Targeting pharmacotherapies for inflammatory and cardiorenal endpoints in kidney disease

Abstract

Inflammation is an important contributor to excess cardiovascular risk and progressive renal injury in people with CKD. Dysregulation of the innate and adaptive immune system is accelerated by CKD and results in increased systemic inflammation, a heightened local vascular inflammatory response leading to accelerated atherosclerosis, and dysfunction of the cardiac and renal endothelium and microcirculation. Understanding and addressing the dysregulated immune system is a promising approach to modifying cardiorenal outcomes in people with CKD. However, targeted pharmacotherapies adopted from trials of non-CKD and cardio-rheumatology populations are only beginning to be developed and tested in human clinical trials. Pharmacotherapies that inhibit activation of the NLRP3 inflammasome and the downstream cytokines IL-1 and IL-6 are the most well-studied. However, most of the available evidence for efficacy is from small clinical trials with inflammatory and cardiorenal biomarker endpoints, rather than cardiovascular event endpoints, or from small CKD subgroups in larger clinical trials. Other pharmacotherapies that have proven beneficial for cardiorenal endpoints in people with CKD have been found to have pleiotropic anti-inflammatory benefits including statins, mineralocorticoid receptor antagonists, SGLT-2 inhibitors, and GLP-1 agonists. Finally, emerging therapies in CKD such as IL-6 inhibition, small-interfering RNA against lipoproteins, AhR inhibitors, and therapies adopted from the renal transplant population including mTOR inhibitors and T regulatory cell promoters may have benefits for cardiorenal and inflammatory endpoints but require further investigation in clinical trials.

Introduction

Chronic kidney disease (CKD) is increasing in prevalence globally¹ and is a strong risk factor for atherosclerotic cardiovascular disease^2,3. Cardiovascular disease is the most common cause of death among people with CKD⁴. Worsening CKD severity, including declining estimated glomerular filtration rate (eGFR) and increasing urine albumin to creatinine ratio (UACR), is associated with increased cardiovascular risk^5,6. Mechanisms of accelerated cardiovascular disease in CKD are multifactorial and incompletely understood; however, they include the combined effects of metabolic risk factors, inflammation, oxidative stress, renin-angiotensin system activation, vascular and endothelial dysfunction, dialysis, and endocrine dysregulation^7,8. Cardiovascular disease management in CKD is challenging, with lower efficacy of statins, and decreased benefit and increased procedural risk of revascularization for obstructive coronary artery disease (CAD)^9–11. People with CKD are underrepresented in randomized trials of cardiovascular pharmacotherapies and interventions¹². Therefore, therapeutic approaches to address excess cardiovascular disease are frequently adopted from research trials in the non-CKD population.

Systemic inflammation is highly prevalent and multifactorial in people with CKD, with up to 50 percent of patients on dialysis having increased biomarkers of inflammation such as C-reactive protein (CRP)^13,14. Systemic inflammation has been consistently linked to the development of atherosclerotic cardiovascular disease^15,16, including in CKD^17,18. Inflammation is also associated with the initiation and worsening of CKD, further increasing the risk of cardiovascular disease^19,20. Elevations of systemic biomarkers of inflammation such as CRP, IL-6, IL-1β, TNF-α, and fibrinogen are common in advanced CKD and dialysis patients^14,21, associate with a decline in eGFR^22,23, and with increased cardiovascular risk^13,17,24,25.

Although there is ample evidence that inflammation has a key role in the development of atherosclerotic cardiovascular disease in CKD, targeted pharmacotherapies to address inflammation and thereby reduce the progression of cardiovascular disease and decrease cardiovascular risk are not yet widely adopted in clinical practice. The purpose of this review is to summarize the key inflammatory mechanisms that may mediate worsening cardiovascular and renal disease in people with CKD, and the available human clinical trial evidence supporting pharmacotherapies that target inflammatory mechanisms both directly and through pleiotropic effects.

Inflammatory mechanisms that promote atherosclerosis among people with CKD

Atherosclerotic plaque is recognized as a local vascular inflammatory and thrombotic response in the context of a systemic inflammatory state and is characterized by deposition of lipids, infiltration of leukocytes, and proliferation of smooth muscle cells in the intima of the arterial wall^26,27. The key innate and adaptive immunity pathways that mediate atherosclerosis are accelerated by CKD¹⁶. Lipoproteins that are deposited in the intima of the arterial wall undergo oxidative modification by reactive oxygen species (e.g. oxidized low-density lipoprotein, oxLDL), trigger innate immune responses, and subsequently trigger expression of adhesion molecules on endothelial cells such as intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Monocytes are recruited by endothelial cell surface signals and differentiate into macrophages, which engulf lipoproteins and transform into foam cells, collecting along with cholesterol crystals and apoptotic cellular debris and forming a necrotic core within an atherosclerotic plaque. Adaptive and cellular immunity with local infiltration of T and B cells and self-tolerance aberrations including the development of autoantigens such as oxLDL in the atherosclerotic plaque also play an important but incompletely understood role.^16,28

Innate Immunity and the NLRP3 inflammasome

Innate immunity, the initial line of immune defense, is mediated by pattern-recognition receptors (PRRs) on and within immune cells and has a key role in the development of sterile inflammation in atherosclerosis. PRRs recognize antigens from damaged cells, called damage-associated molecular patterns (DAMPs), facilitating the formation and activation of inflammasomes. NOD-like receptors (NLRs) and toll-like receptors (TLRs) have been found to be particularly important in atherosclerosis^29,30. NLRs can detect LDL cholesterol and cholesterol crystals and TLRs can detect oxLDL and other ligands released by local tissue damage that are related to chronic atherosclerotic inflammation^30–33.

