
==== Front
Ren Fail
Ren Fail
Renal Failure
0886-022X
1525-6049
Taylor & Francis

39313766
10.1080/0886022X.2024.2401623
2401623
Version of Record
Research Article
Cardio-renal Physiology and Disease Processes
Clinical impact of diastolic dysfunction and atrial fibrillation before and after initiating hemodialysis in patients with end-stage kidney disease
H. Jeon et al.
Jeon Hojin a
Jeon Junseok a*
Lee Kyungho a
Kim Jihoon b
Kim Darae b
Lee Jung Eun a
Huh Wooseong a
Jang Hye Ryoun a*
a Department of Medicine, Division of Nephrology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
b Department of Medicine, Division of Cardiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
* These authors have contributed equally to this study and share correspondence authorship.

CONTACT Hye Ryoun Jang shinehr@skku.edu;
Junseok Jeon junseok.jeon@samsung.com Division of Nephrology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06531, Republic of Korea
23 9 2024
2024
23 9 2024
46 2 240162329 4 2024
11 8 2024
2 9 2024
KnowledgeWorks Global Ltd.23 9 2024
published online in a building issue23 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Background

Diastolic dysfunction with left ventricular hypertrophy and myocardial fibrosis is an important characteristic of uremic cardiomyopathy in end-stage kidney disease (ESKD). Few studies explored the relationship between changes in diastolic dysfunction and the risk of mortality or cardiovascular outcome in patients with ESKD. We investigated the clinical impact of diastolic dysfunction and atrial fibrillation (AF) on patients starting hemodialysis (HD).

Methods

A total of 718 patients who started HD between 2010 and 2020 were included. We classified patients according to the pre- and post-HD diastolic dysfunction grades (DDG) evaluated by echocardiography. Patients with AF were classified separately. The primary outcome was a composite outcome of all-cause mortality and cardiac complication.

Results

The median age was 63 years, and 61.4% were male. Patients were divided into four groups based on pre-HD echocardiography findings. After initiating HD, the patients were classified according to changes in DDG and AF. Composite outcomes were significantly higher in the pre-HD AF groups. However, after adjusting for age and history of ischemic heart disease, pre-HD AF did not affect the composite outcomes. Patients with normal post-HD diastolic function had better outcomes than those with diastolic dysfunction or AF. Furthermore, the deterioration of diastolic dysfunction after HD was associated with an increased risk of composite outcomes.

Conclusions

The deterioration of diastolic dysfunction and newly development of AF after initiating HD were identified as risk factors for mortality and cardiac complications, supporting the clinical importance of the appropriate management of diastolic dysfunction and AF in patients with ESKD.

Keywords

Atrial fibrillation
diastolic dysfunction
echocardiography
end-stage kidney disease
hemodialysis
Korean Fund for Regenerative Medicine (KFRM) 22A0302L1-01 National Research Foundation 10.13039/501100001321 NRF-2019R1A5A2027340 National Research Foundation of Korea 10.13039/501100003725 NRF-2022R1F1A1068198 Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) RS-2023-00222838 HI19C1337 National Research Foundation 10.13039/501100001321 NRF-2022R1A2B5B01001298 NRF-2019R1A5A2027340 HR22C1363 Korean Fund for Regenerative Medicine (KFRM) Ministry of Science and ICT, Ministry of Health & Welfare 22A0302L1-01 Korean government This study was supported by a Korean Fund for Regenerative Medicine (KFRM) grant [Ministry of Science and ICT, Ministry of Health and Welfare, grant number 22A0302L1-01] and National Research Foundation grants [NRF-2019R1A5A2027340] funded by the Korean government. JJ was supported by a National Research Foundation of Korea grant that was funded by the Korean government [NRF-2022R1F1A1068198] and the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) [RS-2023-00222838]. KL was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea [HI19C1337]. HRJ was supported by grants from the National Research Foundation [NRF-2022R1A2B5B01001298, NRF-2019R1A5A2027340, and HR22C1363] and the Korean Fund for Regenerative Medicine (KFRM) grant [Ministry of Science and ICT, Ministry of Health & Welfare, grant number: 22A0302L1-01], funded by the Korean government.
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pmcIntroduction

The increasing prevalence of chronic kidney disease (CKD) is a major public health burden [1,2]. Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in CKD [3]. The high prevalence of CVD in patients with CKD is partly attributed to the presence of several common risk factors such as diabetes mellitus (DM) and hypertension (HTN) [4]. On the other hand, CKD progression and the accompanying pathophysiologic changes substantially contribute to the development of structural cardiac abnormalities, commonly referred to as uremic cardiomyopathy (UCM).

UCM is primarily characterized by diastolic dysfunction, left ventricle hypertrophy (LVH), and myocardial fibrosis in patients with CKD [5]. Initially, LVH was an adaptive response to LV overload. However, continued overload can lead to the loss of cardiomyocytes, which can be exacerbated by decreased perfusion, malnutrition, and uremia [6]. Progressive myocardial fibrosis reduces cardiac compliance and leads to diastolic dysfunction [6,7]. Previous studies examined uremic factors contributing to LVH in CKD, such as uremic toxins, endothelial dysfunction, parathyroid hormone (PTH), fibroblast growth factors 23, and αKlotho [8,9].

