IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD

Abstract

Background and objectives: Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting of CKD. Whether interventions that modify systemic inflammation can improve HDL function in CKD is unknown.

Design, setting, participants, & measurements: We conducted a post hoc analysis of two randomized, clinical trials, IL-1 trap in participants with GFR 15-59 ml/min per 1.73 m² (study A) and IL-1 receptor antagonist in participants on maintenance hemodialysis (study B), to evaluate if IL-1 blockade had improved the anti-inflammatory activity (IL-6, TNF-α, and Nod-like receptor protein 3), antioxidant function (superoxide production), and net cholesterol efflux capacity of HDL. HDL function was measured using LPS-stimulated THP-1 macrophages or peritoneal macrophages of apoE-deficient mice exposed to the apoB-depleted, HDL-containing fraction obtained from the plasma of the study participants, collected before and after the interventions to block IL-1 effects. Analysis of covariance was used for between group comparisons.

Results: The mean age of the participants was 60±13 years, 72% (n=33) were men, and 39% (n=18) were black. There were 32 CKD (16 IL-1 trap and 16 placebo) and 14 maintenance hemodialysis (7 IL-1 receptor antagonist and 7 placebo) participants. Compared with placebo, IL-1 inhibition, in study A and B reduced cellular expression of TNF-α by 15% (P=0.05) and 64% (P=0.02), IL-6 by 38% (P=0.004) and 56% (P=0.08), and Nod-like receptor protein 3 by 16% (P=0.01) and 25% (P=0.02), respectively. The intervention blunted superoxide production in the treated arm compared with placebo, with the values being higher by 17% in the placebo arm in study A (P<0.001) and 12% in the placebo arm in study B (P=0.004). Net cholesterol efflux capacity was not affected by either intervention.

Conclusions: IL-1 blockade improves the anti-inflammatory and antioxidative properties of the HDL-containing fraction of plasma in patients with stages 3-5 CKD, including those on maintenance hemodialysis.

Keywords: Anti-Inflammatory Agents; CKD; Cardiovascular Diseases; Cholesterol; Chronic inflammation; HDL; IL-1 inhibition; IL1RN protein, human; IL6 protein, human; Inflammation; Interleukin 1 Receptor Antagonist Protein; Lipoproteins, HDL; Macrophages, Peritoneal; NLR Proteins; Oxidants; Receptors, Interleukin-1; Renal Insufficiency, Chronic; Superoxides; Tumor Necrosis Factor-alpha; dialysis; macrophages; oxidative stress.