The Association of Kidney Function and Albuminuria With the Risk and Outcomes of Syncope: A Population-Based Cohort Study

Accepted Manuscript The association of kidney function and albuminuria with the risk and outcomes of syncope: A population-based cohort study David Massicotte-Azarniouch, MD, John Paul Kuwornu, PhD, Megan K. McCallum, MPH, Nisha Bansal, MD MAS, Ngan Lam, MD MSc, Amber O. Molnar, MD MSc, Patrick Pun, MD MHS, Deborah Zimmerman, MD MSc, Amit X. Garg, MD PhD, Manish M. Sood, MD MSc PII:

S0828-282X(18)31105-X

DOI:

10.1016/j.cjca.2018.08.033

Reference:

CJCA 3033

To appear in:

Canadian Journal of Cardiology

Received Date: 29 May 2018 Revised Date:

15 August 2018

Accepted Date: 23 August 2018

Please cite this article as: Massicotte-Azarniouch D, Kuwornu JP, McCallum MK, Bansal N, Lam N, Molnar AO, Pun P, Zimmerman D, Garg AX, Sood MM, The association of kidney function and albuminuria with the risk and outcomes of syncope: A population-based cohort study, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.08.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The association of kidney function and albuminuria with the risk and outcomes of syncope: A population-based cohort study.

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David Massicotte-Azarniouch MD1, John Paul Kuwornu PhD2, Megan K McCallum MPH2 Nisha Bansal MD MAS3, Ngan Lam MD MSc4, Amber O Molnar MD MSc2,5, Patrick Pun MD MHS6, Deborah Zimmerman MD MSc7, Amit X Garg MD PhD8, Manish M Sood MD MSc2,8,9 1

Department of Medicine, University of Ottawa, Ottawa, Canada. Institute for Clinical Evaluative Sciences, Ontario, Canada. 3 Kidney Research Institute, Division of Nephrology, University of Washington, Seattle WA USA. 4 Division of Nephrology, University of Alberta, Edmonton, Alberta, Canada. 5 Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada 6 Duke Clinical Research Institute, Division of Nephrology, Duke University, Durham NC, USA. 7 Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada. 8 Division of Nephrology, Western University, London, Ontario, Canada. 9 Ottawa Hospital Research Institute, Ottawa, Canada.

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Correspondence: Dr. Manish M Sood, Ottawa Hospital Research Institute, The Ottawa Hospital, Civic campus, 2-014 Administrative Services Building, 1053 Carling Avenue, Box 693, Ottawa, Ontario, Canada, K1Y 4E9, [email protected]. Phone 613 798 5555 ext 17176, FAX

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Short Title: Syncope in patients with CKD References: 42 Tables: 4

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Figures: 3 Supplementary Figures: 2

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Supplementary Tables: 5

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BRIEF SUMMARY

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Using administrative databases in Ontario, Canada, 272, 146 (age ≥66) individuals with chronic kidney disease (CKD, defined by albuminuria and/or reductions in estimated glomerular

filtration rate eGFR) were examined for the risk and consequence of syncope. Higher albumin

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and/or reductions in eGFR were associated with a higher risk of incident syncopal events,

compared to normal kidney function, and those with a syncopal event were at high subsequent

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risk of a cardiovascular event or death. Evaluation and preventative therapies for CKD patients

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who present with syncope may reduce future adverse cardiac events.

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ABSTRACT Background

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The risks and subsequent outcomes of syncope among seniors with chronic kidney disease (CKD) are unclear. Methods

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We conducted a population-based retrospective cohort study of 272,146 patients ≥66 years old in Ontario, Canada from April 1st 2006 to March 31st 2016. Using administrative healthcare

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databases we examined the association of estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) with incident syncope, and the association of incident syncope with the composite outcome of myocardial infarction, stroke, and death by levels of eGFR/ACR

Results

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using adjusted Cox proportional hazards models.

