PLASMA-LEVELS OF IL-1-BETA, TNF-ALPHA AND THEIR SPECIFIC INHIBITORS IN UNDIALYZED CHRONIC-RENAL-FAILURE, CAPD AND HEMODIALYSIS-PATIENTS

The presence of naturally occurring inhibitors of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in a variety of diseases has been demonstrated. The IL-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and blocks the activity of IL-1, and a soluble form of the p55 TNF receptor CTNFsRp55) binds and neutralizes TNF. In the present study, plasma levels of IL-1 beta, IL-1Ra, TNF alpha and TNFsRp55 were measured in 29 undialyzed patients with chronic renal failure (CRF), 13 patients on continuous ambulatory peritoneal dialysis (CAPD), 42 patients on chronic hemodialysis (HD) and in 15 healthy controls. Of the 29 patients with CRF, 13 had end-stage renal disease (ESRD, estimated GFR < 10 ml/min). Among healthy controls, plasma levels of IL-1 beta, IL-1Ra and TNF alpha were at or below the limit of detection of the assay. In undialyzed patients with ESRD, or in patients on CAPD or HD, plasma levels of IL-1 beta were 428 +/- 134 pg/ml, 378 +/- 83 and 352 +/- 43 pg/ml, respectively. Although plasma levels of IL-IP in each group of patients were higher than those in healthy controls (<160 pg/ml), these differences were not statistically significant. In contrast, plasma levels of IL-1Ra in undialyzed patients with ESRD (629 +/- 125 pg/ml, P = 0.03), CAPD (902 +/- 164 pg/ml, P < 0.0001) and HD patients (642 +/- 73 pg/ml, P = 0.004) were significantly higher than those in healthy controls (103 +/- 15). In the same groups, plasma TNF alpha levels were 1,419 +/- 434 pg/ml, 872 +/- 267 pg/ml and 803 +/- 241 pg/ml, respectively. Although plasma levels of TNF alpha in all three groups of patients with chronic renal failure were also higher than those in controls (<160 pg/ml), these differences were not statistically significant. Plasma levels of TNFsRp55 in undialyzed patients with ESRD, or in patients on CAPD or HD, were 12,754 +/- 2235 pg/ml, 13,373 +/- 1,815 pg/ml and 16,750 +/- 830 pg/ml, respectively. These levels were significantly higher (P < 0.001) than those in healthy controls (1,695 +/- 94 pg/ml). The differences in IL-1 beta, IL-1Ra, TNF alpha or TNFsRp55 between the three groups of patients were not statistically significant. The molar ratios of plasma IL-1Ra:IL-1 beta in ESRD, CAPD and HD patients were 3 +/- 1, 4 +/- 1 and 4 +/- 1, respectively. The molar ratios of plasma TNFsRp55:TNF alpha ratios in these three groups were 13 +/- 3, 21 +/- 6 and 38 +/- 4, respectively. In undialyzed patients with CRF and healthy controls, regression analysis showed a strong correlation between serum creatinine and plasma levels of IL-1Ra (r = 0.497, P = 0.001) or ThTFsRp55 (r = 0.737, P < 0.0001). These results demonstrate that plasma levels of IL-1 beta, TNF alpha and their specific inhibitors are elevated in both undialyzed patients with ESRD as well as patients on CAPD or HD. The elevated plasma levels of these proteins probably reflect inadequate clearance as well as enhanced production.