Morphometrical Analysis of Glomerular Changes Induced by Cyclosporine in the Rat

Functional and morphologic techniques were used to study the renal changes induced by a long-term exposure of normal rats to cyclosporine A (CsA), as well as their potential reversibility. CsA treatment for 3 months resulted in a significant (P < 0.01) reduction of glomerular filtration rate (GFR) as compared with vehicle-treated animals. Histological examination of the kidneys showed mild glomerular damage characterized by ischemic lesions, increased mesangial matrix, and intracapillary hypercellularity in the CsA-treated group, but not in the vehicletreated group. Proximal tubular abnormalities and limited areas of interstitial fibrosis were also present in the CsA group. A complete reconstruction of glomerular corpuscle was used to evaluate the consequence of CsA-induced renal ischemia on capillary tuft volume. The results showed that in rats administered CsA for 3 months glomerular volume distribution was shifted toward small glomeruli. Prolongation of CsA administration for 5 months did not result in a further decrease in GFR, and was associated with the appearance of a subset of glomeruli that became larger than normal. We have also investigated whether, once established, CsA-induced renal injury is reversible. In rats that were administered CsA for 3 months and then treatment discontinued for 2 more months, GFR returned to pretreatment values and partial reversibility of morphologic changes was observed. Morphometric analysis showed that 2 months after withdrawal of CsA, glomerular volume distribution was almost comparable to that observed in vehicle-treated animals. We conclude that CsA given to normal rats as a chronic administration induced a marked decline in GFR associated with change in glomerular tuft volume distribution, consisting in enlargement of a subset of glomeruli and shrinkage of others. These changes were partially reversible after withdrawal of the drug.