A total of 15,074 incident syncopal events occurred during the study period. The adjusted risk

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for syncope was higher with a lower eGFR and higher ACR in a step-wise manner [eGFR 60<90: HR 1.17 (1.09-1.26) vs. eGFR <30: HR 1.67 (1.50-1.87) with eGFR ≥90 referent; ACR

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>30: HR 1.15 (1.07-1.24) with ACR <3 referent]. Among the 12,710 individuals with a first syncope event and 1 year of follow up, the adjusted risk for the composite outcome was higher with a lower eGFR and higher ACR in a step-wise manner [eGFR 60-<90: HR 1.05 (0.90-1.22) vs. eGFR <30: HR 1.62 (1.34-1.96) with eGFR ≥90 referent; ACR >30: HR 1.77 (1.60-1.96), ACR <3 referent]. Conclusions

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A lower eGFR and higher ACR are associated with a higher risk of a hospital encounter for syncope, and of related complications among individuals of an advanced age.

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Keywords: Chronic kidney disease, syncope, eGFR, ACR, epidemiology

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INTRODUCTION Within the general population, syncope has an overall incidence rate of 6.2 per 1000

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person-years within the general population.1 As age increases, there is a rise in incidence to over 11 per 1000 person-years in people 70 years or older.1,2 Syncope is responsible for significant healthcare utilization with an estimated annual cost for syncope-related hospitalizations of 2.4 billion dollars in the United States (US).3 While the most frequent diagnosis associated with

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syncope is orthostatic or vaso-vagal, a significant proportion of episodes are due to heart

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disease.4 Among seniors, a cardiac cause is more common 5 and is associated with an increased risk of death, myocardial infarction, and stroke.1,4 Therefore, a syncopal event may be an ominous sign of a serious underlying condition with a higher risk for adverse outcomes. Chronic kidney disease (CKD) affects between 10-15% of the general population

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reaching prevalence estimates of over 20% in individuals 70 years or older.6–9 Both decreased estimated glomerular filtration rate (eGFR) and increased urine albumin to creatinine ratio (ACR) are associated with an increased risk for cardiovascular events and all-cause mortality.10– Indeed, ventricular arrhythmias and sudden cardiac death are a major cause of mortality in

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patients with advanced kidney disease.16 As such, a syncopal event in this population may be a

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marker for underlying cardiovascular disease. To date, little is known of the risk and prognosis of syncope in patients with kidney disease. The aim of this study was 1) to examine the association of kidney function (as measured

by eGFR and ACR level) with incident syncope and 2) to examine the association of syncope and adverse outcomes in patients with CKD. We hypothesized that a lower eGFR/higher ACR would be associated with i) a greater risk for incident syncope and ii) a greater risk for adverse cardiovascular outcomes among those with a syncopal event.

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METHODS

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Design and Setting We conducted a population-based retrospective cohort study in the province of Ontario, Canada from April 1st 2006 to March 31st 2016 using healthcare databases housed at the Institute

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for Clinical Evaluative Sciences (ICES). This study was approved by the institutional review board at Sunnybrook Health Sciences Centre (Toronto, Ontario, Canada). Due to the

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retrospective nature of our study and the use of de-identified information, informed consent for the study was waived. The reporting of this study follows the RECORD guidelines for

Data Sources

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observational studies.17

We ascertained patient characteristics, laboratory data, and outcome data from linked

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databases. Gamma-Dynacare was used to obtain outpatient laboratory data. Gamma-Dynacare is a laboratory service provider that contains outpatient lab information for individuals who had

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bloodwork drawn at any of their 148 collection sites in Ontario. Demographics and vital status information were obtained from the Ontario Registered Persons Database (RPDB) and physician specialization information was obtained from the ICES Physician Database. Diagnostic and procedural information from all hospitalizations was determined using the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD18). Diagnostic information from emergency room visits was determined using the National Ambulatory Care Reporting System (NACRS). Information was also obtained from the Ontario Health Insurance Plan database,

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which contains all health claims for inpatient and outpatient physician services. Medication information was obtained from the Ontario Drug Benefit Database (ODB) that contains comprehensive prescription information for those aged 65 or older.19 We identified patients with

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a history of kidney transplant or dialysis therapies (exclusion criteria) using the Canadian Organ Replacement Register (CORR20). These datasets were linked using unique encoded identifiers

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validated codes (Supplementary Table 1).