The NOD-like receptor protein 3 (NLRP3) inflammasome is a well-studied mediator of inflammatory atherosclerotic disease. The NLRP3 inflammasome activates caspase-1, which cleaves pro-interleukin-1β (pro-IL-1β) to IL-1β. Through this pathway, NLRP3 has a key role in both atherosclerotic cardiovascular disease³⁴ and the development of chronic kidney injury^35,36. Activation of TLRs by DAMPs is a key step in activation of the NLRP3 inflammasome, as they stimulate expression of NLRP3 inflammasome components and pro-IL-1β via nuclear factor-ΚB (NF-κB) ³⁰. IL-1β further stimulates IL-6, which is also associated with atherosclerotic cardiovascular disease risk³⁷ and progression of CKD³⁸. IL-1α, which is expressed constitutively on the cell surface and does not require caspase-1 cleavage for activation, also may mediate cardiovascular disease in CKD. IL-1α has been found to be expressed on monocytes in CKD patients with acute myocardial infarction and is associated with increased risk of recurrent cardiovascular events³⁹. Cytokines such as IL-1 and IL-6 activate endothelial cells, leading to expression of cell adhesion molecules such as VCAM-1 and ICAM-1 and promoting adhesion of other inflammatory cells³⁴. Pro-inflammatory cytokines also induce the production of the acute phase reactant C-reactive protein from the liver^40,41.

Role of lipoproteins and cholesterol crystals

There are a variety of atherosclerosis-associated DAMPs that mediate activation of the NLRP3 inflammasome and other pro-inflammatory pathways. Lipoproteins, such as the apolipoprotein ApoC3 have been shown to induce IL-1β release from monocytes via the NLRP3 pathway in conjunction with TLR activation⁴². Dyslipidemia and modification in lipoproteins are common among people with CKD, including increased LDL and triglyceride levels, reduced high density lipoprotein (HDL) levels, increased ApoB lipoproteins, increased lipoprotein(a), and modification of LDL including carbamylation (cLDL) and oxidation (oxLDL)^43,44. Carbamylation of LDL has been shown to be associated with increased urea and myeloperoxidase levels in uremia⁴⁵. Additionally, systemic inflammation associated with CKD modifies the composition and function of HDL, and therefore may modify the association of HDL with cardiovascular risk. For instance, in the KNOW-CKD study, there was a loss of the protective effect of high HDL in patients with inflammation as measured by elevated CRP, which may be due to dysfunctional HDL⁴⁶. Finally, CKD is associated with accumulation of proatherogenic cholesterol in a crystalline state (cholesterol crystals)⁴⁵.

Accumulation of serum uric acid

Chronic kidney disease is a risk factor for hyperuricemia and gout, in part because serum uric acid is primarily excreted by the kidneys. Hyperuricemia has been associated with the development of atherosclerotic CV disease in several meta-analyses of prospective studies^47–49. Intracellular uric acid has been shown to induce oxidative stress in pre-clinical studies, triggering down-stream inflammatory signaling pathways including the mitogen-activated protein kinase (MAPK) cascade and NLRP3 inflammasome, as well as influencing macrophage differentiation to foam cells⁵⁰.

Alterations in the gut microbiome and uremic toxins

CKD alters the gut microbiome and impairs intestinal barrier function. Alterations in the gut microbiome have been linked to increased absorption and reduced clearance of uremic toxins that can cause cardiovascular disease⁵¹. For instance, protein-bound toxins such as indoxyl sulfate, p-cresyl sulfate and trimethylamine N-oxide (TMAO) which arise from metabolism of amino acids in the gut by bacteria, have been linked to adverse renal and cardiovascular outcomes^51–53. These toxins are linked to increased IL-1B and NF-κB production through an aryl hydrocarbon receptor (AhR) and MAPK pathway⁵⁴.

Adaptive immunity and the role of T regulatory cells

Following the innate immune response, cells of the adaptive immune system including T cells, B cells and regulatory T cells are recruited in response to antigens on antigen presenting cells (APCs), especially major histocompatibility complex class II (MHC2) on macrophages and dendritic cells. Cells of the adaptive immune system have been shown to have both pathogenic effects, in the case of T helper 1 (T_H1) and B-2 cells, and protective effects, in the case of T regulatory (T_reg) cells²⁸. CKD and uremia are associated with expansion and dysfunction of the atherogenic T helper cell population and depletion of the T_reg population, along with depletion of protective natural anti-oxLDL IgM autoantibodies⁴⁵.

Therapeutic Approaches: Evidence from Clinical Trials

Targeted immunomodulatory pharmacotherapies and non-targeted pharmacotherapies with pleiotropic anti-inflammatory effects have been studied in people with CKD in clinical trials, showing benefit for inflammatory and cardiorenal biomarker endpoints and less commonly cardiovascular outcome endpoints (Table 1). The pharmacotherapies studied and developed to date are primarily targeted against the innate immune system (Figure 1) however novel therapies are being developed to target the adaptive immune system and other inflammatory pathways.

