Cyclosporine (CsA) causes both acute and chronic nephrotoxicity. The goal of the present studies was to examine the nature of the chronic renal pathologic lesions of CsA nephrotoxicity and to determine whether these lesions progress with prolonged exposure to the drug. With this purpose, we examined large sections of kidneys obtained at autopsy from 15 heart transplant recipients, 7 liver transplant recipients, and 10 nontransplanted controls. Tissue sections were examined blindly by light microscopy, histomorphometry, and color computer image analysis. With increasing time following transplantation, there was a progressive increase in renal arteriolar hyalinosis and in the percentage of glomeruli demonstrating global sclerosis. In addition, there was a statistically significant relationship between arteriolar hyalinosis and global glomerulosclerosis (r=0.61, P<0.003). The percentage of glomeruli with focal glomerulosclerosis was also increased in transplant recipients followed for more than 80 days. The kidneys of heart and liver recipients who died less than 80 days after transplantation, that is, those patients who received no CsA or low doses of CsA, demonstrated significantly more interstitial fibrosis than the kidneys of control individuals. Furthermore, there was no significant increase in the amount of renal interstitial fibrosis in aliograft recipients followed for prolonged periods of time. There were no significant relationships between the severity of renal pathologic changes and serum creatinine or systemic blood pressure levels. In conclusion, non-renal transplant recipients demonstrate renal damage that affects primarily the preglomerular arterioles and results in glomerular obliteration. This renal damage increases in relation to the time of exposure to CsA and in relation to the total dose of CsA that the patient receives. These renal structural changes are not reflected initially in changes in glomerular filtration rate, as determined by serum creatinine.
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