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and analyzed at ICES. Whenever possible, we defined patient characteristics and outcomes using

Study Cohort

We included all patients ≥66 years old with an outpatient measure of eGFR and ACR obtained within 12 months of each other and between 2006 and 2015. The index date (date of

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cohort entry) was the date of the ACR measure. In Ontario, patients ≥65 years old have medications covered by the ODB, allowing us to have access to comprehensive medication information of at least one year for the entire study population. We excluded patients with a

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history of dialysis in the year prior to index date to focus our study on the non-dialysis CKD population. We also excluded patients with a previous kidney transplant and a previous diagnosis

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of syncope in the five years prior to index date (Supplementary Table 1). We created two separate study cohorts. First, we looked forward from the ACR measure to the first incidence of syncope. The patients who had syncope during the study period with a minimum of 12 month follow up in the first analysis (to ensure adequate time for determination of outcomes) comprised the cohort for the second analysis looking at recurrence, outcomes and prognosis of syncope (Supplementary Figure 1). For these patients, date of syncope was chosen as the index date.

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Demographics

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For both analyses, demographic variables were ascertained at index date and were compared between different eGFR and ACR groups. They included age, sex, income (using the neighbourhood-level income based on an individual patient’s code for their primary residence),

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place of residence, year of index date, healthcare utilization, co-morbidities and medication use. Comorbidities were ascertained in the five years prior to the index date. Healthcare resource

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utilization was ascertained in the one year prior to the index date, including visits to hospitals, emergency departments, family physicians, and nephrologists. Medications were ascertained 120 days prior to index date.

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Exposures and Outcomes

We used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to calculate eGFR as mL/min/1.73 m2 using serum creatinine measurements.21 Urine ACR

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measurement was calculated as mg albumin/mmol creatinine on spot outpatient urine tests.

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Patients were divided into strata based on eGFR (≥90, 60-<90, 45-<60, 30-<45 and <30) and ACR (<3, 3-30 and >30) corresponding to KDIGO stages of CKD.22 For both analyses, the exposure of interest was the level of eGFR, using eGFR ≥90ml/min/m2 as referent, and ACR, using ACR <3mg/mmol as referent. Syncope was defined using International Classification for Disease, Tenth Revision (ICD-10; Code R55) during hospital admission or emergency department visits. Patients were censored at outcome of interest, until the end of the study period, death, receipt of dialysis or

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kidney transplant (censoring events). The validated ICD code for syncope has positive and negative predictive values of 95% and 99.5%, respectively.23

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Descriptive outcomes of interest included investigations and evaluations conducted in the 30 days after the initial syncope healthcare encounter. Clinical outcomes of interest were death, MI, stroke and arrhythmia. For death, patients were followed until death (event of interest) or end of study period (censoring event). For MI, stroke and arrhythmia, patients were followed

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until MI, stroke, or arrhythmia (event of interest) respectively, death (competing event) or end of

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study period (censoring event). The type of arrhythmia (supraventricular, ventricular, bradyarrhythmia or other) was also ascertained. All outcomes were determined through the use of ICD 10 codes, arrhythmia was also identified through the use of Ontario Health Insurance Plan fee codes, and mortality was identified through the Ontario RPDB (see codes in

Statistical Analysis

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Supplementary Table 1).

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Differences in baseline characteristics were determined using parametric and nonparametric tests as appropriate. Incidence rates (rate per 100 person-year follow-up) were

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calculated for the composite and the subcomponent outcomes of interest. We used Cox proportional hazards models to assess the association of eGFR and ACR categories with a first syncopal event. An eGFR X ACR interaction term was examined for effect modification on the risk for incident syncope. We also examined the association with outcomes using Fine and Grey models with the sub-distribution hazard ratio (sHR) to account for the competing event of death.24 This is useful in CKD studies in elderly patients since death is a common competing

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outcome.25 Lastly limiting our cohort to individuals with a syncopal event only, we used Cox proportional hazards models to examine the association of eGFR/ACR levels and clinically relevant outcomes of death, MI, stroke, arrhythmia and the composite of MI/stroke/death. All

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analyses were adjusted for baseline demographics, comorbidities, index year, healthcare

utilization and medications. All analyses were conducted with SAS software, version 9.4 (SAS

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Institute Inc., Cary, NC, USA). Two-sided p-values <0.05 were treated as statistically significant.