Traditionally, cardiac function has been evaluated by systolic function expressed as the LV ejection fraction (LVEF), and a decline in systolic function is associated with increased risk of mortality in patients with CKD [10–12]. Regardless of systolic function, diastolic dysfunction has also been reported to be a strong predictor of mortality in patients with CKD [13–15], and it becomes more prevalent as CKD progresses [16]. However, the clinical importance of diastolic function has often been overlooked compared with that of systolic function. The changes in and prognostic impact of diastolic dysfunction before and after initiating hemodialysis (HD) in patients with end-stage kidney disease (ESKD) are yet to be elucidated. Although atrial fibrillation (AF) significantly increases the risk of death in patients with ESKD [17,18], the prognostic importance of AF compared to that of diastolic dysfunction is not well known. In this study, we investigated the clinical impact of pre- and post-HD diastolic dysfunction and AF on all-cause mortality and cardiac complications in patients with ESKD.

Methods

Study population

This retrospective cohort study included 718 patients who initiated hemodialysis. We initially identified 1,064 patients whose pre- and post-HD echocardiography data were available and who underwent surgery for arteriovenous access for hemodialysis at the Samsung Medical Center between 2010 and 2020. We excluded 16 patients whose post-HD echocardiography was performed after the occurrence of cardiac complications. To clarify the pure impact of diastolic dysfunction, we also excluded 330 patients with an LVEF of less than 50% in either pre- or post-HD echocardiography. Finally, 718 patients were analyzed (Figure 1).

Figure 1. Study design. This retrospective cohort study initially screened 1,064 patients who initiated hemodialysis between 2010 and 2020. According to the exclusion criteria in this flowchart, a total of 718 patients were finally analyzed. AF: atrial fibrillation; AV: arteriovenous; DDG: diastolic dysfunction grade; HD: hemodialysis; LVEF: left ventricular ejection fraction.

This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB number: SMC 2022-08-001-001). Written informed consent was waived by the IRB owing to de-identified data collection and the retrospective nature of the study.

Data collection

All data were extracted from the Clinical Data Warehouse DARWIN-C of Samsung Medical Center. Comorbidities known as risk factors for diastolic dysfunction, including HTN, DM, history of ischemic heart disease (IHD), and peripheral artery disease (PAD), were also collected. The most recent laboratory findings before starting HD, including hemoglobin (Hb), blood urea nitrogen (BUN), serum creatinine (Cr), calcium (Ca), phosphate (P), sodium (Na), potassium (K), uric acid, total carbon dioxide (tCO2), ferritin, and intact parathyroid hormone (iPTH) were obtained. To evaluate baseline kidney function, the estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [19].

Echocardiographic findings and definition of diastolic dysfunction

We defined ‘pre-HD echocardiography’ as echocardiography results obtained before or within 1 month from the initiation of HD, and ‘post-HD echocardiography’ as echocardiography results obtained at least 6 months after the initiation of HD.

Echocardiographic findings included LVEF, early diastolic velocity of the mitral valve (MV) (E), late diastolic velocity of the MV (A), early diastolic velocity of the mitral annulus (e’), left atrial volume index (LAVI), LV mass index (LVMI), maximum velocity of tricuspid regurgitation (TR Vmax), and presence of pericardial effusion. LVH was defined as an LVMI greater than 115 g/m2 in men and greater than 95 g/m2 in women. Patients were classified according to the grade of diastolic dysfunction on pre- or post-HD echocardiography into normal diastolic function, diastolic dysfunction grade (DDG) low and high groups. The diastolic dysfunction grade was assessed according to the 2016 recommendation of the American Society of Echocardiography (ASE) [20]. The suggested definition of LV diastolic dysfunction was the satisfaction of more than half of the following 4 requirements: (1) average E/e’ >14, (2) septal e’ velocity <7 cm/s or lateral e’ <10 cm/s, (3) TR Vmax >2.8 m/s, and (4) LAVI >34 mL/m2. Normal diastolic function was defined as when less than half of the above requirements were met. Patients with echocardiographic findings that were insufficient for assigning a specific grade of diastolic dysfunction were classified into the ‘DDG undetermined’. The DDG low group included patients with DDG undetermined and 1, while the DDG high group included patients with DDG 2 and 3. Because of the irregular heartbeat and LA filling, the early or late diastolic velocity of MV cannot be measured in patients with AF. Therefore, patients with AF were classified separately into the ‘AF’ group. Finally, the analyzed patients were categorized into the four groups: normal, DDG low, DDG high, and AF.

Changes in the grade of diastolic dysfunction before and after HD

We performed an analysis to evaluate the impact of changes in the DDG following the initiation of HD on outcomes. First, patients whose diastolic function remained as normal or DDG low status after HD were classified as ‘DDG unchanged’. Second, patients who exhibited improvement in diastolic dysfunction (from high to low grade or normal, or from low grade to normal) were classified as ‘DDG improvement’. Third, patients who showed worsening of diastolic dysfunction after HD (from normal to diastolic dysfunction, from low to high grade, or persistent high grade) were classified as ‘DDG deterioration’. Lastly, patients who had preexisting AF before HD or newly developed AF after HD were classified as separate ‘AF’ group.

