Abstract
Introduction
Left atrial enlargement (LAE), a hallmark of heart failure with preserved ejection fraction (HFpEF), is prevalent in chronic kidney disease (CKD), but its prognostic value for cardio-renal outcomes remains unclear. We aimed to investigate the association between left atrial (LA) diameter and adverse cardio-renal outcomes in patients with non-dialysis CKD stages 1–5.
Methods
We conducted a prospective cohort analysis of 2,145 participants from the KNOW-CKD study. Participants were categorised by baseline LA diameter: <40 mm, 40–45 mm and >45 mm (LAE). Primary outcomes included kidney failure requiring renal replacement therapy (KFRT), expanded major adverse cardiovascular events (eMACE), and all-cause mortality during a median 9.3-year follow-up. Cox proportional hazards models were used to assess associations after adjusting for demographics, kidney function, cardiovascular risk factors and medications.
Results
LAE was present in 11.5% of participants. Cumulative incidence of all outcomes increased significantly across LA diameter categories (log-rank P < 0.001 for all). After multivariable adjustment, LAE independently predicted KFRT (adjusted HR 1.60, 95% CI 1.23–2.08, P < 0.001) and eMACE (adjusted HR 1.80, 95% CI 1.10–2.96, P = 0.020), but not all-cause death (adjusted HR 1.25, 95% CI 0.83–1.87, P = 0.286). LA diameter correlated strongly with echocardiographic markers of diastolic dysfunction (E/e′ ratio, r = 0.412, P < 0.001; LVMI, r = 0.296, P < 0.001) but not with left ventricular ejection fraction (r = −0.037, P = 0.096).
Conclusion
In patients with non-dialysis CKD, LA diameter represents an accessible and independent prognostic marker for adverse kidney and cardiovascular outcomes. These findings support the integration of LA diameter assessment into routine cardiovascular risk stratification protocols for CKD patients.
Keywords: Cardiovascular events, Chronic kidney disease, Echocardiography, Heart failure, Left atrial enlargement
Graphical abstract
Highlights
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Left atrial enlargement is a key structural hallmark of HFpEF and is highly prevalent in patients with CKD.
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In 2,145 non-dialysis CKD patients, left atrial diameter independently predicts kidney failure and major CV events.
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Left atrial diameter correlates significantly with LV diastolic dysfunction markers, but not with systolic function.
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Left atrial diameter is a simple, accessible tool for cardiovascular risk stratification in routine clinical CKD care.
Introduction
Heart failure (HF) is one of the leading causes of death in patients with chronic kidney disease (CKD).1, 2, 3 The phenotypic spectrum of HF in CKD patients varies, while the prevalence of HF with preserved ejection fraction (HFpEF) is relatively higher than that in the general population.4, 5, 6 Despite the preservation of left ventricular ejection fraction (LVEF), the mortality resulting from HFpEF is similar to that of HF with reduced ejection fraction (HFrEF), imposing a significant impact on the management of cardiovascular complications in patients with CKD.4 Thus, the Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Clinical Practice Guideline emphasises cardiovascular risk assessment as an integral component of CKD management.7 However, current guidelines provide limited guidance on the role of echocardiographic markers beyond left ventricular function in risk stratification.
The key features in HFpEF have been associated with adverse outcomes in CKD. The increase in the ratio of early diastolic mitral inflow velocity and mitral annular tissue velocity (E/e′ ratio) is associated with the risk of more rapid CKD progression8, 9 and adverse cardiovascular events9, 10 in patients with non-dialysis CKD. The alterations in the left ventricular geometry are also associated with the risk of accelerated decline in estimated glomerular filtration rate (eGFR) and all-cause death.11 Since impaired left ventricular relaxation and elevated end-diastolic pressure are hallmarks of HFpEF, the upstream left atrium is subjected to increased afterload, which subsequently triggers structural remodelling.12, 13 Accordingly, left atrial enlargement (LAE) determined by left atrium (LA) diameter is also one of the features in patients with HFpEF,14 and is directly associated with the outcomes in HF.15, 16, 17, 18
Given the high prevalence of HFpEF and the prognostic impact of left ventricular diastolic dysfunction in CKD, we hypothesise that left atrial enlargement (LAE) is adversely associated with clinical outcomes – an association that has yet to be established. In this study, we aimed to investigate whether LAE is associated with the outcomes in patients with non-dialysis CKD, such as kidney failure requiring renal replacement therapy (KFRT), cardiovascular events and all-cause death.
Method
Study population
The KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease), a prospective cohort study on the Korean patients with CKD, enrolled the patients at stages ranging from 1 to pre-dialysis 5 from the nine tertiary hospitals in South Korea between 2011 and 2016.19 Among 2,238 participants who voluntarily provided informed written consent for the enrolment, after excluding the participants without the baseline measurement of LA diameter (n = 91) and those missing the date on the follow-up duration (n = 2), a total of 2,145 participants were finally included for the analyses in the current study (Fig. 1). The median follow-up duration was 9.3 years.
Fig. 1.
Flow diagram of the study participants. LA, left atrium.
Data collection from the participants
The baseline data including demographic information, anthropometric measurements, medical histories, and laboratory and echocardiographic measurements were recorded at the time of enrolment in accordance with the study protocol.19 Blood and urine samples were obtained following an overnight fast, and were subsequently transported to the central laboratory (Lab Genomics, Seongnam, Korea) for the analyses. eGFR was determined using the Chronic Kidney Disease Epidemiology Collaboration equation using serum creatinine level.20 Spot urine samples were collected preferably as the second void in the morning. The echocardiographic evaluations were performed by cardiologists at each participating hospital, who were blinded to the clinical data of the participants and carried out the assessments in accordance with the guideline from the American Society of Echocardiography.21 Specifically, left atrial diameter was measured using M-mode echocardiography in parasternal long-axis view at end-systole.21
Exposure and study outcome
The participants were categorised into the three groups by LA diameter: <40 mm, 40–45 mm, and >45 mm (Fig. 1). LA diameter longer than 45 mm was defined as LAE.22 The primary outcome of the current study was KFRT, which was defined as kidney transplantation or the initiation of maintenance dialysis. The secondary outcomes were extended major adverse cardiovascular events (eMACE), which was defined as the composite of nonfatal myocardial infarction, unstable angina, non-fatal stroke, hospitalisation due to heart failure, symptomatic arrhythmia or cardiac death, and all-cause death. The study participants were closely monitored to record the outcome events from each centre throughout the entire observational period. The outcome events were cross-validated by the investigators from the other participating centres to exclude reporting errors.