Table 1:

Targeted and non-targeted immunomodulatory therapies in CKD: Human trial evidence of effect on inflammatory and cardiorenal biomarkers and outcomes

Immune Pathway	Therapy	Cardiorenal Biomarkers	Inflammatory Biomarkers	Outcomes	Trials
IL-1	Canakinumab		↓ hsCRP	↓ CV Events	CANTOS59
	Anakinra		↓ hsCRP, ↓ IL-6, ↓ myeloperoxidase activity		Hung et al55, REDHART56
	Rilonacept	↑ FMD	↓ hsCRP, ↓ NADPH oxidase expression		Nowak et al57, Hung et al58
IL-6	Ziltivekimab	↓ Lp(a)	↓ hs-CRP, ↓ fibrinogen		RESCUE62, ZEUS (in progress)63
	Tocilizumab	↑ salvageable myocardium on MRI, ↓ troponin	↓ hs-CRP		ASSAIL-MI67, Kleveland et al68
Nrf2	Bardoxolone methyl	↑ eGFR		↔ ESRD development, ↔ CV deaths, ↑ heart failure hospitalization & death	BEAM72, BEACON73
mTOR	Sirolimus	↓ CIMT			Silva et al76
Nontargeted therapies with pleiotropic anti-inflammatory properties	Methotrexate	↓ eGFR decline	↔ hsCRP, ↔ IL-6	↔ CV events	CIRT (CKD stage 1–3)79,80
	Colchicine	↔ albuminuria	↓ hsCRP, ↓ NLRP3	↔ CV deaths	LoDoCo2 CKD stage 3A subanalyses82,89, Wang et al91
	Other uric acid lowering agents (Allopurinol and Febuxostat)	↔ eGFR decline	↔ CRP, ↓ uric acid	↔ CV events	Goicoechea et al93, CKD-FIX94, PERL95, FEATHER96, FREED97,98
	Statins	↓ LDL, ↓ eGFR decline	↓ hsCRP	↓ CV events, except ↔ in dialysis-dependent in AURORA and 4D	JUPITER CKD subanalysis103, SHARP104, CARE23, AURORA105, 4D106
	MRAs (finerone)	↓ eGFR decline, ↓ proteinuria		↓ CV events	FIDELIO-DKD109, FIGARO-DKD110
	SGLT-2 inhibitors (dapagliflozin, canagliflozin)		↓ IL-1β, ↓ NLRP3, ↑ BHB, ↓ insulin, ↓ IL-6, ↓ MMP-7, ↓ fibronectin-1, ↓ TNF receptor 1	↓ CV events, ↓ adverse renal outcomes	DAPA-CKD113, Kim et al114, CANATA-SU subanalysis115
	GLP-1 agonists	↓ eGFR decline, ↓ albuminuria		↓ CV events	SUSTAIN 6 and LEADER post-hoc analysis116, Zelniker et al metaanalysis117

CV: cardiovascular; hsCRP: high-sensitivity C-reactive protein; IL: interleukin; NADPH: nicotinamide adenine dinucleotide diphosphate; FMD: flow-mediated dilation; Lp(a): Lipoprotein (a); Nrf2: nuclear factor erythroid-2-related factor 2; ESRD: end-stage renal disease; mTOR: mammalian target of rapamycin; CIMT: carotid intima media thickness; eGFR: estimated glomerular filtration rate; LDL: low-density lipoprotein; NLRP3: (NOD)-like receptor protein 3; BHB: beta hydroxybutyrate; MMP-7: matrix metalloproteinase 7; MRAs: mineralocorticoid receptor antagonists; TNF: tumor necrosis factor; SGLT-2: Sodium-glucose cotransporter 2; GLP-1: glucagon-like peptide-1

Figure 1:

Innate immunity cellular signaling pathways involved in atherosclerotic cardiovascular disease in people with CKD, and targeted and pleiotropic immunomodulatory therapeutic approaches

*Have not shown a reduction in cardiorenal or inflammatory biomarkers or favorable impact on outcomes in clinical trials

IL: interleukin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; TLR: Toll-like receptor; MyD88: Myeloid differentiation primary response 88; JAK: Janus kinase; STAT: signal transducer and activator of transcription; NLRP3: (NOD)-like receptor protein 3; ASC: Apoptosis-associated speck-like protein; BHB: beta hydroxybutyrate; SGLT-2: Sodium-glucose cotransporter 2; GLP-1: glucagon-like peptide-1

Targeted immunomodulatory pharmacotherapies

Interleukin-1 (IL-1)

