Effect of cyclosporine on endothelial albumin leakage in rats

Short-term treatment of rats with cyclosporine (cyclosporine A (CsA); Sandimmune®) results in a marked reduction in intravascular plasma volume, a factor that might contribute to the renal dysfunction associated with this potent immunosuppressant. To examine the role of plasma extravasation in CsA-induced hypovolemia, intravascular plasma volumes (PV), blood volumes, (¹²⁵I)albumin disappearance, and changes in hematocrit (Hct) were measured in Inactin-anesthetized rats subjected to minimal surgery. The rats were treated for 3 wk with either 25 mg/kg/day of CsA s.c. or vehicle. Plasma creatinine and urea were significantly elevated, and magnesium was reduced in the CsA group (N = 6) as compared with controls (CON) (N = 6). CsA treatment had no effect on urinary protein and albumin excretion. Blood volume was significantly lower in CsA than in CON (8.4 ± 0.5 versus 10.6 ± 0.3 mL/100 g body wt) as was PV (4.3 ± 0.2 versus 5.5 ± 0.2 mL/100 g body wt). Two hours after injection, plasma (¹²⁵I)albumin concentration had fallen by 41 ± 4% in CsA versus 23 ± 5% in CON. Because Hct, and, hence PV, was unchanged in both groups during these 2 h, these data indicate enhanced endothelial albumin leakage in the CsA group. In two additional groups of six rats each, acute volume expansion with fresh whole blood (2 mL/100 g body wt) resulted in extravasation of plasma. Hct rose by 8.0 ± 0.2% in CsA versus 3.8 ± 0.2% in CON after 150 min, corresponding to 27 ± 3 and 15 ± 2% decreases in total PV, respectively. Similar bulk losses of plasma were observed after the infusion of an identical volume of fresh plasma. Hence, CsA impairs the ability of the endothelium to retain plasma protein and fluid within the circulation, an effect that will contribute to the prerenal azotemia seen in CsA-treated rats and humans.