The pathogenesis of trimethyltin chloride-induced nephrotoxicity.
In exploratory studies aimed at elucidating CNS effects due to heavy metal toxicity, signs of compromised renal function were seen in rats. The studies reported here describe the sequential steps of the development of nephrotoxicity by trimethyltin chloride (TMT) in rats. Single doses of 12.25 mg/kg TMT administered orally to 150- to 175-g Long-Evans rats elicited overt signs of toxicity including behavioral abnormalities and marked weight loss. Concurrent with the development of these signs, nephrotoxicity was manifested as functional kidney compromise and associated histopathologic evidence of tubular damage. Pathological changes in the kidneys from treated rats were hyaline droplet inclusions, attenuated brush border, basolateral vacuolization, and eosinophilic granular casts in the proximal tubule cells. These lesions were detected as early as 2 days post-treatment and progressed with time in an orderly and sequential fashion. Renal lesions between 5 and 8 days were mild to severe cortical tubular dilatation, hydropic degeneration, and diffuse hyaline droplet deposition in the lower nephron tubules. Medullary edema and exfoliation of degenerated tubular epithelial cells with cast formation followed from 8 to 11 days. The morphological changes were accompanied by marked elevation of blood urea nitrogen, parallel with polyuria at Day 2 and oliguria by Day 14. Behavioral abnormalities as well as weight loss correlated well with the time course and severity of renal dysfunction and progression of morphological changes. A second experiment compared the effects of TMT in rats of different weights. Heavier rats were more sensitive than lighter rats to the nephrotoxic effects of TMT. These effects were independent of recognizable neurotoxic effects of TMT in the hippocampus.
D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D007672:Kidney Cortex / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D011507:Proteinuria; D051381:Rats; D014202:Tremor / Q000139:chemically induced; D014220:Trialkyltin Compounds / Q000633:toxicity*; D014298:Trimethyltin Compounds / Q000633:toxicity*
D014220:Trialkyltin Compounds; D014298:Trimethyltin Compounds; C040533:trimethyltin chloride