IL-1β inhibition by canakinumab, antagonism of the IL-1 receptor by anakinra and the high affinity trapping of IL-1β and IL-1α by the soluble decoy receptor rilonacept have shown potential benefit to improve cardiovascular biomarkers and outcomes in clinical trials among people with CKD and dialysis-dependent end-stage renal disease (ESRD). These therapies are currently approved and utilized for treatment of autoimmune inflammatory diseases such as rheumatoid arthritis (anakinra) and recurrent idiopathic pericarditis (rilonacept). Anakinra has been shown to reduce high-sensitivity CRP (hsCRP) and IL-6 levels in a small, randomized placebo-controlled trial of 22 dialysis-dependent patients with elevated baseline hsCRP⁵⁵. In a post-hoc analysis of the Recently Decompensated Heart Failure Anakinra Response Trial (REDHART) study, two weeks of Anakinra was also found to reduce hsCRP and myeloperoxidase activity in 52 patients with eGFR 30–60 ml/min/1.73 m² and heart failure⁵⁶. In a further double-blind trial of 42 patients with stage 3–4 CKD, rilonacept reduced hsCRP and endothelial cell nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression, and improved brachial artery flow-mediated dilation (FMD)⁵⁷. Both anakinra and rilonacept were found to improve HDL anti-oxidant and anti-inflammatory functional properties⁵⁸.

The strongest evidence to support a beneficial effect of IL-1 blockade on cardiovascular outcomes in CKD comes from a post-hoc analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) of patients with prior myocardial infarction. In CANTOS, canakinumab significantly reduced the risk of major adverse cardiovascular events by 18% in the 1,875 participants with eGFR 30–60 ml/min/1.73 m² (HR [95% CI]: 0.82 [0.68–1.00]) and by 14% among those with eGFR > 60 ml/min/1.73 m² (HR [95% CI]: 0.86 [0.77–0.97]; P-heterogeneity = 0.68).⁵⁹ A similar pattern of benefit for canakinumab was observed among participants with albuminuria at baseline, although urine albumin-to-creatinine ratio was obtained only for participants with pre-diabetes or diabetes at baseline.⁵⁹ Canakinumab had minimal effects on eGFR decline, albuminuria progression and the risk of CKD progression.⁵⁹

Inhibition of IL-1α has not been studied as a therapeutic target for cardiovascular disease in CKD, although it has been found to be a key mediator of inflammation in patients with acute myocardial infarction³⁹. Xilonix is a novel therapy targeting IL-1α that has been studied in non-small lung cancer and colorectal cancer⁶⁰, as well as in a phase 2 clinical trial following superficial femoral artery revascularization in which it was not associated with reduced cardiovascular events compared to placebo⁶¹.

Interleukin-6 (IL-6)

In the recent phase 2 RESCUE trial, the IL-6 monoclonal antibody Ziltivekimab was found to reduce inflammation as measured by hsCRP, fibrinogen, serum amyloid A, haptoglobin, and secretory phospholipase A2 as well as reduce lipoprotein(a) levels⁶². Evidence of a benefit of IL-6 inhibition on longitudinal cardiovascular outcomes in people with CKD is lacking, however the large clinical trial Ziltivekimab Cardiovascular Outcomes Study (ZEUS) is ongoing⁶³ and Mendelian randomization analyses provide causal evidence for an effect of IL-6 on cardiovascular events among people with CKD^64–66. In the non-CKD population, the randomized clinical trial Assessing the effect of anti-IL-6 treatment in MI (ASSAIL-MI) found that the IL-6 receptor antibody tocilizumab improved the proportion of salvageable myocardium on MRI after ST elevation myocardial infarction (STEMI)⁶⁷. In a separate trial, tocilizumab attenuated the increase in hsCRP and PCI-related troponin release after non-ST elevation myocardial infarction (NSTEMI)⁶⁸. However, tocilizumab has not been studied in clinical trials of people with CKD, except in renal transplant recipients as described in a separate section. Additionally, tocilizumab has been associated with modest increases in total cholesterol, HDL, LDL and triglyceride levels⁶⁹; however, it has been shown to have a positive effect on lipoprotein (a) and oxLDL which may imply decreased CV risk despite worsening in some lipid parameters⁷⁰.

Nuclear factor erythroid-2-related factor 2 agonists

Targeted therapies for the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which is a genetic regulator that promotes antioxidant activity, have been investigated to improve cardiac and renal outcomes. Bardoxolone methyl is an investigational Nrf2 activator which also inhibits NF-κB⁷¹. In the Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes (BEAM) phase 2 randomized trial, bardoxolone methyl was found to significantly increase estimated GFR compared to placebo among 227 diabetics with CKD stage 3–4⁷². However, in the Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON) randomized phase 3 trial of 2185 diabetics with CKD, there was no difference in the primary outcome of development of ESRD or death from cardiovascular causes for people on bardoxolone methyl compared to placebo, and the trial was terminated early because of higher rates of hospitalization or death from heart failure⁷³.

Adaptive Immunity/Regulatory T-cells

Targeted therapies for adaptive immunity are a promising approach but are not well studied in people with CKD. Even among the non-CKD population, the available evidence for modulating adaptive immunity to reduce atherosclerotic cardiovascular disease is primarily in the pre-clinical stage⁷⁴. Modulation of IL-2 is one potential approach. The mammalian target of rapamycin (mTOR) inhibitor sirolimus blocks the cell-cycle kinase mTOR which has the downstream effect of inhibition of T and B cell activity mediated by IL-2⁷⁵. In a small clinical trial of kidney transplant recipients randomized to tacrolimus/sirolimus vs tacrolimus/mycophenolate, those on sirolimus had a decrease in carotid intima media thickness (CIMT) and had a higher HDL⁷⁶. The favorable impact of sirolimus on carotid atherosclerosis in this trial was seen despite an association in other clinical trials of mTOR inhibitors with adverse metabolic effects after transplant including new-onset diabetes, elevated cholesterol, and elevated triglycerides⁷⁷.

