, Fan He 1,*1 Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
Academic Editors: Giuseppe Nasso and Giuseppe Santarpino
Abstract
Chronic kidney disease (CKD) shows a high prevalence and is characterized by progressive and irreversible loss of renal function. It is also associated with a high risk of cardiovascular disease. The CKD population often suffers from atrial fibrillation (AF), which is associated with cardiovascular and all-cause mortality. There is a pernicious bidirectional relationship between CKD and AF: renal dysfunction can help promote AF initiation and maintenance, while unmanageable AF often accelerates kidney function deterioration. Therefore, it is necessary to determine the interactive mechanisms between CKD and AF for optimal management of patients. However, due to renal function impairment and changes in the pharmacokinetics of anticoagulants, it is still elusive to formulate a normative therapeutic schedule for the AF population concomitant with CKD especially those with end-stage kidney failure. This review describes the possible molecular mechanisms linking CKD to AF and existing therapeutic options.
Keywords
- chronic kidney disease
- atrial fibrillation
- fibroblast growth factor
- uremic toxin
- anticoagulant
- sodium-glucose cotransporter inhibitor
- sacubitril/valsartan
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
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
Ca
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)
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.
When the adverse effects of AF appear due to rapid ventricular rate or loss of
available atrial contraction, medication strategy, including rate and rhythm
control should be considered.
| Registration of the trial | Study design | Estimated date of completing | |
| Drug | Primary outcome | ||
| NCT03987711 | Warfarin vs. apixaban vs. no antithrombotic therapy | Treatment effect and safety | 2021.12 |
| NCT02933697 | Low-dose apixaban vs. warfarin | Treatment safety | 2022.07 |
| NCT02886962 | Warfarin vs. nonuse | Adverse effect | 2023.01 |
| NCT03862359 | Warfarin | Treatment effect and safety | 2024.09 |
| NCT03718273 | Ivabradine vs. digoxin | Treatment effect and serious adverse outcome | 2021.08 |
One of the irreversible outcomes caused by AF is thromboembolism, which usually
results from a detachment of thrombus in the atrium cordis. For long-term
management of the risk between thromboembolism and bleeding, the widely
recognized CHA
Warfarin is a commonly used anticoagulant that mainly inhibit the vitamin K reductase and vitamin K recirculation. After being completely absorbed, warfarin takes nearly a week to reach a steady-state and is eliminated totally by metabolism [63]. Although its renal excretion is negligible, a lower dose is needed in patients with stages 4–5 CKD to achieve the correct international normalized ratio (INR).
In ESRD patients complicated with AF, high-level RCTs to provide the most striking evidence for decision-making are lacking. Previous observational real-world studies on warfarin prescription in ESRD patients do not provide consistent idea (Fig. 5) [64]. Some cohort studies showed the benefits of warfarin in stroke prevention and survival (Fig. 5a,c) [65, 66], while others showed no beneficial effects but greater harm (Fig. 5b) [67, 68]. The American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) 2019 Guideline for AF management ranked warfarin prescription as II b indication, but in patients with ESRD and AF, less than 50% receive oral anticoagulant, and only about 34% of people receive warfarin in the dialysis population [69]. In end-stage CKD patients treated with warfarin, there were no survival benefits and decreased rate of stroke, but an elevated risk of hemorrhage events (Fig. 5) [67, 70, 71]. Warfarin therapy has one obvious drawback compared with direct oral anticoagulants (DOACs). The warfarin therapeutic range is critically questionable to overcome, especially for patients with poor treatment compliance. According to the AHA/ACC/HRS 2019 Guideline, patients should take coagulation function examination to determine the INR at least once a week at the initiation of warfarin treatment, and at least once a month until its efficacy is stable [57].
Fig. 5.Efficiency and safety of warfarin in patients with AF and ESRD. (a) Hazard ratio (HR) for stroke treated with warfarin. (b) Hazard ratio (HR) for bleeding treated with warfarin. (c) Hazard ratio (HR) for mortality treated with warfarin. AF, atrial fibrillation; ESRD, end-stage renal disease.
