INVITRO PRODUCTION OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN CHRONIC-RENAL-FAILURE, CAPD AND HD

Dialysis-related symptoms are believed to be mediated, at least in part, by monocyte/macrophage-derived pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor (TNF). Measuring the production of interleukin-1 receptor antagonist (IL-Ra), a naturally occurring inhibitor of IL-1. opens avenues to study the balance between these two cytokines in patients. We studied the cell content and production of IL-1beta and IL-Ra by unstimulated and endotoxin- or IgG-stimulated peripheral blood mononuclear cells (PBMC) in undialyzed patients with chronic renal failure (CRF). patients on continuous ambulatory peritoneal dialysis (CAPD) and patients on chronic hemodialysis with reuse cuprophan membranes (HD), and compared them to healthy controls. IL-1beta and IL-Ra were measured by specific radioimmunoassay. IL-1beta was undetectable in freshly harvested PBMC from healthy controls, CRF, CAPD or HD. In contrast, the content of IL-Ra in HD patients (2828 +/- 466 pg/ml) was significantly higher than that in healthy controls (643 +/- 53 pg/ml, P < 0.01), CRF (1097 +/- 320 pg/ml, P < 0.01) or CAPD (1398 +/- 390 pg/ml, P < 0.05). In endotoxin-stimulated PBMC, IL-1beta production by HD patients (9375 +/- 1687 pg/ml) was not significantly different from healthy controls (8429 +/- 1621 pg/ml). However, endotoxin-stimulated IL-Ra production by HD patients (32350 +/- 8276 pg/ml) was greater than that from healthy controls (11284 +/- 1250 pg/ml, P < 0.00 1), CRF (12263 +/-2680 pg/ml, P < 0.01) or CAPD patients (11822 +/- 1797 pg/ml, P < 0.01). In PBMC from healthy subjects, IgG and endotoxin induced similar amounts of IL-Ra (15117 +/- 3507 pg/ml and 11284 +/- 1250 pg/ml, respectively). In contrast IgG-stimulated IL-Ra production was significantly lower than that induced by endotoxin in patients with CRF (6312 +/- 1907 pg/ml vs. 12263 +/- 2680 pg/ml, P < 0.0001), CAPD (7906 +/- 3239 pg/ml vs. 11822 +/- 1797 pg/ml, P < 0.0001) and HD (15642 +/- 7181 pg/ml vs. 32350 +/- 8276 pg/ml, P < 0.0008). The relatively low levels of IL-Ra produced by uremic PBMC in response to IgG is consistent with defective Fc receptor number and/or function in patients with chronic renal failure. The present study demonstrates heightened production of IL-Ra in HD patients and suggests that IL-Ra may be a better indicator of host inflammatory response during HD than IL-1.