Pharmacotherapies with nonspecific or pleiotropic immunomodulatory effect

Methotrexate

Methotrexate non-specifically suppresses systemic inflammation through several mechanisms including inhibition of dihydrofolate reductase leading to increased T cell apoptosis, inhibition of aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase (ATIC) leading to adenosine release and cellular binding and suppression of immune reactions, and inhibition of NF-κB⁷⁸. In the Cardiovascular Inflammation Reduction Trial (CIRT), methotrexate did not reduce cardiovascular events nor did it reduce inflammatory biomarkers such as hsCRP, IL-6, and IL-1β⁷⁹. However, those randomized to methotrexate had slightly less decline in eGFR compared to placebo, and it was safe in CKD stage 1–3⁸⁰. Methotrexate has not been studied in people with more advanced CKD in a clinical trial, however given the lack of efficacy in CIRT for cardiovascular or inflammatory endpoints, and the potential risk for dose-dependent and CKD-stage-dependent worsening of renal impairment associated with crystal nephropathy⁸¹, it is less likely to be a promising anti-inflammatory therapy.

Colchicine

Colchicine is a non-specific anti-inflammatory therapy that has been primarily used in gout and pericarditis. In the Colchicine Cardiovascular Outcomes Trial (COLCOT) and Low-Dose Colchicine 2 (LoDoCo2) trials of patients with recent myocardial infarction and chronic CAD respectively, low-dose colchicine 0.5 mg daily has been found to reduce risk for cardiovascular events and mortality^82,83. A new, low-dose formulation of colchicine (0.5 mg daily) was FDA approved in June 2023 to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease (the standard dose in the United States is 0.6 mg)^84,85 and both American and European guidelines endorse the use of colchicine for atherosclerotic cardiovascular disease prevention in select patients^86,87. Colchicine achieves high concentrations in leukocytes and has a variety of anti-inflammatory effects including the inhibition of neutrophil migration and adhesion, smooth muscle proliferation, and NLRP3 inflammasome activation which results in reduction of the release of inflammatory markers such as IL-1β and IL-6⁸⁸. In a sub-analysis of the LoDoCo2 trial, colchicine was found to reduce extracellular vesicle NLRP3 levels along with hsCRP⁸⁹. Low-dose colchicine was well-tolerated in both COLCOT and LoDoCo2, with modestly higher rates of gastrointestinal adverse events, although participants with CKD were excluded from these trials.

The safety profile and efficacy of colchicine for CAD prevention in CKD has not been well studied, with no dedicated clinical trials⁹⁰. In a study of 190 participants with type 2 diabetes mellitus and moderately increased urine albumin-to-creatinine ratio, low-dose colchicine 0.5 mg daily did not slow the progression of albuminuria but also did not increase the risk of gastrointestinal adverse effects⁹¹. Colchicine is contraindicated/not recommended for patients with severe renal impairment⁸⁵, defined as eGFR <15 ml/min/1.73 m² in manufacturer guidelines⁸⁴ and eGFR <30 ml/min/1.73 m² in the 2023 American guidelines for chronic CAD⁸⁶. Colchicine steady-state serum levels may exceed accepted safe limits and increase risk for adverse effects in the setting of renal impairment, based on pharmacodynamic modeling studies⁸⁵. In a subgroup analysis of the LoDoCo2 trial, of patients with stage 3A CKD which included only 148 patients, there was no association of colchicine with cardiovascular events (HR 1.18 [95% CI 0.53–2.63]⁸². There is some evidence that colchicine may be effective for renal endpoints in moderate CKD, including a nested case-control study which found that colchicine use in stage 3 to 4 CKD was associated with reduced risk of CKD progression⁹².

Uric Acid Lowering Therapies

Hyperuricemia has been linked to CKD, CV disease and inflammation, and uric acid lowering therapies for gout including allopurinol and febuxostat have been studied as potential therapies to reduce cardiovascular and renal risk⁵⁰. In a small non-placebo-controlled trial of 113 participants with CKD stage 3 and greater randomized to allopurinol or continuation of their usual therapy, allopurinol was associated with decline in serum uric acid and CRP, fewer cardiovascular events, and slower decline in eGFR⁹³. However, subsequent larger and placebo-controlled trials have not found beneficial effects on cardiovascular and renal outcomes. In the Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase (CKD-FIX), which randomized 369 patients to allopurinol or placebo, there was no difference in the primary outcome of change in eGFR at 104 weeks, or difference in secondary outcomes including development of ESRD or cardiovascular events⁹⁴. The Preventing Early Renal Loss in Diabetes (PERL) trial randomized 267 patients with type 1 diabetes and early to moderate stage CKD to allopurinol or placebo, and did not find a difference in the primary outcome of change in iohexol-based GFR after 3 years, or secondary outcomes of creatine doubling/ESRD or cardiovascular events⁹⁵. In the Febuxostat Versus Placebo Randomized Controlled Trial With Hyperuricemia Complicated by Chronic Kidney Disease Stage 3 (FEATHER), which randomized 467 patients with stage 3 CKD to febuxostat or placebo, there was no difference in the primary outcome of slope of eGFR change after 108 weeks⁹⁶. Finally, in the Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED), which randomized 1070 patients to febuxostat or usual care (which could include allopurinol), the primary composite event of cerebral, cardiovascular, and renal events was lower in the febuxostat group. However, the difference was driven by development of renal impairment, which included the development or worsening of albuminuria, and there was no difference in the slope of eGFR change or in cardiovascular events⁹⁷. Additionally, in a post-hoc analysis there was no difference in hsCRP levels after febuxostat treatment in the FREED trial⁹⁸. In summary, the combined clinical trial evidence of uric acid lowering therapies in people with CKD does not support a benefit for cardiovascular or renal outcomes.

