The prevalence of chronic kidney disease (CKD) and atrial fibrillation (AF) is rising annually. CKD is an insidious disease defined by a progressive drop in kidney function with or without renal structural changes and is a vital contributor to cardiovascular disease. Data from the health system shows that CKD affects 10% population worldwide (Fig. 1), and its global prevalence has augmented 29.3% since 1990 [1].

Fig. 1.

The prevalence of AF in CKD (a) and non-CKD (b) population. AF, atrial fibrillation; CKD, chronic kidney disease.

The most common cardiac dysrhythmia, AF, causes many adverse cardiovascular outcomes. Stroke, chronic heart failure, myocardial infarction, systemic embolic events, dementia, and venous thromboembolism are common complications of atrial fibrillation, and its prevalence ranges from 2% to 4% in adults [2]. Moreover, AF was associated with an increased risk of adverse cardiovascular events and cardiovascular mortality [3, 4].

CKD and AF often share multiple common risk factors, such as age, male sex, cardiovascular disease, hypertension, diabetes, heart failure, and obesity (Fig. 2) [5, 6, 7]. A prospective cohort study including 235,818 general subjects indicated that estimated glomerular filtration rate (eGFR) decline increased the risk of AF, meanwhile, the occurrence of AF promoted the deterioration of renal function [8]. In CKD patients, 15–20% were estimated to suffer from AF, and 7.0% of the dialysis population had AF [9, 10, 11]. Conversely, CKD acts as an independent risk factor of AF. Urine albumin-to-creatinine ratio (UACR) represents a common kidney function indicator. A recent study focusing on the incidence of AF in CKD patients showed that the risk of AF increased approximately twice in UACR $>$300 mg/g compared with UACR 30 mg/g [Hazard Ratio (HR) 2.69; p 0.0001] [12]. On the other hand, AF might play a significant role in CKD progression. In the Chronic Renal Insufficiency Cohort Study (CRIC) which included 3,091 participants, patients complicated with AF were at a considerably higher probability of progression to end-stage renal disease (ESRD) (HR 3.2; p 0.0001) [13]. Similarly, a systematic review of 25 literature showed that the presence of AF among the dialysis population was associated with a higher risk of stroke (5.2 vs. 1.9 per 100 person-years) and mortality (26.9 vs. 13.4 per 100 person-years) [14]. Thus, management of AF in CKD patients is extremely imperative for physicians. This review aimed to elaborate our argument on the knowledge about patients with AF and CKD.

Fig. 2.

Mutual influence between AF and CKD, sharing a series of common risk factors. AF, atrial fibrillation; CKD, chronic kidney disease; CVD, cardiovascular disease; HF, heart failure.

Ineffective and disordered atrial contraction and diastole lead to an impaired or loss of atrial contribution to ventricular filling. Thus, patients with AF may have symptoms like palpitation, breathlessness, fatigue, and dizziness due to irregular and inappropriately rapid ventricular rhythm and loss of “atrial kick”, while some are asymptomatic. On the other hand, sympathetic nervous system hyperactivity in CKD patients promotes conduction of atrial impulses to the ventricles with rapid ventricular rate then influence cardiac output [15]. In addition to hemodynamic disturbance resulting from AF, AF is also associated with poor clinical consequence such as stroke and death in dialysis patients [16, 17, 18]. Moreover, a cohort study named CRIC indicated that incident AF was linked independently with an elevated incidence of heart failure, stroke, and death [19]. In another study on stages 3–4 CKD population, incident AF elevated the risk of renal function deterioration [20]. Except for the poor prognosis of AF in the CKD population, changes in the CKD coagulation systems lead to an increased risk of thrombosis and bleeding. CKD’s bleeding tendency is influenced by many aspects relevant to the secondary platelet function disorder and the heparin application in dialysis [21, 22]. In conclusion, the pro-hemorrhagic state poses a challenge for the management of thromboembolism events prophylaxis in CKD patients.

Generally, the AF pathophysiology includes three essential parts (Fig. 3): AF initiation, maintenance and progression to persistent state [23]. Atrial risk factors cause atrium changes like fibrosis, inflammation, cellular and molecular dysfunction, subsequently electrophysiological and structural remodeling raised by persistent AF leads to its perpetuation [3].