Subgroup analysis according to the timing of post-HD echocardiography

We performed the subgroup analysis based on the interval between initiating HD and post-HD echocardiography. The ‘early post-HD echo’ group comprised patients whose echocardiography was conducted within 442 days of initiating HD, while the ‘late post-HD echo’ group included those whose post-HD echocardiography was conducted after 982 days. The remaining patients were categorized into the ‘mid post-HD echo’ group.

Outcomes

The primary outcomes were all-cause mortality and cardiac outcomes. Mortality and the occurrence of cardiac complications up to 5 years after the initiation of HD were analyzed. Due to the lack of data on the specific causes of death, we analyzed all-cause mortality. The cardiac outcome was defined as follows: percutaneous intervention (PCI) or coronary artery bypass grafting (CABG) surgery for coronary artery disease; admission for HF aggravation; therapeutic intervention for arrhythmia; and surgery for valvular heart disease or aortic disease. Furthermore, the composite outcome was defined as the first occurrence of either all-cause mortality or any cardiac event.

Statistical analysis

Continuous variables were presented as mean ± standard deviation for normally distributed data or median (interquartile range) for non-normally distributed data. Normality was tested using the Shapiro–Wilk test. Continuous variables following a normal distribution were compared using Student’s t-test for independent samples when comparing values between different groups. Other continuous variables were compared using one-way analysis of variance (ANOVA) with Tukey’s test to assess differences among multiple groups. Categorical variables were compared using the Chi-square test or Fisher’s exact test. The survival probability for the composite outcome was analyzed using the Kaplan–Meier survival analysis by calculating the log-rank p-value. The risks of all-cause mortality and cardiac complications were assessed using the Cox proportional hazard analysis. Multivariable analyses were performed with diastolic dysfunction, AF, changes in DDG, time of echocardiography after HD, age, underlying IHD and PAD, and pre-HD laboratory data, including BUN, eGFR, serum Na, uric acid, P, ferritin, and iPTH. For Cox proportional hazard analysis, a 95% confidence interval (CI) was applied. Statistical analyses were performed using Python (Python Software Foundation, Beaverton, OR, USA), and GraphPad Prism version 8.0.0 (GraphPad Software, San Diego, CA, USA). Statistical significance was set at two-sided p < 0.05.

Results

Patient characteristics

The median age was 63 years and 441 (61.4%) patients were male. The patients were classified into four groups according to the DDG and the presence of AF during the pre-HD period: normal (n = 204), DDG low (n = 342), high (n = 133) and AF (n = 39). The baseline characteristics, including pre-HD echocardiographic findings, are shown in Table 1. Almost 90% patients had HTN in all groups, whereas approximately 82% of patients with normal diastolic function had HTN. The proportion of patients with underlying DM or IHD increased with the grade of diastolic dysfunction. There was no significant difference in the prevalence of PAD between the groups. The pre-HD AF group started HD with higher Hb and eGFR than the other groups. Serum K levels in the pre-HD DDG low group were higher than those in other groups. The pre-HD BUN, serum uric acid, tCO2, Na, Ca, P, ferritin, and iPTH levels were comparable between the groups.

Table 1. Baseline characteristics according to pre-HD diastolic function and AF.

