Cyclosporine CsA nephrotoxicity was examined in male Sprague-Dawley rats with or without prior uninephrectomy, injected daily with 12.5 mg/kg CsA, and fed a salt-depleted or normal diet for 3-10 weeks. Control rats received the CsA vehicle. CsA induced a fall in creatinine clearance in salt-depleted rats, from 1.3 +/- 0.1 to 0.8 +/- 0.1 ml/min (P less than 0.001), and in normally fed rats from 1.8 +/- 0.2 to 1.0 +/- 0.2 ml/min (P less than 0.02). Vehicle treatment had no effect. The most striking morphologic changes were those of thick ascending limb cell atrophy with concomitant fibroblastic proliferation and collagen formation; these alterations were present in the inner stripe of the outer medulla and the medullary ray. The medullary-ray findings included S2-S3 degenerative changes as well and apparently correspond to the striped fibrosis described in human CsA nephropathy. The alterations were specific to the CsA group, progressive, and most severe in the salt-depleted, CsA-injected rats (on a scale of 0-4: 1.7 +/- 0.2 for medullary rays, and 2.0 +/- 0.2 for inner stripe, P less than 0.001). Morphologic changes predicted renal failure (r = 0.3, P less than 0.01 for cortical alterations, and r = 0.5, P less than 0.001 for medullary alterations). Prior uninephrectomy did not enhance these changes. Thus, chronic CsA administration impaired kidney function and induced morphologic alterations found in regions characterized by, and in nephron segments particularly vulnerable to, limited O2 availability. Salt depletion appears to accelerate the development of chronic CsA renal injury in the rat.