PLASMA-LEVELS OF TUMOR-NECROSIS-FACTOR (TNF) AND SOLUBLE TNF RECEPTORS IN KIDNEY-TRANSPLANT RECIPIENTS

Tumor necrosis factor-alpha is elevated in plasma during kidney transplant rejection. However, the measurement and biological activity of TNF alpha is influenced by inhibitory soluble TNF receptors. We therefore determined plasma levels of TNF alpha and the 2 soluble TNF receptors, the 55-kDa TNF receptor (TNF-sR55) and the 75-kDa TNF receptor (TNF-sR75), by immunoassays in 25 patients before and daily after kidney transplantation. Plasma samples were retrospectively assigned to 3 groups: (1) patients with well-functioning grafts (n=14); (2) patients with biopsy-proven graft rejections (n=7 patients with 10 rejections); and (3) patients with episodes of CsA nephrotoxicity (n=4 patients with 9 samples). On the day of biopsy-proven graft rejection, TNF(li increased from 8.6+/-0.9 pg/ml to 14.8+/-3.5 pg/ml (P<0.02), TNF-sR55 from 6.6+/-1.3 ng/ml to 9.0+/-1.2 ng/ml (NS), and TNF-sR75 from 10.3+/-1.0 ng/ml to 15.3+/-2.0 ng/ml (P<0.01). During episodes of CsA toxicity, TNF alpha levels did not change, TNF-sR55 increased from 5.2+/-0.5 ng/ml to 10.5+/-0.5 ng/ml (P<0.01), and TNF-sR75 increased from 10.2+/-0.8 ng/ml to 17.5+/-0.9 ng/ml (P<0.01). There was a strong correlation between serum creatinine and plasma TNF-sR55 (r=0.7, P<0.001) and TNF-sR75 (r=0.7, P<0.001), but not with TNF alpha. Therefore, levels of TNF-sR55 and TNF-sR75 were corrected for serum creatinine. An index expressing TNF alpha over actively released soluble receptors (index = TNF alpha/(corr.TNF-sR55 + corr.TNF-sR75)) detected rejection episodes with a sensitivity of 70-80% and a specificity of 89%. We conclude that the measurement of plasma TNF alpha in combination with its soluble receptors is superior to isolated TNF alpha determinations in discriminating acute graft rejection from episodes of CsA toxicity in kidney transplant recipients.