Targeting Interleukin-6 for Treatment of CKD and Cardiovascular Disease

Abstract

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have multiple shared pathophysiological risk factors and often coexist. Inflammation, particularly mediated by the interleukin-6 (IL-6) pathway, plays an important role in the development and progression of both conditions. In this review, we examine the mechanisms of IL-6 production and signaling and summarize clinical evidence for IL-6 upregulation in CKD and CVD. We discuss the impact of IL-6 on kidney and cardiovascular outcomes, the interplay between CKD, CVD, and associated complications, and the limitations of standard-of-care strategies in attenuating risks related to the presence of inflammation. We also provide an overview of recent advances in anti-inflammatory therapies, including IL-6 inhibitors in development. Finally, we highlight future research directions that are required to establish the efficacy and long-term safety of targeted anti-inflammatory therapies in CKD and CVD.

Nearly 800 million people worldwide have CKD.¹ The global prevalence of CKD has more than doubled since 1990, when it affected an estimated 378 million people.¹ If current trends do not change, CKD is projected to become the fifth leading cause of death globally.²

Diabetes³ and hypertension^4,5 are the most common attributable causes of CKD and, in turn, CKD is a risk multiplier for diabetes and hypertension.^3,4 These conditions are also major risk factors for atherosclerotic CVD (ASCVD),6, 7, 8 among multiple other shared risk factors, including dyslipidemia,6, 7, 8, 9, 10 smoking,6, 7, 8 obesity,^8,10,11 and arterial stiffness.^12,13 The presence of either CKD or CVD increases the risk of the other, as recognized in the 2021 European Society of Cardiology guidelines⁶ and the 2024 Kidney Disease: Improving Global Outcomes clinical practice guideline.¹⁴ The link between CVD and CKD is also supported by evidence from epidemiologic studies. In a cohort of patients with ASCVD from the US National Health and Nutrition Examination Survey, 36% had CKD,¹⁵ and in a US sample of people aged ≥ 66 years with CKD, 65% had CVD.¹⁶ Lower estimated glomerular filtration rate (eGFR) and higher urinary albumin-to-creatinine ratio are both associated with the occurrence of cardiovascular (CV) events,¹⁷ and hospitalization for CVD is associated with a decline in eGFR.¹⁸ CKD also increases the risk of individual CVD components, including stroke,^19,20 myocardial infarction,²¹ peripheral vascular disease,^20,22 and arrhythmia.^20,23

In the year 2023 alone, 1.5 million deaths were attributed to CKD worldwide.¹ Moreover, CV events account for half of all deaths in the population with CKD^5,24 or kidney failure treated by dialysis.²⁵ Conversely, 12% of deaths from CVD in 2023 were ascribed to impaired kidney function, more than both diabetes and obesity as contributors to CVD death.¹ People with reduced eGFR, increased urinary albumin-to-creatinine ratio, or both, have a much higher risk of CV mortality (approximately 5- to 30-fold depending on eGFR and urinary albumin-to-creatinine ratio) than patients without CKD, especially with concurrent diabetes.^20,26,27

Inflammation is a key risk factor for the development of both ASCVD and CKD.⁷ Shared risk factors, including diabetes,28, 29, 30 hypertension,^31,32 and dyslipidemia^33,34 are associated with elevated levels of inflammatory biomarkers reflecting chronic systemic inflammation. In established CVD and CKD, inflammation continues to drive risk. Persistent, low-grade inflammation is associated with CKD progression³⁵ and increases the risk of CV events.³⁶ Disease mechanisms in CVD and CKD, such as endothelial dysfunction³⁶ and oxidative stress,³⁵ interact with traditional risk factors to sustain systemic inflammation. Activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3 inflammasome, leading to the downstream release of IL-6, is a key pathway for inflammation in cardiovascular-kidney-metabolic conditions.

Various inflammatory pathways may operate upstream or in parallel with IL-6. For example, tumor necrosis factor (TNF)-α and toll-like receptors activate the nuclear factor kappa B signaling pathway in response to injury and oxidative stress in CKD.^37,38 Chemokines such as the monocyte chemoattractant protein-1 promote monocyte and/or macrophage infiltration.³⁹ Inflammatory activation in CKD is further exacerbated by renin–angiotensin system signaling,⁴⁰ the gut–kidney axis (microbial dysbiosis and uremic toxins),⁴¹ adipokines with excess or dysfunctional adiposity,^42,43 increased sympathetic activity and reduced parasympathetic tone within the autonomic nervous system,^44,45 and the innate immune system including T-cell dysregulation⁴⁶ and complement activation,⁴⁷ all of which may add to inflammatory risk.

Anemia is an important CKD complication that contributes to CV risk.^17,48 Approximately 25% of people with CKD stage 3 to 5 have anemia,⁴⁹ owing to a combination of factors, including impaired production of erythropoietin, iron deficiency, and chronic inflammation.⁵⁰ The prevalence of anemia increases with worsening CKD severity.^17,49 Reduced oxygen-carrying capacity leads to tissue hypoxia, prompting increased heart rate and stroke volume, which over time drives left ventricular hypertrophy.⁵¹

The purpose of this review is to provide a current synopsis of inflammation in CKD with a focus on IL-6 as a rationale for therapeutic targeting to reduce inflammatory risks and improve CV and kidney outcomes in this population.

