Elevated Troponin T and enlarged left atrium predict the incidence of atrial fibrillation in patients with chronic kidney disease stage 4-5

Background Atrial fibrillation (AF) and chronic kidney disease (CKD) are commonly co-existing conditions. However, data on epidemiology of AF in patients with CKD stage 4–5 is scarce. Methods We prospectively enrolled 210 consecutive non-dialysis patients with CKD stage 4–5 between 2013 and 2017. Follow-up data on AF incidence along with medical history, laboratory tests and echocardiography at baseline were gathered. Results At baseline, mean age was 62 years, estimated glomerular filtration rate 12.8 ml/min and 73/210 (34.8%) of the participants were female. Altogether 41/210 (19.5%) patients had a previous diagnosis of AF. After median follow-up of 46 [IQR 27] months, new-onset AF occurred in 33/169 (19.5%) patients (69.9 events/1000 person-years). Overall, 22/33 (66.7%) of patients with new-onset AF were identified with a triggering condition and 21/33 (63.6%) were receiving renal replacement therapy (dialysis or acquired kidney transplant) at the time of AF detection, respectively. In Cox proportional hazard model age > 60 years (HR 4.27, CI95% 1.57–11.64, p < 0.01), elevated troponin T (TnT) > 50 ng/l (HR 3.61, CI95% 1.55–8.37, p < 0.01) and left atrial volume index (LAVI) > 30 ml/m 2 (HR 4.82, CI95% 1.11-21.00, p = 0.04) independently predicted the incidence of new-onset AF. Conclusions The and AF was markedly high in this prospective study on patients with CKD stage 4–5. Elevated TnT and increased LAVI were identified as independent predictors for new-onset AF in patients with severe CKD. most new-onset AFs with a predisposing condition by surgery (50%) These are possibly explained by the relative lability of CKD patients due to the high burden of comorbidities and shared risk factors with AF as well as susceptibility to infections, fluid overload and electrolyte imbalance compared to patients without CKD These data suggest that CKD patients recovering from a major surgery or suffering from an acute infection might benefit from screening of AF.


Introduction
Atrial fibrillation (AF) and chronic kidney disease (CKD) are both common diseases with estimated prevalence rates of 2% and 13%, respectively, in the general population and projected to become more frequent further encumbering the healthcare system in the future (1,2). Furthermore, AF is associated with increased risk for stroke, congestive heart failure, myocardial infarction, CKD progression and death in CKD patients (3,4). AF and CKD share many common risk factors and worsening kidney function appears to increase the risk of AF (5). Overall, data on the prevalence and incidence of AF in patients with CKD stage 4-5 has been inconsistent (4, 6-9).
Thus, we sought to explore the occurrence and predictors of AF in a cohort of patients with CKD stage 4-5 in this prospective follow-up study.

Methods
The Chronic Arterial Disease, quality of life and mortality in chronic KIDney injury (CADKID)-study (http://www.ClinicalTrials.gov NCT04223726) is an ongoing prospective follow-up study protocol assessing arterial disease, quality of life, and mortality in patients with CKD stage 4-5. The present study is a prespecified report from the CADKID study.
The study enrolled 210 consecutive patients referred to the predialysis outpatient clinic in Kidney Center of Turku University Hospital between August 2013 and September 2017. All eligible patients had CKD stage 4-5 defined as estimated glomerular filtration rate (eGFR) < 30 ml/min per 1.73 m 2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at baseline.
Relevant medical history and medications were manually gathered from the hospital electronic patient records by the researchers and laboratory tests and a 12-lead surface electrocardiogram (ECG) by the certified laboratory services of Turku University Hospital (TYKSLAB).
The ECGs were recorded at the paper speed of 50 mm per second and the standardized voltage ratio of 1 mm per 1 mV. All ECGs were manually assessed by the researchers.
The echocardiographic measures were collected from a standardized transthoracic echocardiography performed at rest before stress testing by The Department of Clinical Physiology of Turku University Hospital. The systolic and diastolic dimensions and function of the left ventricle as well as left ventricular wall thicknesses and aortic and left atrial dimensions were measured. Since the traditional method (anteroposterior linear dimension of the left atrium in the parasternal view) in measuring left atrial size is inaccurate, we chose to assess the body surface area corrected left atrial volume index (LAVI) by using planimetry in apical 4-and 2-chamber views at end-systole while excluding the confluences of the pulmonary veins and left atrial appendage (10).
The primary outcome of the study was defined as the incidence of new-onset AF (in a patient with no prior AF history) confirmed by ECG or pacemaker log (defined as an overt AF episode lasting over 30 seconds) at 2 years of follow-up. Follow-up data were manually collected from the patient records.

Ethics
The study was approved by the Medical Ethics Committee of the Hospital District of Southwest Finland. Each participant gave written informed consent before entering the study. Research was performed in accordance with the Declaration of Helsinki

Statistics
Demographics were reported as mean ± standard deviation (SD) and median [inter-quartile range (IQR)] for normally distributed covariates and skewed continuous variables, respectively. Normality in continuous covariates was tested with Kolmogorov-Smirnov and Shapiro-Wilk tests. The unpaired t-test or Mann-Whitney test and Pearson x2 or Fisher's exact test were used to compare continuous covariates and categorical covariates, respectively, in the study subgroups. Categorical covariates were reported with absolute and relative (percentage) frequencies. Due to the large number of tested covariates and limited sample size the baseline covariates correlating at p ≤ 0.01 significance level with the dependent variable in the univariate model were entered in multivariate logistic regression analysis or Cox proportional hazard analysis, as appropriate. All tests were two-sided and significance was set at p = 0.05. IBM SPSS Statistics software version 26.0 was used to perform all analyses.

