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Renal injury induced by long-term administration of cyclosporin A to rats
Abstract:
Chronic administration of cyclosporin A (CyA) to animals and humans results in renal damage characterized by tubulointerstitial lesions and renal insufficiency. This nephrotoxicity limits the use of CyA in the management of graft rejection. Despite recent investigations in this area, relatively few studies correlate structural and functional abnormalities in animals undergoing long-term CyA treatment. The authors therefore treated 30 rats with CyA at the dose of 40 mg/kg/48 hr for up to 5 months. An additional group of 30 rats was given the vehicle alone and was considered as a control group. Renal morphology and function were studied. For evaluation of the effect of drug withdrawal, a third group of 25 animals received CyA for 3 months and was followed for another 2 additional months after drug withdrawal. The results show that the chronic administration of CyA to rats induced complex renal morphologic changes, associated with renal insufficiency, polyuria, and enhanced sodium excretion. Withdrawal of the drug resulted in almost complete normalization of morphologic and functional parameters. The early morphologic expression of CyA nephrotoxicity was isometric vacuolization and loss of brush border involving the proximal tubular cells, followed by a peculiar lesion in distal tubular cells due to glycogen accumulation. Glomerular and interstitial damage was mild and appeared only after 3 months of CyA administration. No vascular abnormalities were found in rats treated with CyA for 5 months. A CyA-induced decrease in the glomerular filtration rate (GFR) correlates with brush border loss but not with isometric vacuolization. The distal tubular glycogen accumulation was associated with the development of polyuria and enhanced sodium excretion. Given the high blood sugar level and severe glycosuria in animals treated chronically with CyA, it is also concluded that CyA possesses a diabetogenic effect which is likely to be responsible for glycogen accumulation at the tubular level.
Insights
Chronic cyclosporin A (CyA) administration causes kidney damage and functional decline in rats. Drug withdrawal led to near-complete recovery, suggesting reversibility of CyA nephrotoxicity.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Chronic cyclosporin A (CyA) administration is known to cause nephrotoxicity, limiting its clinical use.
- Few studies correlate structural and functional renal changes with long-term CyA treatment.
- Understanding CyA's effects on kidney structure and function is crucial for managing immunosuppression.
Purpose of the Study:
- To investigate the long-term structural and functional effects of cyclosporin A (CyA) on rat kidneys.
- To assess the reversibility of CyA-induced nephrotoxicity upon drug withdrawal.
- To explore the potential diabetogenic effects of CyA contributing to renal pathology.
Main Methods:
- Rats were administered CyA (40 mg/kg/48 hr) for up to 5 months, with control groups receiving vehicle alone.
- Renal morphology and function (GFR, sodium excretion, polyuria) were assessed.
- A separate group received CyA for 3 months followed by a 2-month drug withdrawal period.
Main Results:
- Chronic CyA induced tubular lesions (vacuolization, brush border loss, glycogen accumulation), renal insufficiency, polyuria, and increased sodium excretion.
- Glomerular and interstitial damage were mild and appeared after 3 months; no vascular lesions were observed.
- Drug withdrawal resulted in almost complete normalization of renal morphology and function.
Conclusions:
- CyA causes significant, dose-dependent nephrotoxicity characterized by proximal and distal tubular damage.
- The observed renal damage and functional impairment are largely reversible after CyA withdrawal.
- CyA exhibits diabetogenic properties, contributing to tubular glycogen accumulation and associated functional changes.