IL-1 Inhibition and Vascular Function in CKD

Abstract

Vascular endothelial dysfunction and increased arterial stiffness contribute to increased cardiovascular risk in patients with CKD who exhibit chronic systemic inflammation. Because chronic inflammation contributes to vascular dysfunction, blocking inflammation may reduce cardiovascular risk in patients with CKD. In a two-site, double-blind trial, we randomized 42 adult patients with stage 3-4 CKD who were already receiving optimal background therapy to receive either IL-1 trap rilonacept or placebo for 12 weeks. Coprimary end points included change in brachial artery flow-mediated dilation (FMD) and aortic pulse-wave velocity (aPWV) after 4, 8, and 12 weeks. Exploratory end points included change in high-sensitivity C-reactive protein (hsCRP), FMD after acute ascorbic acid infusion, and vascular endothelial cell protein expression of NADPH oxidase. Participants were 63±11 (mean±SD) years of age and 24% were women; mean eGFR was 38±13 ml/min per 1.73 m Compared with placebo, rilonacept improved FMD (baseline: 3.36%±2.06% [mean±SD], 12 weeks: 2.45%±2.29% with placebo and baseline: 3.75%±3.12%, 12 weeks: 4.86%±3.20% with rilonacept; <0.01), without changing aPWV (=0.56). Rilonacept also reduced hsCRP levels (median [interquartile range]) (baseline: 4.60 [1.90-8.22] mg/L, 12 weeks: 2.16 [0.92-7.38] mg/L; <0.01) and endothelial cell NADPH oxidase expression (<0.05). Acute infusion of ascorbic acid to inhibit superoxide production associated with a nonsignificant trend toward increased FMD in the placebo group (=0.07) but not the rilonacept group (=0.56). Rilonacept was well tolerated (five adverse events versus two with placebo). In conclusion, treatment with an IL-1 trap improved FMD without changing aPWV and reduced systemic inflammation in patients with CKD.

A guiding map for inflammation

“…IL-1β contributes to tubular interstitial fibrosis, promotes tubular epithelial-myofibroblast trans-differentiation, interstitial renal fibroblasts, cytokine gene expression, production of prostaglandins E2 by mesangial cells, and TGF-β-mediated interstitial fibrosis44. Treatment with the IL-1 soluble receptor trap (rilonacept) reduced CRP concentrations, improved brachial artery flow-mediated dilation, and reduced vascular oxidative stress in patients with CKD45.…”

Does inflammation affect outcomes in dialysis patients?

“…More recently, in a randomized, double-blind trial in stage 3-4 CKD patients, twelve weeks of treatment with the IL-1 trap rilonacept also reduced CRP levels as compared to placebo. 127 Notably, IL-1 inhibition also improved brachial artery flow-mediated dilation, an index of vascular endothelial function and independent predictor of incident cardiovascular events and mortality. 128 Furthermore, this improvement was associated with reduced vascular oxidative stress, and the drug was well-tolerated.…”

“…In 2011, 4 weeks of IL‐1β antagonism with anakinra was shown to be efficacious to reduce systemic inflammation, as evidenced by reduced CRP levels, and also improved adiponectin levels, in a small study of chronic hemodialysis patients. More recently, in a randomized, double‐blind trial in stage 3‐4 CKD patients, twelve weeks of treatment with the IL‐1 trap rilonacept also reduced CRP levels as compared to placebo . Notably, IL‐1 inhibition also improved brachial artery flow‐mediated dilation, an index of vascular endothelial function and independent predictor of incident cardiovascular events and mortality .…”

Vascular Dysfunction, Oxidative Stress, and Inflammation in Autosomal Dominant Polycystic Kidney Disease

“…All measurements were made following standard recommendations, including an overnight fast (19). Brachial artery flow-mediated dilation (FMD BA ) was determined using duplex ultrasonography (Xario 200; Toshiba, Tustin, CA) with ECG-gated end diastolic ultrasound images analyzed by a single blinded analyst using a commercially available software package (Vascular Analysis Tools 5.8.1; Medical Imaging Applications, Coralville, IA) as described in detail previously (20,21). Endothelium-independent dilation (brachial artery dilation to 0.4 mg of sublingual nitroglycerin) was assessed as a standard index of smooth muscle cell sensitivity to exogenous nitric oxide (NO) (21,22).…”