Statistical analysis
Continuous and categorical variables related to the baseline characteristics were compared by LA diameters using one-way analysis of variance (ANOVA) and χ2 test, respectively. To visualise the correlations of LA diameters with LVEF, E/e′ and left ventricular mass index (LVMI), a scatter plot with Pearson’s correlation coefficient analysis was depicted. The cumulative incidences of the study outcomes were visualised by Kaplan–Meier survival curves, and were subsequently compared by log-rank tests. The last visit date was considered as the censoring date for the participants lost to follow-up. To determine the independent association of LA diameters with the study outcomes, Cox proportional hazard regression models were developed. The models were adjusted as follows: Model 1 reported unadjusted hazard ratios (HRs); Model 2 adjusted for age and gender; Model 3 incorporated adjustments for medical history – specifically, Charlson comorbidity index, primary cause of CKD, smoking status and medications (eg angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (ACEIs/ARBs), diuretics, lipid-lowering agents and antiplatelet/anticoagulant agents) – as well as anthropometric data, such as body mass index (BMI) and systolic blood pressure (SBP). Model 4 further adjusted for the baseline laboratory parameters including haemoglobin, albumin, low-density lipoprotein cholesterol (LDL-C), fasting glucose, 25-hydroxyvitamin D (25(OH)D), high-sensitivity C-reactive protein (hs-CRP), eGFR and spot urine albumin-to-creatinine ratio. The outcomes of the Cox regression analyses were reported as HRs with 95% confidence intervals (CIs). While participants with any missing data for the models were excluded from the initial analysis, missing values were replaced by multiple imputation using random sampling method to impute ten independent copies of the data to repeat Cox regression analyses. The proportion of the missing values in most variables included for the adjustment was far less than 5%. Penalised spline curves were adopted to illustrate the linear relationship between LA diameters and the risk of KFRT, eMACE or all-cause death. Sensitivity analyses included the Cox regression analyses with the adoption of log-transformed LA diameters as a continuous variable, the exclusion of the participants with LVEF <40%, the exclusion of the participants with eGFR ≥90 or <15 mL/min/1.73 m2 and the indexation of LA diameter to the body surface area. The pre-specified subgroup analyses were intended to address whether the association between LA diameter and the study outcomes was modified by certain clinical contexts, including age (<60 vs. ≥60 years), BMI (<23 vs. ≥23 kg/m2), eGFR (<45 vs. ≥45 mL/min/1.73 m2) and spot urine ACR (<300 vs. ≥300 mg/g), as well as sex (male vs. female) as a sex-stratified analyses to evaluate potential differences in the association between LA diameter and outcomes. Two-sided P values <0.05 were considered statistically significant. Statistical analysis was performed using SPSS for Windows version 22.0 (IBM Corp., Armonk, NY) and R (version 4.1.1; R Project for Statistical Computing, Vienna, Austria).
Results
Baseline characteristics
The baseline characteristics of the participants were analysed by LA diameter (Table 1). The increase in LA diameter was significantly related to higher mean age, higher proportion of male participants and more complex comorbid conditions and higher prevalence of diabetes mellitus as the primary cause of CKD and ever-smoking history. The more frequent use of medications such as ACEIs/ARBs, diuretics, statins and antiplatelet/anticoagulant agents was related to the longer LA diameter. Elevations in BMI, systolic blood pressure, triglycerides and hs-CRP were significantly related to the increase in LA diameter, whereas total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and 25(OH)D levels were inversely related to LA diameters. Importantly, longer LA diameters were significantly related to decreased eGFR and increased albuminuria/proteinuria. These collectively suggest that LAE is significantly related to the unfavourable clinical features at the baseline.
Table 1.
Baseline characteristics of the study participants by LA diameters.
