Cyclosporine induces glomerulosclerosis: Three-dimensional definition of the lesions in a rat model of renal transplant

Cyclosporine induces glomerulosclerosis: Three-dimensional definition of the lesions in a rat model of renal transplant. Previous description of chronic cyclosporine (CsA) renal toxicity commonly included vascular changes, tubular atrophy, and interstitial fibrosis. Glomerular injury was only occasionally documented and it is not clear whether glomerular changes may have an impact on the clinical syndrome of CsA toxicity observed in experimental animals and humans. At the moment the prevailing view is that when patients given CsA have glomerular lesions at a renal biopsy, these were due to concomitant chronic rejection or renal hypoperfusion rather than to CsA itself. As a follow-up of our previous work on the subject (abstract; J Am Soc Nephrol 2:1398, 1992) the present study was undertaken to clarify whether CsA is a direct cause of glomerular injury. We used a model of renal transplant among Lewis rats to better mimic the condition in which CsA is given to humans. Animals underwent kidney isografts and were given daily CsA or vehicle for as long as 12 months. At the end of the experiment specimens of renal tissue were analyzed by a serial section morphometric analysis technique, which allows precise evaluation at the individual glomerular level, glomerular volume and percentage of the capillary tuft affected by sclerosis. Among 85 glomeruli from CsA-treated rats, examined by three-dimensional morphometric analysis, only 12% were normal and 88% revealed segmental sclerosis. Data of single-section analysis compared with three-dimensional morphometric reconstruction showed that the former markedly underestimated the extent of glomerular injury. By three-dimensional analysis we showed that chronic CsA administration was associated with profound changes in glomerular capillary tuft volume distribution as compared to normal. Specifically, a subset of smaller than normal glomeruli emerged in CsA-treated animals in addition to a population of glomeruli which were larger than normal. No significant correlation was found between capillary tuft volume and sclerosis volume. These findings indicate that chronic administration of CsA induces in rats glomerular lesions comparable to the ones reported in human renal or heart transplant. Our present model may help investigating the mechanism(s) of chronic CsA renal toxicity, and will provide important clues for pharmacological manipulations aimed at reducing the long-term consequences of CsA on the kidney