title: Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent.
abstract: Alpha 2u-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2u-globulin. The objective of this study was to investigate if the newer and more sensitive renal biomarkers would be altered with HDN as well as be able to distinguish between HDN and oxidative stress-induced kidney injury. Rats were dosed orally for 7 days to determine (1) if HDN (induced by 2-propanol or D-limonene) altered the newer renal biomarkers and not BUN or creatinine, (2) if renal biomarkers could distinguish between HDN and oxidative stress-induced kidney injury (induced by potassium bromate), (3) sensitivity of HDN-induced renal biomarker changes relative to D-limonene dose, and (4) reversibility of HDN and renal biomarkers, using vehicle or 300 mg/kg/day D-limonene with 7 days of dosing and necropsies scheduled over the period of Days 8-85. HDN-induced renal biomarker changes in male rats were potentially compound specific: (1) 2-propanol induced mild HDN without increased renal biomarkers, (2) potassium bromate induced moderate HDN with increased clusterin, and (3) D-limonene induced marked HDN with increased αGST, μGST and albumin. Administration of potassium bromate did not result in oxidative stress-induced kidney injury, based on histopathology and renal biomarkers creatinine and BUN. The compound D-limonene induced a dose dependent increase in HDN severity and renal biomarker changes without altering BUN, creatinine or NAG: (1) minimal induction of HDN and no altered biomarkers at 10 mg/kg/day, (2) mild induction of HDN with increased αGST and μGST at 50 mg/kg/day and (3) marked induction of HDN with increased αGST, μGST and albumin at 300 mg/kg/day. HDN induced by D-limonene was reversible, but with a variable renal biomarker pattern over time: Day 8 there was increased αGST, μGST and albumin; on Day 15 increased clusterin, albumin and Kim-1. In summary, HDN altered the newer and more sensitive renal biomarkers in a time and possibly compound dependent manner.
authors.affiliation: Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA. david.brott@astrazeneca.com
authors.forename: David A
authors.initials: DA
authors.lastname: Brott
authors.forename: Patricia
authors.initials: P
authors.lastname: Bentley
authors.forename: Murali V P
authors.initials: MV
authors.lastname: Nadella
authors.forename: Dale
authors.initials: D
authors.lastname: Thurman
authors.forename: Jim
authors.initials: J
authors.lastname: Fikes
authors.forename: Letitia
authors.initials: L
authors.lastname: Cheatham
authors.forename: Frank
authors.initials: F
authors.lastname: McGrath
authors.forename: Wenli
authors.initials: W
authors.lastname: Luo
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Kinter
mesh_terms: D000433:1-Propanol / Q000008:administration & dosage / Q000633:toxicity; D000510:Alpha-Globulins / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001806:Blood Urea Nitrogen; D001959:Bromates / Q000633:toxicity; D003404:Creatinine / Q000378:metabolism; D053138:Cyclohexenes / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D006818:Hyalin / Q000378:metabolism*; D007674:Kidney Diseases / Q000175:diagnosis / Q000473:pathology*; D000077222:Limonene; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013729:Terpenes / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors
chemical_list: D000510:Alpha-Globulins; D015415:Biomarkers; D001959:Bromates; D053138:Cyclohexenes; D013729:Terpenes; C013803:alpha 2u globulin; C019536:potassium bromate; D000433:1-Propanol; D000077222:Limonene; D003404:Creatinine