Impact of chronic kidney disease on clinical outcomes in patients with Stage B progressive aortic regurgitation (mild to moderate and moderate grades)

Abstract Background Chronic kidney disease (CKD) is a significant comorbidity in patients with heart failure and valvular heart disease. Renal impairment is not well evaluated in the patients with Stage B progressive aortic regurgitation (AR) (mild to moderate and moderate grades in this study), for estimating outcome. Hypothesis We sought to investigate the prognostic factor, especially CKD, in the patients with progressive AR. Methods We enrolled 262 patients with Stage B progressive AR and preserved left ventricular systolic function (ejection fraction ≥ 50%). Based on the presence of CKD, the patients were divided into CKD (n = 70) and non‐CKD (n = 192) groups, which CKD was defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2. The primary outcome was major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, hospitalization for heart failure, and aortic valve replacement. Results The median follow‐up duration was 41.5 (interquartile range: 16.2–71.7) months. Between groups, the CKD patients were older; they had a higher pulse pressure and higher incidence of hypertension, diabetes mellitus, dyslipidemia, cerebrovascular accident, and atrial fibrillation. Compared to the non‐CKD group, the CKD group had lower eʹ velocity (4.36 ± 2.21 vs. 5.20 ± 2.30 cm/s, p = .009), higher right ventricular systolic pressure (38.02 ± 15.79 vs. 33.86 ± 11.77 mmHg, p = .047). The CKD group was associated with increased risk of MACEs (41.4% vs. 22.4%; unadjusted hazard ratio [HR]: 1.78, 95% confidence interval [CI]: 1.11–2.85, p = .017). In multivariate Cox regression analyses, the risk of MACEs was significantly different between groups (adjusted HR: 1.71, 95% CI: 1.11–2.62, p = .015); furthermore, the risk of hospitalization for heart failure (10.0% vs. 2.6%; adjusted HR: 2.30, 95% CI: 1.16–4.55, p = .017) was significantly higher in the CKD group than in the non‐CKD group. Conclusions In patients with Stage B progressive AR, CKD is an independent prognostic factor for clinical outcomes (composite clinical outcome, hospitalization for heart failure).


| INTRODUCTION
Aortic regurgitation (AR) is one of the causes of left-sided structural heart disease. The natural history of AR is well defined; it has a gradually progressive clinical course with effects on the left ventricle, including eccentric hypertrophy, fibrosis, and ultimately, cardiac failure. 1 In addition, many studies have been conducted on factors that influence AR progression.
Approximately 6% of the patients with AR develop symptoms of left ventricular (LV) systolic dysfunction each year; moreover, the mortality rate is about 10% per year in the presence of LV systolic dysfunction. 1 However, for Stage B progressive AR (mild to moderate and moderate grades of AR), 2 relevant studies are scarce. Further, the clinical features progressing to heart failure or cardiovascular outcome have not been elucidated. In the context of mild and moderate AR, there is only very limited data on the long-term progression and follow-up. 3,4 The current guidelines for surveillance echocardiography recommends appropriate periodic testing, every 2-3 years, for monitoring Stage B progressive AR patients. 5,6 Chronic kidney disease (CKD) is a significant comorbidity for most major cardiovascular diseases 7,8 ; it is associated with significant mortality and morbidity in patients with valvular heart disease or those undergoing valvular procedures, especially for calcified valvular disease (such as aortic stenosis or mitral stenosis). [9][10][11] There is not much clinical evidence on the prognostic factors for Stage B progressive AR, and little information is available on the effects of CKD in these patients. This study aimed to evaluate the prognostic factors, especially the impact of CKD, in patients with Stage B progressive AR.

| Study population and clinical characteristics
In this retrospective cohort study, we retrieved data of patients with a mild to moderate or higher grade of valvular heart disease from the echocardiographic registry of our institution, between 2010 and 2019.
First, we searched the registry to identify patients with AR (n = 645) and reviewed their medical records. Next, we selected patients with a medical record of follow-up and excluded those with the following conditions: severe grade of AR (Stages C and D) 5  For all patients, the data, including clinical characteristics and laboratory findings, were carefully reviewed by a single cardiologist.
The study protocol was approved by the institutional review board of our institution, and the need for informed consent was waived.
We divided our study cohort into two groups based on their renal function: the CKD group and the non-CKD group. The CKD was defined as estimated glomerular filtration rate (eGFR) less than 60 ml/ min/1.73 m 2 . The values of laboratory findings (such as creatinine) were collected between 1 month before and after the echocardiography was performed. For eGFR values, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used.