Prevalence and incidence of AF
Out of the 210 patients with CKD stage 4-5, a total of 41/210 (19.5%) patients had a prior diagnosis of AF. The mean overall duration of AF was 76 months in the patients with a prior AF diagnosis. The patients with a prior diagnosis of AF were markedly older and had a higher burden of comorbidities compared to those with no history of AF (Table 1). In a logistic regression analysis age > 60 years (OR 9.63, CI95% 2.17-42.80, p < 0.01) and LAVI > 30 ml/m 2 (OR 4.98, CI95% 1.01-22.73, p = 0.04) independently predicted the prior diagnosis of AF. Table 1 Baseline characteristics of patients according to prevalence of AF. Altogether, 26 new-onset AF episodes were detected during hospital visits and 7 cases were detected in an outpatient setting ( Table 3). The most common triggering conditions for AF were infection 11/33 (33.3%), major surgery 5/33 (15.2%) and congestive heart failure 4/33 (12.1%), respectively.

Discussion
The present study demonstrated a high prevalence and incidence of AF in patients with CKD stage 4-5. By the end of the follow-up period a third of the patients had been diagnosed with AF. Older age, elevated TnT and increased LAVI assessed from transthoracic echocardiography independently predicted the occurrence of newonset AF in the study patients.
Our study demonstrated for the first time the association between AF incidence and elevated TnT or increased LAVI in patients with CKD stage 4-5. While older age and greater left atrial diameter have been linked to AF incidence in CKD patients in previous studies, there are no prior data on the association between TnT or LAVI and AF incidence in patients with CKD stage 4-5 (9). Reasons for higher troponin levels in new-onset AF patients remain unknown. However, these findings have important clinical implications in AF prediction in the CKD population. In fact, our results suggest that almost every other CKD stage 4-5 patient with TnT > 50 ng/l and LAVI > 30 ml/m 2 was at risk for developing new-onset AF within 4 years, and the risk among patients aged over 60 years was even higher (~ 60%). Conversely, only 3% of patients with new-onset AF had TnT ≤ 50 ng/l and LAVI ≤ 30 ml/m 2 (Fig. 3).
The association between elevated high-sensitivity troponin and incidence of new-onset AF in CKD patients was explored in a recent study but the cohort comprised patients with only mild to moderate CKD (11). Nevertheless, elevated TnT and increased LAVI are common findings in CKD patients and associated with the risk of left ventricular hypertrophy and heart failure -predictors of AF themselves (12)(13)(14)(15). Thus, measurement of TnT and LAVI especially in elderly CKD patients might be reasonable in predicting AF.
Nearly one fifth of the study patients had a prior diagnosis of AF and this was in line with previous reports on CKD patients (7,8). Older age and dilatation of the left atrium were associated with the history of AF in our study and have consistently predicted AF prevalence in CKD patients irrespective of dialysis treatment in previous studies. Other consistent predictors for positive AF history have been congestive heart failure and male sex (7,8,16).
The incidence rate of AF was remarkably high in our study compared to previous studies -even those on dialysis patients. This might be partly explained by the high prevalence of hypertension in our study compared to previous reports (5,9,12). Furthermore, two thirds of the patients with new-onset AF were receiving RRT at the time of AF detection. In fact, hemodialysis procedure itself has been identified as a trigger for AF (17). Studies comparing the incidence rate of AF in non-dialysis and dialysis patients with CKD do not exist, but AF incidence has been numerically higher in CKD patients undergoing dialysis (5,9,(11)(12)(13). One previous trial reported a higher incidence rate of AF in dialysis patients compared to healthy controls (13).
Interestingly, most new-onset AF cases were detected during hospital treatment and in two thirds of the patients a predisposing condition was identified ( Table 3). The figure is higher compared to previous studies and the most common predisposing condition in our study was infection (33%) while in the study by Lubitz et al most newonset AFs with a predisposing condition were triggered by surgery (50%) (18). These findings are possibly explained by the relative lability of CKD patients due to the high burden of comorbidities and shared risk factors with AF as well as susceptibility to infections, fluid overload and electrolyte imbalance compared to patients without CKD (19)(20)(21). These data suggest that CKD patients recovering from a major surgery or suffering from an acute infection might benefit from screening of AF.
This study has the limitations of an observational study. The study sample of patients was relatively small and the echocardiography data was partly incomplete. However, the patients were extensively and consistently examined by the same clinicians and the quality of the data is high. Some new-onset AF episodes may have been missed since AF is commonly asymptomatic. Nevertheless, all the study patients resided in the catchment area of the research hospital and all AF episodes are recorded in the patient registry of the same hospital. Despite these limitations, we believe that these data can benefit clinical practice and guide future research.

Conclusions
The prevalence and incidence of AF was high in our study exploring patients with CKD stage 4-5. Furthermore, elevated TnT and increased LAVI were identified as predictors for new-onset AF in this patient group. Thus, screening for AF in hospitalized CKD patients might be reasonable.

Ethics approval and consent to participate
The study received approval of the Medical Ethics Committee of the Hospital District of Southwest Finland and the ethics committee of the National Institute for Health and Welfare. The study adheres to the Declaration of Helsinki. Each patient provided written informed consent for the study. Figure 1 Kaplan-Meier survival curve for AF incidence according to increased LAVI Kaplan-Meier survival curve for AF incidence according to elevated TnT Figure 3