Biology of IL-6 Function, Activation, and Signaling

IL-6 is a pleiotropic proinflammatory cytokine that is involved in fundamental biological processes including the immune response to pathogens, hematopoiesis, bone integrity, and embryonic development.⁵² In addition to these vital functions, IL-6 may contribute to pathophysiologic processes of chronic inflammation, autoimmune diseases, and cancer.⁵²

IL-6 expression is primarily activated by toll-like receptors and TNF-α via the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3 inflammasome.⁵³ Upon activation, this inflammasome cleaves procaspase-1 to its activated form, which, in turn, leads to the activation and release of IL-1β and IL-18. This activates downstream production of IL-6 (Figure 1a).53, 54, 55, 56, 57, 58, 59, 60 IL-6 signaling stimulates the liver to produce C-reactive protein (CRP),⁵⁷ a clinical biomarker for systemic inflammation.

Figure 1.

The IL-6 signaling pathway. (a) Production of IL-6 via upstream activation of the NLRP3 inflammasome.53, 54, 55, 56 Arrows (→) indicate activation or downstream signaling steps. Blunt-ended lines (—|) indicate inhibition of a pathway component. Boxes indicate therapeutic agents and their corresponding targets in the IL-6 pathway. (b) The 3 IL-6-mediated signaling modes: classical signaling, trans-signaling, and cluster signaling.57, 58, 59, 60 CRP, C-reactive protein; gp130, glycoprotein 130; IL, interleukin; IL-6R, interleukin-6 receptor; JAK/STAT3, Janus kinase signal transducer and activator of transcription 3; NLRP3, nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3; sIL-6R, soluble interleukin-6 receptor.

There are 3 IL-6-mediated signaling modes, as follows: classical signaling, trans-signaling, and cluster signaling (Figure 1b).⁵⁸ IL-6 forms a complex with either a soluble or membrane-bound IL-6 receptor (IL-6R) that then binds to glycoprotein 130.⁵⁸ Activated glycoprotein 130 homodimerizes and activates multiple downstream signaling cascades, including the Janus kinase signal transducer and activator of transcription 3 pathway.⁵⁹ In classical signaling, IL-6 binds to membrane-bound IL-6R, which is found only on specific cell types, including monocytes, macrophages, dendritic cells, and podocytes.^59,60 Conversely, all somatic cells express glycoprotein 130, meaning that trans-signaling is the main pathway associated with systemic processes via IL-6 binding to soluble IL-6R.⁵⁹ The classical pathway primarily mediates anti-inflammatory effects of IL-6,^58,61 whereas the trans-signaling pathway mediates proinflammatory properties of IL-6.⁵⁸ Cluster signaling was first described only recently and its role in pathogenesis is poorly understood. From a therapeutic perspective, monoclonal antibodies that target either the IL-6 ligand or the IL-6 receptor have been developed (Figure 1a)^53,55; these agents inhibit both the classical and trans-signaling pathways.

Pathophysiology and Complications of Inflammation and IL-6 Signaling

CKD

Chronic and persistent local inflammation within the kidney occurs in CKD,^7,62 driving both CKD progression and associated ASCVD.⁶³ Fibrosis of the tubulointerstitial compartment represents a final common pathway of different CKD etiologies and leads to deterioration of kidney function.⁶³

Local inflammation in the kidney is initiated when pathogen-associated molecular patterns and damage-associated molecular patterns are released in response to injury or oxidative stress in the kidney.⁵⁶ The pathogen-associated and damage-associated molecular patterns bind to toll-like receptors on monocytes and resident kidney cells, which activate inflammasomes. This cascade triggers the release of proinflammatory cytokines, recruitment of monocytes into the glomerular and tubulointerstitial compartments of the kidney, activation of programmed cell death pathways, including apoptosis and pyroptosis, and polarization of monocytes into macrophages. Two subsets of macrophages are recognized, classically activated macrophages (M1) and alternatively activated macrophages (M2).⁶⁴ M1 macrophages activate T helper 1 cells, which secrete IL-6,⁶⁴ that, in turn, promotes differentiation of monocytes to M2 macrophages.^60,62 M2 macrophages are associated with anti-inflammatory responses, activation of T helper 2 cells, angiogenesis, and tissue healing by modifying the extracellular matrix. However, M2 macrophages may also increase fibrosis with persistent inflammation.⁶⁴

IL-6 is directly implicated in local inflammation within the kidney as part of a broader network of interacting inflammatory pathways. Kidney resident cells, including podocytes, mesangial cells, endothelial cells, and tubular epithelial cells, produce and respond to IL-6.⁶⁰ Production of IL-6 by podocytes and endothelial cells may be stimulated by immunomodulatory molecules such as IL-1, lipopolysaccharide, and TNF-α.⁶⁰ Mesangial cells can also produce IL-6, for example, in response to increased glucose uptake because of overexpression of glucose transporter 1.⁶⁵ Tubular epithelial cells may also produce IL-6 in response to various stimuli such as hypoxemia, nephrotoxins, oxidized lipids, advanced glycation end products, immune complexes, cytokines, and chemokines.^60,66

Cells within the kidney respond to IL-6 via both the classical and trans-signaling pathways, both of which lead to the activation of the Janus kinase signal transducer and activator of transcription 3 signaling cascade (Figure 1b).^53,60,67 Podocytes are the only cell types within the kidney that express membrane-bound IL-6R and therefore are the only cells that respond to IL-6 via the classical signaling pathway. In contrast, in mesangial cells, endothelial cells, and tubular epithelial cells, signaling in response to IL-6 occurs via the trans-signaling pathway. The role of cluster signaling (a paracrine interaction) and autocrine signaling modes in kidney physiology and pathophysiology is uncertain.⁶⁷

