toxicity are possible explanations for the seemingly later induction of uKIM-1 in our study. However, it has also been suggested that uKIM-1 may not be as sensitive and early a marker of AKI in dogs compared to humans (47,48). Urinary uKIM-1/uCr and absolute uKIM-1 concentrations in healthy dogs in our study were lower than reported previously, also in one study using the same assay (33,49).…”

Kidney Injury Molecule-1 Is Upregulated in Renal Lipotoxicity and Mediates Palmitate-Induced Tubular Cell Injury and Inflammatory Response

“…KIM-1 upregulation has been shown to correlate with damage to the proximal tubule in both acute and chronic kidney diseases [18,19,20,21,22]. We have previously reported an induction of KIM-1 in proximal tubules of diabetic ZD rats [11,13,23].…”

Proteomic Analysis of Urine from California Sea Lions (Zalophus californianus): a Resource for Urinary Biomarker Discovery

“…In dogs with leishmaniasis, characterized by glomerular mesangial proliferation and interstitial nephritis, urinary clusterin was elevated in more advanced renal cases 38 . Gentamicin-induced tubular necrosis also resulted in an increase in urinary clusterin in beagles, suggesting that tubular dysfunction alone can cause increased urinary levels of this protein 39 . In the current study, the elevation in urinary clusterin in sea lions suggests a similar urinary clusterin response is conserved in sea lions experiencing renal compromise.…”