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


METHODS
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.


RESULTS
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.


CONCLUSIONS
This study suggests that nephrotoxic and immunosuppressive effects of low-dose CsA are strictly linked.
De Nicola
L
L
Division of Nephrology, School of Medicine, I University, Naples, Italy.
Libetta
C
C
Memoli
B
B
Bellizzi
V
V
Colucci
G
G
Imperatore
P
P
Taccone
W
W
Oriente
L
L
Sepe
V
V
Conte
G
G
D000284:Administration, Oral; D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis / Q000097:blood; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012079:Renal Circulation / Q000187:drug effects; D017595:Renal Plasma Flow / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016572:Cyclosporine