| LA diameter |
|||||
|---|---|---|---|---|---|
| All | <40 mm | 40–45 mm | >45 mm | P value | |
| Follow-up duration (year) | 8.415±3.465 | 8.631±3.349 | 8.059±3.639 | 7.949±3.639 | 0.001 |
| Age (year) | 53.642±12.251 | 51.619±12.348 | 56.664±11.296 | 58.672±10.827 | <0.001 |
| Male | 1,312 (61.2) | 762 (55.1) | 361 (70.1) | 189 (76.5) | <0.001 |
| CCI | <0.001 | ||||
| 0–3 | 1,537 (71.7) | 1,081 (78.2) | 311 (60.4) | 145 (57.7) | |
| 4–5 | 572 (26.7) | 288 (20.8) | 193 (37.5) | 91 (36.8) | |
| ≥6 | 36 (1.6) | 14 (1.0) | 11 (2.1) | 11 (4.4) | |
| Primary cause of CKD | <0.001 | ||||
| DM | 536 (25.0) | 260 (18.8) | 180 (35.0) | 96 (38.9) | |
| HTN | 422 (19.7) | 245 (17.7) | 107 (20.8) | 70 (28.3) | |
| GN | 682 (31.8) | 521 (37.7) | 130 (25.2) | 31 (12.6) | |
| PKD | 347 (16.2) | 260 (18.8) | 56 (10.9) | 31 (12.6) | |
| Others | 157 (7.3) | 96 (7.0) | 42 (8.2) | 19 (7.7) | |
| Smoking status | <0.001 | ||||
| Non-smoker | 1,143 (53.3) | 796 (57.6) | 241 (46.9) | 106 (42.9) | |
| Ex-smoker | 341 (15.9) | 218 (15.8) | 87 (16.9) | 36 (14.6) | |
| Current smoker | 659 (30.8) | 368 (26.6) | 186 (36.2) | 105 (42.5) | |
| Medication | |||||
| ACEi/ARBs | 1,835 (85.5) | 1,164 (84.2) | 453 (88.0) | 218 (88.3) | 0.049 |
| Diuretics | 676 (31.5) | 389 (28.1) | 178 (34.6) | 109 (44.1) | <0.001 |
| Lipid-lowering agents | 1,156 (53.9) | 715 (51.7) | 294 (57.1) | 147 (59.5) | 0.019 |
| Antiplatelets/anticoagulants | 658 (30.7) | 342 (24.7) | 205 (39.8) | 111 (44.9) | <0.001 |
| BMI (kg/m2) | 24.570±3.405 | 23.755±3.211 | 25.763±3.084 | 26.657±3.486 | <0.001 |
| SBP (mmHg) | 127.779±16.168 | 125.524±15.388 | 131.658±16.722 | 132.341±16.819 | <0.001 |
| DBP (mmHg) | 76.978±11.088 | 76.701±10.671 | 77.570±11.597 | 77.293±12.235 | 0.3 |
| Laboratory findings | |||||
| Haemoglobin (g/dL) | 12.843±2.017 | 12.917±1.986 | 12.670±2.053 | 12.793±2.094 | 0.06 |
| Albumin (g/dL) | 4.177±0.424 | 4.193±0.411 | 4.158±0.437 | 4.128±0.466 | 0.06 |
| Total cholesterol (mg/dL) | 173.875±39.049 | 176.296±39.382 | 170.439±38.774 | 167.619±36.611 | <0.001 |
| LDL-C (mg/dL) | 96.647±31.740 | 98.620±32.409 | 94.042±30.521 | 91.195±29.511 | <0.001 |
| HDL-C (mg/dL) | 49.255±15.427 | 50.725±15.721 | 46.916±14.761 | 46.036±14.052 | <0.001 |
| TG (mg/dL) | 157.506±98.927 | 150.945±91.946 | 170.422±113.412 | 166.527±100.445 | 0.001 |
| Fasting glucose (mg/dL) | 110.739±39.442 | 108.369±37.963 | 116.341±43.472 | 112.237±37.533 | 0.001 |
| 25(OH)D (ng/mL) | 17.788±7.855 | 18.262±8.333 | 17.167±6.981 | 16.412±6.463 | <0.001 |
| hs-CRP (mg/dL) | 0.060 [0.020, 0.160] | 0.048 [0.002, 6.800] | 0.080 [0.005, 5.270] | 0.090 [0.010, 6.700] | <0.001 |
| Spot urine ACR (mg/g) | 352.586 [77.893, 1,078.891] | 0.416 [0.005, 19.489] | 0.663 [0.014, 14.964] | 0.605 [0.016, 20.585] | <0.001 |
| Spot urine PCR (g/g) | 0.489 [0.142, 1.498] | 298.554 [0.698, 11,669.720] | 493.987 [1.432, 10,099.950] | 422.926 [1.291, 12,586.840] | <0.001 |
| Creatinine (mg/dL) | 1.809±1.144 | 1.709±1.067 | 1.954±1.271 | 2.062±1.213 | <0.001 |
| eGFR (mL/min./1.73 m2) | 50.603±30.176 | 53.300±31.295 | 46.607±27.800 | 43.833±26.437 | <0.001 |
| CKD stages | <0.001 | ||||
| Stage 1 | 349 (16.3) | 266 (19.2) | 60 (11.7) | 23 (9.3) | |
| Stage 2 | 408 (19.0) | 279 (20.2) | 90 (17.5) | 39 (15.8) | |
| Stage 3a | 350 (16.3) | 228 (16.5) | 82 (15.9) | 40 (16.2) | |
| Stage 3b | 455 (21.2) | 281 (20.3) | 118 (22.9) | 56 (22.7) | |
| Stage 4 | 454 (21.2) | 256 (18.5) | 129 (25.0) | 69 (27.9) | |
| Stage 5 | 129 (6.0) | 73 (5.3) | 36 (7.0) | 20 (8.1) | |
Values for categorical variables given as number (percentage); values for continuous variables given as mean ± standard deviation or median [range]. Abbreviations: 25(OH)D, 25-hydroxyvitamin D; ACEi/ARBs, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers; ACR, albumin-to-creatinine ratio; BMI, body mass index; CKD, chronic kidney disease; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GN, glomerulonephritis; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; HTN, hypertension; LDL-C, low-density lipoprotein cholesterol; PCR, protein-to-creatinine ratio; PKD, polycystic kidney disease; SBP, systolic blood pressure; TG, triglycerides.
The echocardiographic measurement (Table S1) demonstrated that increased LA diameter is significantly correlated with the structural remodelling associated with LVDD, such as E/e′, left ventricular chamber size, wall thickness, and LVMI. LA diameter was not significantly correlated with LVEF, a surrogate of left ventricular systolic function. Accordingly, scatter plot analyses (Fig. 2) visualised a moderate positive correlations of LA diameters with E/e′ (R = 0.360, P < 0.001) and LVMI (R = 0.400, P < 0.001), but barely with LVEF (R = −0.051, P = 0.019).
Fig. 2.
