title: Mild tubular damage induces calcium oxalate crystalluria in a model of subtle hyperoxaluria: Evidence that a second hit is necessary for renal lithogenesis.
abstract: Environment and diet have a major role in calcium nephrolithiasis by affecting urine saturation, but this is not enough to cause lithogenesis; the crystals must adhere to the tubular epithelium (TE), but it is hard to say how environment and nutrition may be involved in this step. The hypothesis that TE damage (known to enhance crystal attachment) is lithogenic in mild hyperoxaluria was tested. Mild hyperoxaluria was induced in male Wistar rats using ethylene glycol (EG; 0.5% in water) for 21 d, and TE damage was induced by intraperitoneal administration of hexachloro-1:3-butadiene (HCBD; an industrial nephrotoxin) at 10, 25, and 50 mg/kg body wt on days 7 and 14. These EG and HCBD concentrations were chosen to span from suboptimal to very low doses as far as effects on crystalluria and TE damage are concerned. Enzymuria, proteinuria, oxaluria, crystalluria, and renal pathology were investigated. All HCBD dosages induced crystalluria in mildly hyperoxaluric rats, but no intrarenal crystals were found. EG alone induced very mild hyperoxaluria but no damage to the renal tubule observable on transmission electron microscopy, and it did not cause crystalluria or intrarenal crystals. HCBD with the concomitant administration of EG caused apoptosis of the TE at the two highest dosages after the second injection. Apoptosis did not correlate with crystalluria. A TE toxin is needed for crystallogenesis to occur in borderline metabolic conditions. It may take more than just a metabolic predisposition for calcium nephrolithiasis to occur, and the second hit could come from an environmental pollutant such as HCBD.
authors.affiliation: Department of Biomedical and Surgical Sciences, Division of Nephrology, University of Verona, Verona, Italy. giovanni.gambaro@univr.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Valente
authors.forename: Edoardo
authors.initials: E
authors.lastname: Zanetti
authors.forename: Mila
authors.initials: M
authors.lastname: Della Barbera
authors.forename: Dorella
authors.initials: D
authors.lastname: Del Prete
authors.forename: Angela
authors.initials: A
authors.lastname: D'Angelo
authors.forename: Andrea
authors.initials: A
authors.lastname: Trevisan
mesh_terms: D000818:Animals; D002129:Calcium Oxalate / Q000652:urine*; D003460:Crystallization; D004195:Disease Models, Animal; D019855:Ethylene Glycol; D006959:Hyperoxaluria / Q000139:chemically induced / Q000378:metabolism* / Q000652:urine; D007669:Kidney Calculi / Q000209:etiology* / Q000652:urine; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D002129:Calcium Oxalate; D019855:Ethylene Glycol