Mechanisms Underlying Atrial Fibrillation in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a serious and progressive worldwide health problem affecting 15% of the global population. CKD is associated to greater mortality rates due to secondary complications such as cardiovascular disease. Usual cardiovascular complications found in CKD patients include left ventricular hypertrophy, heart failure, and cardiac arrhythmias. The most common type of cardiac arrhythmia in CKD patients is atrial fibrillation (AF). Proper management of AF is important due to its high risk of cardiovascular complications and stroke. The incidence of AF remains higher in CKD patients than in the healthy population, highlighting the need for improving our understanding of the mechanisms underlying CKD-induced AF. In this review, we discussed well-known systemic factors linking CKD to AF pathogenesis. We highlighted the involvement of several inflammatory mediators in the CKD-induced atrial arrhythmogenesis. We also addressed special considerations for experimental models of CKD and the management of AF in CKD patients. Finally, we emphasize the need for a deeper understanding of the molecular underpinning, and for high-quality clinical investigations into the CKD-AF connection.

Graphical Abstract

Potential CKD-induced inflammatory effects on left atria responsible of atrial fibrillation (AF). We highlighted how kidney dysfunction induces a cytokine storm that in turn stimulates bone marrow cytokine production and travel to the heart where it stimulates left atrial dilatation, electrical, and structural remodeling in cardiomyocytes, causes activation of fibroblasts, and recruitment of macrophages, creating a substrate for the development of atrial fibrillation (AF). CM: cardiomyocyte; CF: cardiac fibroblast; FGF-23: fibroblast growth factor 23; IL-1β: interleukin 1 beta; IL-6: interleukin 6; IL-17: interleukin 17; IL-18: interleukin 18; RyR2: ryanodine receptor type 2; STAT3: signal transducer and activator of transcription 3; TGFβ: transforming growth factor beta; TNFα: tumor necrosis factor alpha.

1. INTRODUCTION

Chronic kidney disease (CKD), a pathology characterized by the progressive loss of kidney function, is affecting 10–15% of the global population [1], and is responsible for significant morbidity and mortality [2, 3]. The ‘Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines’ defined CKD as abnormal kidney structure or function for at least 3 months with implications for health [4]. Cardiovascular disease is responsible of almost half of all the deaths in CKD patients [5]. Common cardiac events in CKD patients are left ventricular hypertrophy (LVH), heart failure (HF) [6], ischemic heart disease, vascular calcification [7], and arrhythmias [8, 9]. Among cardiac complications, atrial fibrillation (AF) is the most common arrhythmia in CKD patients with an estimate rate of 37.6 episodes of AF per person-year [10, 11]. AF is a supraventricular tachyarrhythmia characterized by rapid and uncoordinated atrial electrical activation and ineffective atrial contraction. Clinically, AF is classified based on the duration of episodes and whether it self-terminates within 7 days: paroxysmal AF (terminates spontaneously within 7 days), persistent AF (lasts more than 7 days), and permanent AF (long-lasting and refractory to rhythm control) [12]. The initiation and maintenance of AF is due to two major mechanisms, ectopic electrical activity (triggered activity) and reentry because of structural and/or electrical remodeling, respectively [13]. The aberrant Ca²⁺ handling that can lead to early or delayed after depolarizations (EADs and DADs, respectively) or enhanced automaticity are the primary causes of triggered activity. Electrical remodeling plays a key role in reentry and to the maintenance of AF by shortening of the action potential duration (APD) due to altered activities of repolarizing ion channels. On the other hand, structural remodeling, characterized by atrial fibrosis and enlargement, impairs conduction and promotes the heterogeneity in electrical conduction, facilitating the maintenance of reentry [14]. In this review, we examine the clinical evidence of the heightened association between CKD and AF development, discuss the mechanisms linking CKD and AF pathogenesis, and highlight special considerations for AF management in CKD patients. We also provide our perspectives on future research opportunities in this area.

2. Heightened Association Between AF and CKD

It has been reported that AF occurs in approximately one in five non-dialysis CKD patients [15] and one in three dialysis-dependent CKD patients [16]. AF incidence rises as kidney function declines, with more than a two-fold increase in CKD patients whose estimated glomerular filtration rate (eGFR) is below 30 ml/min/1.73 m² compared to those with an eGFR above 60 ml/min/1.73m² [17]. A recent meta-analysis has shown that kidney dysfunction increases the risk of AF by almost 65% compared to healthy controls [18]. Among adults younger than 55 years, the rate of AF was more than 10 times higher in CKD patients compared to the general population (females: 1.9% vs. 0.1%; males: 2.5% vs. 0.2%) [16]. In the United States, 18–22% of CKD patients develop AF. Patients who suffer from both CKD and AF pathologies have a worse prognosis than those with only one of these conditions. CKD patients who develop AF have an elevated risk of stroke, heart failure, myocardial infraction, kidney dysfunction progression, and all-cause mortality [19–21]. The interrelatedness between AF and CKD is, in part, caused by shared risk factors, such as hypertension, heart failure, vascular disease, diabetes mellitus (DM), and aging [22]. Nevertheless, recent studies have proposed that CKD itself serves as an independent risk factor for new onset AF [23, 24]. Studies have shown that both paroxysmal and non-paroxysmal AF are more prevalent in CKD patients. Electrolyte imbalances during dialysis have been associated with paroxysmal AF episodes [25], while chronic CKD-induced oxidative stress and inflammation have been linked to persistent AF in CKD patients [26]. Furthermore, CKD-induced systemic alterations often lead to cardiac fibrosis, which disrupts electrical conduction in the heart and increases the risk of developing persistent AF [27]. However, it remains unclear whether improved kidney function in CKD patients can reverse atrial remodeling, particularly in those with persistent AF.

The CKD-associated AF risk differs by sex. Studies have shown that males with CKD have a higher risk of AF development than females with CKD, partly due to the protective effect of estrogens and deleterious effects of testosterone in CKD patients [28, 29]. Recent studies indicate that testosterone deficiency is common in CKD patients, and male hypogonadism may both impact and be influences by CKD [30]. On the other hand, in the menopausal woman, the ovarian senescence and the loss of estrogen are directly associated with a decline in renal function and indirectly with an accumulation of cardiometabolic risk factors [31].

3. Molecular alterations linking CKD and AF Pathogenesis

The increased cardiovascular risk associated with CKD is largely driven by systemic changes, such as the accumulation of uremic toxins, electrolyte imbalances, and neurohormonal dysregulation. These factors contribute to tissue and systemic oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and inflammation [32], which in turn are key mechanisms underlying the development of a pro-arrhythmic substrate. Below, we discuss common pathological changes that are associated with CKD development including hyperglycemia, RAAS, mineral bone disorders, and oxidative stress (Figure 1, Table 1). We also highlight the inflammatory cytokines associated with AF pathogenesis in the context of CKD.