Scatter plot of LA diameters with LVEF, E/e′ and LVMI. Note: The correlations of LA diameters with LVEF (A), E/e′ (B), and LVMI (C) were assessed by the Pearson correlation coefficient (R). Abbreviations: E/e′, the ratio of the early transmitral blood flow velocity to early diastolic velocity of the mitral annulus; LA, left atrium; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index.
Association of LA diameter with outcomes in CKD
The event rates of the study outcomes throughout the entire follow-up duration differed significantly by LA diameters (Table 2). More specifically, 14 cases (0.7%) of hospitalisation for HF and 17 cases (0.8%) of sudden cardiac death occurred during the follow-up. All of KFRT, eMACE and all-cause death were most frequently occurred in the participants with LAE. Accordingly, Kaplan–Meier survival curves demonstrated that the cumulative incidences of KFRT (Fig. 3), eMACE (Fig. 4) and all-cause death (Fig. S1) were also significantly differed by LA diameters (All P < 0.001, by log-rank tests). Cox regression analyses revealed that LAE is significantly associated with the risks of KFRT (adjusted HR 1.598, 95% CI 1.225–2.084, Table 3) and eMACE (adjusted HR 1.800, 95% CI 1.096–2.958, Table 4), but not with that of all-cause death. Cox regression analyses repeated after multiple imputations showed the similar results (Table 3, Table 4). Penalised spline curve analyses illustrated a significant, linear and positive correlation between LA diameter and the risks of KFRT and eMACE (Fig. 5).
Table 2.
Event rates for the primary and secondary outcomes by LA diameters.
| Outcome | LA diameter | Events, n (%) | P value |
|---|---|---|---|
| KFRT | <40 mm | 448 (32.4) | <0.001 |
| 40–45 mm | 202 (39.2) | ||
| >45 mm | 107 (43.3) | ||
| eMACE | <40 mm | 84 (6.1) | <0.001 |
| 40–45 mm | 53 (10.3) | ||
| >45 mm | 33 (13.4) | ||
| All-cause death | <40 mm | 123 (8.9) | <0.001 |
| 40–45 mm | 73 (14.2) | ||
| >45 mm | 48 (19.4) |
Abbreviations: CI, confidence interval; eMACE, expanded major adverse cardiovascular events; HR, hazard ratio; KFRT, kidney failure requiring replacement therapy; LA, left atrium.
Fig. 3.
Kaplan–Meier survival curve for the cumulative incidence of KFRT by LA diameters. LA, left atrium; KFRT, kidney failure requiring replacement therapy.
Fig. 4.
Kaplan-Meier survival curve for the cumulative incidence of eMACE by LA diameters. eMACE, expanded major adverse cardiovascular events LA, Left atrium.
Table 3.
HRs for the primary outcome by LA diameters.
| Outcome | Processing of missing data | LA diameter | Model 1 |
Model 2 |
Model 3 |
Model 4 |
||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR (95%CIs) |
P value | HR (95%CIs) |
P value | HR (95%CIs) |
P value | HR (95%CIs) |
P value | |||
| KFRT | Before multiple imputation |
<40 mm | Reference | Reference | Reference | Reference | ||||
| 40–45 mm | 1.459 (1.210, 1.760) |
<0.001 | 1.326 (1.118, 1.573) |
0.001 | 1.183 (0.985, 1.420) |
0.072 | 0.986 (0.800, 1.217) |
0.899 | ||
| >45 mm | 1.750 (1.380, 2.220) |
<0.001 | 1.561 (1.255, 1.941) |
<0.001 | 1.534 (1.217, 1.933) |
<0.001 | 1.598 (1.225, 2.084) |
<0.001 | ||
| After multiple imputation |
<40 mm | Reference | Reference | Reference | Reference | |||||
| 40–45 mm | 1.400 (1.186, 1.654) |
<0.001 | 1.326 (1.118, 1.573) |
0.001 | 1.202 (1.003, 1.441) |
0.046 | 1.080 (0.898, 1.299) |
0.414 | ||
| >45 mm | 1.673 (1.354, 2.066) |
<0.001 | 1.561 (1.255, 1.941) |
<0.001 | 1.543 (1.224, 1.944) |
<0.001 | 1.497 (1.177, 1.904) |
0.001 | ||
Note: Model 1, unadjusted model. Model 2, model 1 + adjusted for age, and sex. Model 3, model 2 + adjusted for Charlson comorbidity index, primary cause of CKD, smoking history, medications (antithrombotic agents, ACEi/ARBs, diuretics, lipid-lowering agents), BMI, and SBP. Model 4, model 3 + adjusted for haemoglobin, albumin, fasting glucose, LDL-C, hs-CRP, eGFR and spot urine ACR. Abbreviations: CI, confidence interval; HR, hazard ratio; KFRT, kidney failure requiring replacement therapy; LA, left atrium.
Table 4.
HRs for the secondary outcomes by LA diameters.
