Patients with chronic renal failure have a decreased secretion of calcitriol (CTR). They also show an impaired cellular immune response including a defective natural killer (NK) cell-mediated activity. The aim of this study was to analyze, in vivo and in vitro, the effect of CTR on NK cell cytotoxicity in healthy control subjects and in hemodialyzed (HD) patients. Our results show that HD patients had baseline-depressed NK cell activity when compared with controls (P < 0.001), which increased significantly after 1 month of oral CTR treatment (0.5 microgram/day) (P < 0.001). Calcitriol treatment also induced a significant increase in CTR serum levels (P < 0.001) and a significant decrease (P < 0.001) in total parathyroid hormone (PTH). In vitro CTR treatment (10(-7) M) of peripheral blood mononuclear cells (PBMC) increased NK cell-mediated cytotoxicity after 24 hours of incubation with a maximum at 48 hours (P < 0.001). In vitro CTR treatment at doses of 10(-11) and 10(-9) M did not significantly increase NK cytotoxic activity. The enhanced NK activity after CTR treatment was not the consequence of increased numbers of CD56 positive cells, nor to lymphocyte activation, as tested by the expression of the interleukin 2 receptor p55 alpha chain (CD25) on their surface. In vitro treatment of PBMC from HD patients with CTR (10(-7) M, during 48 hours) also induced a strong increase in NK cell cytotoxicity (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)