Figure 1. Intracellular pathways activated in cardiomyocytes in response to chronic kidney disease (CKD) that might lead to atrial fibrillation (AF).

Important pathways activated in cardiomyocytes from CKD patients in response to high glucose levels, angiotensin II, hyperphosphatemia, FGF-23 and PTH, and inhibited pathways due to low levels of vitamin D and Klotho, that might lead to structural or electrical remodeling in atrial cardiomyocytes. 1,25-OH-VitD: 1,25-dihidroxy-vitamin D; AC: adenyl cyclase; AMPK: AMP-activated protein kinase; AngII: angiotensin II; ANP: atrial natriuretic peptide; AT-II: angiotensin receptor II; ATP: adenosin-triphosphate; BNP: brain natriuretic peptide; Ca²⁺: calcium ion; CaMKII: calmodulin kinase type II; cAMP: cyclic adenosin-monophosphate; ETRA/B: endothelin receptor A/B; FGF-23: fibroblast growth factor 23; FGFR4: FGF receptor 4; GLUT1/4: glucose transporter 1/4; IP3: inositol-triphosphate; IP3R: IP3-receptor; JAK2: janus kinase 2; LTCC: L-type calcium channel; MHC: major histocompatibility complex; mTOR: mammalian target of rapamycin; NOX2: NADPH oxidase 2; NFAT: nuclear factor of activated T cell; Nrf2: nuclear factor erythroid 2-related factor 2; Pi: phosphate; PIP3: phosphor-inositol triphosphate; Pit1/2: phosphate transporter ½; PKA: protein kinase A; PLCγ: phospholipase C gamma; PLN: phospholamban; PP1: protein phosphatase 1; PTH: parathyroid hormone; PTHR: PTH receptor; Rcan: regulator of calcineurin gene; ROS: reactive oxygen species; RYR2: ryanodine receptor type 2; SERCA2a: sarcoplasmic reticulum Ca²⁺ ATPase 2a; Sirt3: sirtuin 3; SOD2: superoxide dismutase 2; STAT3: signal transducer and activator of transcription 3; TGFβ: transforming growth factor beta; TRPC: transient receptor potential cation channel subfamily C; VDR: vitamin D receptor.

Table 1.

Key Mediators Altered in Chronic Kidney Disease and Their Reported Arrhythmogenic Effects

Mediators	Status in CKD	Reported arrhythmogenesis effects
Glucose	Increased	• Enlargement of left atria [37] • Cardiomyocyte apoptosis [38] • Mitochondrial dysfunction [39] • Hyperactivity of RyR2 channel [40]
Angiotensin	Increased	• Increased atrial fibrosis [53] • Decreased SERCA2a activity [52] • Enhanced CaMKII oxidation [51]
Phosphate	Increased	• Vascular calcification [61] • Hyperphosphorylation of RyR2 and enhanced activation of STAT3 [65]
Vitamin D	Decreased	• Increased cardiac fibrosis [74]
PTH	Increased	• Increased Ca2+ current [83] • Cardiomyocyte hypertrophy [83]
FGF-23	Increased	• Cardiomyocyte hypertrophy [88] • Hyperactivity of RyR2 channel, increased SCaEs, and contractile dysfunction [91]
ROS	Increased	• CaMKII hyperactivity [102] • Increased late INa,L [104]
IL-6	Increased	• Increased cardiac fibrosis [116] • Enhanced activation of STAT3 [115]
TNFα	Increased	• Atrial fibrosis [137] • Decreased SERCA2a activity [138] • Contractile dysfunction [138]
IL-1β/IL-18	Increased	• Hyperphosphorylation of RyR2 [142] • Enlargement of left atria [152]
IL-17	Increased	• Increased atrial fibrosis [167]
NLRP3	Increased	• Enlargement of left atria, atrial fibrosis, ectopic activity [156]
TGF-β	Increased	• Increased atrial fibrosis [198]

3.1. Hyperglycemia

Diabetes mellitus (DM) and CKD are two of the strongest risk factors for developing cardiovascular complications [33], including cardiac arrhythmias. DM is a metabolic disorder characterized by persistent elevations of serum glucose levels. DM is known to independently increase AF risk and further exacerbate it in CKD patients [34]. Interestingly, DM is also a known risk factor for kidney disease. It is estimated that almost 40% of DM patients develop CKD [35], commonly known as diabetic nephropathy (DN). forrelationship between DM and CKD, as kidney disease can exacerbate DM by impairing glucose filtration and reabsorption, which leads to insulin resistance and further elevates blood glucose [36]. Glucose resistance in DM has been associated with glycogen granule accumulation in the myocardium, which leads to stiffness of cardiac tissue and left atrial (LA) enlargement [37], an established pro-AF substrate. The diabetic milieu can directly affect cardiac muscle contractility by inducing cardiomyocyte apoptosis and malformation of contractile structures [38]. Recent studies also show that high glucose levels induce cardiomyocyte mitochondrial dysfunction mediated by endothelin-1 (ET-1) receptor activation and the AMPK-mTOR pathway [39]. High glucose levels can directly activate G-proteins that increase calcium influx into cardiomyocytes via the L-type calcium channels, and subsequently induce the calcium release via the ryanodine receptor type-2 (RyR2) [40], increasing the propensity for pro-AF triggered activity. Moreover, DM is also associated with inflammation and oxidative stress [41], whose effects on AF are discussed later in this review.

3.2. Renin-angiotensin-aldosterone system (RAAS)

CKD promotes hypertension through mechanisms like fluid retention and increased plasma volume, along with the local activation of the RAAS in response to renal injury. This activation increases the production of angiotensin II (Ang II), a known vasopressor. RAAS activation plays an important role in the intertwining progression of both CKD and hypertension [42]. Notably, hypertension is a common risk factor of AF, with over 70% of cases reporting this comorbidity [43, 44]. Though the molecular mechanisms connecting hypertension and AF pathogenesis are multifactorial, it is widely accepted that hypertension leads to structural remodeling of the atria via either hemodynamic changes or RAAS activation [43]. Consistently, atrial cardiomyocytes of AF patients exhibit elevated levels angiotensin converting enzyme (ACE) and angiotensin II receptors (AT-II) compared to patients in sinus rhythm [45], while RAAS antagonists have been shown to reduce atrial fibrosis [46, 47] and electrical remodeling [48], leading to a lower recurrence of AF in patients with paroxysmal AF [49]. Activation of angiotensin receptor 2 (AT-II) activates the JAK-STAT pathway leading to the expression of important pro-hypertrophic genes [50].