In healthy kidneys, IL-6 plays a role in essential functions, including maintaining the integrity of the glomerular filtration barrier.⁶⁷ However, IL-6 is also implicated in the development of CKD as it promotes a local inflammatory state in the kidney by mediating cytokine release and driving the upregulation of endothelin-1, a potent vasoconstrictor and profibrotic mediator.^68,69 Importantly, sustained or excessive activation of IL-6 trans-signaling stimulates glycoprotein 130 expression on endothelial, mesangial, and tubular cells, and drives the proliferation of mesangial cells and fibroblasts.^54,63 Collectively, these events promote endothelial dysfunction, inflammation, glomerulosclerosis, tubular fibrosis, tubulointerstitial damage, hypertrophy, and vascular leakage.^54,63 These processes progressively disrupt the kidney’s structural integrity through increased podocyte damage and epithelial-mesenchymal transition.^53,67 Activation and perpetuation of repair mechanisms (e.g., expression of vascular endothelial growth factor and TNF-α) ultimately contributes to persistent inflammasome activation and kidney inflammation.⁷⁰ Kidney damage related to excessive IL-6 signaling leads to albuminuria and eGFR decline.^71,72 As CKD progresses, IL-6 levels increase in a stepwise manner across CKD stages and independently predict eGFR decline among patients with CKD stage 2 to 5.⁷³

ASCVD in CKD

Inflammation is one of the major shared mechanisms for development and progression of ASCVD and CKD.^7,36 The elevated plasma IL-6 levels in CKD may result from various pathologic factors, including reduced IL-6 clearance because of impaired kidney function.^56,60As kidney function declines, circulating levels of toxins, such as indoxyl sulfate and p-cresyl sulfate,⁷⁴ rise as a result of decreased clearance and increased production by gut-derived dysbiosis related to uremia.⁴¹ An in vitro study found that indoxyl sulfate upregulated IL-6 expression in the human monocytic THP-1 cell line,⁷⁵ and a cross-sectional study in 149 patients with advanced CKD showed positive associations between both indoxyl sulfate and p-cresyl sulfate and IL-6 levels.⁷⁶ However, in another study including 67 patients with earlier stages of CKD, no correlation between these uremic toxins and IL-6 or high-sensitivity CRP (hsCRP) was detected.⁷⁴

Uremic toxins overproduced by dysbiosis are associated with intestinal permeability and activation of innate immune signaling pathways that drive proinflammatory cytokine production, including IL-6.^41,77 Uremic toxins also activate the cyclic adenosine monophosphate response element binding protein and activating transcription factor 1 pathway in endothelial cells, thereby exacerbating endothelial dysfunction,⁷⁸ a central mechanism of ASCVD.⁷⁹ Furthermore, treatment of kidney failure by dialysis promotes a proinflammatory state that exacerbates CV mortality risk, particularly in the first year of kidney replacement therapy.⁸⁰ Poor clearance of protein-bound indoxyl sulfate and p-cresyl sulfate by dialysis may contribute to this heightened inflammatory risk.⁸¹

In patients with CKD, a positive correlation has been identified between plasma IL-6 levels and ASCVD risk scores and CV mortality.⁸² IL-6 contributes to development of atherosclerosis,⁸³ and has been linked to hypertension in healthy individuals³² and in patients with CKD through an IL-6-mediated increase in angiotensin II.⁶⁸ Additionally, IL-6 is a mediator between angiotensin II and increased endothelin-1, while also upregulating the angiotensin II type 1 receptor.⁸⁴ Angiotensin II type 1 signaling enhances production of reactive oxygen species and oxidative stress, ultimately contributing to endothelial dysfunction and atherosclerotic plaque formation.⁸⁵ IL-6 also promotes the migration of circulating monocytes to sites of injury by upregulating monocyte chemoattractant protein-1, a cytokine for macrophage recruitment.⁸⁶ Once in the intima, monocytes differentiate into macrophages which perpetuate plaque inflammation and progression.⁸⁷ In vitro, IL-6 promotes monocyte to macrophage differentiation over other cell types.⁸⁸ IL-6 also promotes a procoagulant state by increasing platelet numbers via upregulation of thrombopoietin,^89,90 and increasing platelet reactivity via the priming of glycoprotein VI-mediated signaling.⁹¹ Another proposed mechanism of IL-6-mediated atherosclerosis development is the downregulation of adiponectin, a hormone involved in reducing inflammation and preventing fat accumulation in people with obesity and ASCVD. In vitro studies report that IL-6 directly downregulates adiponectin gene expression in both adipocytes (3T3-L1 cells) and adipose tissue cultures.^92,93

