Interleukin-6 and the inflammatory origins of chronic kidney disease

This editorial refers to ‘The role of inflammation in longitudinal renal function decline and incident chronic kidney disease: the Multi-Ethnic Study of Atherosclerosis’, by O.J. Agboola et al., https://doi.org/10.1093/eurjpc/zwaf779. Inflammation is a well-established driver of cardiovascular disease (CVD) and a hallmark of chronic kidney disease (CKD).1 Individuals with impaired kidney function exhibit elevated circulating inflammatory biomarkers, which are in turn associated with incident cardiovascular events. These shared inflammatory pathways in CVD and CKD underscore the biological interdependence among metabolic, vascular, and kidney dysfunction, now captured in the cardiovascular-kidney-metabolic (CKM) syndrome framework.2 While the role of inflammation in atherosclerosis is well established, its contribution to the initiation and progression of kidney dysfunction has been less clear. In this issue of the Journal, Agboola and colleagues provide important new evidence that helps clarify this relationship by examining whether circulating inflammatory biomarkers predict long-term decline in kidney function in a community-based cohort with preserved kidney function at baseline.3 Leveraging the prospective study design of Multi-Ethnic Study of Atherosclerosis (MESA), the authors studied 4680 participants with estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 at enrolment and followed them for nearly 17 years. Baseline levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were examined in relation to subsequent trajectories of eGFR decline, changes in albuminuria, and incident CKD. Across multiple analytic approaches, IL-6 emerged as a consistently stronger predictor of adverse renal outcomes than hsCRP. Participants in the highest tertile of IL-6 experienced faster annual declines in eGFR, greater increases in the urinary albumin-to-creatinine ratio, and a 65% higher risk of developing CKD compared with those in the lowest tertile. Notably, these findings persisted when inflammatory markers were modelled continuously and after adjustment for coronary artery calcification, suggesting that the observed relationships were not merely a reflection of subclinical atherosclerotic burden. Collectively, these results highlight IL-6 as an informative marker of future decline in kidney function and support the role of inflammation in the early pathogenesis of CKD. These findings carry several important implications. First, circulating inflammatory biomarkers, particularly IL-6, are associated with future trajectories of kidney function. A previous cohort study of ∼5000 individuals showed that, in line with the current study, IL-6 but not hsCRP was associated with incident CKD.3 Biologically, IL-6 is a pleiotropic cytokine produced by activated immune cells and adipocytes that promotes endothelial activation, vascular inflammation, and downstream acute-phase responses. Within the NLRP3 inflammasome signalling cascade, upstream activation leads to IL-1β and IL-18 release, which stimulate IL-6 production and subsequent hepatic CRP synthesis. While therapeutic targeting of IL-1β or IL-6 lowers circulating hsCRP, IL-6 functions as a proximal mediator of inflammatory signalling and may therefore provide greater biological specificity than hsCRP. Supporting this concept, IL-6 has shown stronger associations than hsCRP with atherosclerotic events, heart failure, and mortality in multiple cohorts, including MESA and the STABILITY trial.4 Its causal role is also supported by Mendelian randomization studies implicating IL-6 receptor signalling in the development of coronary heart disease,5 while the same has not been shown for hsCRP. Despite these strengths, routine clinical implementation of IL-6 testing remains limited by assay variability, lack of standardization, and sensitivity to physiologic and clinical confounders. Further work is therefore needed before IL-6 is integrated into routine clinical kidney risk stratification. Second, these findings support inflammation as an inciting or aggravating driver of kidney injury rather than merely a marker of existing disease. Experimental data suggest that IL-6 contributes directly to CKD development and progression through trans-signalling, whereby circulating IL-6-soluble IL-6 receptor complexes activate gp130 expressed on mesangial, tubular, and endothelial cells.1 Activation of this pathway promotes mesangial cell proliferation, extracellular matrix accumulation, and chemokine release, thereby amplifying inflammation and promoting glomerulosclerosis, while also accelerating tubular fibrosis and endothelial dysfunction through downstream STAT3 and oxidative stress pathways.1 In parallel, kidney injury induces a senescence-associated secretory phenotype (SASP) characterized by increased expression of VEGF, IL-6, and TNF-α, which initially supports tissue repair but ultimately sustains inflammatory cell