 	Normal	DDG low	DDG high	AF	
(N = 204)	(N = 342)	(N = 133)	(N = 39)	
Age (year)	57.0 (45.0–66.25)	65.0 (54.0–72.75)	63.0 (54.0–70.0)	72.0 (62.0–77.0)	
Sex (male)	137 (67.16%)	202 (59.06%)	75 (56.39%)	27 (69.23%)	
HTN	167 (81.86%)	305 (89.18%)	126 (94.74%)	35 (89.74%)	
DM	82 (40.2%)	181 (52.92%)	92 (69.17%)	22 (56.41%)	
IHD	30 (14.71%)	71 (20.76%)	44 (33.08%)	8 (20.51%)	
PAD	7 (3.43%)	13 (3.8%)	6 (4.51%)	2 (5.13%)	
Pre-HD laboratory findings	 	 	 	 	
 BUN (mg/dl)	84.2 (66.97–104.12)	85.6 (69.08–99.62)	78.3 (63.1–97.8)	87.5 (66.4–99.3)	
 Cr (mg/dl)	7.66 (5.99–9.48)	7.54 (5.93–9.84)	7.22 (5.51–8.8)	6.51 (5.36–8.02)	
 eGFR (ml/min/1.73m2)	6.4 (5.0–8.4)	6.3 (4.7–8.1)	6.7 (5.2–8.7)	7.4 (6.0–9.1)	
 Uric acid (mg/dl)	7.8 (6.55–9.1)	7.8 (6.3–9.25)	7.7 (6.35–9.45)	7.3 (6.1–8.7)	
 tCO2 (mmol/l)	17.4 (14.5–19.8)	17.2 (14.1–19.7)	17.35 (14.95–19.38)	18.3 (15.7–21.6)	
 Hb (g/dl)	9.3 (8.3–10.15)	9.0 (7.93–9.9)	8.6 (7.8–9.9)	9.5 (8.5–10.45)	
 Ca (mg/dl)	8.3 (7.7–8.8)	8.1 (7.5–8.6)	8.0 (7.6–8.43)	8.2 (7.6–8.8)	
 P (mg/dl)	5.2 (4.6–6.7)	5.5 (4.6–6.4)	5.4 (4.5–6.4)	4.7 (4.07–6.3)	
 Na (mmol/l)	139.0 (136.0–141.0)	138.0 (136.0–141.0)	139.0 (135.0–141.0)	138.0 (135.0–141.0)	
 K (mmol/l)	4.8 (4.1–5.2)	4.9 (4.3–5.48)	4.7 (4.3–5.2)	4.7 (4.22–5.2)	
 Ferritin (log, ng/ml)	2.4 (2.13–2.65)	2.37 (2.11–2.61)	2.32 (2.07–2.55)	2.31 (2.1–2.54)	
 iPTH (log, pg/ml)	2.35 (2.12–2.57)	2.37 (2.18–2.57)	2.34 (2.13–2.55)	2.41 (2.23–2.59)	
Pre-HD echocardiographic findings	 	 	 	 	
 Time of echo from HD initiation (days)	1.0 (–1.0–48.0)	1.0 (–1.0–43.75)	2.0 (–1.0–36.0)	10.0 (–1.5–66.5)	
 LVEF (%)	64.0 (60.0–68.0)	63.0 (58.0–68.0)	60.0 (56.0–65.0)	62.0 (55.5–65.0)	
 E (m/s)	0.64 (0.51–0.78)	0.65 (0.54–0.78)	1.03 (0.88–1.14)	0.9 (0.71–1.12)	
 e’ (m/s)	0.07 (0.06–0.09)	0.05 (0.05–0.06)	0.06 (0.05–0.07)	0.07 (0.06–0.08)	
 A (m/s)	0.81 ± 0.21	0.96 ± 0.23	0.93 ± 0.28	0.7 ± 0.28	
 E/e’	9.41 (7.58–10.89)	12.2 (10.0–14.6)	17.9 (15.63–22.25)	13.13 (10.0–19.25)	
 LAVI (ml/m2)	32.0 (28.3–39.1)	44.0 (37.35–54.0)	53.2 (46.8–65.2)	59.2 (48.7–72.4)	
 LVMI (g/m2)	103.73 (90.0–121.37)	124.14 (105.44–141.76)	133.94 (118.27–159.42)	132.71 (105.83–162.67)	
 TR Vmax (mmHg)	26.0 (23.0–28.1)	30.0 (25.3–35.4)	38.9 (32.0–47.0)	33.8 (28.3–41.6)	
 LVH	82 (41.84%)	236 (70.45%)	117 (88.64%)	27 (72.97%)	
Pre-HD pericardial effusion	 	 	 	 	
 None	171 (83.82%)	244 (71.35%)	82 (61.65%)	35 (89.74%)	
 Scanty to mild	30 (14.71%)	86 (25.15%)	46 (34.59%)	3 (7.69%)	
 Moderate to severe	3 (1.47%)	12 (3.51%)	5 (3.76%)	1 (2.56%)	
Continuous variables are presented as mean ± standard deviation or median (interquartile range) as appropriate, and categorical variables are presented as counts (%).

A: late diastolic velocity of MV; AF: atrial fibrillation; BUN: blood urea nitrogen; Ca: serum calcium; Cr: serum creatinine; DDG: diastolic dysfunction grade; DM: diabetes mellitus; E: early diastolic velocity of mitral valve; e’: early diastolic velocity of mitral annulus; eGFR: estimated glomerular filtration rate; Hb: hemoglobin; HD: hemodialysis; HTN: hypertension; IHD: ischemic heart disease; iPTH: intact parathyroid hormone; K: serum potassium; LAVI: left atrial volume index; LVEF: left ventricle ejection fraction; LVH: left ventricle hypertrophy; LVMI: left ventricle mass index; Na: serum sodium; P: serum phosphate; PAD: peripheral artery disease; tCO2: total carbon dioxide; TR Vmax: maximum velocity of tricuspid regurgitation.

Pre-HD echocardiographic findings

Pre-HD echocardiography was performed around the initiation time of HD in all groups [total, 1 (−1, 48) days before HD]. Several important indicators, such as E, E/e’, A, LAVI, and TR Vmax, tended to be higher in proportion to the DDG. LVMI was significantly greater and a higher proportion of patients with LVH was found in all DDG and AF groups than in the normal group. Patients with diastolic dysfunction had a greater incidence and amount of pericardial effusion than those with normal or AF.

Outcomes after HD

Among a total of 718 patients, 62 (8.63%) died and 50 (6.96%) experienced cardiac complication within 5 years after initiating HD. All-cause mortality and cardiac complications within 5 years after initiating HD are shown in Table 2. All-cause mortality was higher in the pre-HD AF group than in other groups. Cardiac complications tended to be higher in proportion to the DDG. PCI for coronary artery disease was the most frequent event (n = 36), followed by CABG surgery (n = 9), therapeutic intervention for arrhythmia (n = 4), aorta surgery (n = 4) and admission for HF aggravation (n = 2).

Table 2. The primary outcomes according to pre-HD echocardiography.