RAAS activation during CKD can contribute to both triggered activities and electrical/structural remodeling. On one hand, Ang II has been linked to AF development independently of kidney function. The Ang II infusion model has been shown to induce AF as a result of increased atrial fibrosis, electrical remodeling, and inflammation [51]. Ang II increases levels of NADPH oxidase 2 (NOX2) in cardiomyocytes, driving the production of reactive oxygen species (ROS) [52]. Excess ROS can evoke abnormal calcium release and decrease SERCA activity by impeding the dephosphorylation of phospholamban (PLN) through inhibition of protein phosphatase 1 (PP1) or by oxidizing CaMKII, thereby promoting triggered activity and arrhythmogenesis [51]. Furthermore, recent studies have identified platelet activation as a mediator of Ang II effects. Platelets conjugate with fibroblasts and activates them by secreting TGF-β1, which promotes atrial fibrosis and AF [53]. On the other hand, during the CKD-associated hypertension, pressure overload-induced atrial enlargement not only impairs electrical conduction but also facilitates the formation of reentrant circuits within the atria. Furthermore, pressure overload can induce macrophage infiltration, which in turn affects the functions of cardiomyocytes and cardiac fibroblasts through paracrine signaling mechanisms [54, 55].

3.3. Mineral Bone Disorders

Mineral bone disorders (MBD) consist of mineral disturbances closely associated with CKD [56]. MBD includes altered serum calcium concentrations, increased serum phosphate levels (hyperphosphatemia), augmented parathyroid hormone (PTH) levels, reduced active vitamin D, increased fibroblast growth factor (FGF)-23, and decreased levels of the antiaging protein Klotho [57]. Alterations in mineral homeostasis are known to increase the risk of cardiovascular disease by augmenting atherosclerosis and vascular calcification [58]. The latter has been found to increase mortality in CKD patients [59]. MBDs have been demonstrated to be strongly associated with AF development in CKD patients, especially for FGF-23 [60]

3.3.1. Phosphate

It is well known that electrolyte imbalances, including high phosphate levels, can disrupt normal cardiac rhythm, leading to arrhythmias. Hyperphosphatemia is a significant cardiovascular risk factor and shows the strongest correlation to vascular calcification in CKD patients [61]. Increased coronary artery calcium score has been associated to increased risk of AF development [62]. Consistent with this, several large population-based studies have found an association between higher phosphate levels and an increased incidence of AF [63, 64]. Hsu et al. recently demonstrated that hyperphosphatemia in a 5/6 nephrectomy animal model induced atrial remodeling and increased the AF incidence by activating STAT3/NF-κB signaling and oxidative stress [65]. Exposure of myocytes to high phosphate levels in vitro induced hyperphosphorylation of RyR2, which may predispose to the increased incidence of arrhythmias [66]. Furthermore, reduced phosphorus excretion due to renal dysfunction induces secondary hyperparathyroidism and increases serum FGF-23 levels, contributing to additional cardiovascular complications.

3.3.2. Vitamin D

CKD patients often exhibit low serum vitamin D levels [67] due to reduced activity of 1α-hydroxylase CYP27B1, an enzyme responsible for converting inactive vitamin D to its active form, along with compromised skin xerosis, dietary restrictions, and loss of vitamin D binding proteins due to proteinuria [68]. Data from National Health and Nutrition Examination Survey (NHANES) and the National Death Index (NDI) (2007‒2018) database show that low vitamin D levels in CKD patients are associated to higher cardiovascular disease-related mortality [69]. Observational studies have suggested that vitamin D deficiency is linked to an increased risk of AF development even in general population [70]. A recent 5-year follow-up study in a large cohort of healthy population showed that the risk of new onset AF is reduced in those supplemented with vitamin D [71]. Additionally, CKD patients with AF have significantly lower calcidiol (25-hydroxy-vitamin D) levels compared with those without AF [72]. This protective effect of vitamin D might be due to the reduction in cardiac fibrosis mediated by the activation of the vitamin D receptors (VDRs). It has been shown that VRD activation suppressed preproendothelin gene expression in cardiac fibroblast [73]. In this sense, it has been shown that mice lacking VRDs showed increased cardiac fibrosis [74]. Activation of VRDs in CKD rats has been also shown to reduce LVH and cardiac fibrosis [75, 76] reducing the risk of developing AF. Furthermore, it has been shown that activation of VDR activates the nuclear factor erythroid 2-related factor 2 (Nrf2) promoting the expression of sirtuin-3 (Sirt3) which induces SOD2 expression in the mitochondria to protect against ROS [77].

3.3.3. Parathyroid hormone (PTH)

Increased serum phosphate levels due to kidney dysfunction stimulate the parathyroid glands, leading to increased PTH synthesis, a condition known as secondary hyperparathyroidism. The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) guideline highlight that PTH levels rise as kidney function declines [78]. Although the Atherosclerosis Risk in Communities (ARIC) study failed to show any association between PTH levels and HF, peripheral artery disease and cardiovascular mortality [79], recent findings from the PTH Target Trial show that reducing PTH levels can significantly lower mortality and cardiovascular complications in CKD patients [80]. Additionally, PTH levels correlate with left atrial enlargement [81], and have been found to be higher in patients with AF compared to healthy population [82], being further elevated in persistent AF compared to those with paroxysmal AF. Mechanistically, activation of PTH1R, a receptor for PTH, in cardiomyocytes triggers calcium influx and PLC-PKC pathway activation, promoting cell proliferation and cardiac hypertrophy in rats [83]. PTH also increases cAMP levels in cardiomyocytes, activating PKA which phosphorylates RyR2 increasing calcium leak that might lead to cardiac arrhythmias [84]. Furthermore, lowering the PTH concentrations improves cell shortening by increasing calcium load in isolated cardiomyocytes from rats [85].

3.3.4. FGF-23

Phosphate dysregulation in CKD increases the expression of the phosphaturic hormone FGF-23 expression, leading to elevated systemic FGF-23 levels. Serum FGF-23 levels have been found to be 1000-fold higher in late-stage CKD compared to the healthy population [86]. Under normal conditions, FGF-23 promotes kidney phosphate excretion. However, pathological elevations in FGF-23 levels are correlated with cardiovascular complications. FGF-23 has been shown to cause LVH and cardiovascular mortality, particularly in CKD patients [87]. It induces cardiac hypertrophy in a kotho-independent FGFR4-mediated mechanism by activating the PLCγ-calcineurin-NFAT signaling pathway [88, 89]. Activation of PLC increases the levels of inositol-3-phosphate (IP3), activating the IP3 receptors (IP3R) that releases calcium from sarcoplasmic reticulum activating calcineurin that promotes the expression of pro-hypertrophic genes by activation of the nuclear factor of activated T cells (NFAT). FGF-23 has been widely associated with prevalent and incident AF in patients with CKD [60, 90]. This association with AF might be due to increased incidence of LVH but also electrophysiological changes in cardiomyocytes. Thus, FGF-23 has also been shown to cause contractile dysfunction and intracellular calcium mishandling in cardiomyocytes, even in the absence of kidney disease [87, 91]. However, Pastor-Arroyo et al. found that FGF-23 alone, without kidney disease, does not induce any cardiovascular alterations [92]. Together, this evidence suggests that other CKD-induced factors may work synergistically with FGF-23 to promote AF pathogenesis.