Although mechanistic findings support a role for IL-6 in atherosclerosis, in clinical studies, IL-6 and CRP are primarily characterized as biomarkers for adverse clinical outcomes. Approximately half or more of patients with both ASCVD and CKD have serum hsCRP levels of ≥ 2 mg/l, a biomarker of systemic inflammation.^15,94, 95, 96 Plasma IL-6 levels are also high in CKD.⁹⁷ In CKD populations and various observational cohorts, high circulating levels of IL-6 and hsCRP have been independently associated with CV events, all-cause mortality, and CV mortality.98, 99, 100, 101 In a post hoc analysis of the CANVAS trial of patients with type 2 diabetes at high CV risk, baseline IL-6 levels were positively correlated with risks of both kidney and CV events.¹⁰² Similarly, in patients with ASCVD, high hsCRP has been associated with adverse kidney outcomes in addition to CV events and mortality.^103,104 More recently, the prospective Multiethnic Study of Atherosclerosis cohort study revealed that elevated IL-6 levels predicted eGFR decline, urinary albumin-to-creatinine ratio increase, and CKD development.¹⁰⁵ In addition, IL-6 was found to be a stronger predictor of adverse kidney outcomes than hsCRP.¹⁰⁵ Of note, these observations of IL-6 and hsCRP in CKD and ASCVD provide hypothesis-generating associations but do not establish causality. Therefore, the possibility of residual confounding or reverse causality, that is, elevations in IL-6 and hsCRP driven by worsening of CKD or CVD, must be taken into consideration.

Anemia in CKD

Anemia is a common complication of CKD, affecting approximately 25% of people with advanced CKD.⁴⁹ A meta-analysis estimated that among patients with CKD not undergoing dialysis, anemia increased the risk of CKD progression, major adverse CV events, and hospitalization by 41% to 65%, 44%, and 46%, respectively.¹⁰⁶ Similarly, anemia is associated with poor prognosis in patients with CKD and CVD.^107,108 Compared with CVD only, the presence of CKD and CVD was associated with a 2-fold increase in mortality, whereas having CKD, CVD, and anemia was associated with a 4-fold increase in mortality.¹⁰⁷ Inflammation worsens anemia in CKD. High IL-6 levels correlate with reductions in hemoglobin levels,¹⁰⁹ and elevated hsCRP is a predictor of anemia.¹¹⁰

Inflammation also reduces responsiveness to erythropoietin treatment for anemia.¹¹¹ In particular, IL-6 increases the expression of hepcidin, a master regulator of systemic iron homeostasis that blocks erythropoiesis. IL-6 activates the Janus kinase signal transducer and activator of transcription 3 signaling pathway, leading to the formation of phosphorylated signal transducer and activator of transcription 3 homodimers, which translocate to the nucleus and upregulate hepcidin transcription by binding to signal transducer and activator of transcription-responsive elements in its promoter (Figure 2a).112, 113, 114, 115, 116 Excess hepcidin causes the proteolysis of ferroportin, attenuating iron transport, trapping iron inside cells, and limiting its supply to erythroid precursors for hemoglobin synthesis.¹¹² In addition to hepcidin stimulation, IL-6 can impair mitochondrial function and inhibit erythropoiesis by suppressing the late stages of erythropoietin-dependent Tokyo First-1 erythroid maturation, possibly by downregulating expression of SLC4a1, an essential gene for late erythroid development.¹¹⁷ Correspondingly, both IL-6 and hepcidin are elevated in patients with anemia of chronic disease,¹¹⁸ pointing to IL-6 as a potential therapeutic target for CKD-related anemia.

Figure 2.

(a) Role of IL-6 in iron metabolism and anemia and (b) therapeutic modulation of iron metabolism and anemia. (a) The IL-6/IL-6R/gp130 complex activates the JAK/STAT3 signaling pathway, leading to the phosphorylation and dimerization of STAT3.¹¹² These STAT3 homodimers translocate to the nucleus and upregulate hepcidin transcription by binding to STAT-responsive elements in its promoter.¹¹² Excess hepcidin causes the proteolysis of ferroportin, thus attenuating iron transport and trapping iron inside cells.¹¹² (b) IL-6 signaling increases hepcidin production and suppresses erythropoiesis, promoting functional iron deficiency and anemia. Dietary iron in the context of inflammation is associated with enhanced IL-6 signaling, which can further amplify hepcidin expression.^113,114 In contrast, ESAs lower hepcidin by stimulating erythropoiesis, and IL-6 inhibitors lower hepcidin by blocking IL-6 signaling.¹¹² Thus, hepcidin levels reflect the balance between hepcidin-raising stimuli (inflammation and dietary iron) and hepcidin-lowering stimuli (ESAs and IL-6 inhibitors). When IL-6 levels are elevated, persistent hepcidin elevation despite ESA therapy contributes to ESA hyporesponsiveness.^115,116 Arrows (→) indicate activation or downstream signaling steps. Blunt-ended lines (—|) indicate inhibition of a pathway component. ESA, erythropoiesis-stimulating agent; Fe, iron; gp130, glycoprotein 130; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; JAK/STAT3, Janus kinase signal transducer and activator of transcription 3; P, phosphorylated; STAT3, signal transducer and activator of transcription 3.

