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Renal papillary necrosis and urinary protein alterations induced in Fischer-344 rats by D-ormaplatin
G J Kolaja1, W H Packwood, R R Bell
1Drug Safety Research, Upjohn Company, Kalamazoo, Michigan 49001.
Abstract:
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.
Insights
D-ormaplatin causes dose-related kidney damage, specifically renal papillary necrosis, in rats. While some kidney function markers were altered, the damage showed signs of repair within nine days in lower dose groups.
Area of Science:
- Nephrology
- Toxicology
- Pharmacology
Background:
- D-ormaplatin, a platinum-based chemotherapy agent, is being evaluated for its therapeutic potential.
- Understanding its toxicological profile, particularly nephrotoxicity, is crucial for clinical application.
Purpose of the Study:
- To investigate the dose-related renal toxicity of D-ormaplatin in Fischer-344 rats.
- To characterize the temporal changes in kidney function and morphology following D-ormaplatin administration.
Main Methods:
- Intravenous administration of D-ormaplatin at doses of 2, 4, and 9 mg/kg to Fischer-344 rats.
- Assessment of renal papillary necrosis, kidney weights, body weights, and clinical chemistry parameters (blood urea nitrogen, creatinine clearance).
- Analysis of urinary proteins using SDS-PAGE and measurement of specific urinary markers like N-acetyl-beta-glucosaminidase (NAG) and alpha 1-microglobulin.
Main Results:
- D-ormaplatin induced dose-related renal papillary necrosis, most severe at day 4 and showing repair by day 9 at lower doses.
- Elevated blood urea nitrogen, increased NAG:creatinine ratio, and decreased creatinine clearance were observed at day 4.
- Urinary protein analysis revealed increased excretion of high molecular weight proteins, suggesting glomerular filtration of albumin and transferrin.
Conclusions:
- D-ormaplatin exhibits significant nephrotoxicity, primarily affecting the renal papilla.
- Proximal tubules were affected, as indicated by elevated NAG:creatinine ratio, but were not the main site of toxicity.
- SDS-PAGE is a valuable tool for detecting and localizing D-ormaplatin-induced renal toxicity when combined with morphologic and clinical chemistry data.
