Interleukin-18, interleukin-18 binding protein and impaired production of interferon-γ in chronic renal failure

Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-gamma (IFNgamma) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. Methods: Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n=29), in patients with chronic renal insufficiency (CRI, n=29), and in patients on hemodialysis (HD, n=40). In addition, Staphylococcus epidermidis-induced production of IFNgamma and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. Results: Plasma IL-18 (mean+/-SEM) in NKF was 17.9+/-3.6 pg/ml, in CRI 42.6+/-7.0 pg/ml (p<0.01), and in HD 93.5±13.6 pg/ml (p<0.001). The level of IL-18BP in NKF was 3.4+/-0.4 ng/ml, in CRI 7.5+/-0.7 ng/ml (p<0.001), and in HD 13.1±0.8 ng/ml (p<0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479). The level of free IL-18 was calculated in NKF to be 13.8+/-3.3 pg/ml, in CRI 23.6+/-3.9 pg/ml (not significant), and in HD 39.6+/-5.9 pg/ml (p<0.001). Stimulated whole blood production of IFNγ in NKF was 185±74 pg/10(6) mononuclear cells (PBMC), but suppressed in HD to 27.3±16 pg/10(6) PBMC (p<0.05). Conclusion: In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNgamma production in whole blood is reduced in patients on HD. Therefore, suppression of IFNgamma production in uremia may be due to inhibitors of IFNgamma production other than IL-18BP.