| Outcome | Processing of missing data | LA diameter | Model 1 |
Model 2 |
Model 3 |
Model 4 |
||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR (95%CIs) |
P value | HR (95%CIs) |
P value | HR (95%CIs) |
P value | HR (95%CIs) |
P value | |||
| eMACE | Before multiple imputation |
<40 mm | Reference | Reference | Reference | Reference | ||||
| 40–45 mm | 1.895 (1.296, 2.772) |
<0.001 | 1.330 (0.938, 1.885) |
0.109 | 1.280 (0.889, 1.841) |
0.184 | 1.355 (0.904, 2.030) |
0.141 | ||
| >45 mm | 2.468 (1.575, 3.867) |
<0.001 | 1.579 (1.047, 2.383) |
0.030 | 1.745 (1.125, 2.707) |
0.012 | 1.800 (1.096, 2.958) |
0.020 | ||
| After multiple imputation |
<40 mm | Reference | Reference | Reference | Reference | |||||
| 40–45 mm | 1.839 (1.304, 2.593) |
<0.001 | 1.330 (0.938, 1.885) |
0.111 | 1.838 (0.888, 1.838) |
0.189 | 1.286 (0.892, 1.853) |
0.179 | ||
| >45 mm | 2.445 (1.635, 3.658) |
<0.001 | 1.579 (1.047, 2.383) |
0.031 | 1.739 (1.121, 2.700) |
0.015 | 1.788 (1.146, 2.788) |
0.011 | ||
| All-cause death | Before multiple imputation |
<40 mm | Reference | Reference | Reference | Reference | ||||
| 40–45 mm | 1.843 (1.324, 2.566) |
<0.001 | 1.157 (0.863, 1.550) |
0.330 | 1.043 (0.766, 1.421) |
0.790 | 1.062 (0.748, 1.506) |
0.737 | ||
| >45 mm | 2.561 (1.748, 3.750) |
<0.001 | 1.328 (0.944, 1.870) |
0.139 | 1.369 (0.950, 1.970) |
0.091 | 1.247 (0.816, 1.906) |
0.309 | ||
| After multiple imputation |
<40 mm | Reference | Reference | Reference | Reference | |||||
| 40–45 mm | 1.723 (1.290, 2.303) |
<0.001 | 1.157 (0.863, 1.550) |
0.331 | 1.052 (0.774, 1.430) |
0.747 | 0.996 (0.734, 1.351) |
0.978 | ||
| >45 mm | 2.392 (1.713, 3.340) |
<0.001 | 1.328 (0.944, 1.870) |
0.105 | 1.363 (0.947, 1.963) |
0.097 | 1.195 (0.827, 1.727) |
0.344 | ||
Note: Model 1, unadjusted model. Model 2, model 1 + adjusted for age, and sex. Model 3, model 2 + adjusted for Charlson comorbidity index, primary cause of CKD, smoking history, medications (antithrombotic agents, ACEi/ARBs, diuretics, lipid-lowering agents), BMI and SBP. Model 4, model 3 + adjusted for haemoglobin, albumin, fasting glucose, LDL-C, hs-CRP, eGFR, and spot urine ACR. Abbreviations: CI, confidence interval; eMACE, expanded major adverse cardiovascular events; HR, hazard ratio; LA, left atrium.
Fig. 5.
Penalised spline curve of LA diameter on the study outcomes. Note: Adjusted for age, sex, Charlson comorbidity index, primary cause of CKD, smoking history, medications (antithrombotic agents, ACEi/ARBs, diuretics, lipid-lowering agents), BMI, SBP, haemoglobin, albumin, fasting glucose, LDL-C, hs-CRP, eGFR and spot urine ACR. All HRs were log-transformed. Abbreviations: CI, confidence interval; eMACE, expanded major adverse cardiovascular events; HR, hazard ratio; KFRT, kidney failure requiring replacement therapy; LA, left atrium.
Sensitivity and subgroup analyses
The Cox regression analysis adopting log-transformed LA diameter as a continuous variable demonstrated that the risks of KFRT and eMACE are still significantly associated with the increase of LA diameter (Table S2). The exclusion of the participants with LVEF <40% demonstrated that the association of LAE and the risks of KFRT and eMACE is still robust (Table 5). The exclusion of the participants with eGFR ≥90 or <15 mL/min/1.73 m2 show the similar result to the primary analyses (Table S3). The association of LAE with the risks of KFRT and eMACE, but not with the risk of all-cause mortality, remained robust after the indexation of LA diameter to body surface (Table S4). Subgroup analyses revealed that the association between LA diameter and the risks of KFRT (P for interaction = 0.046) and eMACE (P for interaction = 0.024) is significantly modified by albuminuria (Table 6), with the more prominent impact of LAE among the participants with spot urine ACR ≥300 mg/g. Sex-stratified analysis showed that the association between LAE and outcomes was consistent in both male and female participants, suggesting that LA diameter is a reliable prognostic marker regardless of sex.
Table 5.
HRs for the primary and secondary outcomes by LA diameters after excluding the participants with LVEF <40%.
| Outcome | LA diameter | Events, n (%) | Model 1 |
Model 2 |
Model 3 |
Model 4 |
||||
|---|---|---|---|---|---|---|---|---|---|---|
| HR (95%CIs) |
P value | HR (95%CIs) |
P value | HR (95%CIs) |
P value | HR (95%CIs) |
P value | |||
| KFRT | <40 mm | 448 (32.4) | Reference | Reference | Reference | Reference | ||||
| 40–45 mm | 200 (39.2) | 1.454 (1.205, 1.755) |
<0.001 | 1.320 (1.112, 1.567) |
0.002 | 0.958 (0.799, 1.150) |
0.645 | 0.975 (0.790, 1.204) |
0.815 | |
| >45 mm | 106 (43.6) | 1.752 (1.380, 2.224) |
<0.001 | 1.561 (1.254, 1.943) |
<0.001 | 1.483 (1.173, 1.876) |
<0.001 | 1.596 (1.218, 2.092) |
<0.001 | |
| eMACE | <40 mm | 84 (6.1) | Reference | Reference | Reference | Reference | ||||
| 40–45 mm | 52 (10.2) | 1.902 (1.301, 2.782) |
<0.001 | 1.313 (0.924, 1.864) |
0.128 | 1.251 (0.866, 1.806) |
0.232 | 1.351 (0.902, 2.205) |
0.144 | |
| >45 mm | 31 (12.8) | 2.306 (1.454, 3.658) |
<0.001 | 1.489 (0.978, 2.268) |
0.064 | 1.647 (1.053, 2.576) |
0.029 | 1.676 (1.011, 2.780) |
0.045 | |
| All-cause death | <40 mm | 123 (8.9) | Reference | Reference | Reference | Reference | ||||
| 40–45 mm | 72 (14.1) | 1.817 (1.303, 2.533) |
<0.001 | 1.147 (0.855, 1.538) |
0.362 | 0.986 (0.724, 1.343) |
0.929 | 1.077 (0.757, 1.532) |
0.680 | |
| >45 mm | 46 (18.9) | 2.448 (1.659, 3.611) |
<0.001 | 1.275 (0.901, 1.805) |
0.170 | 1.231 (0.825, 1.778) |
0.269 | 1.205 (0.784, 1.852) |
0.395 | |
Note: Model 1, unadjusted model. Model 2, model 1 + adjusted for age, and sex. Model 3, model 2 + adjusted for Charlson comorbidity index, primary cause of CKD, smoking history, medications (antithrombotic agents, ACEi/ARBs, diuretics, lipid-lowering agents), BMI, and SBP. Model 4, model 3 + adjusted for haemoglobin, albumin, fasting glucose, LDL-C, hs-CRP, eGFR, and spot urine ACR. Abbreviations: CI, confidence interval; eMACE, expanded major adverse cardiovascular events; HR, hazard ratio; KFRT, kidney failure requiring replacement therapy; LA, left atrium.