 	Normal	DDG low	DDG high	AF	
 	(N = 204)	(N = 342)	(N = 133)	(N = 39)	
All-cause mortality	17 (8.33%)	30 (8.77%)	6 (4.51%)	9 (23.08%)	
Cardiac complications	11 (5.39%)	24 (7.02%)	12 (9.02%)	3 (7.69%)	
The number of patients in column is presented as ‘counts (percentage of each pre-HD group in column)’. All-cause mortality and cardiac complications within 5 years after initiating HD are shown. All-cause mortality was higher in the pre-HD AF group than in other groups. Cardiac complications tended to be higher in proportion to the DDG.

AF: atrial fibrillation; DDG: diastolic dysfunction grade; HD: hemodialysis.

Impacts of pre-HD DDG or AF on the primary outcome

The risk of the primary outcomes according to the pre-HD diastolic function and AF is shown in Figure 2. Patients with pre-HD AF exhibited higher composite outcomes compared to those in other groups.

Figure 2. Kaplan–Meier survival curve for primary outcomes according to pre-HD diastolic function and AF. Patients with AF exhibited higher composite outcomes compared to those in other groups (normal, p = 0.003; DDG low, p = 0.035; DDG high, p = 0.022). There were no significant differences between normal and diastolic dysfunction groups. AF: atrial fibrillation; DDG: diastolic dysfunction grade; HD: hemodialysis.

In Table 3, univariable analysis showed that the risk of composite outcome was comparable between the pre-HD DDG groups. Several pre-HD factors, such as old age; underlying IHD and PAD; high BUN; low eGFR, were associated with an increased risk of composite outcomes in univariable analysis. After adjusting for pre-HD clinical and laboratory variables, pre-HD DDG and AF did not affect composite outcome, whereas old age and underlying IHD were identified as significant risk factors for composite outcome in multivariable analysis (age, HR 1.04, 95% CI 1.02–1.07, p < 0.001; IHD, HR 4.38, 95% CI 2.81–6.83, p < 0.001).

Table 3. Risk for composite outcomes according to pre- or post-HD diastolic dysfunction and AF.

 	Univariable	Multivariable (1); pre-HD	Multivariable (2); post-HD	Multivariable (3); DDG changes	
HR (95% CI)	p-Value	HR (95% CI)	p-Value	HR (95% CI)	p-Value	HR (95% CI)	p-Value	
Pre-HD DDG groups	 	 	 	 	 	 	 	 	
 Pre-HD normal	Reference	 	Reference	 	 	 	 	 	
 Pre-HD DDG low	1.38 (0.85 − 2.23)	0.196	0.97 (0.57 − 1.65)	0.897	 	 	 	 	
 Pre-HD DDG high	1.13 (0.61 − 2.10)	0.706	0.69 (0.36 − 1.34)	0.274	 	 	 	 	
 Pre-HD AF	2.87 (1.37 − 6.01)	0.005	0.99 (0.38 − 2.57)	0.977	 	 	 	 	
Post-HD DDG groups	 	 	 	 	 	 	 	 	
 Post-HD normal	Reference	 	 	 	Reference	 	 	 	
 Post-HD DDG low	5.62 (1.77 − 17.87)	0.003	 	 	3.59 (1.10 − 11.68)	0.034	 	 	
 Post-HD DDG high	5.29 (1.55 − 18.04)	0.008	 	 	4.55 (1.31 − 15.82)	0.017	 	 	
 Post-HD AF	8.31 (2.41 − 28.71)	0.001	 	 	4.57 (1.23 − 16.94)	0.023	 	 	
Changes in DDG	 	 	 	 	 	 	 	 	
 DDG improvement	Reference	 	 	 	 	 	Reference	 	
 DDG unchanged	2.04 (1.03 − 4.06)	0.042	 	 	 	 	2.24 (1.07 − 4.70)	0.032	
 DDG deterioration	1.83 (0.91 − 3.70)	0.091	 	 	 	 	2.78 (1.31 − 5.91)	0.008	
 AF	3.03 (1.36 − 6.75)	0.007	 	 	 	 	2.73 (1.10 − 6.75)	0.030	
Age (years)	1.05 (1.03 − 1.06)	<0.001	1.04 (1.02 − 1.07)	<0.001	1.04 (1.02 − 1.06)	0.001	1.04 (1.02 − 1.07)	<0.001	
IHD	5.03 (3.41 − 7.41)	<0.001	4.38 (2.81 − 6.83)	<0.001	4.22 (2.72 − 6.57)	<0.001	4.34 (2.78 − 6.76)	<0.001	
PAD	2.70 (−1.36 − 5.34)	0.004	1.06 – (0.50 − 2.25)	0.874	0.99 (0.47 − 2.09)	0.987	1.08 (0.51 − 2.30)	0.843	
BUN (mg/dl)	0.99 – (0.99 − 1.00)	0.070	1.00 (0.99 − 1.01)	0.647	1.00 (0.99 − 1.01)	0.606	1.00 (0.99 − 1.01)	0.501	
eGFR (ml/min/1.73m2)	1.05 (1.02 − 1.08)	0.001	1.02 (0.97 − 1.08)	0.361	1.02 (0.97 − 1.07)	0.448	1.02 (0.97 − 1.08)	0.401	
Na (mmol/l)	1.00 (0.96 − 1.04)	0.894	1.03 (0.98 − 1.08)	0.214	1.03 (0.98 − 1.08)	0.217	1.04 (0.99 − 1.09)	0.131	
Uric acid (mg/dl)	0.96 (0.89 − 1.05)	0.398	1.04 (0.94 − 1.15)	0.444	1.03 (0.94 − 1.14)	0.535	1.05 (0.95 − 1.15)	0.366	
P (mg/dl)	0.89 (0.78 − 1.01)	0.075	1.09 (0.91 − 1.29)	0.350	1.09 (0.92 − 1.30)	0.304	1.10 (0.93 − 1.30)	0.283	
Ferritin (log, ng/ml)	1.53 (0.94 − 2.50)	0.090	1.31 (0.74 − 2.32)	0.362	1.32 (0.74 − 2.38)	0.350	1.39 (0.78 − 2.47)	0.268	
iPTH (log, pg/ml)	0.70 (0.42 − 1.16)	0.164	1.61 (0.84 − 3.11)	0.152	1.38 (0.74 − 2.58)	0.313	1.57 (0.83 − 3.00)	0.167	
AF: atrial fibrillation; BUN: blood urea nitrogen; DDG: diastolic dysfunction grade; eGFR: estimated glomerular filtration rate; HD: hemodialysis; IHD: ischemic heart disease; iPTH: intact parathyroid hormone; Na: serum sodium; P: serum phosphate; PAD: peripheral artery disease.

