Related Experiment Videos
Chronic cyclosporine nephrotoxicity. A rodent model
D M Gillum1, L Truong, J Tasby
1Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Abstract:
The lack of a suitable rodent model has hampered the study of chronic cyclosporine nephrotoxicity. Proximal tubule vacuolization and inclusions are consistently reported in rat studies, but changes associated with chronic CsA nephrotoxicity in humans (interstitial fibrosis, tubular atrophy, arteriolopathy) are difficult to reproduce. Using male Sprague-Dawley (SD) rats we have administered CsA in olive oil (o.o.) at 25 mg/kg/d i.p. for 28 consecutive days. This protocol consistently results in a lesion of patchy interstitial fibrosis, tubular atrophy, interstitial inflammation, and marked juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia. Control animals were pair-fed and received only o.o. i.p. Despite pair feeding, CsA-treated animals gained only 9.4 +/- 12 g, while controls gained 69 +/- 18 g. Minimal JGA hypertrophy was noted in some control animals, but no other significant changes were identified. The protocol was well tolerated and did not result in peritonitis. GFR was significantly depressed in the CsA-treated animals at the end of the 28-day period (0.44 +/- .26 vs. 1.12 +/- .13 ml/min) and BP tended to be lower, but this difference did not achieve statistical significance. We conclude that this model results in a reproducible lesion with many of the features of chronic CsA nephrotoxicity in humans, and that it will permit study of this problem to advance.
Insights
Researchers developed a new rat model for chronic cyclosporine (CsA) nephrotoxicity, accurately mimicking human kidney damage. This model shows interstitial fibrosis, tubular atrophy, and JGA changes, advancing CsA toxicity research.
Area of Science:
- Nephrology
- Toxicology
- Animal Models
Background:
- Chronic cyclosporine (CsA) nephrotoxicity is a significant clinical issue.
- Existing rodent models fail to fully replicate human-specific CsA-induced kidney damage, hindering research.
- Key human pathological features like interstitial fibrosis and tubular atrophy are poorly represented in current models.
Purpose of the Study:
- To establish and validate a reproducible rodent model for chronic CsA nephrotoxicity.
- To develop a model that accurately reflects human pathological changes in the kidney.
- To facilitate further investigation into the mechanisms and treatment of CsA-induced kidney injury.
Main Methods:
- Male Sprague-Dawley rats were administered CsA (25 mg/kg/d i.p.) in olive oil for 28 days.
- Control animals received olive oil only and were pair-fed.
- Histopathological analysis, body weight, and glomerular filtration rate (GFR) were assessed.
Main Results:
- The CsA-treated group developed interstitial fibrosis, tubular atrophy, interstitial inflammation, and juxtaglomerular apparatus (JGA) hypertrophy/hyperplasia.
- CsA-treated rats exhibited significantly reduced weight gain and depressed GFR compared to controls.
- The model was well-tolerated, without peritonitis, and JGA changes were minimal in controls.
Conclusions:
- This CsA administration protocol in rats successfully reproduces key features of chronic human CsA nephrotoxicity.
- The developed model offers a valuable tool for studying CsA-induced kidney disease.
- Further research utilizing this model can advance understanding and therapeutic strategies for CsA nephrotoxicity.