3.3.5. Klotho

Klotho, known as an anti-aging protein, is mainly secreted by the kidneys and binds to FGF-23 receptor 1 (FGFR1), increasing the receptor’s affinity for FGF-23 to promote phosphate excretion. Klotho levels decrease as kidney disease progresses [86]. The incidence of AF is higher in CKD patients with lower serum Klotho levels [93, 94] and klotho levels are significantly smaller in dialysis-dependent CKD patients with AF compared to those in sinus rhythm [93]. However, more studies are needed to elucidate if only a Klotho reduction without increasing FGF-23 levels is associated to increased incidence of AF or whether that is a casual association. It has been shown that klotho prevents fibrosis by inhibiting PLC pathway in atrial fibroblast and suppressing TRP currents [95] that might confer protection against AF even in the CKD milieu.

3.4. Oxidative Stress

Oxidative stress results from an imbalance between the production of ROS and the antioxidant capacity, which leads to oxidative damage to protein, lipids, and DNA. Oxidative stress is a major mediator of the cardiovascular diseases, including CKD and AF [96]. CKD is associated with both overproduction of ROS and a reduction of antioxidant defense activity (catalase, glutathione peroxidase, and glutathione). Pro-oxidants activity is usually a consequence of CKD risk factors, such as age, diabetes, chronic inflammation, uremic toxins, and dialysis treatment [97]. Besides Ang-II induced NOX2 activation discussed earlier, CKD is linked to increased levels of oxidized low-density lipoprotein (LDL) [98], xanthine oxidase (XOD) [99], and indoxyl sulfate (IS)-mediated oxidative stress [100], as well as reduced levels of antioxidants SOD and GSH [101]. Increased ROS has been shown to directly affect CaMKII activity [102], a key protein kinase regulating intracellular calcium handling in cardiomyocytes. ROS-dependent CaMKII activation occurs via oxidation at methionines 281 and 282 by NADPH oxidase [103]. Oxidized CaMKII can promote AF pathogenesis by enhancing the late sodium current (I_Na,L) or increased diastolic calcium leak through increased RyR2 phosphorylation [51, 104]. For further details on oxidative stress in atrial arrhythmogenesis, readers are referred to another expert review in this issue [105].

3.5. Inflammation in CKD and AF

Chronic systemic inflammation is a central driver of AF in CKD [106]. It is well documented that that systemic inflammation correlates with the AF development in patients. C-reactive protein (CRP) levels, an indicator of systemic inflammation, increase in a dose-dependent manner with AF burden [107]. Circulating cytokines, key modulators of immune and inflammatory response [108], can exert a wide range of effects on various organ systems such as the heart [109] and kidney. Within the atria, the elevated levels of inflammatory cytokines can promote atrial remodeling and adrenergic hyperactivation, both of which promote AF [110, 111]. In this section, we discuss key inflammatory cytokines that have been mechanistically linked to AF pathogenesis in the context of CKD (Figure 2, Table 1).

Figure 2. Intracellular pathways activated in cardiomyocytes by CKD-induced interleukins that may cause atrial fibrillation (AF).

Key pathways activated in response to CKD-induced increases in inflammatory cytokines that lead to electrical and structural remodeling in atria. ATA2a2: sarcoplasmic reticulum Ca²⁺-ATPase 2a gene; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); Ca²⁺: calcium ion; CACNA1c: Ca²⁺ voltage-gated channel subunit alpha 1c gene; CaMKII: Ca²⁺/calmodulin-dependent protein kinase type II; GSDM: gasdermin D; gp130: glycoprotein 130; IL-1β: interleukin 1 beta; IL1R: IL-1 receptor; IL-6: interleukin 6; IL6Rα: IL-6 receptor α; IL-17: interleukin 17; IL17R: IL-17 receptor; IL-18: interleukin 18; JAK2: janus kinase 2; NF-kB: nuclear factor kappa-B; NLRP3: nucleotide-binding oligomerization domain (NOD)-, leucin-rich repeat protein (LRR)- and pyridine domain-containing protein 3; PLN: phospholamban; ROS: reactive oxygen species; RYR2: ryanodine receptor type 2; SERCA2a: sarcoplasmic reticulum Ca²⁺ ATPase 2a; STAT3: signal transducer and activator of transcription 3; TNFα: tumor necrosis factor alpha; TNFR: TNFβ receptor.

3.5.1. Interleukin (IL)-6

IL-6 belongs to a family of cytokines including IL-11 and cardiotrophin-1 that signal through a common transmembrane receptor glycoprotein 130 (gp130) [112]. IL-6 signaling can be pro- or anti-inflammatory, depending on the manner of signaling [113]. Classical IL-6 signaling is anti-inflammatory and involves binding of IL-6 to gp130 and membrane-bound IL-6 receptor alpha (IL-6Ra), which is only expressed on leukocytes and hepatocytes [113]. In contrast, trans-signaling is pro-inflammatory and involves binding of IL-6 to soluble IL-6Ra, which is cleaved from leukocytes via ADAM17 [114], and then to gp130 [113]. Thus, pro-inflammatory IL-6 trans-signaling occurs in all cells including cardiomyocytes, except for those that express IL-6Ra [113]. Regardless of the mode of IL-6 signaling, IL-6 activation results in STAT3 dimerization and subsequent transcriptional upregulation of its target genes [112]. Unlike IL-6Ra, IL-6 is secreted by all cell types [113]. CKD can increase IL-6 levels through a variety of mechanisms. CKD can activate the RAAS, mediated through angiotensin II, which can activate STAT3 in cardiomyocytes and cardiac fibroblasts via the AT1 receptor, increasing IL-6 synthesis [115]. Angiotensin II-induced IL-6 synthesis has been shown to be a key mediator of angiotensin II-induced cardiac hypertrophy and fibrosis [116]. Lastly, sympathetic nervous system activation in CKD [117] can also induce IL-6 synthesis [118].

