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Cyclosporine-induced renal dysfunction: correlations between cellular events and whole kidney function.
W M Bennett1, D C Houghton, W C Buss
1Department of Medicine, Oregon Health Sciences University, Portland 97201.
Summary
Cyclosporine causes kidney dysfunction in rats, with reduced blood flow and filtration. While protein synthesis in the kidney cortex is inhibited, this is unlikely to be the direct cause of acute kidney injury.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cyclosporine is an immunosuppressive drug known for causing dose-dependent renal dysfunction.
- Previous research suggests cyclosporine may inhibit renal cortical microsomal protein synthesis, alongside known renal vasoconstriction.
Purpose of the Study:
- To investigate the relationship between cyclosporine dosage, renal dysfunction, and renal cortical microsomal protein synthesis in Sprague-Dawley rats.
- To determine if inhibited protein synthesis is the direct cause of acute cyclosporine-induced nephrotoxicity.
Main Methods:
- Rats received oral cyclosporine (5-50 mg/kg/day) for up to 10 days, with pair-fed controls.
- Assessed glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and fractional excretion of lithium.
- Measured renal cortical microsomal protein synthesis using [3H]leucine incorporation and "run-off" translation assays.
Main Results:
- A dose-dependent decline in GFR and ERPF occurred, peaking by day 3 and stabilizing despite continued dosing.
- Microsomal protein synthesis inhibition was dose-dependent, reaching its lowest point on day 4, after renal dysfunction was evident.
- Tubular function remained largely intact, with no evidence of tubular necrosis; protein synthesis normalized faster than renal hemodynamics after drug withdrawal.
Conclusions:
- Cyclosporine induces dose-dependent renal dysfunction characterized by hemodynamic changes, with preserved tubular function.
- While cyclosporine reduces renal cortical microsomal protein synthesis, this effect appears to be a consequence rather than the primary cause of acute nephrotoxicity.