Impacts of post-HD DDG or AF on the composite outcome

The median follow-up time for post-HD echocardiography after HD initiation was 623 (387, 1183) days. The risk of the primary outcomes according to post-HD DDG is shown in Figure 3. Patients with post-HD normal diastolic function exhibited significantly lower composite outcomes compared to other groups.

Figure 3. Kaplan–Meier survival curve for primary outcomes according to post-HD diastolic function and AF. Patients with normal diastolic function exhibited lower composite outcomes compared to those in other groups (DDG low, p = 0.001; DDG high, p = 0.003; AF, p < 0.001). There were no significant differences between diastolic dysfunction and AF groups. AF: atrial fibrillation; DDG: diastolic dysfunction grade; HD: hemodialysis.

In Table 3, post-HD diastolic dysfunction and AF were associated with an increased risk of composite outcome compared to post-HD normal diastolic function in univariable analysis (DDG low, HR 5.62, 95% CI 1.77–17.87, p = 0.003; DDG high, HR 5.29, 95% CI 1.55–18.04, p = 0.008; AF, HR 8.31, 95% CI 2.41–28.71, p = 0.001). After adjusting for baseline clinical and laboratory variables, post-HD diastolic dysfunction and AF were still associated with an increased risk of composite outcome compared with post-HD normal diastolic function (DDG low, HR 3.59, 95% CI 1.10–11.68, p = 0.034; DDG high, HR 4.55 95% CI 1.31–15.82, p = 0.017; AF, HR 4.57, 95% CI 1.23–16.94, p = 0.023).

Changes in DDG after HD and the composite outcome

Patients were classified according to changes in the severity of DDG or the development of AF as follows: DDG unchanged (n = 281), DDG improvement (n = 125), DDG deterioration (n = 241), and AF (n = 71). In the pre-HD normal group, only 53 (25.98%) patients remained with the unchanged status (Table 4). In the pre-HD DDG high group, a total of 88 (66.17%) patients exhibited an improvement in diastolic dysfunction. In the subgroup attaining pre-HD DDG low group, all-cause mortality occurred in only one patient without any cardiac complication in the DDG improvement group.

Table 4. The changes of diastolic function and composite outcomes according to pre-HD diastolic function.

 	Pre-HD normal	Pre-HD DDG low	Pre-HD DDG high	
Changes	Mortality	Cardiac complications	Changes	Mortality	Cardiac complications	Changes	Mortality	Cardiac complications	
DDG improvement	–	–	–	37 (10.82%)	25 (83.33%)	18 (75.00%)	88 (66.17%)	4 (66.67%)	5 (41.67%)	
DDG unchanged	53 (25.98%)	1 (5.88%)	1 (9.09%)	228 (66.67%)	1 (3.33%)	0 (0%)	–	–	–	
DDG deterioration	143 (70.1%)	15 (88.24%)	9 (81.82%)	60 (17.54%)	3 (10.00%)	5 (20.83%)	38 (28.57%)	2 (33.33%)	6 (50.00%)	
AF	8 (3.92%)	1 (5.88%)	1 (9.09%)	17 (4.97%)	1 (3.33%)	1 (4.17%)	7 (5.26%)	0 (0%)	1 (8.33%)	
Total	204	17	11	342	30	24	133	6	12	
The number of patients in ‘Changes’ column is presented as ‘counts (percentage of each pre-HD group in column)’. The number of patients in ‘Mortality’ and ‘Cardiac complications’ column is presented as ‘counts (percentage of each DDG changes group in row)’.

AF: atrial fibrillation; DDG: diastolic dysfunction grade; HD: hemodialysis.