Table 6.
HRs for the primary and secondary outcomes by LA diameters in various subgroups.
| KFRT |
eMACE |
All-cause death |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Events, n (%) | Adjusted HR (95%CIs) |
P for interaction |
Events, n (%) | Adjusted HR (95%CIs) |
P for interaction |
Events, n (%) | Adjusted HR (95%CIs) |
P for interaction |
||
| Age <60 years | <40 mm | 309 (31.1) | Reference | 0.172 | 40 (4.0) | Reference | 0.694 | 41 (4.1) | Reference | 0.040 |
| 40–45 mm | 113 (40.1) | 0.921 (0.684, 1.239) | 16 (5.7) | 1.332 (0.651, 2.726) | 23 (8.2) | 1.999 (1.004, 3.980) | ||||
| >45 mm | 48 (42.1) | 1.630 (1.102, 2.410) | 10 (8.8) | 2.289 (0.938, 5.583) | 12 (10.5) | 2.232 (0.877, 5.677) | ||||
| Age ≥60 years | <40 mm | 139 (35.7) | Reference | 44 (11.3) | Reference | 82 (21.1) | Reference | |||
| 40–45 mm | 89 (38.2) | 1.217 (0.876, 1.691) | 37 (15.9) | 1.427 (0.851, 2.393) | 50 (21.5) | 0.826 (0.543, 1.257) | ||||
| >45 mm | 59 (44.4) | 1.717 (1.166, 2.530) | 23 (17.3) | 1.784 (0.963, 3.304) | 36 (27.1) | 1.057 (0.651, 1.715) | ||||
| Male | <40 mm | 241 (31.6) | Reference | 0.393 | 53 (7.0) | Reference | 0.800 | 84 (11.0) | Reference | 0.725 |
| 40–45 mm | 132 (36.6) | 0.859 (0.655, 1.128) | 42 (11.6) | 1.377 (0.853, 2.225) | 58 (16.1) | 1.140 (0.746, 1.742) | ||||
| >45 mm | 79 (41.8) | 1.487 (1.071, 2.064) | 30 (15.9) | 1.887 (1.072, 3.321) | 40 (21.2) | 1.313 (0.790, 2.183) | ||||
| Female | <40 mm | 207 (33.3) | Reference | 31 (5.0) | Reference | 39 (6.3) | Reference | |||
| 40–45 mm | 70 (45.5) | 1.282 (0.913, 1.800) | 11 (7.1) | 1.367 (0.624, 2.999) | 15 (9.7) | 0.873 (0.446, 1.707) | ||||
| >45 mm | 28 (48.3) | 1.722 (1.054, 2.814) | 3 (5.2) | 1.663 (0.460, 6.006) | 8 (13.8) | 1.264 (0.532, 3.007) | ||||
| BMI ≤25 kg/m2 | <40 mm | 307 (32.8) | Reference | 0.324 | 63 (6.7) | Reference | 0.155 | 83 (8.9) | Reference | 0.430 |
| 40–45 mm | 93 (42.1) | 1.078 (0.801, 1.451) | 27 (12.2) | 1.007 (0.582, 1.741) | 41 (18.6) | 1.070 (0.660, 1.735) | ||||
| >45 mm | 36 (44.4) | 1.644 (1.073, 2.519) | 17 (21.0) | 2.397 (1.229, 4.673) | 21 (25.9) | 1.873 (0.481, 1.618) | ||||
| BMI >25 kg/m2 | <40 mm | 21 (4.7) | Reference | 21 (4.7) | Reference | 40 (8.9) | Reference | |||
| 40–45 mm | 26 (8.8) | 0.937 (0.678, 1.294) | 26 (8.8) | 1.821 (0.948, 3.498) | 32 (10.9) | 0.889 (0.506, 1.561) | ||||
| >45 mm | 16 (9.6) | 1.553 (1.078, 2.237) | 16 (9.6) | 1.554 (0.719, 3.358) | 27 (16.3) | 0.882 (0.481, 1.618) | ||||
| eGFR ≥45 mL/min/1.73 m2 | <40 mm | 65 (9.0) | Reference | 0.503 | 36 (5.0) | Reference | 0.435 | 25 (3.4) | Reference | 0.123 |
| 40–45 mm | 26 (11.9) | 1.290 (0.736, 2.260) | 22 (10.1) | 1.532 (0.808, 2.903) | 20 (9.2) | 1.744 (0.807, 3.771) | ||||
| >45 mm | 11 (11.3) | 2.059 (0.963, 4.403) | 16 (16.5) | 2.392 (1.158, 4.941) | 12 (12.4) | 3.251 (1.377, 7.674) | ||||
| eGFR <45 mL/min/1.73 m2 | <40 mm | 383 (58.2) | Reference | 48 (7.3) | Reference | 98 (14.9) | Reference | |||
| 40–45 mm | 176 (59.3) | 0.959 (0.763, 1.206) | 31 (10.4) | 1.062 (0.609, 1.850) | 53 (17.8) | 0.952 (0.637, 1.424) | ||||
| >45 mm | 96 (64.0) | 1.575 (1.184, 2.096) | 17 (11.3) | 1.406 (0.690, 2.865) | 36 (24.0) | 1.011 (0.615, 1.661) | ||||
| Spot urine ACR <300 mg/g | <40 mm | 248 (24.1) | Reference | 0.046 | 65 (6.3) | Reference | 0.024 | 75 (7.3) | Reference | 0.061 |
| 40–45 mm | 104 (30.9) | 0.996 (0.733, 1.352) | 36 (10.7) | 1.142 (0.709, 1.839) | 45 (13.4) | 1.053 (0.665, 1.668) | ||||
| >45 mm | 51 (33.3) | 1.659 (1.144, 2.404) | 19 (12.4) | 1.205 (0.647, 2.246) | 23 (15.0) | 0.953 (0.541, 1.677) | ||||
| Spot urine ACR ≥300 mg/g | <40 mm | 200 (56.5) | Reference | 19 (5.4) | Reference | 48 (13.6) | Reference | |||
| 40–45 mm | 98 (55.1) | 0.822 (0.600, 1.126) | 17 (9.6) | 2.113 (0.811, 5.503) | 28 (15.7) | 0.865 (0.470, 1.591) | ||||
| >45 mm | 56 (59.6) | 1.731 (1.159, 2.584) | 14 (14.9) | 4.861 (1.632, 14.479) | 25 (26.6) | 2.130 (1.041, 4.357) | ||||
Note: Model 1, unadjusted model. Model 2, model 1 + adjusted for age, and sex. Model 3, model 2 + adjusted for Charlson comorbidity index, primary cause of CKD, smoking history, medications (antithrombotic agents, ACEi/ARBs, diuretics, lipid-lowering agents), BMI and SBP. Model 4, model 3 + adjusted for haemoglobin, albumin, fasting glucose, LDL-C, hs-CRP, eGFR and spot urine ACR. Abbreviations: ACR, albumin-to-creatinine ratio; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; eMACE, expanded major adverse cardiovascular events; HR, hazard ratio; KFRT, kidney failure requiring replacement therapy; LA, left atrium.
Discussion
