Cyclosporine-induced chronic nephropathy: an obliterative microvascular renal injury

Abstract

Physiologic and morphologic techniques have been used to study kidneys of 200 cardiac transplant recipients treated with either low- or high-dose cyclosporine. After 12 months, both low- (4.6 +/- 0.4) and high-dose cyclosporine (6.3 +/- 0.3 mg/kg/24 h; P less than 0.01) were associated with depression of glomerular filtration rate below values in a third group of 100 recipients never exposed to cyclosporine by 40 to 47%. Determination of renovascular pressures and flows as well as analysis of transglomerular sieving of dextrans revealed renal vascular resistance in cyclosporine-treated recipients to be elevated greater than twofold, due largely to an increase in preglomerular resistance. Morphologic changes in renal tissue of both cyclosporine groups included an occlusive afferent arteriolopathy with downstream collapse or sclerosis of glomeruli. Ischemic nephrons were associated with patchy fibrosis of the surrounding interstitium. Follow-up for up to 9 yr reveals persistent but stable azotemia, on average. Longitudinal physiologic studies over a 48-month period (N = 15) during which cyclosporine was reduced in dosage (to 3.1 +/- 0.3 mg/kg) or withdrawn revealed a persistently reduced but constant level of glomerular filtration rate. Increasing ischemic glomerular collapse and sclerosis were observed at repeat renal biopsy. Remnant (spared) glomeruli exhibited hypertrophy; presumably elevated single nephron glomerular filtration rate maintained two-kidney glomerular filtration rate constant despite the declining fraction of functional glomeruli. By actuarial analysis, the cumulative incidence of end-stage renal failure in cardiac transplant recipients treated at this institution from 1980 onwards with continuous cyclosporine therapy has reached 10%.(ABSTRACT TRUNCATED AT 250 WORDS)