Iron supplementation is commonly used to treat anemia in CKD. Concerns have been raised about the long-term safety of i.v. iron, particularly the risk of CV complications and infections.¹¹⁹ Mouse models show that dietary iron supplementation has a proinflammatory effect and is associated with elevated IL-6,¹¹³ and in humans, iron treatment is associated with increased hepcidin levels (Figure 2a).¹¹⁴ Erythropoietin-stimulating agents (ESAs), which decrease hepcidin levels by stimulating erythropoiesis,¹¹² are often used in the management of anemia in patients with CKD. However, ESA effectiveness may be counteracted by high levels of IL-6 through upregulating hepcidin and inhibiting erythropoiesis. Elevated IL-6 is an independent predictor of resistance or hyporesponsiveness to ESAs in patients undergoing hemodialysis.^115,116 In addition, ESA use may be associated with an increase, rather than decrease, in hepcidin levels in patients with advanced CKD.¹¹⁴

Hypoxia-inducible factor prolyl hydroxylase inhibitors are a class of oral agents for the treatment of anemia in CKD that stimulate the production of endogenous erythropoietin and reduce hepcidin levels.¹²⁰ Although hypoxia-inducible factor prolyl hydroxylase inhibitors are efficacious in patients with ESA hyporesponsiveness, their use in clinical practice is currently limited to certain populations and access varies across geographic regions.¹²⁰ In addition, concerns remain regarding their CV safety profile,¹²⁰ which is particularly relevant to patients with ASCVD. Targeting inflammation-driven hepcidin upregulation with IL-6 inhibitors has been shown to downregulate hepcidin and improve anemia (Figure 2b),¹¹² and may offer a complementary approach to treatment of anemia in patients with CKD.

Clinical Approaches to CVD and CKD

Standard-of-Care

Recognition of the need for wider hsCRP testing to identify CV risk is growing. The Inflammation and CVD: 2025 American College of Cardiology Scientific Statement marks a shift towards wider adoption of hsCRP as a marker of CV risk, calling for universal screening of hsCRP in at-risk individuals for both primary and secondary CV prevention.¹²¹ In the 2025 focused update of the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines, hsCRP > 2 mg/l is identified as a CV risk modifier.¹²² Finally, in the 2026 American College of Cardiology/American Heart Association/Multisociety guideline on the management of dyslipidemia, elevated hsCRP is proposed as a risk-enhancing factor to help inform the use of high-intensity statin therapy to reduce ASCVD risk.¹²³

Management of concurrent ASCVD and CKD focuses on holistic risk reduction strategies,¹²⁴ with an emphasis on treating dyslipidemia and achieving recommended blood pressure (BP) targets. In patients with CKD, the 2021 European Society of Cardiology guidelines recommend use of a statin with or without ezetimibe to achieve a low-density lipoprotein cholesterol goal of < 100 mg/dl as a first step for the prevention of ASCVD. Goals of < 70 mg/dl or < 55 mg/dl are specified for moderate and severe CKD, respectively.⁶ Initiation of statins is not recommended for patients with kidney failure receiving dialysis, but statins may be continued in patients already receiving this therapy.⁶

The 2024 Kidney Disease: Improving Global Outcomes guideline recommends a systolic BP target of < 120 mm Hg for CV protective benefits in patients with CKD and high BP,¹⁴ whereas the European Society of Hypertension 2023 guidelines set a goal of BP < 130/80 mm Hg for most patients with CKD,¹²⁵ and the 2024 European Society of Cardiology guidelines for hypertension for patients with moderate-to-severe CKD set a systolic BP target of 120 to 129 mm Hg.¹²⁶ The 2024 Kidney Disease: Improving Global Outcomes guideline recommends an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker as first-line drug therapies for achieving BP targets because these agents reduce the risk of losing kidney function, kidney failure, and major CV events.^14,127 Sodium-glucose cotransporter-2 inhibitors are also recommended as a first-line therapy to reduce the risk of major adverse CV and kidney outcomes for patients with CKD,^6,14 and, therefore, are recommended alongside renin–angiotensin system inhibition.

Persistent albuminuria is an important risk factor for adverse cardiovascular-kidney-metabolic outcomes, including kidney failure, stroke, heart failure, and arrhythmias.¹²⁸ For this reason, the 2024 Kidney Disease: Improving Global Outcomes guideline recommends that a nonsteroidal mineralocorticoid receptor antagonist is added to a renin–angiotensin system inhibitor and a sodium-glucose cotransporter-2 inhibitor in patients with CKD and diabetes with persistent albuminuria.¹⁴ Finally, glucagon-like peptide-1 receptor agonists are also recommended because of clear benefits for kidney and CV outcomes in patients with diabetes, CKD, and albuminuria despite first-line therapies.¹²⁹

Anti-Inflammatory Properties of Standard-of-Care Therapies

Inflammation has emerged as a focus of therapeutic development in CKD,^130,131 and current standard-of-care therapies provide some off-target anti-inflammatory actions. Statins and proprotein convertase subtilisin/kexin type 9 inhibition may have lipid-independent anti-inflammatory and immunomodulatory effects.¹³² For example, simvastatin reduced inflammatory swelling of the footpad in a murine model of acute inflammation even in the absence of lipid level changes¹³³ and has been shown to inhibit inflammatory arthritis without affecting cholesterol concentrations.¹³⁴ Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers also have anti-inflammatory effects.¹³⁵ In randomized controlled trials, angiotensin-converting enzyme inhibitors showed a beneficial lowering effect on CRP, IL-6, and TNF-α, whereas angiotensin II receptor blockers were effective as a class in reduction of IL-6.¹³⁶ Similarly, finerenone has been found to significantly reduce IL-1β and TNF-α levels in patients with CKD and diabetes.¹³⁷ Other studies in patients with diabetes suggest that glucagon-like peptide-1 receptor agonists have anti-inflammatory effects,138, 139, 140, 141 including reductions in CRP levels¹³⁸ by approximately half along with decreased IL-6 levels.¹⁴¹ Sodium-glucose cotransporter-2 inhibitors similarly yield reductions in inflammatory biomarkers, including IL-6.¹⁴²

Anti-Inflammatory Therapeutic Targets

Despite standard-of-care therapies, inflammatory risk remains high in patients with CKD and ASCVD. Importantly, CKD-related inflammation arises from complex and overlapping pathways. Targeting a single cytokine or signaling axis may not provide sufficient inhibition, and anti-inflammatory therapies may not address the most relevant pathogenic pathways. In CKD, uremic toxin accumulation, anemia, and hemodynamic stress may additionally contribute to CV risk through mechanisms that are left unaddressed.