Fig. 3.

The parts of the AF pathophysiology stage. AF, atrial fibrillation; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species.

Pulmonary vein sleeves (PVs) play a major role in introducing AF [24]; its unique location, tissue construction, and ion channels conduce to ectopic electrical activity and re-entry [25]. The PV sleeves lack adjacent tissue and continuous fibers, leading to spontaneous activity and AF onset. The early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) generation underlies ectopic activity. In the setting of prolonged action potential duration (APD), usually caused by reducing K${}^{+}$ currents or enhanced depolarizing currents (including Na${}^{+}$ and L-type Ca${}^{2+}$ currents), L-type Ca${}^{2+}$ channels recover from inactivation and facilitate the occurrence of inward current [26]. Compared with EADs, DADs have a more active role in triggering ectopic activity. Ca${}^{2+}$-handling abnormalities resulting from cardiac ryanodine receptor channel type2 (RyR2) dysfunction, and spontaneous sarcoplasmic reticulum (SR) Ca${}^{2+}$ release events (SCaEs) promote DAD both in animal models and patients with AF [27, 28, 29]. However, as the original link of DAD, Ca${}^{2+}$/calmodulin-dependent kinase II (CaMK II) hyperphosphorylation is a crucial target in arrhythmia initiation and perpetuation. The autonomic system provides a substrate for AF development, and triggers the AF-pathophysiology by promoting Ca${}^{2+}$-handling abnormalities. Sympathetic activation leads to CaMK II phosphorylation through $\beta$-adrenoceptor and cyclic adenosine monophosphate (cAMP) production [30]. In addition, sympathetic stimulation results in increased SR Ca${}^{2+}$ load, with concurrent positive inotropic action of cardiomyocytes.

Ca${}^{2+}$ overload plays a vital role in the persistence of CaMK II phosphorylation [30]. Oxidative stress is a feature of many diseases and is involved in Ca${}^{2+}$-handling abnormalities. A study comparing patients with AF and sinus rhythm concluded that oxidative stress promotes AF through oxidating CaMK II. However, in CKD patients, overactive inflammatory response and the renin-angiotensin-aldosterone system (RAAS) promote reactive oxygen species (ROS) accumulation and atrial fibrosis; thus, contributing to AF progression [31, 32].

Fibroblast growth factor-23 (FGF-23) is a hormone involved in the regulation of calcium-phosphorus metabolism balance and bone mineralization [33]. Elevated level of FGF-23 is associated with a higher risk of heart failure, all-cause mortality, cardiovascular mortality, and left-ventricular hypertrophy [34, 35, 36]. Both myocyte culture and animal experiments confirmed that FGF-23 can induce hypertrophic growth of cardiac cells [37, 38]. Furthermore, in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), increased FGF-23 concentration was associated with an increased risk of AF [39]. In addition, FGF-23 binds to the FGF-receptor 4 (FGFR4) in cardiac myocytes in the defect of klotho, and induces hypertrophy through activating phospholipase C (PLC) $\gamma$/calcineurin/Nuclear factor of activated T-cells (NFAT) pathway [37, 40]. FGF-23 also stimulated PLC $\gamma$/calcineurin/NFAT cascade in hepatic cells during klotho deficiency, causing elevated inflammatory cytokine secretion (tumor necrosis factor-$\alpha$ (TNF-$\alpha$), interleukin-2 (IL-2), and IL-6) [41]. FGF-23 and FGFR 4 expression increased in the atrial tissues of AF patients compared with the sinus rhythm population, consistent with the expression of $\alpha$-smooth muscle actin ($\alpha$-SMA) and collagen-1. Dong and his colleagues illuminated that FGF-23/FGFR4 accentuated atrial fibrosis by inducing ROS accumulation and then regulating signal transducer and activator of transcription 3 (STAT3) and small mother against decapentaplegic 3 (SMAD3) pathways [42]. Therefore, FGF-23/FGFR4 provides a vulnerable substrate for AF (Fig. 4). In patients with uremic syndrome, indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are classic toxins with high protein affinity and cardiotoxicity. It has been shown that IS promotes AF by producing atrium fibrosis and inflammatory response, and treatment with uremic toxin absorbent AST-120 alleviated these undesirable effects and then attenuated AF [43, 44]. Lekawanvijit et al. [45] also demonstrated that IS might play a role in pro-fibrotic and pro-inflammation via the P38 mitogen-activated protein kinase (MAPK), P22/44 MAPK, nuclear factor kappa-B (NF-$\kappa$B) signaling pathway in vitro. In 5/6 nephrectomy rat models by Aoki et al. [43], oxidative stress is increased in the left atrium. In another animal experiment on rabbits, IS induced more DAD, burst firing events, and larger Ca${}^{2+}$ leakage in pulmonary vein cells, which trigger AF occurrence [44]. Furthermore, IS played a part in impairing the Mas receptor’s ability to counter the pernicious effect of angiotensin II (Ang II) via the organic anion transporter 3 (OAT3)/aryl hydrocarbon receptor (AHR)/STAT3 pathway, which reduced the number of Mas receptor [46]. Thus, we conclude that IS plays a vital role in AF via the effects of inflammation, fibrosis, and oxidative stress on atrial remodeling (Fig. 4). Uremic toxin pCS may have effects similar to IS.