Statins

Statins are among the most well-studied therapies to reduce cardiovascular disease risk, including in people with CKD⁹⁹, and have been found to reduce systemic inflammation¹⁰⁰. Some, but not all, statins have been found to have pleiotropic anti-inflammatory effects, including through lipid-lowering and inhibition of the NLRP3 inflammasome and Toll-like receptors^30,101. In a meta-analysis of 25 studies in patients with CKD, statin therapy decreased CRP by −2.06 mg/L (95% CI −2.85 to −1.27)¹⁰⁰. In the Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which enrolled healthy individuals with elevated hsCRP, rosuvastatin lowered risk of cardiovascular events and the hsCRP concentration¹⁰². In a sub-analysis of the JUPITER trial, in patients with eGFR <60 ml/min/1.73 m², rosuvastatin also lowered risk of cardiovascular events and the hsCRP concentration¹⁰³. The Study of Heart and Renal Protection (SHARP) trial found that simvastatin plus ezetimibe reduced risk of cardiovascular events in both dialysis-dependent and non-dialysis dependent CKD¹⁰⁴. In a sub-analysis of participants with eGFR <60 in the Cholesterol and Recurrent Events (CARE) trial of pravastatin therapy in patients with history of myocardial infarction, higher CRP was associated with renal function decline and pravastatin was associated with prevention of renal function decline²³. Conversely, in the A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Event (AURORA) and Die Deutsche Diabetes Dialyse (4D) randomized trials of hemodialysis patients, rosuvastatin and atorvastatin lowered LDL cholesterol and either lowered or stabilized CRP compared to placebo but did not reduce the risk for cardiovascular events^105–107. In a post-hoc analysis of 4D, although baseline inflammation as measured by CRP was high, and higher CRP was predictive of cardiovascular events, atorvastatin did not have an influence on outcomes regardless of quartile of baseline CRP¹⁰⁷. In summary, based on current trial evidence, statins have pleiotropic anti-inflammatory benefits in patients with both dialysis-dependent and non-dialysis dependent CKD, however the benefit on CV outcomes is attenuated or absent in patients on dialysis.

Mineralocorticoid Receptor Antagonists

Mineralocorticoid receptor antagonists have been found to reduce proteinuria,¹⁰⁸ and reduce CKD progression and cardiovascular events in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) randomized trials.^109,110 Mineralocorticoid activation and hyperaldosteronism are associated with adverse myocardial remodeling secondary to fibrosis, mitochondrial dysfunction, and dysregulation of beta-adrenergic receptor and insulin signaling¹¹¹. In pre-clinical studies, mineralocorticoid receptor activation has also been linked to increases in NADPH oxidase activity and reactive oxygen species that mediate pro-inflammatory cytokines such as TGF- β and IL-1β^108,112. Therefore, it is plausible that the benefit of MR blockade on CKD progression and cardiovascular events goes beyond direct effects on myocardial structure and function and is partially mediated by anti-inflammatory mechanisms. However clinical trial evidence is not currently available to demonstrate this hypothesis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase urinary glucose excretion and reduce blood glucose, but also have been found to reduce cardiovascular risk which may be mediated by pleiotropic anti-inflammatory effects. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial of CKD stage 2–4, dapagliflozin was associated with lower risk of adverse renal outcomes and cardiovascular events¹¹³. In a small randomized trial of diabetics, the SGLT2-inhibitor empagliflozin was found to reduce activation of the NLRP3 inflammasome and reduce IL-1β secretion in macrophages, which was in part found to be mediated by an increase in β-hydroxybutyrate (BHB) and a decrease in insulin.¹¹⁴ In a sub-analysis of blood samples from the Canagliflozin Treatment And Trial Analysis versus Sulfonylurea (CANTATA-SU) trial of people with diabetic kidney disease, the SGLT2-inhibitor canagliflozin was found to have potential anti-inflammatory and anti-fibrotic effects including decrease in IL-6, fibronectin 1, TNF receptor 1, and matrix metalloproteinase 7 (MMP-7) levels compared with glimepiride¹¹⁵.