Previous studies of anti-inflammatory therapies for CKD in type 2 diabetes populations have included selonsertib (an apoptosis signal-regulating kinase 1 inhibitor),^143,144 bardoxolone (a nuclear factor erythroid 2-related factor 2 inhibitor),^145,146 ruboxistaurin (a protein kinase C-beta inhibitor),^147,148 baricitinib (a Janus kinase 1/2 inhibitor),^149,150 and pentoxifylline (phosphodiesterase inhibitor).^151,152 However, none of these agents moved forward into large-scale, phase 3 trials because of issues ranging from a lack of demonstrated efficacy (selonsertib) or safety signals (selonsertib, bardoxolone) to business and regulatory decisions (ruboxistaurin, baricitinib), or waning interest as more targeted therapies were developed (pentoxifylline). Small sample sizes and short follow-up, as well as dose modifications because of safety concerns, may have also precluded the demonstration of clinical benefit in some cases. Additionally, most available evidence in CKD studies has been derived from biomarker outcomes, which may not necessarily translate into improved clinical outcomes. Nevertheless, baricitinib has been brought forward in a phase 2 clinical trial in apolipoprotein L-1-associated kidney disease (NCT05237388).¹⁵³

Colchicine targets the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing protein 3 inflammasome and was recently approved by the US Food and Drug Administration for secondary prevention in patients with established ASCVD.¹⁵⁴ However, colchicine is associated with an increased risk of myotoxicity in advanced CKD and is contraindicated in patients with severe impairment of kidney function,¹⁵⁴ whereas use in patients with moderate impairment requires dose adjustments and careful monitoring.¹⁵⁵

Modulation of the autonomic nervous system through vagus nerve stimulation has been proposed as a potential disease-modifying approach to reduce inflammation in CKD, myocardial infarction, and stroke.⁴⁵ Pharmacological therapies including β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, which are part of standard-of-care for CKD or CVD, have been associated with anti-inflammatory effects and modulate the autonomic nervous system by reducing sympathetic activity.⁴⁵ Although clinical evidence remains limited, acetylcholine, the primary neurotransmitter of the parasympathetic nervous system, has been shown to inhibit IL-6 release in a preclinical study in lipopolysaccharide-stimulated human macrophage cultures.¹⁵⁶

Rationale for Development of IL-6 Inhibitors

The anti-IL-1β monoclonal antibody canakinumab was previously investigated for ASCVD. The Canakinumab Anti-inflammatory Thrombosis Outcome Study evaluated whether IL-1β blockade could prevent recurrent CV events in patients with a previous myocardial infarction and an hsCRP level ≥ 2 mg/l. Participants in the canakinumab group who achieved greater than the median reduction in IL-6 levels had a significantly lower risk of CV events than those in the placebo group.¹⁵⁷ In contrast, canakinumab had no significant benefit in participants who did not achieve substantial reductions in IL-6 levels,¹⁵⁷ suggesting that risk reduction may have been modulated by the magnitude of IL-6 reduction. An inference of this finding is that downstream targeting of IL-6 may be more effective than IL-1 blockade. Consistent with this, TNF-α inhibition in patients with acute myocardial infarction was associated with a reduction in IL-6 levels but ultimately was considered unlikely to be clinically beneficial because of an increase in thrombogenicity.¹⁵⁸ As such, neither anti-IL-1β nor TNF-α inhibition have moved forward in clinical trials for ASCVD. Instead, IL-6 may represent a promising target connecting inflammation to clinical risk, with therapeutic benefit more closely aligned with reductions in IL-6 levels than with upstream cytokine inhibition or downstream effectors alone. The rationale for blocking the IL-6 ligand versus the IL-6R also needs to be considered for treatment of ASCVD in CKD. Although IL-6R inhibitors are well-established therapies for autoimmune diseases as they block IL-6 signaling, there is potential to override this inhibition via high IL-6 levels.¹⁵⁹ Since anti-IL-6 ligand inhibitors neutralize circulating IL-6, they may offer a therapeutic advantage to reduce the high systemic inflammatory burden characteristic of CKD.

Several IL-6 inhibitors are in development for ASCVD in CKD (Table 1).160, 161, 162, 163 The anti-IL-6 monoclonal antibody clazakizumab reduced inflammatory biomarkers in patients undergoing maintenance dialysis and with hsCRP ≥2 mg/l in a phase 2 trial,¹⁶³ in which hsCRP levels decreased by 86% to 92% across clazakizumab doses compared with an increase of 19% with placebo.¹⁶³ Although clazakizumab was well tolerated, with grade 3 and 4 thrombocytopenia and neutropenia each observed in 7% of patients, the rate of severe infections was numerically higher in the highest clazakizumab dose group than in the placebo group (19% and 7%, respectively).¹⁶³

Table 1.

