Two soluble tumor necrosis factor receptors (sTNFRs) were detected in the plasma of patients with different degrees of chronic renal failure (CRF) and of long-term hemodialysis (HD) patients. In uremic undialyzed patients, plasma levels of both sTNFRs increased progressively with declining renal function. A linear correlation was found between sTNFR plasma levels and plasma creatinine concentration. sTNFR levels in end-stage uremic patients shortly before commencement of first HD treatment were approximately tenfold higher than in normal subjects. Long-term HD patients showed a further increase in plasma sTNFRs. The origin of sTNFRs, as well as their physiological role remains to be elucidated.

The effect of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] deficiency, as well as of replacement therapy with lα-hydroxyvitamin D₃ [1α-(OH)D₃], on the production of tumor necrosis factor-α (TNF-α) by peripheral blood mononuclear cells (PBMC) and on the serum levels of soluble TNF receptors (sTNFRs) in hemodialysis (HD) patients was investigated. PBMC from HD patients without prior therapy with hydroxylated vitamin D₃ analogs and from normal controls produced similar amounts of TNF-α, either spontaneously or after stimulation with lipopolysaccharide (LPS). After oral administration of 1α-(OH)D₃, a precursor of 1,25-(OH)₂D₃, LPS-induced TNF-α production by PBMC of HD patients was significantly higher than that of HD patients prior to the treatment or of healthy controls. Such treatment did not, however, affect spontaneous TNF-α production by PBMC. Serum concentrations of both soluble TNF receptors [sTNFR-A(p75) and sTNFR-B(p55)] were significantly higher in HD patients than in controls. The ratio of sTNFR-A/sTNFR-B decreased significantly in HD patients following lα-(OH)D₃ therapy. These results suggest that therapy with 1α-hydroxylated vitamin D₃ analogs normally given to HD patients for the management of renal osteodystrophy may also regulate the in vivo activity of TNF-α.