Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome

Abstract

IMPORTANCEInflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.OBJECTIVE To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function. DESIGN, SETTING, AND PARTICIPANTSThis multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.EXPOSURES Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs Ն2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [Ն90 mL/min/1.73 m 2 ], mildly decreased eGFR level [60-90 mL/min/1.73 m 2 ], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m 2 ]).MAIN OUTCOMES AND MEASURES Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. RESULTSThis substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (Ն2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]). CONCLUSIONS AND RELEVANCEIn patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.

Higher Soluble ACE2 Levels and Increased Risk of Infection-Related Hospitalization in Patients on Maintenance Hemodialysis

“…This is likely because most all-cause deaths in dialysis patients are CVD due to left ventricular hypertrophy, as well as non-traditional risk factors, such as chronic volume overload, anemia, inflammation, oxidative stress, CKD-mineral bone disorder, and uremic factors ( 34 – 36 ). Many previous studies, including a recent large observational study, have suggested that plasma IL-6 was an independent predictor of mortality, not only in all CKD strata, but also in dialysis patients, reflecting chronic inflammation ( 37 – 40 ). Similarly, in the present study, not sACE2 levels, but higher IL-6 levels were significantly associated with an increased risk of all-cause death and CVD.…”

Ferroptosis and Autophagy-Related Genes in the Pathogenesis of Ischemic Cardiomyopathy

“…IL-6, as a protective cytokine, promoted cellular dedifferentiation and led to pericardial ADSC-induced cardiac repair ( 32 ). Higher IL-6 levels were independently correlated to the risk of major adverse cardiovascular events (MACE), and elevated IL-6 level was associated with an increased risk of MACE at normal kidney function, mild chronic kidney disease (CKD), and moderate to severe CKD ( 33 ). A PTGS2 variant rs20417 (COX-2 encoded) polymorphism can reduce the risk of MACE ( 34 ).…”

Pathophysiology of Circulating Biomarkers and Relationship With Vascular Aging: A Review of the Literature From VascAgeNet Group on Circulating Biomarkers, European Cooperation in Science and Technology Action 18216

“…A wealth of data exists confirming the association between increased IL-6 levels and CV mortality and morbidity ( Libby et al, 2002 ; Rao et al, 2005 ; Danesh et al, 2008 ; Compté et al, 2013 ; Ridker et al, 2018 ; Batra et al, 2021 ).…”