Overview of trials investigating IL-6 inhibitors for CKD

Trial name, number, and phase	Investigational producta	Patient population	Primary outcome	Timing of expected results
RESCUE NCT03926117 Phase 2	Ziltivekimab vs. placebo	Stage 3–4 CKD and hsCRP ≥2 mg/l	Change in hsCRP levels	Completed160,161
RESCUE-2 NCT04626505 Phase 2	Ziltivekimab vs. placebo	Stage 3–4 CKD and hsCRP ≥2 mg/l	Change in hsCRP levels	Completed162
ZEUS NCT05021835 Phase 3	Ziltivekimab vs. placebo	ASCVD, stage 3–4 CKD and hsCRP ≥2 mg/l	Time to 3-point MACE Secondary: time to eGFR decline ≥40%, kidney failure, dialysis, kidney transplant, death because of kidney or CV causes; change in hsCRP levels	Q3 2026
POSIBIL6ESKD NCT05485961 Phase 2b/3	Clazakizumab vs. placebo	Kidney failure with maintenance dialysis, hsCRP ≥2 mg/l, and ASCVD or diabetes	Phase 2b: change in hsCRP levels Phase 3: time to CV death or MI Secondary: change in hepcidin levels	Phase 2b: completed163 Phase 3: Q3 2029
TRANQUILITY NCT06362759 Phase 2	Pacibekitug vs. placebo	Stage 3–4 CKD and hsCRP ≥2 mg/l	Change in hsCRP levels	Completed (results not yet published)

ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; MACE, major adverse cardiovascular events; MI, myocardial infarction; Q, quarter.

^aAll investigational agents listed in the table are anti-IL-6 ligand inhibitors.

Another monoclonal antibody targeting IL-6, ziltivekimab, was associated with reductions in inflammatory biomarkers and markers of anemia in patients with stage 3 to 5 CKD and hsCRP ≥2 mg/l in the RESCUE and RESCUE-2 phase 2 trials.160, 161, 162 In the RESCUE trial, median hsCRP values were reduced by 77% to 92% across ziltivekimab doses compared with 4% with placebo.¹⁶¹ Hemoglobin levels increased by 0.34 to 0.82 g/dl, compared with a decrease of 0.22 g/dl with placebo.¹⁶⁰ Ziltivekimab was also associated with a decrease in hepcidin levels, although the changes were not statistically significant compared with placebo.¹⁶⁰ No cases of grade 3 and 4 thrombocytopenia or neutropenia were observed.¹⁶⁰ In the Japanese RESCUE-2 trial, median hsCRP values were reduced by 93% to 96% across ziltivekimab doses, compared with 27% with placebo.¹⁶² No significant differences in the rate of infection between either dose of ziltivekimab and placebo were observed.¹⁶² No cases of grade 3 and 4 thrombocytopenia or neutropenia were observed.¹⁶²

Whether the reported anti-inflammatory properties of IL-6 inhibitors translate to reductions in CV events or improved kidney outcomes is not yet known, and thus the clinical benefit of these therapies remains unproven. Several phase 2 and 3 trials of IL-6 inhibitors are ongoing.¹⁵⁴ A phase 2 study of pacibekitug assessing hsCRP in patients with stage 3 and 4 CKD (TRANQUILITY) was completed in late 2025, though final results are yet to be published (NCT06362759).¹⁶⁴ Clazakizumab is also being evaluated in a phase 2/3 trial in patients with hsCRP ≥2 mg/l receiving maintenance dialysis. The ongoing ZEUS placebo-controlled phase 3 trial includes patients with ASCVD, stage 3 and 4 CKD, and hsCRP ≥2 mg/l and is designed to assess the impact of ziltivekimab on CV events, with kidney outcomes as a main secondary outcome.

Of note, most trials of IL-6 inhibitors in CKD use change in hsCRP levels as a primary outcome (Table 1). Although biomarker-based outcomes are useful for confirming that a therapeutic agent engages the intended target, these outcomes cannot determine whether modifying that biomarker corresponds to altering the disease course. Therefore, it cannot be assumed that reductions in hsCRP translate into clinical improvement, making outcomes-driven trials essential to prove the therapeutic benefit of IL-6 inhibition.

Safety and Practical Challenges of IL-6 Inhibitors

Although IL-6 represents a promising therapeutic target, the clinical use of IL-6 inhibitors has limitations, including safety considerations and practical challenges. Potential limitations include exacerbation of immunosuppression and, subsequently, increased risk of severe or opportunistic infections, particularly in patients with CKD who often exhibit immune dysfunction and are susceptible to infections.¹⁶⁵ Importantly, clinical monitoring of infections, or autoimmune diseases, may be challenging because IL-6 signaling blockade can attenuate downstream inflammatory biomarkers (e.g., CRP), potentially masking disease activity and delaying diagnosis.¹⁶⁵ In addition, increased risk of hematological toxicities, including severe neutropenia and thrombocytopenia, has been reported.¹⁶³