Incidence and risk for first syncope

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RESULTS

A total of 272,146 patients ≥66 years old with eGFR and ACR measurements were included during the study period. Tables 1a and 1b outline the patient characteristics. The mean age was

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75 years and the mean eGFR was 68 ml/min/1.73m2 with nearly 90,000 patients having an eGFR <60 ml/min/1.73m2. Median ACR was 8 mg/mmol, and over 75,000 patients had an ACR >3. A total of 15,074 first syncope events occurred during the study period. For patients with eGFR

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≥90, the incidence of syncope was 0.62 events per 100 person-years and this increased as eGFR and ACR worsened (Figure 1). The hazard ratio (HR) for syncope was significantly greater for

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lower levels of eGFR and higher levels of ACR, in both unadjusted and adjusted models [adjusted HR: 1.17 (1.09-1.26), 1.37 (1.27-1.49), 1.49 (1.37-1.63) and 1.67 (1.50-1.87) for eGFR 60-<90, 45-<60, 30-<45 and <30 respectively, eGFR ≥90 referent; 1.09 (1.05-1.13) and 1.15 (1.07-1.24) for ACR 3-30 and >30 respectively, ACR <3 referent] (Table 2). Similar results were found when looking at the risk for recurrent syncope (Supplementary Table 2). When accounting for the competing risk of death, the sub-hazard ratio (sHR) for syncope remained significant for

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eGFR but was no longer significant for ACR (Table 2). There was no interaction between eGFR

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and ACR for the adjusted risk of syncope (ACR X eGFR interaction 0.097).

Investigations, health services and diagnoses for first syncopal event

Of the 15,074 patients with a first syncopal episode, 12,710 patients had a minimum of 12

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months follow-up. The characteristics of these patients are shown in Supplementary Table 3. In 52% of cases, a diagnosis of syncope led to a hospital admission within 30 days. Investigations

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and evaluations done for the syncope episode by eGFR and ACR are shown in Figure 2. The most frequent investigations done within 30 days of diagnosis of incident syncope were ECG, chest X-ray and CT of the chest occurring in a total of 93%, 63%, and 52% of cases respectively. One third (33%) of patients received an echocardiogram and 19% underwent a Holter monitor.

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Thirty five percent of patients received an Internal Medicine consultation, 29% a Cardiology consultation and 7% a Nephrology consultation. Apart from chest X-ray, the frequencies of investigations were similar across eGFR and ACR strata. In 3% of patients with a first syncope,

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a diagnosis of death, MI or stroke occurred during the hospital admission precipitated by that syncopal event, and the frequency of this composite diagnosis increased with worsening kidney

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function. In 15% of patients, a diagnosis of arrhythmia occurred (Supplementary Figure 2).

Outcomes in patients with syncope Table 3 and Figure 3 show outcomes for patients with incident syncope based on eGFR and ACR levels. Compared to patients with normal kidney function, the adjusted HR for developing the composite of MI, stroke or death was 1.31 (1.23-1.39) and 1.77 (1.60-1.96) for ACR 3-30 and

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>30 respectively, ACR <3 referent, and 1.05 (0.90-1.22), 1.12 (0.96-1.32), 1.28 (1.08-1.51) and 1.62 (1.34-1.96) for eGFR 60-<90, 45-<60, 30-<45 and <30 respectively, eGFR ≥90 referent. Patients with higher ACR had a greater adjusted HR for developing any of the individual adverse

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outcomes of death, MI, stroke, and arrhythmia when compared to ACR <3 [death: 1.35 and 2.00 for ACR 3-30 and >30 respectively; MI: 1.30 and 1.76 for ACR 3-30 and >30 respectively; stroke 1.20 and 1.34 for ACR 3-30 and >30 respectively; arrhythmia 1.15 for both ACR 3-30 and

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>30]. In the competing risk model, the sHRs attenuated but remained significant for MI [1.24 and 1.52 for ACR 3-30 and >30 respectively]. When looking at eGFR groupings and comparing

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to eGFR ≥90, the adjusted HR for death was greater at lower levels of eGFR [death: 1.06, 1.15, 1.37 and 1.84 for eGFR 60-<90, 45-<60, 30-<45 and <30 respectively]. The adjusted risks at all eGFR levels for the individual outcomes of MI, stroke and arrhythmia were not significant compared to eGFR ≥90.

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The type of arrhythmia diagnosed in patients with syncope was examined by strata of eGFR and ACR. After having a syncopal event, 23.4% of patients were diagnosed with a supraventricular arrhythmia, 3.2% a ventricular arrhythmia and 12.0% a bradyarrhythmia. The incidence rates for

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each type of arrhythmia was greater at lower levels of eGFR and higher levels of ACR (Table 4).

