NATURE AND EXTENT OF GLOMERULAR INJURY INDUCED BY CYCLOSPORINE IN HEART-TRANSPLANT PATIENTS

We sought to clarify whether low-dose cyclosporine (5.0 +/- 2.2 mg/kg/day) given for more than two years to prevent cardiac graft rejection induced glomerular injury and to quantify the extent of the lesions. After renal hemodynamic studies, renal biopsy specimens were obtained from 10 patients on cyclosporine and analyzed by a novel morphometric technique consisting of a tridimensional reconstruction of the glomerular tuft. Autopsy kidney specimens from three patients with no clinical history of renal disease, and from four patients who died with dilatative cardiomyopathy served as controls. The glomerular filtration rate and renal plasma flow were significantly depressed below normal values in transplant recipients given cyclosporine, averaging 35 +/- 8 and 325 +/- 94 ml/min/1.73 m2, respectively. Conventional light microscopy of specimens from controls and from patients who died with dilatative cardiomyopathy did not reveal renal structural abnormalities. By contrast kidney specimens from cyclosporine-treated patients had obliterative arteriolopathy and ischemic-type changes, with thickening and wrinkling of glomerular capillary wall. Morphometrical analysis of 28 control glomeruli and 40 glomeruli from patients with dilatative cardiomyopathy showed glomerular capillary tuft volumes (V(CT)) ranging between 1.2 and 2.3-mu-m3 x 10(-6), whereas of 102 glomeruli from cyclosporine-treated patients 42.1% had V(CT) lower than 1.2-mu-m3 x 10(-6) and 24.4% V(CT) higher than 2.3-mu-m3 x 10(-6). Tridimensional reconstruction revealed that 40.1% of glomeruli of cyclosporine-treated patients but none of controls were affected by global or segmental sclerosis which was confined to glomeruli with small and normal V(CT). Thus, only 2 out of 25 large glomeruli had sclerotic changes involving, however, less then 0.2% of V(CT). We conclude that cyclosporine given for more than two years induced moderate to severe renal failure in all patients associated with obliterative arteriolopathy and glomerular ischemia. In these patients two subpopulations of glomeruli of abnormal size emerged. Lower than normal glomeruli had global or segmental sclerosis. Thus, cyclosporine should be better employed for diseases in which the expected benefits are likely to outweigh its potential for inducing major glomerular functional and structural damage.