Approved IL-6 inhibitors have both contraindications and cautions for their use. Contraindications include severe active infection (e.g., tuberculosis or viral hepatitis).166, 167, 168 Caution is warranted in patients with liver injury, neutropenia or thrombocytopenia, a history of gastrointestinal perforation, and in older individuals.166, 167, 168 Available clinical evidence does not support increased rates of malignancy with tocilizumab,¹⁶⁹ but IL-6 has been implicated in tumor development through its role in immune regulation and activation of downstream pro-tumorigenic pathways.¹⁷⁰ IL-6 blockade could therefore be beneficial, but long-term observational data are limited. A consensus statement recommends avoiding administration of live vaccines (e.g., rubella and shingles vaccines) during treatment with tocilizumab (an IL-6 inhibitor)¹⁶⁹; however, currently available evidence suggests that IL-6 inhibitors do not impair immunogenicity against nonlive vaccines such as pneumococcal, SARS-CoV-2, and tetanus vaccines.¹⁷¹

Strategies to minimize these risks include careful pretreatment screening for chronic infections, regular monitoring of liver enzymes, neutrophil and platelet counts, prompt evaluation and treatment of incident infections, patient education on early symptom reporting, and dose interruption or discontinuation of IL-6 agents when clinically indicated.

Furthermore, the use of IL-6 inhibitors may have practical challenges. Given that systemic inflammation, CKD, and ASCVD frequently coexist and are managed with complex, overlapping pharmacologic regimens, the introduction of IL-6 inhibitors requires careful consideration of potential drug–drug interactions. For example, tocilizumab is predicted to decrease the exposure to statins (atorvastatin, simvastatin), calcium channel blockers (amlodipine, nifedipine), and calcineurin inhibitors such as cyclosporine, which is particularly relevant for transplant recipients.¹⁶⁸

Collectively, these factors represent important considerations for IL-6 inhibitors in clinical practice, especially in the absence of long-term safety and clinical outcomes data and suggest that their use may require careful patient selection and monitoring.

Outlook

Inflammation in CKD is linked to decline in kidney function and CV events. IL-6 is a pleiotropic cytokine that plays a key role in mediating inflammation in CKD and CVD, thus making IL-6 a potential therapeutic target to improve clinical outcomes. Recent trials of IL-6 inhibitors (e.g., clazakizumab, ziltivekimab) have provided proof-of-concept that directly targeting IL-6 signaling reduces inflammatory biomarkers and may favorably impact anemia in CKD. Although current IL-6 inhibitors block both the classical and trans-signaling pathways, it remains unclear whether selectively targeting 1 pathway versus the other would yield different clinical outcomes or safety profiles. Furthermore, it remains to be determined whether IL-6 represents a modifiable causal mediator of disease or a marker of underlying inflammatory burden. A meta-analysis of clinical trials with different anti-inflammatory agents used for a variety of conditions (CV, dermatologic, and rheumatologic) found that these agents (bardoxolone, colchicine, darapladib, canakinumab, CCX140-B, and methotrexate) did not have a detectable effect on CV events or CKD progression.¹⁷² Long-term, robust safety data are also needed especially for risks including thrombocytopenia, neutropenia, and infectious complications. Additionally, evaluation of the cost-effectiveness of IL-6 inhibitors will be required to inform their appropriate adoption and integration into clinical care. Ongoing and future studies will determine whether therapies targeting IL-6 inhibition can deliver improved kidney and CV outcomes for the large and growing population with CKD.

Disclosure

KRT is supported by United States federal research grants from NIMHD, NIDDK, NHBLI, NCATS, the NIH Director's Office, and the CDC. She has also received investigator-initiated grant support from Bayer, Benaroya Research Institute, Breakthrough T1D (formerly the Juvenile Diabetes Research Foundation), Doris Duke Charitable Foundation, Otsuka, and Travere. She has received royalty payments from Up-to-Date. She reports consultancy fees from Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Otsuka, ProKidney, and Roche, as well as speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, and Travere. Additionally, she reports being Chair of data safety monitoring boards for the National Institute of Diabetes and Digestive and Kidney Disease, and George Clinical Institute, and member of the data safety monitoring board for AstraZeneca. She reports leadership roles as Chair for the Diabetic Kidney Disease Collaborative for the American Society of Nephrology, and Chair for Kidney Week 2025 Program Committee, both for the American Society of Nephrology, and is a member of the American Heart Association/American College of Cardiology Cardiovascular-Kidney-Metabolic Guideline Committee and a member of the Kidney Disease Improving Global Outcomes Diabetes and CKD Guideline Committee.

DZC has received honoraria from AbbVie, Altimmune, Amgen, AstraZeneca, Bayer, Biobridge, BMS, Boehringer Ingelheim-Lilly, CSL-Behring, Gilead, GSK, Inversago, Janssen, Lexicon, Maze, Merck, Mitsubishi-Tanabe, Novartis, Novo Nordisk, Otsuka, Prometic, Sanofi, Vantage, and Youngene, and has received operational funding for clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim-Lilly, CSL-Behring, Janssen, Lexicon, Merck, Novo Nordisk, and Sanofi.

RP-F is an employee of Arbor Research Collaborative for Health, which receives global support for the ongoing Dialysis Outcomes and Practice Patterns Study (DOPPS) Programs (without restriction on publications) by a variety of funders (for details see https://www.dopps.org/AboutUs/Support.aspx), and has received research grants from Fresenius Medical Care; consulting fees (paid to the employer) from Akebia, AstraZeneca, Bayer, Boehringer Ingelheim, and Novo Nordisk.

MP and KY declared no competing interests.

MS is a site principal investigator for the ZEUS trial.