ENHANCED HEXACHLORO-13-BUTADIENE NEPHROTOXICITY IN RATS WITH A PREEXISTING ADRIAMYCIN-INDUCED NEPHROTIC SYNDROME

Renal damage was assessed by histopathology and urinalysis in male Wis tar rats treated with either hexachloro-1:3-butadiene (HCBD; a single 170-mg/kg ip dose that caused proximal tubule necrosis), adriamycin (A DR; a single 5-mg/kg ip dose that caused minimal glomerular changes up to 35 days), or HCBD given 2 wk after ADR and compared with age-match ed control rats for 21 days. Urinalysis values in ADR-treated rats sho wed minimal renal changes. HCBD significantly elevated urine volume (1 0-fold), protein (5-fold), glucose (175-fold), and brush border enzyme s (10-600-fold), indicating severe proximal tubular damage, but most p arameters returned to pretreatment levels 6 days after treatment. In A DR-pretreated rats subsequently given HCBD, both the urinary alkaline phosphatase and the ratio of kidney:body weight were significantly hig her for longer periods. Histopathology demonstrated that the HCBD-indu ced proximal tubular lesion was confined to the outer stripe of the ou ter medulla. Advanced regeneration and repair was evident 21 days afte r HCBD treatment. In the ADR-pretreated rats the HCBD-induced lesion w as more severe and affected the entire cortex and was characterized by marked tubular epithelial calcification, with little evidence of repa ir and tubular restitution 21 days alter treatment. Enzyme histochemis try showed gamma-glutamyltranspeptidase localized to the proximal tubu les. After HCBD treatment the enzyme staining was lost and subsequentl y returned in parallel with histological recovery up to 21 days. The d istribution and intensity of gamma-glutamyltranspeptidase was unchange d in ADR-treated rats. The distribution and intensity of gamma-glutamy ltranspeptidase in kidneys of ADR-pretreated rats given HCBD had not r eturned to normal by day 21. The results of this study indicate that p retreatment with ADR increases HCBD-induced nephrotoxic damage and dec reases renal cortical repair capacity.