recruitment and inflammasome activation. Together, these processes establish a self-perpetuating cycle in which IL-6 both arises from and perpetuates kidney injury. These inflammatory pathways represent shared biological mechanisms across the CKM syndrome spectrum. The same IL-6-driven processes that promote renal fibrosis also operate in cardiac tissue to induce myocardial hypertrophy and fibrosis, in adipose tissue to drive insulin resistance through inflammatory macrophage polarization, and in the vasculature to accelerate atherosclerosis through endothelial activation and foam cell formation. Moreover, IL-6 regulates haematopoiesis in bone marrow, skewing differentiation towards myelopoiesis and generating pro-inflammatory monocytes that infiltrate multiple organ systems simultaneously. This cross-organ inflammatory crosstalk is driven in part by IL-6 signalling through pathways, such as NF-κB, JAK-STAT, and PI3K-AKT, creating positive feedback loops among the heart, kidneys, and metabolic tissues that worsen oxidative stress, endothelial dysfunction, and fibrosis (Figure 1). Collectively, these findings suggest that IL-6 functions not only as a downstream marker of kidney injury but also as an active mediator linking inflammatory, fibrotic, and metabolic dysfunction across the CKM syndrome spectrum. Central role of IL-6-mediated inflammatory crosstalk in cardiovascular-kidney-metabolic syndrome pathophysiology and its therapeutic inhibition. Third, targeting IL-6-driven inflammation may represent a promising therapeutic approach for both cardiovascular risk reduction and kidney protection. The CANTOS trial demonstrated that upstream inflammatory modulation via IL-1β inhibition reduces major adverse cardiovascular events.6 Building on these findings, direct IL-6 ligand inhibition with ziltivekimab produced an up to 92% reduction in hsCRP among patients with CKD and elevated inflammatory burden in the phase 2 RESCUE trial.7 These results provided the rationale for the ongoing ZEUS trial (NCT05021835), which is designed to test whether IL-6 ligand inhibition improves cardiovascular and renal outcomes in a high-risk CKD population. Nevertheless, immunomodulatory therapies carry potential safety concerns. In CANTOS, canakinumab was associated with higher rates of fatal infection and neutropenia, including increased pneumonia risk. Therapies targeting the IL-6 receptor have been linked to neutropenia, elevation in hepatic enzymes, bacterial infections, and rare gastrointestinal perforation.8 In contrast, ziltivekimab targets the IL-6 ligand rather than the receptor and was well tolerated over 24 weeks of treatment in RESCUE, with no serious injection-site reactions and no sustained grade 3 or 4 neutropenia or thrombocytopenia. However, longer-term safety and efficacy data from larger populations are needed. A central unanswered question is how best to identify patients most likely to benefit from anti-inflammatory therapy. CANTOS enriched for individuals with heightened inflammatory risk by requiring elevated hsCRP, which is also the case in ZEUS, reflecting a strategy that targets treatment to individuals with residual risk driven by active inflammatory signalling. While hsCRP-based thresholds provide a pragmatic approach to patient selection, they may not fully capture biologically high-risk subgroups. Emerging data indicate that individuals with clonal haematopoiesis, somatic blood stem cell mutations linked to accelerated cardiovascular and other morbidity, may represent another population particularly responsive to targeted anti-inflammatory therapies.9 Pre-clinical evidence and post hoc analyses of CANTOS suggest that individuals with certain clonal haematopoiesis variants derive disproportionate cardiovascular benefit from IL-1β inhibition.10 If ZEUS demonstrates that IL-6 inhibition reduces cardiovascular events and slows kidney function decline, it would further establish inflammation as a modifiable driver of CKM syndrome and clarify the role of IL-6-targeted therapies and other anti-inflammatory strategies in high-risk populations. In summary, the work by Agboola and colleagues extends the inflammatory paradigm into the earliest stages of kidney dysfunction, identifying IL-6 as a prognostic biomarker and a potential mediator of CKD progression. As large-scale trials of IL-6–targeted therapies mature, an opportunity now exists to test whether interrupting these inflammatory circuits can meaningfully alter the trajectory of both cardiovascular and kidney disease. Ultimately, integrating inflammatory biology into risk stratification and therapeutic decision-making may represent a critical next step towards more precise, mechanism-driven prevention across the CKM spectrum. Annie Chang [Writing—original draft (equal)], Niekbachsh Mohammadnia [Writing—original draft (equal)], and Michael C. Honigberg (Supervision [lead]; Writing—review & editing [lead]) A.C. is supported by the Sarnoff Cardiovascular Research Foundation.