Moreover, warfarin may have side effects other than bleeding due to its pharmacological mechanism to inhibit vitamin K-dependent gamma-glutamyl carboxylase enzyme. Decreased vitamin K-dependent gamma-glutamyl carboxylase enzyme activation impairs matrix G1a protein (MPG). However, MPG is demonstrated to attenuate vascular calcification significantly [72]. Vascular calcification is prevalent in CKD patients, and is associated with an increased risk of cardiovascular, cerebrovascular, peripheral vascular disease [73, 74]. Despite the untoward effects limit warfarin application, it is still a deemed medicine for anticoagulation when the INR is stable and the risk of bleeding is lower than stroke.
NOACs, also known as DOACs, and currently dabigatran, rivaroxaban, apixaban, and edoxaban are commonly used for anticoagulation. Dabigatran is a thrombin inhibitor unlike other three coagulation factor Xa inhibitors. NOACs are preferable to warfarin in NOACs-eligible AF patients [57]. However, top-level evidence for NOACs prescription is scarce in AF patients with severe renal dysfunction. Food and Drug Administration (FDA) approved only apixaban for anticoagulation in patients with ESRD, and the AHA/ACC/HRS 2019 Guideline for AF management is consistent with FDA [57]. On the contrary, the 2018 European practical guideline refused apixaban therapy in ESRD patients [75].
4.2.2.1 Apixaban
In studies comparing the efficacy and safety of apixaban with warfarin, apixaban showed its advantage in stroke and embolism prevention or less major bleeding events with fewer mortality [59, 76, 77]. Although warfarin was associated with a lower risk of stroke and systematic embolism in the subgroup analysis of severe or moderate renal impairment, it was statistically insignificant [59]. In a matched-cohort study, apixaban had a lower major bleeding occurrence; however, there was no significant difference [77]. In another retrospective cohort study, there were significant differences in both overall and major hemorrhagic events between apixaban and warfarin groups (18.9% vs. 42.0%; p = 0.01 and 5.4% vs. 22.0%; p = 0.01 respectively) (Fig. 6, Ref. [78]) [76]. A meta-analysis of observational studies in dialysis population showed that apixaban was significantly associated with lower risk of bleeding than warfarin and other DOACs (Fig. 6b) [78]. Thus, apixaban may be effectively and safely used in ESRD patients (Fig. 6a,c). We have to be aware that the therapeutic dosage of apixaban needs to be prudently adjusted according to the stroke and bleeding risks. In a small-scale study including seven dialysis patients, 5 mg twice daily was beyond a reasonable therapeutic level [79]. On the contrary, routine 5 mg twice daily was significantly associated with reduced risks of stroke and mortality (HR 0.61, 95% CI 0.37–0.98, p = 0.04) [80]. Thus, ESRD is not a contraindication to apixaban, but a standard dose of 5 mg twice daily is not recommended for all patients.
Fig. 6.Efficiency and safety of NOACs in patients with AF and ESRD. (a) Hazard ratio (HR) for stroke treated with NOACs. (b) Hazard ratio (HR) for bleeding treated with NOACs. (c) Hazard ratio (HR) for mortality treated with NOACs. Kuno et al. [78] is a systematic review that compared high and low-dose apixaban with no anticoagulants. AF, atrial fibrillation; ESRD, end-stage renal disease; NOACs, the non-Vitamin K oral anticoagulant.
4.2.2.2 Dabigatran
Dabigatran is not approved in patients with eGFR
4.2.2.3 Rivaroxaban and Edoxaban
Rivaroxaban therapy did not show significantly reduced rates of stroke and
systematic embolism (RR 1.8; 95% CI 0.89–3.64) [81], and was associated with
adverse effects of both severe (RR 1.38; 95% CI 1.03–1.83, p = 0.04)
and slight (RR 1.35; 95% CI 1.11–1.65, p = 0.001) bleeding events. In
a double-blinded trial, the rivaroxaban (20 mg) group did reduce stroke and
systemic embolism compared with the warfarin group (RR 0.88; 95% CI 0.74–1.03,
p
Although we can get instructive information from observational studies with large subjects, the surrounding evidence from RCTs is limited. Several ongoing RCTs on anticoagulation drugs may provide a direction for improving embolism prophylaxis (Table 1).
