title: Use of urinary renal biomarkers to evaluate the nephrotoxic effects of  melamine or cyanuric acid in non-pregnant and pregnant rats.
abstract: Although traditional assessments of renal damage detect loss of kidney function, urinary renal biomarkers are proposed to indicate early changes in renal integrity. The recent adulteration of infant formula and other milk-based foods with melamine revealed a link between melamine ingestion and nephropathy. Thus, the effects of melamine and related analogs (e.g., cyanuric acid) should be assessed in other potentially sensitive groups. We evaluated whether urinary Kim-1, clusterin, and osteopontin could detect the effects of high doses of melamine or cyanuric acid in pregnant and non-pregnant female rats gavaged with 1000 mg/kg bw/day for 10 days. We demonstrate that these biomarkers can differentiate the severity of effects induced by melamine or cyanuric acid. All melamine-treated animals experienced adverse effects; however, pregnant rats were most sensitive as indicated by increased SCr, BUN, and kidney weights, decreased body weight, and presence of renal crystals. These effects coincided with elevated urinary biomarker levels as early as day 2 of exposure. One cyanuric acid-treated rat displayed effects similar to melamine, including increased urinary biomarker levels. This work illustrates that these biomarkers can detect early effects of melamine or cyanuric acid crystal-induced nephropathy and further supports the use of urinary protein immunoassays as a powerful, non-invasive method to assess nephrotoxicity.
authors.affiliation: Division of Toxicology, Office of Applied Research and Safety Assessment, CFSAN, U.S. FDA, Laurel, MD, United States. omari.bandele@fda.hhs.gov
authors.forename: O J
authors.initials: OJ
authors.lastname: Bandele
authors.forename: C B
authors.initials: CB
authors.lastname: Stine
authors.forename: M
authors.initials: M
authors.lastname: Ferguson
authors.forename: T
authors.initials: T
authors.lastname: Black
authors.forename: N
authors.initials: N
authors.lastname: Olejnik
authors.forename: Z
authors.initials: Z
authors.lastname: Keltner
authors.forename: E R
authors.initials: ER
authors.lastname: Evans
authors.forename: T C
authors.initials: TC
authors.lastname: Crosby
authors.forename: R
authors.initials: R
authors.lastname: Reimschuessel
authors.forename: R L
authors.initials: RL
authors.lastname: Sprando
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000652:urine*; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000652:urine*; D007677:Kidney Function Tests; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D014227:Triazines / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D014227:Triazines; C004632:cyanuric acid; C011907:melamine