Renal papillary necrosis and urinary protein alterations induced in Fischer-344 rats by D-ormaplatin.
D-ormaplatin (previously called tetraplatin) produced dose-related renal papillary necrosis when given intravenously to Fischer-344 rats at doses of 2, 4, and 9 mg/kg. The lesions were most severe at 4 days postdosing and had repaired by day 9 in the 2- and 4-mg/kg dose groups. Blood urea nitrogen and the N-acetyl-beta-glucosaminidase (NAG): creatinine ratio were slightly elevated at day 4 while creatinine clearance was decreased. Body weight was reduced in a dose-related manner while kidney weights increased. Total protein excretion in male and female rats was elevated at day 4 postdosing. The evaluation of urinary proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed an increase, primarily in high molecular weight proteins at 4 days postdosing, indicating an increase in glomerular filtration of albumin and transferrin. The morphologic appearance of the glomeruli was normal by light microscopy. At day 4 postdosing, alpha 1-microglobulin was elevated. This correlated with an increase in the NAG: creatinine ratio also seen at this time and the morphologic appearance of the kidney, indicating that the proximal tubules were affected but were not a major site of toxicity. Although the change in urinary proteins occurred at the same time as morphologic alterations in the renal papilla, these findings were not considered to be related. SDS-PAGE provided a useful method for detecting and localizing renal toxicity when used in conjunction with morphologic and clinical chemistry methods.
Kolaja
G J
GJ
Drug Safety Research, Upjohn Company, Kalamazoo, Michigan 49001.
Packwood
W H
WH
Bell
R R
RR
Ratke
C C
CC
Stout
C L
CL
D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000473:pathology; D007681:Kidney Papillary Necrosis / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011507:Proteinuria / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D003404:Creatinine; D000118:Acetylglucosaminidase; C049777:ormaplatin