Sodium glucose cotransporter-2 (SGLT-2) is a cotransporter of Na
There are multiple possible molecular signaling pathways through which SGLT2i
reduce the underlying risk of AF (Fig. 7). Sesterins are cytoplastic stress
proteins that prevent atria from oxidative damage and structural remodeling by
alleviating ROS accumulation and fibrosis in cardiac fibroblasts [96]. SGLT2i
upregulated Sesterin2 and then activated downstream AMPK/mammalian target of
rapamycin complex 1 (mTORC1) signaling pathway, thus accounting for SGLT2i’s role
in abating inflammation response, oxidative stress, and atrial fibrosis [97].
Normal physiological activities and energy metabolism of cells or organs depend
on effective and functional mitochondrial respiration. Sesterin2/AMPK pathway
activation enhances peroxisome proliferator-activated receptor-gamma coactivator
1
Fig. 7.SGLT2i exerts an influence on protecting the cardiovascular system. SGLT2i, sodium-glucose cotransporter inhibitor; Glu, glucose.
Sacubitril/Valsartan (SAC/VAL) is an inhibitor of Ang II and neprilysin receptor
that blocks Ang II binding to angiotensin receptor 1 (AT-R1) and amplifies the
effects of natriuretic peptides by decreasing their degradation [101]. It has
been a first-class medicine for chronic heart failure, and trials by Prospective
Comparison of ARNI with ACEI to Determine Impact on Global Mortality and
Morbidity in Heart Failure (PARADIGM-HF) investigators showed that
sacubitril/valsartan significantly reduced the risk of cardiovascular mortality
and admission in patients with reduced ejection fraction heart failure [102]. In
severe renal insufficiency patients, the risk of death from cardiovascular
disease reduced 28% in the sacubitril/valsartan group compared with conventional
management [103]. Treatment with sacubitril/valsartan improved systolic cardiac
function after myocardial infarction (MI), and decreased the arrhythmias tendency
by decreasing CaMK II phosphorylation in rodent chronic MI and HF model [104].
Martens et al. [105] used a retrospective study including 151 eligible
patients with heart failure with reduced ejection fraction (HFrEF) to demonstrate
the benefit of sacubitril/valsartan therapy for ventricular arrhythmia and
reversal of left ventricular structural remodeling. Data from pre-clinical trials
suggested that sacubitril/valsartan ameliorates cardiac fibroblast transition by
accommodating protein kinase G (PKG) signaling [106]. Li et al. [107]
also found NF-
Li et al. [109] demonstrated that SAC/VAL altered atrial fibrillation propensity by suppressing Ang II-induced AF in rat models. Interestingly, they also noticed p-Smad 2/3, phosphorylation of c-jun-NH2-terminal kinase (p-JNK) and p-p38MAPK downregulated expression, indicating that it might be a potential therapeutic target pathway. Sacubitril/valsartan could strongly improve left atrial (LA) and left atrial appendage (LAA) function even in AF patients [110]. Fully effective LA and LAA function are essential for escaping from blood stagnation and thrombogenesis and reducing cardioembolic stroke risk [111]. A meta-analysis of SAC/VAL in renal failure and AF patients showed that it reserved kidney function without adverse drug reaction [112]. In a mouse model of CKD, LCZ696 attenuated oxidative stress, fibrosis and inflammation in the kidney as well as the cardiovascular system [113, 114]. The above evidence (Fig. 8) adds to our understanding of sacubitril/valsartan therapy’s role in preventing AF occurrence and stroke in patients with AF and CKD. Atrial disease is an important part in the development and progression of HF, meanwhile, patients with HF prone to AF [115], which suggests that it is necessary to treat HF in patients with CKD.
Fig. 8.Sacubitril/valsartan was demonstrated to be a beneficial option for AF patients. AF, atrial fibrillation; CKD, chronic kidney disease; LA, left atrium; LAA, left atrial appendage.
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.
Not applicable.
Not applicable.
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.