We found that, in the present study of the patients with non-dialysis CKD, LA diameter significantly correlates with the echocardiographic indices related LVDD, such as E/e′ and LVMI, but not with LVEF, which is a surrogate of left ventricular systolic function. The event rates and cumulative incidences of the study outcomes, including KFRT, eMACE and all-cause death, were significantly differed by LA diameters, and were highest among the participants with LAE. LAE was, even after the adjustment with potential compounding factors, significantly associated with the risks of KFRT and eMACE, but not with that of all-cause death, in patients with CKD.
Previous studies reported the association of LA diameters not only with HFpEF, but also with HFrEF.23, 24 A previous study on the patients with HF reported that LA diameter was negatively correlated with LVEF across the entire range of LVEF,23 indicating that severe HFrEF may present with LAE. It seems acceptable that LAE could be a predictive index of the outcomes in both HFpEF and HFrEF, because left ventricular end-diastolic pressure may also be increased in patients with HFrEF.24 The impact of LAE on the outcomes in CKD shown in the current study, however, is most likely to rely on the context of HFpEF. The effect imposed by HFrEF was difficult to determine from the dataset exclusive of the patients with end-stage kidney disease in the present study, as the mean value of LVEF of the participants was over 60%. Moreover, a sensitive analysis confirmed that the exclusion of the participants with LVEF <40% barely affects the overall trend in the association between LAE and CKD outcomes.
The association between LAE and adverse outcomes in CKD reflects the complex interplay within the cardiovascular-kidney-metabolic (CKM) syndrome, as recently defined by the American Heart Association. LAE represents a structural manifestation of this systemic syndrome, where cardiovascular remodelling and kidney dysfunction reinforce each other through shared pathophysiological mechanisms.25 Albeit the precise mechanism remains to be further addressed, the possible explanation for the association of LAE with the cardio-renal outcomes in patients with non-dialysis CKD could be in part attributed to ‘shared pathophysiology’ between CKD and HFpEF.4, 26 The pathophysiological hallmark of HFpEF is LVDD, which is an abnormal relaxation of the left ventricle.27 This essentially leads to the elevation of left ventricular end-diastolic pressure that is conducted to the anatomical upstream, LA.13 The structural remodelling is subsequently triggered, where a shape change initially begins in the LA roof region and a global dilation of LA chamber follows later.14 In terms of a mechanistic insight, LVDD results from relaxation due to fibrosis and negative cardiovascular remodelling of the left ventricle, which process is contributed by systemic inflammation, elevated neurohormones (eg enhanced renin-angiotensin-aldosterone system), and venous congestion.28, 29, 30 Of particular interest, all of these pathophysiological alterations have been also well-characterised in the course of CKD progression.2 In this context, it seems reasonable that increased LA diameters, which is a relatively later structural finding, is significantly associated with the important clinical outcomes in CKD.
It is possible that the severity of HFpEF could be underestimated only if LA diameter is solely evaluated, because a global dilation of LA chamber is one of the late-stage consequences of the elevated left ventricular end-diastolic pressure.13, 14, 31 Due to the anatomical asymmetry, the conduction and distribution of left ventricular end-diastolic pressure inside LA should be uneven.32 The structural remodelling triggered in HFpEF, therefore, usually begins in n the LA roof region, at which stage the elongation of LA diameter may not be distinct.32 It does not necessarily mean that, however, LAE is a less sensitive predictor for the adverse events in patients with CKD. We rather assume that the presence of LAE is a sign of suboptimal medical intervention for heart–kidney interaction in CKD, and should present compelling evidence to more intensify the treatment regimen. Moreover, LA diameter measurement is readily available in routine echocardiographic assessment and does not require advanced imaging techniques or specialised training,33 making it a practical screening tool for risk stratification in CKD patients. We believe that general internists can use LA diameter as a simple risk stratification tool when reviewing echocardiography reports for CKD patients.