The survival effect of changes in the degree of DDG to outcomes after initiating HD are shown in Figure 4. Patients with improvement of diastolic dysfunction after HD exhibited better composite outcomes than those in AF group (p = 0.007). In Table 3, after adjusting for baseline clinical and laboratory variables in multivariable analysis, the deterioration of diastolic dysfunction and AF after HD were associated with an increased risk of composite outcome compared to the improvement of diastolic dysfunction (DDG deterioration, HR 2.78, 95% CI 1.31–5.91, p = 0.008; AF, HR 2.73, 95% CI 1.10–6.75, p = 0.03).

Figure 4. Kaplan–Meier survival curve for the primary outcomes according to the changes of diastolic dysfunction and the development of AF after HD. Patients with improvement of diastolic dysfunction after HD exhibited better composite outcomes than those in unchanged and AF group (unchanged, p = 0.038; AF, p = 0.009). AF: atrial fibrillation; DDG: diastolic dysfunction grade; HD: hemodialysis.

Subgroup analysis according to the timing of post-HD echocardiography

Patients were classified according to the time interval between HD initiation and post-HD echocardiography as follows: early post-HD echo (n = 232), mid post-HD echo (n = 273), and late post-HD echo (n = 213). After adjusting for variables in a multivariable analysis, changes in diastolic dysfunction or the development of AF were not associated with composite outcomes in the early and late post-HD groups. However, deteriorations in diastolic dysfunction were associated with an increased risk of composite outcomes in the mid post-HD group (HR 10.11, 95% CI 1.22–84.13, p = 0.032) (Table 5).

Table 5. Risk for composite outcomes in subgroup analysis according to the changes of diastolic dysfunction and AF.

 	Early post-HD echo (N = 232)	Mid post-HD echo (N = 273)	Late post-HD echo (N = 213)	
HR (95% CI)	p-Value	HR (95% CI)	p-Value	HR (95% CI)	p-Value	
Changes in DDG	 	 	 	 	 	 	
DDG improvement	Reference	 	Reference	 	Reference	 	
DDG unchanged	2.13 (0.79 − 5.75)	0.134	6.49 (0.75 − 56.28)	0.090	0.68 (0.11 − 4.13)	0.677	
DDG deterioration	2.25 (0.79 − 6.37)	0.128	10.11 (1.22 − 84.13)	0.032	0.75 (0.11 − 5.26)	0.771	
AF	2.34 (0.64 − 8.55)	0.197	6.67 (0.61 − 73.21)	0.120	1.91 (0.17 − 21.09)	0.596	
Multivariable analysis was adjusted with age, BUN, eGFR, Na, serum uric acid, P and the history of IHD and PAD.

AF: atrial fibrillation; BUN: blood urea nitrogen; DDG: diastolic dysfunction grade; eGFR: estimated glomerular filtration rate; HD: hemodialysis; IHD: ischemic heart disease; iPTH: intact parathyroid hormone; Na: serum sodium; P: serum phosphate; PAD: peripheral artery disease.

Discussion

In this study, we demonstrated that post-HD diastolic dysfunction and AF were associated with all-cause mortality and cardiac complications in patients with ESKD. In addition, the improvement of diastolic function after HD initiation was associated with good prognosis. In contrast, pre-HD diastolic dysfunction did not affect the outcomes after adjusting for clinical factors, including age and history of IHD. Our data strongly suggest the clinical importance of careful monitoring and management of diastolic dysfunction and AF, even after initiating HD in patients with ESKD.

Previous studies have reported that diastolic dysfunction is an important prognostic factor in patients with ESKD. Increased E/e’ and LAVI, indicating diastolic dysfunction, independently predicted mortality in patients with ESKD [13,21–23]. Furthermore, E/e’ > 15 and LAVI > 32 mL/m2 were reported as risk factors for major adverse cardiac events (MACE) in patients receiving HD [15]. However, these studies exclusively focused on diastolic dysfunction either at the initiation of HD, during HD, or when MACE occurred. Because worsened diastolic function is correlated with a higher risk of mortality or MACE [24,25], we specifically examined changes in echocardiographic parameters and their impact on clinical outcomes in patients with ESKD. We hypothesized that HD might affect diastolic dysfunction and systolic function, considering a previous study reporting improvements in LV internal diameter and significant increases in LVEF among patients initiating hemodialysis [26]. Following the initiation of HD, uremic toxins, including urea, phosphorus, middle molecules, and protein-bound compounds, are removed. For example, indoxyl sulfate, one of the protein-binding uremic toxins, is not only associated with vascular calcification and cardiac fibrosis but also increased cardiac oxidative stress [27,28]. Diastolic dysfunction may be improved by the removal of uremic toxins, improvement in nutritional status, and appropriate volume control after initiating HD. However, diastolic dysfunction can be also worsened due to the aggravation or occurrence of cardiac disease, excessive interdialytic weight gain and suboptimal dry weight, or inadequate dialysis. These factors are well known to be associated with the prognosis of patients. Therefore, the improvement or worsening of diastolic dysfunction may serve as an indicator of the overall medical condition or management status of UCM in patients with ESKD. We demonstrated that post-HD diastolic dysfunction and its changes were more crucial than pre-HD diastolic dysfunction. Pre-HD diastolic dysfunction may be more influenced by secondary changes in aging and underlying IHD than by UCM. After initiating HD, a significant proportion of patients with normal pre-HD diastolic function developed post-HD diastolic dysfunction, and the deterioration in diastolic dysfunction was associated with worse outcomes.

