ACUTE RENAL AND IMMUNOLOGICAL EFFECTS OF LOW-DOSE CYCLOSPORINE IN HUMANS

Background. In recent years a reduction of oral cyclosporin A (CsA) do se has been adopted to minimize its adverse renal effects. To date, ho wever, little is known about the intrinsic renal and immunological eff ects of low-dose CsA. Methods. Four oral doses of the drug (2, 3, 4 an d 5 mg/kg body wt) and placebo (P) were randomly administered in two h alf-doses to seven healthy subjects. Studies were performed during wat er diuresis 4 h after administration of the 2nd half-dose, i.e. when t he biological activity of the drug is considered maximal. Renal functi on was evaluated after all doses. In the same subjects, the levels of interleukin-2 (IL-2) and IL-2 receptor (IL-2R), that are the main immu nological targets of CsA, were measured in the supernatant of peripher al blood mononuclear cells cultured with phytohaemagglutinin (PHA) aft er P, 3 and 5 mg/kg of the drug. Results. CsA induced a dose-dependent and proportional decrease of GFR and RPF associated with increasing r enal vascular resistances (RVR) in presence of unmodified blood pressu re. Similarly, Na+ urinary excretion decreased in a dose-dependent man ner due to both GFR reduction and to an higher tubular reabsorption ma inly localized at the level of the proximal nephron. All these changes were significant only after 4 and 5 mg/kg. A significant suppression of PHA-stimulated IL-2 and IL-2R cell release was observed following 5 mg/kg only. Conclusions. This study suggests that nephrotoxic and imm unosuppressive effects of low-dose CsA are strictly linked.