Our findings align with the KDIGO 2024 guideline’s emphasis on comprehensive cardiovascular risk assessment in CKD patients.7 The identification of LAE as an independent predictor of adverse outcomes suggests that echocardiographic assessment of LA diameter should be considered as part of routine cardiovascular evaluation in this population. This approach may facilitate early identification of high-risk patients who may benefit from intensified guideline-directed medical therapy and closer monitoring.
The clinical implication of HFpEF as a comorbid condition has been more and more emphasised in patients with CKD, because, while the treatment outcome of HFrEF has been recently improved with newer therapeutic agents, the prognosis of the patients with HFpEF has long been relatively stagnant until the introduction of type 2 sodium-glucose co-transporter inhibitors (SGLT2i).34, 35, 36 SGLT2i are the only class of agents that is proven to be effective in patients with HFpEF via randomised controlled trials.35, 36 Interestingly, the use of SGLT2i has revolutionised both the kidney and cardiovascular outcomes in patients with CKD.37 Although the use of SGLT2i in non-albuminuric CKD patients is so far less strongly supported by clear evidence,38 the findings of the present study suggest that a pharmaceutical intervention with SGLT2i may also improve the outcomes in CKD by interrupting a vicious cycle of heart–kidney interaction. In other word, our findings suggest that patients with CKD and LAE may benefit from more aggressive cardiovascular risk modification strategies, including optimised use of SGLT2i, which have demonstrated benefits in both HFpEF and CKD progression.
Some limitations are to be noted in the present study. First, the causal relation between LAE and the outcomes in the present study cannot be confirmed due to the limitation of the observational study design. Second, LA diameter is one of various indices to define LAE, and may underestimate the severity of LAE resulting from HFpEF, due to the asymmetric three-dimensional structure of LA. This might be more obviously problematic in the use of echocardiography rather than more objective measurements, such as cardiac magnetic resonance imaging. Nevertheless, while LA volume may provide more comprehensive geometric assessment, LA diameter remains the most widely employed measure in routine clinical practice and has been extensively validated as a prognostic marker in large cohorts.33, 39, 40 Moreover, LAD is more readily available and more widely employed in clinical practice despite volume being more reliable.33 Third, more severe phenotypes of HF usually observed among dialysis-dependent patients could not be analysed, because the findings in the present study have been derived from the patients with non-dialysis CKD. Fourth, the extrapolation of the results from the current study requires a caution, because the KNOW-CKD enrolled only ethnically Korean patients resident in South Korea. For example, the incidence of cardiovascular events in the KNOW-CKD is relatively low in comparison to that of the CRIC, reflecting a potential ethnic predisposition to cardiovascular events among the Western populations.41
In conclusion, we report that LAE is significantly associated with the risks of KFRT and eMACE in patients with CKD. LA diameter is a reliable echocardiographic index that predicts the cardio-renal outcomes in patients with non-dialysis CKD. Prospective studies are needed to determine whether LA diameter-guided therapeutic interventions can improve outcomes in CKD patients, particularly regarding the optimal timing of SGLT2i initiation in patients with LAE.
CRediT authorship contribution statement
Soo Wan Kim: Writing – review & editing, Supervision, Funding acquisition, Data curation. Kook-Hwan Oh: Writing – review & editing, Supervision, Funding acquisition, Data curation. Sang Heon Suh: Writing – review & editing, Writing – original draft, Funding acquisition, Formal analysis, Data curation, Conceptualization. Seong Kwon Ma: Writing – review & editing, Supervision. Eun Hui Bae: Writing – review & editing, Data curation. Chang Seong Kim: Writing – review & editing, Data curation. Hong Sang Choi: Writing – review & editing, Data curation.
Ethics approval and consent to participate
The KNOW-CKD was conducted in adherence to the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of each participating centre: Seoul National University Hospital (1104-089-359, 25 May 2011), Seoul National University Bundang Hospital (B-1106/129-008, 24 August 2011), Yonsei University Severance Hospital (4-2011-0163, 2 June 2011), Kangbuk Samsung Medical Center (2011-01-076, 16 June 2012), Seoul St. Mary’s Hospital (KC11OIMI0441, 30 June 2011), Gil Hospital (GIRBA2553, 8 August 2011), Eulji General Hospital (201105-01, 10 June 2011), Chonnam National University Hospital (CNUH-2011-092, 5 July 2011), and Busan Paik Hospital (11-091, 26 July 2011). All participants provided written informed consent.
Clinical trial number
The KNOW-CKD is registered at http://www.clinicaltrials.gov (NCT01630486, June 28, 2012).
Funding
This research was supported by the National Institutes of Health (NIH) research project (2025E110100) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00217317 and RS-2023-00278258).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.clinme.2026.100603.
Appendix A. Supplementary material
Supplementary material
.
Data availability
The data that support the findings of this study are available from the KNOW-CKD investigators on reasonable request. The request should be initially sent to the corresponding author, and will be subsequently distributed to the KNOW-CKD investigators. The relevant data, analytical methods and study materials will be open to researchers after a comprehensive discussion between the KNOW-CKD investigators.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material
Data Availability Statement
The data that support the findings of this study are available from the KNOW-CKD investigators on reasonable request. The request should be initially sent to the corresponding author, and will be subsequently distributed to the KNOW-CKD investigators. The relevant data, analytical methods and study materials will be open to researchers after a comprehensive discussion between the KNOW-CKD investigators.