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                <term xml:lang="en">cardiovascular diseases</term>
                <term xml:lang="en">interleukins</term>
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              <p>Background and Aims Chronic kidney disease (CKD) is associated to increased inflammation and elevated cytokine levels. Interleukins, a group of cytokines, play a crucial role in immune system development and activity, serving as key effectors and signalling molecules. In CKD patients, pro-inflammatory interleukins tend to be elevated. While interleukin 6 (IL-6) has been extensively studied in the context of CKD, other interleukins, such as interleukin 8 (IL-8), deserve further attention. IL-8 is a chemoattractant cytokine primarily involved in neutrophil activation, which is produced by a wide range of cell types, mainly monocytes and macrophages. IL-8 is produced early in the inflammatory response but can persist for prolonged periods, even days or weeks. Despite experimental data suggesting its potential harmful effects, notably in cardiovascular disease, IL-8 has been poorly studied in patients with CKD. Thus, the objectives of the present study were to (i) describe the serum IL-8 concentration in patients at various CKD stages, (ii) assess the correlation between the estimated glomerular filtration rate (eGFR) and IL-8 concentration, (iii) identify the factors associated with IL-8 levels, and (iv) explore the association between IL-8 levels and the risk of major adverse cardiovascular event (MACE). Method CKD-REIN is a French, prospective, nationally representative cohort of 3,033 patients with stage 3 to 5 CKD (eGFR &amp;lt;60 mL/min/1.73 m²), recruited from 40 nephrology facilities. Participants were neither on maintenance dialysis nor had received a kidney transplant, and were followed-up for 5 years. Baseline IL-8 serum concentrations were measured centrally using an ELISA method. Since IL-8 concentration was not normally distributed in this population, it was log-transformed for analysis. IL-8 levels were compared across CKD stages using analysis of variance. Multivariate linear regression was performed to identify factors associated with serum IL-8 concentrations (log-transformed). Cox proportional hazards model was used to estimate hazard ratio (HR) for the first major adverse cardiovascular event (MACE, defined as a composite of nonfatal stroke, nonfatal myocardial infarction, hospitalization for heart failure, and cardiovascular death). The models were adjusted for baseline comorbidities, laboratory data and medications. Results Among the 2,389 patients included, 66% were men, with a median age of 68 [Q1–Q3: 60–76] years, and a mean (SD) eGFR of 34.8 (13.4) mL/min/1.73 m². The median serum IL-8 concentration was 12.2 [Q1–Q3: 8.0-17.7] pg/mL. IL-8 concentrations were significantly inversely correlated with eGFR (r=−0.21, P &amp;lt; 0.001). IL-8 levels varied across CKD stages, with higher concentrations observed in advanced stages (P &amp;lt; 0.001). Serum IL-8 concentration was independently and positively associated with decreasing eGFR, diabetes, history of cardiovascular disease, anaemia, C-reactive protein (CRP) levels, and proton pump inhibitor use. It was negatively associated with serum albumin. CRP (eβCRP = 1.01), eGFR (eβeGFR = 0.99), albumin (eβalbumin = 0.98), and diabetes (eβdiabetes = 1.16) were the strongest predictors of IL-8 levels. The risk of MACE increased with higher baseline serum IL-8 concentrations (HR [95% Confidence Interval] for 1-unit change in log(IL-8), 1.30 [1.09; 1.56]), after adjusting for age, sex, smoking status, history of diabetes, cardiovascular disease, anaemia, eGFR, pulse pressure, body mass index, C-reactive protein, serum albumin, serum urea, urinary albumin-to-creatinine ratio, and baseline prescriptions for proton pump inhibitors, diuretics, statins, and antithrombotic agents. Conclusion Decline of kidney function was associated with an increase in serum IL-8 levels in patients with moderate-to-advanced CKD. Higher levels of IL-8 were associated to higher risk of MACE, independently of eGFR. These results suggest that IL-8 may serve as a potential biomarker for cardiovascular risk in CKD patients. Further studies are needed to evaluate whether targeting IL-8 could mitigate the risk of cardiovascular outcomes in CKD.</p>
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