Clinical studies have demonstrated a strong association between plasma IL-6 levels and renal function in CKD. A longitudinal study of 899 CKD individuals from the Chronic Renal Insufficiency Cohort (CRIC) found that baseline plasma IL-6 levels correlated with GFR decline over a median follow-up of 6.3 years [119]. Importantly, the association between IL-6 and GFR decline remained significant after adjustment for key risk factors including baseline GFR, age, sex, race, cholesterol, hypertension, diabetes, RAAS inhibitor therapy, body mass index, alcohol use, and smoking, whereas the association between IL-1β and GFR decline became nonsignificant [119] – indicating that IL-6 is a specific and direct mediator of CKD pathophysiology. With regard to AF in CKD, a cohort study of 3,762 CKD patients showed that baseline plasma IL-6 was independently associated with prevalent and new-onset AF over a mean follow-up of 3.7 years [120]. Indeed, plasma IL-6 levels are predictive of all-cause and cardiovascular mortality in CKD patients [121]. Moreover, a phase 2 randomized controlled trial comparing anti-IL-6 monoclonal antibody to placebo in hemodialysis patients demonstrated that IL-6 inhibition decreased inflammation-driven anemia of chronic disease [122], in conjunction with decreased markers of systemic inflammation such as CRP and fibrinogen [123]. These results indicate that targeting the IL-6 signaling axis in CKD has the potential to abrogate deleterious complications of CKD. However, it remains unclear whether anti-IL-6 monoclonal antibody can also reduce AF incidence in CKD patients.

Mechanistically, CKD-mediated IL-6 upregulation can lead to AF through a variety of mechanisms, one of which is via IL-6-mediated FGF-23 upregulation [124]. As discussed earlier, in CKD, FGF-23 is upregulated in a compensatory manner to combat hyperphosphatemia by inhibiting proximal tubular phosphate resorption and decreasing parathyroid gland parathyroid hormone secretion [125, 126]. However, upregulated FGF-23 may also be detrimental for AF development in CKD patients [60]. Within the atria, FGF-23 has been shown to promote atrial remodeling and fibrosis [127], and IL-6 was shown to increase FGF-23 in a STAT3-dependent manner [124]. Indeed, global knockout of Il-6 in adenine-high-phosphorus diet-induced CKD mice prevented pathologic increases in circulating FGF-23 and rescued CKD-associated hypocalcemia. Taken together, CKD-induced IL-6 upregulation can lead to AF through IL-6-mediated FGF-23 upregulation and resulting FGF-23-mediated atrial remodeling, which is discussed in more detail within the mineral bone disorders section of this review.

Fibrosis is another key mechanism by which IL-6 leads to AF in CKD. Administration of soluble gp130, which selectively inhibits pro-inflammatory IL-6 trans-signaling [113], abrogates STAT3-induced renal fibrosis and kidney function deterioration in a unilateral ureteral occlusion mouse model [128]. In the heart, IL-6 also promotes atrial fibrosis and AF in a STAT3-dependent manner and inhibition of STAT3 with S3I-201 decreases AF inducibility in rats [129]. Lastly, IL-6 has been shown to directly promote arrhythmogenic changes in calcium handling as IL-6 perfusion of isolated rat hearts increased time to peak calcium transient amplitude and susceptibility to calcium transient alternans [50].

3.5.2. Tumor necrosis factor (TNF)-α

TNF-α, a central mediator of systemic inflammation, is the only other cytokine (in addition to IL-6) that predicts risk of new-onset AF in CKD patients [130]. Serum TNF-α levels are positively correlated with histologic kidney damage, indicating that it plays a direct role in CKD pathophysiology [131]. Indeed, a study of rats that underwent renal reduction surgery to induce CKD demonstrated that systemic administration of a soluble TNF-α neutralizing receptor (PEG-sTNFR1) for six weeks ameliorated CKD-related hypertension, renal inflammation and fibrosis, and albuminuria [132]. TNF-α neutralization in mice with diabetic nephropathy has also been shown to protect against renal dysfunction and ameliorate CKD progression [133], indicating that TNF-α mediates CKD pathology of various etiologies. Interestingly, macrophage-specific TNF-α conditional knockout in a mouse model of diabetic nephropathy reduced albuminuria and histologic evidence of renal damage, demonstrating that TNF-α produced by macrophages is sufficient to recapitulate its systemic pathologic effects in CKD [133].

With regard to AF, serum TNF-α is elevated in AF compared to sinus rhythm patients [134], and a study of human atrial tissue showed that intra-atrial TNF-α and IL-6 levels were greater in valvular disease patients with AF compared to those without AF [135]. Indeed, treating human atrial cardiac fibroblasts in vitro with TNF-α increases release of IL-6 [136], indicating that these two cytokines function in tandem. Mechanistically, TNF-α can promote atrial structural and electrical remodeling. Recombinant TNF-α administered via tail vein injection to mice was sufficient to increase atrial fibrosis and reduce connexin-40 [137] – substrate alterations that promote reentry. Consistently, cardiac-specific TNF-α overexpression resulted in atrial dilatation and spontaneous AF, with prolonged calcium reuptake [138]. Notably, transgenic TNF-α overexpression is one of only four documented mouse models of spontaneous AF [139], with AF starting at five months-of-age at 77% incidence [138, 139]. Altogether, there is strong preclinical and clinical evidence that elevated TNF-α in CKD directly promotes AF through atrial structural and electrical remodeling.

3.5.3. IL-1β/IL-18

Unlike IL-6 and TNF-α, IL-1β and IL-18 show a weaker association in clinical studies of CKD-related AF. A post hoc analysis of the REDHART (Recently Decompensated Heart Failure Anakinra Response Trial) found no benefit of Anakinra, an IL-1β neutralizing monoclonal antibody, in preventing decline of renal function in patients with cardiorenal syndrome, although patients in the Anakinra treatment group exhibited decreased markers of systemic inflammation such as CRP and myeloperoxidase [140]. Similarly, the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial, a double-blind randomized controlled trial comparing IL-1β inhibition via canakinumab versus placebo in patients after myocardial infarction with high-sensitivity CRP of at least 2 mg per liter, showed no improvement of renal function despite a reduction in overall cardiovascular disease risk in the treatment group [141]. Nonetheless serum IL-1β are elevated in CKD patients [119] prior to multivariate adjustment, and elevated serum IL-1β has been shown to lead to AF by augmenting calcium mishandling [142]. Acute IL-1β application to HL-1 atrial cardiomyocytes in vitro increases arrhythmogenic calcium release events, likely secondary to RyR2-Ser2814 phosphorylation, which increases RyR2 channel open probability and arrhythmogenic diastolic calcium leak [142, 143]. IL-1β also induces IL-6 synthesis [144], and thus increased IL-1β can lead to AF through mechanisms related to IL-6 discussed above. In line with this, anti-inflammatory agent colchicine was shown to abrogate AF inducibility in rats through inhibition of IL-1β-induced IL-6 synthesis and subsequent IL-6-mediated atrial fibrosis [145].

