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Abstract

Alpha 2µ-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2µ-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 (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 300mg/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 10mg/kg/day, (2) mild induction of HDN with increased αGST and µGST at 50mg/kg/day and (3) marked induction of HDN with increased αGST, µGST and albumin at 300mg/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.