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Renal morphology and function and urine electrolytes in experimental acute renal failure produced by cyclosporine and
Abstract:
It has been difficult to produce a good animal model for cyclosporine nephrotoxicity. It has been suggested that by following 20 minutes of renal ischemia with four daily doses of cyclosporine 60 mg/kg intraperitoneally, one can create a model of reproducible renal failure. We observed excessive mortality (65%), due in part to cyclosporine's CNS effects, with these combined insults in the Munich Wistar rat. In contrast, cyclosporine alone in this dosage produced only 17% mortality and resulted in a similar degree of renal failure. Pair-fed and pair-watered vehicle and saline controls were used. The morphologic changes brought about by the castor oil vehicle of the parenteral cyclosporine solution were qualitatively similar to those brought about by cyclosporine by light microscopy, although the severity of the changes was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum also were seen in other groups. Urine sodium determined by flame photometry and urine chloride determined by Saltex reagent strips tended to be high in the initiation phase of cyclosporine-induced acute renal failure and low in the maintenance phase. In animals that developed acute renal failure following the combination of ischemia and cyclosporine, the initial urine sodium and chloride were significantly correlated with the eventual degree of renal failure. The use of Saltex urine chloride sticks in clinical urine samples showed that the readings correlated well with urine sodium and chloride determined by conventional methods, suggesting that these strips may be useful in making a quick diagnosis in the setting of acute renal failure.
Insights
Developing a reliable animal model for cyclosporine nephrotoxicity proved challenging. Cyclosporine alone, not combined with ischemia, effectively induced renal failure with lower mortality in rats, suggesting a better model for studying drug-induced kidney injury.
Area of Science:
- Nephrology
- Toxicology
- Animal Modeling
Background:
- Establishing a reproducible animal model for cyclosporine-induced nephrotoxicity is difficult.
- Previous models combining renal ischemia with cyclosporine administration resulted in high mortality due to cyclosporine's central nervous system effects.
Purpose of the Study:
- To evaluate cyclosporine's efficacy in inducing renal failure in rats.
- To compare the effects of cyclosporine alone versus combined with ischemia.
- To assess the utility of urine electrolytes in diagnosing acute renal failure.
Main Methods:
- Munich Wistar rats were subjected to either renal ischemia followed by cyclosporine, or cyclosporine alone.
- Control groups received vehicle or saline.
- Renal function, mortality, and morphologic changes were assessed.
- Urine sodium and chloride levels were measured using flame photometry and Saltex reagent strips.
Main Results:
- Cyclosporine alone caused significant renal failure with only 17% mortality, unlike the combined ischemia-cyclosporine group (65% mortality).
- Morphologic changes varied between light and electron microscopy, with lipid vacuoles specific to cyclosporine treatment.
- Urine sodium and chloride levels correlated with the degree of renal failure and could be reliably assessed with Saltex strips.
Conclusions:
- Cyclosporine administration alone is a more suitable model for studying cyclosporine nephrotoxicity than models involving prior ischemia.
- Urine electrolyte measurements, particularly using Saltex strips, can aid in the rapid diagnosis of acute renal failure.