IL-18 belongs to the IL-1β family and is produced primarily by macrophages and monocytes. However, renal IL-18 expression is upregulated in renal pathology, particularly diabetic nephropathy [146]. IL-18 levels show a strong positive correlation with albuminuria and renal disease progression in diabetic nephropathy [146]. In the heart, IL-18 can lead to AF through a variety of mechanisms, including induction of IL-1β synthesis [147, 148], oxidative stress [149], and recruitment of immune cells through upregulation of cellular adhesion molecules [150, 151]. Indeed, circulating IL-18 levels are elevated in AF patients compared to sinus rhythm controls, with greater levels seen with increasing AF burden and correlating with left atrial diameter [152, 153]. Furthermore, a study performed on 87 AF patients undergoing cryoablation showed that those with persistent or permanent AF had higher IL-18 levels in the left atrial blood compared to paroxysmal AF patients, and that levels in the left atrial blood were higher than those in the venous blood, indicating that IL-18 plays a key role in local atrial inflammation [154]. Indeed, intra-atrial Il-18 gene expression was upregulated in a mouse model of postoperative atrial fibrillation [155]. In a recent study, we show that serum level of IL-1β was increased in hemodialysis patients with AF compared with those in sinus rhythm [156]. Because most of studies to date show that a role of IL-1β and IL-18 in CKD-related AF may be weaker than that for IL-6 and TNF-α, we speculate that IL-1β and IL-18 likely mediate AF progression in CKD, albeit in tandem with other cytokines and mechanisms discussed throughout this review.

3.5.4. IL-17

IL-17 has been implicated in CKD pathogenesis [157]. IL-17 production is increased in Th17 cells in end-stage renal disease patients compared to healthy controls [158], and a separate study of hemodialysis patients found that the percentage of circulating Th17 cells correlated with serum phosphate levels, indicating that Th17 cells are key mediators of renal damage in CKD [159]. Indeed, IL-17 has been shown to accurately predict severity of kidney damage in lupus nephritis with a C-statistic of 0.91 [160]. Importantly, the IL-17 signaling axis is promoted by IL-6 via skewing of naïve T-cell differentiation towards a Th17 phenotype [161]. In the heart, IL-17 signaling is increased in AF patients compared to sinus rhythm controls [162]. While the same study did not find a correlation between serum IL-17 and AF burden, there was a strong positive correlation between IL-17 and neutrophil to lymphocyte ratio, indicating that IL-17 may perpetuate macrophage-mediated inflammation in AF [163]. Furthermore, a rat model of chronic AF induced by 28 days of acetylcholine and CaCl₂ tail vein injection found upregulation of IL-17 signaling pathways in AF compared to sham rats [164]. As discussed above, IL-17 can promote monocyte recruitment [165], which is implicated in AF pathogenesis [163], and forms a positive feedback, self-amplifying loop with IL-6 [166], which is involved in AF pathophysiology as discussed above. IL-17 may also promote atrial fibrotic remodeling as anti-IL-17 monoclonal antibody treatment of rats was shown to ameliorate atrial fibrosis in a rat sterile pericarditis model of postoperative atrial fibrillation [167].

3.5.5. IL-10

Unlike IL-17, IL-10 is considered an anti-inflammatory cytokine [168]. Genetic polymorphisms in the IL-10 gene that increase serum IL-10 levels protect against diabetic nephropathy [169]. A study of rats that underwent 5/6 nephrectomy to induce CKD found that IL-10 overexpression via administration of a recombinant adeno-associated virus serotype 1 (AAV1) IL-10 vector attenuated renal inflammation, interstitial fibrosis, proteinuria, and GFR decline [170]. Consistently, administration of IL-10 in mice fed a high-fat diet for 12 weeks reduced fibrotic and inflammatory atrial remodeling as well as AF inducibility [171]. Similar findings were observed in rat model of AF induced by pressure overload, where depletion of spleen-derived IL-10 increased AF susceptibility secondary to inflammation-mediated atrial fibrosis [172]. While the evidence is strong that IL-10 mechanistically protects against CKD and AF progression, studies linking CKD-mediated dysregulation of IL-10 signaling in AF pathogenesis are lacking.

3.5.6. Inflammasomes

Inflammasomes are a key component of the innate immune system that has been shown to play a critical role in the pathogenies and development of AF [173]. Inflammasomes are multiprotein complexes composed of receptor proteins, adaptor proteins, and caspases that regulate cytokine maturation, inflammation, and cell death. Formation of functional inflammasome can be initiated by pattern recognition receptors (PRRs), which can sense pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). PRRs that can assemble inflammasomes include the nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein (NLR) family members NLRP1, NLRP3, and NLRC4, as well as the proteins absent in melanoma 2 (AIM2) and toll-like receptor (TLR). Assembly of the inflammasome components involves the interaction of inflammasome receptors with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and effector protein pro-caspase-1 (canonical pathway). This activates the effector caspase through proteolytic cleavage. The activated caspase cleaves full-length pro-IL-18 and pro-IL-1β, producing their active forms [174].

Increased activity of atrial NLRP3 inflammasome has been linked to the development of AF in patients [174, 175]. Various studies have investigated the role of the NLRP3 inflammasome in various models of kidney disease, such as 5/6 nephrectomy, acute kidney injury (AKI), and hypertension-related renal damage, among others [176–178]. It has been reported that nephrectomy-induced CKD rats developed left atrial enlargement, interstitial fibrosis, and pacing-induced AF through the activation of TGFβ-1/Smad2/3 and NLRP3 inflammasome signaling [179]. Consistently, we recently show that genetic ablation of NLRP3 attenuates electrical remodeling, prevents atrial fibrosis, and reduces AF susceptibility in the 5/6 nephrectomy-induced CKD model [156]. The effect of NLRP3 inflammasome activation on CKD-associated AF is primarily mediated by IL-1β, and the increased circulating IL-1β in CKD mice promotes a positive feedforward relationship with the activity of NLRP3 inflammasome in atria. Administration of an IL-1β neutralizing antibody in CKD mice not only prevents atrial enlargement, atrial fibrosis, and AF susceptibility, but also reduces the activity of inflammasome in atria of CKD mice [156].

AIM2 is a cytoplasmic sensor of double-stranded DNA (dsDNA) from pathogens, including bacteria, viruses, fungi, and parasites [180]. AIM2 also responds to dsDNA released from damaged cellular organelles, resulting in the secretion of downstream cytokines, thereby promoting sterile inflammatory diseases such as skin disease, neuronal disease, CKD, and CVD [181]. AIM2 is expressed in kidney and can be activated in the diabetic or nondiabetic CKD patients [182]. In a renal injury model induced by the unilateral urethral obstruction, genetic ablation of AIM2 ameliorates renal injury, fibrosis, and inflammation [182]. This is accompanied by reduced levels of the inflammasome effector cytokines IL-β and IL-18 in the kidney. It has been suggested that AIM2 inflammasome recognizes the necrotic DNA and subsequently drives the IL-1β and IL-18 release from macrophages in the kidney. The role of AIM2 in the cardiovascular diseases has been documented, including coronary atherosclerosis [183], myocardial infarction [184], and myocarditis [185], and heart failure [186]. While direct evidence of AIM2 in CKD associated AF is currently lacking, we recently showed that AIM2 plays a role in the high-protein-diet induced AF by promoting mitochondrial dysfunction [187].