| Echocardiographic measurement
Commercially available ultrasound equipment was used for echocardiographic studies. Conventional two-dimensional echocardiography was performed, and echocardiographic parameters were obtained following the American Society of Echocardiography guidelines. LV end-diastolic and end-systolic volumes were measured using apical two-and fourchamber views, and the ejection fraction was calculated using Simpson's rule. 12 Left atrial volume was calculated using the modified biplane arealength formula and was indexed to the patient's body surface area for the left atrial volume index. Early diastolic mitral inflow velocity (E velocity) was measured using the pulsed-wave Doppler method by placing the sample volume at the tip of the leaflets of the mitral valve. Tissue Doppler-derived early-diastolic mitral annular velocity (eʹ velocity) was measured at the septal corner of the mitral annulus in the apical T A B L E 1 Baseline clinical characteristics of study population divided into the groups with and without chronic kidney disease

| Clinical outcomes
The date of the patient's baseline echocardiography was considered the beginning of the observation period. All enrolled patients were followed up via a chart review, and the date of last follow-up or death was recorded. The patients, whose end point was unknown, were treated as follow-up loss patients using statistics. All outcome events were adjudicated by investigators.
The primary outcome was a composite clinical outcome-major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, hospitalization for heart failure, and aortic valve replacement. The secondary outcome was hospitalization for heart failure.

| Statistical analysis
Continuous variables were compared using Student's t-test and presented as the mean with standard deviation or median with interquartile range (IQR In addition, a Kaplan-Meier analysis was used to describe the event-free survival, and the log-rank test was used to analyze the differences between the groups with and without CKD.
All tests were two-tailed, and values of p < .05 were considered statistically significant. All statistical analyses were performed using Abbreviations: CKD, chronic kidney disease; NT-proBNP, N-terminal probrain natriuretic peptide; NYHA, New York Heart Association.

| Baseline characteristics between the group with and without CKD
Our final cohort consisted of 262 patients, divided into two groups: CKD (n = 70) and non-CKD (n = 192). Table 1  NT-proBNP level in blood is affected by creatinine level, that is, renal function. Since the two groups were divided according to the presence or absence of CKD, we considered that the NT-proBNP level was inevitably statistically different between two groups.

| Echocardiographic parameters
The parameters obtained by echocardiography are shown in Table 2.
Of the 262 patients, 140 patients had a mild-moderate grade of AR, and 122 patients had a moderate grade of AR; however, there was no statistically significant difference in the grades of AR between the groups with and without CKD.  The results of the Cox regression analysis for primary and secondary outcomes are shown in Table 4. Multivariate Cox proportional hazard model with adjustment revealed that the presence of CKD was an independent prognostic factor for clinical outcomes (composite clinical outcome and heart failure for hospitalization).

| DISCUSSION
This study evaluated the impact of CKD, a prognostic factor for hospitalization due to heart failure in patients with Stage B progressive AR. The principal findings were as follows: (1) the patients in the CKD group were significantly older and had higher pulse pressure and higher incidence of HTN, DM, dyslipidemia, cerebrovascular accident, and atrial fibrillation; (2) on multivariate Cox regression analyses, the risk of clinical outcomes (composite clinical outcome and hospitalization for heart failure) was significantly higher in the CKD group than in the non-CKD group.
In the multivariate analysis about the risk of MACEs, CKD, hyperlipidemia, and eʹ velocity were the statistically significant  subclinical LV myocardial dysfunction occurs early in the compensated stage when the LV ejection fraction is still preserved, that is, before the development of overt symptoms and often before reaching the current guideline-recommended surgical thresholds. 16,17 A long asymptomatic period with adverse LV remodeling in response to persistent disease progression complicates and confuses the optimal timing of intervention. While estimating the outcomes, based on the progression of AR or occurrence of LV dysfunction, in patients with Stage B progressive AR, we should consider that the optimal timing of treatment may be too late. Therefore, hospitalization for heart failure might serve as an important endpoint for monitoring in these patients.
Patients with CKD suffer from a high burden of cardiovascular disease with increased cardiovascular mortality, an accelerated progression of atherosclerosis and valvular heart disease, an increased risk of congestive heart failure, and an increased risk of sudden cardiac death. 6,8,18 Hence, patients with renal impairment frequently have a higher burden of severe morbidities, which may adversely affect long-term survival. 19 CKD might be the important metabolic cause associated with risk factors such as age and correlated with general calcification, degeneration, and inflammatory processes, as affecting the heart valve. Considering the gradual volume overload with respect to compensation in patients with AR, impaired renal function may affect the incidence of heart failure. This is because a proper volume control balance cannot be achieved. On adjustedmultivariate analysis, we found that CKD was a factor of prognostic  Note: MACEs included cardiac death, myocardial infarction, hospitalization for heart failure, and aortic valve replacement.