Glucagon-like peptide-1 receptor agonists

In a post hoc analysis of the trials of the glucagon-like peptide-1 (GLP-1) receptor agonists semaglutide and liraglutide, people with diabetes and CKD on GLP-1 receptor agonists had lower albuminuria and less decline in eGFR in addition to their previously described beneficial effects on cardiovascular events¹¹⁶. Additionally, in a metanalysis of 5 trials of GLP-1 receptor agonists (Lixisenatide – ELIXA; Liraglutide – LEADER; Semaglutide – SUSTAIN-6; Exenatide – EXSCEL; Albiglutide – HARMONY) compared to 3 trials of SGLT2 inhibitors (Empaglifloxin - EMPA-REG OUTCOME; Canagliflozin – CANVAS; Dapagliflozin – DECLARE TIMI 58), both had similar benefit for reduction of cardiovascular events and also reduced development of macroalbuminuria. However, only SGLT2 inhibitors reduced risk of worsening eGFR, renal death, or ESRD¹¹⁷. There is limited prospective human data on whether GLP-1 agonists modify inflammatory biomarkers in people with CKD. However, in the non-CKD population there is extensive human prospective study evidence of the anti-inflammatory effect including inhibition of the expression of NF-κB, IL-1β and TLRs and reduction in hsCRP and oxidative stress^118,119. These anti-inflammatory effects are likely to translate to people with CKD.

Role of Inflammation in Renal transplant Recipients

Renal transplantation is associated with increased activation of the immune system¹²⁰. Furthermore, renal transplantation is associated with a reduction of cardiovascular risk, although the absolute risk remains high even after transplant^121,122. Inflammatory markers are elevated among renal transplant recipients and associated with increased risk of graft loss and mortality¹²³. Targeting innate and adaptive immunity after transplant may provide beneficial effects against inflammation, reduce risk for allograft injury and rejection, and improve cardiorenal outcomes. However, most trials of immunomodulatory therapies in renal transplant recipients have focused on antibody mediated rejection and allograft loss and have not included cardiovascular endpoints.

Among renal transplant recipients in the Assessment of Lescol in Renal Transplantation (ALERT) trial who were randomized to Fluvastatin, IL-6 and hsCRP were associated with increased risk of cardiovascular events and all-cause mortality in a post-hoc analysis¹²⁴. Fluvastatin was associated with a reduction in cardiovascular death and myocardial infarction, which was a secondary outcome¹²⁵.

IL-6 inhibition has shown promise for improving renal transplant outcome; small studies have targeted IL-6 inhibition through Tocilizumab (IL-6 receptor antibody) and Clazakizumab (direct IL-6 antibody) and demonstrated reduced rates of acute rejection and improvement in graft survival, renal function and patient survival¹²⁶. However, human trials have not been performed to assess the efficacy of targeting IL-6 to modify cardiovascular endpoints in the post-transplant population. Additionally, IL-6 receptor inhibition by Tocilizumab has been associated with increased IL-6 levels¹²⁷ and potential rebound inflammation when discontinued¹²⁶, and therefore direct inhibition of IL-6 with Clazakizumab or Ziltivekimab may be more promising to improve cardiorenal outcomes.

The mTOR pathway and adaptive immunity may be another possible target for patients after renal transplant. Sirolimus use was associated with a decrease in carotid intima media thickness (CIMT) and an increase in HDL in a small clinical trial comparing tacrolimus/sirolimus vs tacrolimus/mycophenolate⁷⁶. However, in the ELEVATE trial of conversion from a calcineurin inhibitor to everolimus, there was no change in eGFR or left ventricular mass index, and acute rejection rate was higher compared to patients remaining on a calcineurin inhibitor¹²⁸.

T regulatory cell stimulation is another potential therapeutic target, which has shown initial promise for managing acute rejection and maintaining tolerance of the transplanted organ¹²⁹. Because T regulatory cells are also potentially protective in the inflammatory pathways involved with atherosclerosis, they may also improve cardiovascular outcomes, however this has not been explored in a human trial.

Future Directions

NLRP3 inflammasome mediated IL-1 and IL-6 cytokine release is a promising pharmacotherapeutic pathway to improve renal and cardiovascular outcomes. The phase 3 randomized clinical trial ZEUS which began enrollment in 2021 and will complete in 2025, has the objective of comparing IL-6 inhibition with ziltivekiumab to placebo for cardiorenal outcomes in people with CKD⁶³. Larger trials of therapies targeting IL-1, the IL-1 receptor, the NLRP3 inflammasome and IL-1α in people with CKD with assessment of cardiorenal and inflammatory outcomes are needed. Targeted lipoprotein therapies have also shown promise in the non-CKD population. The small-interfering RNA Olpasiran has been found to reduce lipoprotein(a) levels in the Olpasiran Trials of Cardiovascular Events and Lipoprotein[a] Reduction–Dose Finding Study (OCEAN(a) DOSE) trial¹³⁰, and whether it improves CV outcomes is currently being investigated in a phase 3 trial. Lipoprotein(a) is linked to arterial wall and systemic inflammation, by acting as a DAMP that can trigger an inflammatory response along with oxLDL and through interactions with IL-6¹³¹. People with CKD, and especially dialysis dependent ESRD, may especially benefit from novel lipid modifying therapies because they have been found to have a higher prevalence of elevated lipoprotein(a) along with other lipid abnormalities⁴³. However, patients with CKD stage 4 and greater are excluded from the OCEAN(a) trials¹³⁰ and thus further trials of people with CKD will need to be designed.