Fig. 4.

The role of FGF-23 and uremic toxins in AF initiation and progression in patients with CKD. Here, we summarize the relevant molecular pathways and their effects. AF, atrial fibrillation; CKD, chronic kidney disease; FGF-23, fibroblast growth factor-23; IS, indoxyl sulfate; pCS, p-cresyl sulfate; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; TNF, tumor necrosis factor.

The left atrial appendage (LAA) is the main thrombogenesis region in AF for its poor function, and if that the thrombus falls off, a systematic embolic outcome follows. The left atrial appendage occlusion (LAAO) is an optimal mechanical strategy for preventing AF-related stroke [116]. In real-world clinical practice, patients who received LAAO therapy had a lower risk of stroke and hemorrhage [117]. Considering the uncertainty in the pros and cons of anticoagulants use in patients with advanced renal failure, LAAO may be a suitable stroke prevention strategy [118]. Kefer et al. [119] highlighted that LAAO greatly reduced the risk of stroke, transient ischemic attacks (TIA), and bleeding events. In a meta-analysis comparing the benefits and adverse outcomes between LAAO and anticoagulants, it has been indicated that LAAO acquired more effective embolism prevention with a lower risk of bleeding than oral anticoagulants [120]. Therefore, LAAO can be proposed for CKD patients with absolute contraindication to oral anticoagulants.

Early identification of AF is beneficial for patients with renal insufficiency, and early diagnosis of asymptomatic AF helps prevent stroke effectively. However, screening for AF is not routinely performed in patients with CKD. LA imaging technology, such as 2-dimensional echocardiogram, 3-dimensioanl echocardiogram, cardiac magnetic resonance, and cardiac computed tomography, have been used to accurately assess LA size and function [121]. Besides, cardiac troponin and natriuretic peptide are serological markers suggestive of cardiovascular dysfunction. Molecular imaging may also enable accurate and early detection of AF [122]. Patients with CKD are at high risk for AF, therefore, we need a comprehensive strategy, which includes risk factor assessment, sensitive serum biomarkers, precise imaging, and promising molecular imaging for better management.

AF and CKD usually coexist and share several common traditional risk factors. CKD patients possess underlying pathophysiological mechanisms in the initiation and development of AF, and making treatment decisions for stroke prevention in this population remains a challenge. In this review, a series of innovative measures for AF management in CKD patients were brought forward, but these strategies were just hypotheses with sound reasoning. Thus, individualized prevention and therapy strategies for AF are still required in patients with CKD.

FH and YY provided conceptualization. YW prepared the original draft. YY and YW contributed to editorial changes in the manuscript. FH contributed to supervision. All authors read and approved the final manuscript.

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This work was supported by National Natural Science Foundation of China Grants NSFC [81974089], and the Frontier Application Basic Project of the Wuhan Science and Technology Bureau [2020020601012235].

The authors declare no conflict of interest.