Although HD improves uremia and volume status, pathophysiological and interdialytic or intradialytic hemodynamic changes in patients undergoing HD may adversely affect diastolic dysfunction and lead to poor outcomes. The potential factors that exacerbate post-HD diastolic dysfunction include inadequate HD, excessive interdialytic weight gain, poorly controlled hyperphosphatemia with secondary hyperparathyroidism, persistent anemia, and IHD or valvular heart disease [29–33]. Additionally, the optimal timing for long-term follow-up echocardiography to assess changes in diastolic function has not yet been established although a single session of HD can improve diastolic dysfunction [34,35]. In our study, deteriorations in diastolic dysfunction were associated with an increased risk of composite outcomes in the ‘mid post-HD echo’ group, which included patients who underwent echocardiography between 1 year and 3 years after initiating HD. These findings may suggest the clinical necessity of a follow-up echocardiography at least within 3 years after initiating HD in patients with diastolic dysfunction. Therefore, our findings suggest that comprehensive care and regular follow-up of echocardiography for patients with ESKD after initiating HD may be more important than the pre-HD heart status in terms of cardiovascular outcomes.

Our study identified post-HD AF as an independent risk factor for all-cause mortality and cardiac complications in patients with ESKD who underwent HD. The incidence of AF has been increasing (2.31 in 1958–1967 vs. 12.1/1000 person-years in 1998–2007) [36], and patients with AF have a higher risk of all-cause mortality than the general population [36–38]. Furthermore, there has been a notable increase in the number of cardiovascular deaths associated with AF [39]. In our cohort, 34 patients (9.8/1000 person-years in patients without pre-HD AF) developed new-onset AF within 5 years of initiating HD. The crude incidence rate of AF in our cohort was similar to that in the Framingham Heart Study (12.1/1000 person-years in 1998–2007) [36] and significantly higher than recent data from the Korean general population (1.58/1000 person-years in 2008–2015) [37]. With the continued aging of the population with ESKD, we anticipate a further increase in the incidence of AF [40]. Therefore, it is imperative to closely monitor and implement appropriate management strategies for patients with ESKD and AF.

Our study has several limitations. First, potential confounders may have affected the results because of the retrospective study design. We attempted to include as many relevant factors as possible that could affect diastolic function, to minimize the impact of confounders on our analysis. Second, assessing diastolic dysfunction in patients with ESKD is complicated due to volume overload on non-dialysis days and fluctuations in LAVI and E velocity caused by changes in volume status [34,35]. The ideal timing for echocardiography in HD patients is not clearly established, which can result in varying incidence and severity of diastolic dysfunction based on the timing of the assessment relative to HD sessions [34]. This variability makes accurate diagnosis of diastolic dysfunction to be challengeable. Nonetheless, our study demonstrated the potential usefulness of severity and changes in diastolic dysfunction before and after initiating dialysis as valuable prognostic indicators in HD patients. Third, a relatively small number of patients with high-grade diastolic dysfunction before HD (pre-HD DDG high, n = 133) were included; therefore, the effects of the risk factors on this subgroup could not be fully elucidated in the multivariable analysis. Fourth, reliable indicators assessing malnutrition were not incorporated into our analysis. Given that worsening protein-energy malnutrition is associated with an increased risk of CV death in patients with ESKD [41], malnutrition may be a potential confounder. Although the levels of BUN, serum uric acid, and serum phosphate could partially reflect nutritional status, these laboratory data might not accurately represent nutritional status in HD patients as they were affected by the detailed prescription of HD including the type of dialyzer and blood flow rate. Further prospective studies including appropriate indicators of nutritional status are required to address this issue. Despite these limitations, we demonstrated that a normal diastolic function after HD was associated with good composite outcomes. Consequently, our findings provide valuable insights into the prognostic significance of post-HD diastolic dysfunction in patients with ESKD.

Conclusion

Diastolic dysfunction and AF after initiating HD may serve as prognostic markers in patients with ESKD, emphasizing the clinical importance of early diagnosis through regular follow-up echocardiography. While diastolic dysfunction can be improved by the removal of uremic toxins, improved nutritional status, and appropriate volume control after initiating HD, it can be also worsened due to accompanied cardiac disease, excess interdialytic weight gain, and inadequate dialysis. Thus, changes in diastolic dysfunction may indicate the overall medical condition and management status of UCM in patients with ESKD, highlighting the need for comprehensive management, including AF detection and appropriate treatment.

Acknowledgment

The authors would like to thank So Hyun Kwon, a research coordinator of the Nephrology Division, Department of Medicine, Samsung Medical Center, for her dedicated efforts in collecting data.

Author contributions

HRJ conceptualized the study. HJ, JJ, and HRJ designed the study. HJ and JJ analyzed the data. HJ, JJ, KL, JK, DK, JEL, WH, and HRJ interpreted the data. HJ and JJ wrote the manuscript. HJ, KL, JJ, and HRJ revised the manuscript for intellectual content. JK, DK, JEL, and WH supervised the study. All the authors have read and approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data available on reasonable request due to privacy/ethical restrictions
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