There are also promising targeted anti-inflammatory therapies to address cardiorenal disease that are still in the pre-clinical phase. Uremic toxins such as the gut metabolite indoxyl sulfate have been linked to atherosclerosis and impairment in microcirculatory angiogenesis through the aryl hydrocarbon receptor (AhR)^53,132. AhR has been linked to atherosclerosis through a role in foam cell formation, upregulation of ICAM-1 and monocyte chemoattractant protein 1 (MCP-1) and activation of NF-κB with release of IL-1β^54,132–134. AhR inhibitors are being studied in non-cardiovascular applications such as cancer chemotherapy,¹³⁵ and could potentially be adapted for the treatment of cardiovascular disease in people with CKD. Other therapies that target adaptive immunity including IL-2 modulation, mTOR inhibitors, and T regulatory cells are potential future areas of investigation, which could be adapted from pre-clinical models and the renal transplant recipient population into human clinical trials of people with CKD.

Finally, more specific biomarkers of cardiovascular and renal inflammation are needed to serve as intermediate endpoints in initial therapeutic trials prior to larger studies which are powered for cardiovascular outcome endpoints. Trials of immunomodulatory therapy in CKD have relied on non-specific systemic biomarkers of inflammation such as hsCRP and IL-6. Advanced imaging approaches are especially promising. These included targeted imaging of vascular inflammation using radiotracer-labeled fluorodeoxyglucose (FDG) and DOTATATE positron emission tomography (PET)^136,137, assessment of coronary vascular function with myocardial perfusion PET imaging¹³⁸, and assessment of coronary artery inflammation from measurement of perivascular fat attenuation with cardiac CT¹³⁹.

Conclusions

Inflammation is a key mediator of worsening cardiovascular and renal disease in people with CKD, however targeted pharmacotherapies that address inflammatory mechanisms such as IL-1, IL-6 and the NLRP3 inflammasome are only beginning to be developed and studied in clinical trials assessing longitudinal cardiovascular and renal outcomes. Clinical trials have increasingly incorporated assessment of inflammatory endpoints in people with CKD^{23,57,58,63,103}, and therapies with proven cardiorenal benefit such as statins, SGLT-2 inhibitors, GLP-1 agonists and MRAs have been recognized to have pleiotropic anti-inflammatory effects, even though they are not directly targeted against the immune system^{23,103,114,115}. As the cardio-nephrology community is increasingly recognizing the importance of the innate and adaptive immune system in the development of atherosclerosis in CKD, much can be learned from the approach to studying cardiovascular disease in people with rheumatologic systemic inflammatory disorders. It will be important to prioritize pharmacotherapies that target entwined inflammatory and cardiorenal mechanisms. The safety of immunomodulatory therapies in advanced CKD and dialysis-dependent patients, especially the potential increased risk of infection, will need to be established in clinical trials. Incorporating more specific measures of cardiovascular and renal microcirculatory inflammation and dysfunction, which serve as intermediate endpoints in individual patients and smaller trials, will be particularly important. These include promising advanced imaging measures such as vascular inflammation and myocardial perfusion PET, myocardial and pericardial tissue inflammation characterization on MRI, and perivascular adipose tissue-based coronary inflammation assessment on CT. Although there may be challenges ahead in the adoption of immunomodulatory therapies to CKD, early data from clinical trials has demonstrated that there is great promise to the therapeutic targeting of inflammation to address the excess atherosclerotic CV risk in people with kidney disease.

Abbreviations:

CKD

chronic kidney disease

ESRD

end-stage renal disease

eGFR

estimated glomerular filtration rate

UACR

urine albumin to creatine ratio

CAD

coronary artery disease

CRP

C-reactive protein

hsCRP

high-sensitivity CRP

IL-6

Interleukin-6

IL-1β

Interleukin-1 beta

TNF-α

Tumor necrosis factor alpha

NF-κB

nuclear factor kappa-light-chain-enhancer of activated B cells

LDL

low-density lipoprotein

oxLDL

oxidized LDL

cLDL

carbamylated LDL

HDL

high-density lipoprotein

ICAM-1

intracellular adhesion molecule 1

VCAM-1

vascular cell adhesion molecule 1

PRRs

Pattern-recognition receptors

DAMPs

damage-associated molecular patterns

NLRs

NOD-like receptors

TLRs

Toll-like receptors

NLRP3

(NOD)-like receptor protein 3

TMAO

trimethylamine N-oxide

AhR

aryl hydrocarbon receptor

MAPK

mitogen-activated protein kinase

APCs

antigen presenting cells

MHC-2

major histocompatibility complex class II

T_H1

T helper

T_reg

T regulatory cell

NADPH

nicotinamide adenine dinucleotide phosphate

FMD

flow-mediated dilation

STEMI

ST elevation myocardial infarction

NSTEMI

non-ST elevation myocardial infarction

Nrf2

nuclear factor erythroid-2-related factor 2

mTOR

mammalian target of rapamycin

CIMT

carotid intima media thickness

ATIC

aminoimidazole-4-carboxamide ribonucleotide transformylase

MMP-7

matrix metalloproteinase 7

MCP-1

monocyte chemoattractant protein 1