3.5.7. Transforming growth factor beta (TGF-β)

TGF-β is a key mediator of fibrosis, and cardiac-specific overexpression of TGF-β1 in mice was sufficient to cause atrial fibrosis and inducible AF [188, 189]. Strikingly, whole heart cardiomyocyte-specific TGF-β1 transgenic overexpression driven by the myosin heavy chain promoter selectively affects the atria without substantial alterations in ventricular fibrosis [190], suggesting that atria may be particularly sensitive to the pro-fibrotic effects of TGF-β1. TGF-β1 can promote fibrosis in the kidneys [191]. Elevated serum TGF-β levels in type II diabetic patients are associated with greater risk of nephropathy [192]. However, the effects of TGF-β1 inhibition are complicated by the fact that the latent form of TGF-β1 can protect renal function. Transgenic mice with overexpression of latent TGF-β1 are protected against renal inflammation and fibrosis after unilateral ureteral obstruction [193]. Most clinical trials have failed to show that systemic TGF-β neutralization can rescue the GFR decline in CKD [194–196], perhaps owing to the fact that most circulating TGF-β1 is the latent (i.e., protective) form [197]. Targeting pathologic pathways downstream of TGF-β1 signaling may bypass this effect. For instance, neutralization of TGF-β1 downstream mediator SMAD3 via small molecule inhibitor petchiether A in a mouse model of obstructive uropathy protected against renal fibrosis [198]. Overall, TGF-β1 plays a role in pathologic fibrotic and inflammatory remodeling in the kidneys and atria, although a direct link between the two organs remains elusive. One possibility is that the elevated levels of circulating TGF-β1 in CKD can promote atrial fibrosis, creating a substrate for AF development. Another possibility is that fibrocytes, which are circulating fibroblast progenitor cells, can mediate crosstalk between the kidney and atria, particularly in relation to TGF-β1 [199]. Nonetheless, further investigations are needed to clarify how TGF-β1-mediated fibrosis in the kidney can lead to atrial fibrosis and AF.

4. Experimental models of CKD

To date, a substantial body of work has studied the CKD in animal models. Table 2 highlights several commonly used murine models of CKD, which are established through methods that induce renal mass reduction, glomerular injury, nephropathy, nephritis, or polycystic kidney disease, among others [200, 201]. Most studies examining the cardiac consequences of kidney dysfunction in these models have primarily been focusing on the ventricular function and structure. Notably, the 5/6 nephrectomy (also known as subtotal nephrectomy model) is the most used model for studying AF pathogenesis in kidney diseases. In this model, atrial fibrosis and inflammation, key contributors to AF pathogenesis, are consistently reproduced [156, 179]. While each model has its advantages and disadvantages, the choice of CKD model should be guided by the following criteria: 1) the targeted stage of CKD, 2) surgical reproducibility, 3) the rate and progression of CKD, and 4) the specific context of CKD development (e.g., polycystic kidney disease).

Table 2.

Comparison of Various Murine Models of Chronic Kidney Disease.

Model	Cardiac outcomes	Advantages	Disadvantages
5/6 nephrectomy [156, 178]	• Cardiac hypertrophy • Cardiac fibrosis • Increased inflammation • Atrial enlargement	• Well-stablished model • Mimics the late stages of CKD • Reliable CKD induction	• Surgery induced
Unilateral nephrectomy [233, 234]	• Cardiac hypertrophy • Cardiac fibrosis	• High survival rate • Mimics early stages of CKD • Reliable CKD induction	• Surgery induced • Low reproducibility
Renal ischemia/reperfusion injury [235, 236]	• Cardiac fibrosis • Cardiac hypertrophy	• Mimics early stages of CKD • Reliable CKD induction	• Surgery induced • High mortality rate • Slower progression to CKD
Adenine diet [237, 238]	• Cardiac fibrosis • Cardiac hypertrophy • Increased inflammation	• Diet induced • Reliable CKD induction	• Limited relevance to humans
Oxalate nephropathy [239, 240]	• Cardiac fibrosis	• Diet induced • Recapitulate common CKD complications • Reliable CKD induction	• Possible cardiac toxicity • Limited relevance to humans
Alport mice [241]	• Cardiac fibrosis • Cardiac hypertrophy • Increased inflammation	• Genetic model	• Slower progression to CKD (19 – 21 weeks)
Polycystic kidney disease [242]	• Cardiac hypertrophy	• Genetic model	• Translational relevance limited to polycystic kidney disease patients

5. AF Management in CKD

The main treatment for CKD patients involves renal replacement therapy, including dialysis and renal transplantation. AF incidence has been reported to be nearly 30% in dialysis-dependent CKD patients [202] and around 7% in patients undergoing kidney transplantation within the first 3 years post-transplant [203]. Additionally, AF incidence in kidney transplant recipients is associated with post-transplant mortality [204], which underscores the critical need for improved AF management in CKD patients. However, medication in CKD patients presents unique challenges due to impaired kidney function affecting drug metabolism and excretion. While rhythm control is a standard therapeutic strategy, selecting appropriate antiarrhythmic drugs requires caution. Water-soluble agents such as sotalol, which is renally excreted, should be avoided in CKD patients due to an increased risk of Torsades de Pointes in dialysis patients [205]. Similarly, flecainide toxicity is more severe in CKD patients [206]. Catheter ablation has shown reduced efficacy in CKD patients, with recurrence rates as high as 57%, especially in patients on dialysis [207, 208]. Cardioversion for sinus rhythm also has demonstrated lower success rates in CKD patients compared to those with normal kidney function [209]. Careful consideration should also be given to patients with impaired cardiac conduction system and reduced ejection fraction, as they do not tolerate class IC anti-arrhythmic drugs [210]. In fact, comorbidities should be considered in tandem with, if not prioritized over, kidney function when determining which therapies to withhold and which to prescribe for CKD-AF patients [211]. AF management in this population is not only focused on rate and rhythm control but also consider stroke prevention strategies. Anticoagulation therapy in CKD patients is particularly complex, as these patients are at an elevated risk of bleeding, complicating the safe use of anticoagulants like warfarin [212]. Unfortunately, limited clinical trials have specifically examined the effects of anticoagulation in CKD patients.

