Title:Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs
VOLUME: 17 ISSUE: 24
Author(s):M. P. Wagoner*, Y. Yang, J. E. McDuffie, M. Klapczynski, W. Buck, L Cheatham, D. Eisinger, F. Sace, K. M. Lynch , M. Sonee, J-Y. Ma, Y. Chen, K. Marshall, M. Damour , L. Stephen, Y. P. Dragan, J. Fikes, S. Snook and L. B. Kinter
Affiliation:Takeda Pharmaceuticals, 35 Landsdowne St., Cambridge, MA, 02139, Abbvie, North Chicago, IL, Janssen Research & Development, La Jolla, CA, Abbvie, North Chicago, IL, Abbvie, North Chicago, IL, AstraZeneca Pharmaceuticals, Waltham, MA, USA; 2Abbvie, North Chicago, IL, Takeda, Cambridge, MA, Biogen Idec, Waltham, MA, Abbvie, North Chicago, IL, Janssen Research & Development, La Jolla, CA, Janssen Research & Development, La Jolla, CA, Janssen Research & Development, La Jolla, CA, Janssen Research & Development, La Jolla, CA, Janssen Research & Development, La Jolla, CA, Janssen Research & Development, La Jolla, CA, Takeda, Cambridge, MA, Myriad RBM, TX, Janssen Research & Development, La Jolla, CA, Pfizer, Inc., New York City, NC
Keywords:Acute Drug Induced Kidney Injury (DIKI), Rats, Protein biomarkers, Metabolomics, NGAL, EMA.
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.
