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Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent. 2013

David A Brott, and Patricia Bentley, and Murali V P Nadella, and Dale Thurman, and Jim Fikes, and Letitia Cheatham, and Frank McGrath, and Wenli Luo, and Lewis B Kinter
Global Safety Assessment, AstraZeneca Pharmaceuticals, Wilmington, DE 19850, USA. david.brott@astrazeneca.com

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.

UI MeSH Term Description Entries
D007674 Kidney Diseases Pathological processes of the KIDNEY or its component tissues. Disease, Kidney,Diseases, Kidney,Kidney Disease
D008297 Male Males
D001806 Blood Urea Nitrogen The urea concentration of the blood stated in terms of nitrogen content. Serum (plasma) urea nitrogen is approximately 12% higher than blood urea nitrogen concentration because of the greater protein content of red blood cells. Increases in blood or serum urea nitrogen are referred to as azotemia and may have prerenal, renal, or postrenal causes. (From Saunders Dictionary & Encyclopedia of Laboratory Medicine and Technology, 1984) BUN,Nitrogen, Blood Urea,Urea Nitrogen, Blood
D001959 Bromates Negative ions or salts derived from bromic acid, HBrO3. Bromate
D003404 Creatinine Creatinine Sulfate Salt,Krebiozen,Salt, Creatinine Sulfate,Sulfate Salt, Creatinine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005260 Female Females
D006818 Hyalin A clear, homogenous, structureless, eosinophilic substance occurring in pathological degeneration of tissues. Hyalin Substance,Hyaline,Hyaline Substance,Hyalins,Substance, Hyalin,Substance, Hyaline
D000077222 Limonene A naturally-occurring class of MONOTERPENES which occur as a clear colorless liquid at room temperature. Limonene is the major component in the oil of oranges which has many uses, including as flavor and fragrance. It is recognized as safe in food by the Food and Drug Administration (FDA). (+)-(R)-4-isopropenyl-1-methylcyclohexene,(+)-Limonene,(-)-Limonene,(4R)-1-methyl-4-(1-methylethenyl)cyclohexene,(4S)-1-methyl-4-isopropenylcyclohex-1-ene,(D)-Limonene,(R)-(+)-Limonene,(R)-4-isopropenyl-1-methylcyclohexene,1-Methyl-4-(1-methylethenyl)cyclohexene,4-Mentha-1,8-diene,AISA 5203-L (+)Limonene,Cyclohexene, 1-methyl-4-(1-methylethenyl)-, (4R)-,Dipentene,Limonene, (+)-,Limonene, (+-)-,Limonene, (+-)-isomer,Limonene, (R)-isomer,Limonene, (S)-isomer,d-Limonene,4 Mentha 1,8 diene,d Limonene
D000433 1-Propanol A colorless liquid made by oxidation of aliphatic hydrocarbons that is used as a solvent and chemical intermediate. Alcohol, Propyl,Propanol,n-Propanol,Propyl Alcohol

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