Some studies have shown a protective renal effect of estrogen administration in menopausal women with CKD [213]. However, dosage adjustment are necessary, as CKD women showed higher estrogen levels than those with normal renal function after receiving the same dose [214]. It is worth noting that estrogen replacement therapy has been associated with an increased risk of AF in the general population [215]. Manson et al. found that more than 60% of postmenopausal women treated with estrogen plus progestin developed new-onset AF, based on the Women’s Health Initiative study [216]. This proarrhythmic effect may be a consequence of estrogen’s modulation of RAAS and its ability to increase the expression of atrial natriuretic factor [217, 218]. Estrogen has also been shown to prolong APD and slow atrial conduction in murine atria, independently of the sex [219].

The effects of N-acetyl cysteine (NAC), a scavenger of free radicals and drug that binds to toxic metabolites, has been tested in CKD patients. Several studies showed that NAC did not provide protection against postoperative acute renal failure in patients with CKD undergoing cardiac surgery [220, 221]. On the other hand, other studies have shown that NAC can reduce the risk of CKD progression of any etiology to End-Stage Renal Disease (ESRD). For example, a Taiwanese cohort study of 123,000 CKD patients found that NAC use was associated with a reduced risk of progression to dialysis-dependent ESRD [222]. A meta-analysis of 15 trials with 768 CKD patients found that NAC improved eGFR and reduced serum creatinine compared to placebo, suggesting a benefit to kidney function. Additionally, NAC reduced cardiovascular events, which are closely linked to CKD progression [223]. Finally, a recent clinical trial (NCT04916080) has completed evaluating NAC in pediatric CKD patients, though results are pending.

Targeting inflammation is another emerging approach. A pilot, multicenter, randomized, placebo-controlled trial of the IL-1 receptor antagonist, anakinra, was tested in eight hemodialysis patients with CKD. The drug was well tolerated and did not increase infections or cytopenia. The median decrease in hsCRP over a 24-week study period was 41% in the anakinra group and 6% in the placebo group, which was not statistically significant due to the small sample size [224]. AstraZeneca recently launched a phase 1b clinical trial to assess the safety, tolerability, and pharmacodynamics of NLRP3 inhibitor AZD4144 in patients with established atherosclerotic cardiovascular and chronic kidney disease (NCT06675175). While AF is not a primary endpoint in these trials, post-hoc analyses may reveal effects on arrhythmia susceptibility. A separate feasibility trial (NCT00561093) examined the effects of a CKD-specific high-protein oral nutritional supplement with anti-inflammatory and antioxidant properties. Over 16 weeks, the results showed that this supplement was well tolerated and associated with a small but significant increase in serum albumin levels. However, the study was underpowered to determine effects on disease outcomes [225].

Finally, renal denervation (RDN) has emerged as a promising therapy. Combining RDN and with AF ablation has shown efficacy in reducing AF in CKD patients [226, 227]. Mechanistically, the beneficial effect of RDN on AF susceptibility, observed in a rodent CKD model induced by adenine-enriched diet, is attributed to the improve structural remodeling, reduced fibrosis, and enhanced electrical conduction within left atria of CKD rats [228]. Additionally, in a canine model of renal impairment, RDN also suppresses AF inducibility, which is associated with a significant decrease in pro-inflammatory NF-kB activation and IL-6 production [229]. Clinically, concurrent treatment utilizing both RDN and catheter ablation promote hemodynamic stability and reduces the risk of AF recurrence, especially in patients with hypertension [226, 227]. The efficacy of RDN on AF incidence depends on the type of AF, and the reduction of AF after RDN might be a secondary consequence of improved blood pressure or reduced sympathetic nervous system activity. Thus, renal denervation may be a good therapeutic treatment for preventing AF in CKD patients with concomitant resistant hypertension.

6. Perspectives

CKD constitutes a systemic risk factor for AF, promoting atrial arrhythmias in affected patients. Conversely, successful treatment of CKD may reduce the incidence of AF in certain patients suffering from both disorders. Nevertheless, studies have shown that even dialysis treatment may be insufficient to prevent the onset of AF in patients with advanced stages of CKD [230]. A deeper understanding of the molecular mechanisms underlying increased AF susceptibility in CKD patients could lead to the development and implementation of better treatment strategies. For example, an in-depth assessment of electrophysiological changes in atrial cardiomyocytes of CKD patients is currently lacking. Experimental models of CKD have shown prolonged APD in ventricular cardiomyocytes, attributed to increased late sodium current (I_Na,L) and decreased slowly inactivating potassium current (I_to,slow) [231]. The elevated I_Na,L can lead to intracellular Na⁺ overload, which subsequently enhances inward Ca²⁺ current through L-type Ca²⁺ channels. This prolongation may also be driven by the accumulation of uremic toxins due to impaired kidney function. Consistently, indoxyl sulfate, kynurenine, and kynurenic acid have been shown to prolong APD in hiPSC-derived cardiomyocytes by suppressing the rapid delayed rectifier potassium current (I_Kr) in a dose-dependent manner [232]. Additionally, increased cytoplasmic Ca²⁺ has been observed in pulmonary vein cardiomyocytes, resulting from enhanced PKA-mediated phosphorylation of RyR2 channels [3], supporting the role of triggered activity in AF development in CKD patients. Together, these findings support the notion that electrical remodeling and triggered activity are key proarrhythmic substrates induced by CKD. While electrophysiological studies in ventricular cardiomyocytes from CKD models may provide insights into potential AP changes in the context of CKD-associated AF, further research is needed to characterize the electrophysiological properties of atrial cardiomyocytes across different stages of CKD patients, with or without dialysis treatment. This line of investigation could help establish a foundation for research aimed at model validation and therapy development.

We discussed how multiple factors altered by kidney dysfunction, contribute to the development of cardiovascular disease, particularly AF. Given this connection, clinical studies are needed to evaluate whether preventing or treating kidney dysfunction can reduce the risk of AF. However, the etiology of kidney disease is highly diverse, and studies should be tailored accordingly. For example, the RAINIER study focuses on immunoglobulin A nephropathy by inhibiting B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), which are involved in B cell-mediated immune responses. Suppressing immune activity in this context may not only benefit kidney function but could also potentially lower the risk of AF. Notably, most CKD clinical trials to date have focused on showing CKD progression or reducing general cardiovascular events as outcome. AF remains an underexplored endpoint, a critical gap that should be addressed in future studies.

7. CONCLUSIONS

CKD is a pathology associated with various metabolic disorders that are significant risk factors for cardiovascular outcomes, such as AF. Structural and electrical atrial remodeling are key substrates for AF development. How CKD increases AF predisposition is not fully understood. A comprehensive review of systemic alterations commonly found in CKD patients showed that hyperglycemia, RAAS hyperactivations, mineral bone disorders, oxidative stress, and inflammation are all related to important AF substrates like triggered activity, atrial fibrosis, enlargement, and electrical remodeling. Whether these alterations exert a synergic or independent contribution to CKD-induced AF onset needs further investigation.