Acute renal and immunological effects of low-dose cyclosporin in humans

Abstract

In recent years a reduction of oral cyclosporin A (CsA) dose has been adopted to minimize its adverse renal effects. To date, however, little is known about the intrinsic renal and immunological effects of low-dose CsA. Four oral doses of the drug (2, 3, 4 and 5 mg/kg body wt) and placebo (P) were randomly administered in two half-doses to seven healthy subjects. Studies were performed during water diuresis 4 h after administration of the 2nd half-dose, i.e. when the biological activity of the drug is considered maximal. Renal function 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 immunological targets of CsA, were measured in the supernatant of peripheral blood mononuclear cells cultured with phytohaemagglutinin (PHA) after P, 3 and 5 mg/kg of the drug. CsA induced a dose-dependent and proportional decrease of GFR and RPF associated with increasing renal vascular resistances (RVR) in presence of unmodified blood pressure. Similarly, Na+ urinary excretion decreased in a dose-dependent manner due to both GFR reduction and to an higher tubular reabsorption mainly 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. This study suggests that nephrotoxic and immunosuppressive effects of low-dose CsA are strictly linked.