DISCUSSION

In this retrospective, population-based cohort study of seniors, patients with CKD

(eGFR<60) had a 1.37 to 1.67-fold greater annual risk of syncope compared to patients with preserved eGFR, and there was a graded association between the incidence of syncope and lower eGFR/higher ACR. Syncopal events in individuals with kidney disease were associated with a

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higher risk of death, MI, stroke and arrhythmia. Syncope also lead to a frequent number of investigations, hospitalizations and healthcare specialist referrals. Our findings illustrate how common syncopal events are in patients with CKD and the prognostic importance of the severity

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of kidney dysfunction.

Prior to our study, the incidence of syncope in the CKD population represented an

important knowledge gap. One study of 78 hemodialysis patients reported that 24% of patients

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experienced a syncopal event over a 6 month period, which is a much higher incidence than that

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seen in the general population.26 A prospective study that examined outcomes in 395 patients presenting with syncope or near syncope to the emergency department reported lower eGFR as an independent risk factor for subsequent adverse outcomes.27 In our study, we found an incidence of syncope of 0.62 events per 100 person-years in elderly patients with normal eGFR (≥90ml/min), consistent with what has previously been reported in the general population.1

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Among patients with CKD, we found a significant elevation in the incidence of syncope ranging from 1.32 to 2.09 events per 100 person-years in patients with eGFR <60 and 1.29 to 1.52 events per 100 person-years in patients with albuminuria. The adjusted risk for syncope was

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significantly greater with lower eGFR, as well as higher albuminuria, but to a lesser extent.

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We found that both eGFR and urine ACR were important determinants for adverse outcomes in elderly patients with syncope. Those with lower levels of eGFR had a significantly higher adjusted risk for the composite outcome of MI, stroke or death, however, in patients with albuminuria, this risk was even greater. Albuminuria was also significantly associated with each of the individual adverse outcomes of death, MI, stroke and arrhythmia, and when accounting for the competing risk of death, the risk for MI remained significantly increased. These findings highlight the importance of ACR as a marker of kidney disease independent of eGFR and its

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potential role to prognostic for future syncopal events. Also, the increased risk for cardiac arrhythmia seen in patients with CKD may account for the poor outcomes after a syncopal event found in our study. While atrial fibrillation occurs more frequently in patients with worsening

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kidney function,28 limited data exists on the frequency and incidence of ventricular arrhythmias in patients with CKD.29 Advanced CKD may lead to diffuse coronary artery calcification,30 as well as ventricular remodelling and myocardial fibrosis leading to left ventricular hypertrophy31

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which may cause cardiac arrhythmias even in the absence of significant coronary artery

disease.32 The risk for sudden cardiac death has previously been shown to increase by 11% for

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every 10ml/min decrease in eGFR.33 Therefore, the development of syncope in patients with kidney dysfunction may be a harbinger for a more serious underlying cardiovascular condition, which could account for the increased adverse outcomes noted in our study population. We found that 20% of first diagnosed syncope events leading to hospital admission were

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accompanied by a diagnosis of arrhythmia, MI, stroke, or death, pointing to a cardiac cause for the syncopal event. Furthermore, a non-negligible proportion of patients with syncope went on to develop a malignant ventricular arrhythmia, either ventricular tachycardia or ventricular

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fibrillation, and the incidence increased as kidney function worsened. Due to the likelihood of many events not being captured, our findings likely underestimate the potentially life-threatening

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nature of a syncopal event in an elderly patient with kidney dysfunction and suggest a high occurrence of cardiac syncope. Electrolyte imbalances resulting from medications used in CKD or from deteriorating kidney function, as well as the high cardiovascular risk inherent to patients with kidney dysfunction may account for cardiac syncope in this population. Our findings emphasize the need to properly evaluate for underlying arrhythmia and cardiovascular disease in a patient with significant kidney dysfunction having sustained a syncopal event.

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We demonstrated that syncope in older patients with CKD led to high healthcare resource utilization. More than half of all first syncope episodes led to hospital admission in our cohort. Concern for a potential cardiac cause to a syncopal event often leads to hospital admission for

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further evaluation.34 Underlying heart disease has been shown to be a reliable predictor for a cardiac cause of syncope35,36 and for increased mortality,37,38 particularly in the elderly

population.39 Therefore, a syncopal event in an elderly patient with renal impairment should

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prompt considerations for appropriate investigations to rule out a cardiac cause for syncope. Major society guidelines recommend cardiovascular testing for patients with syncope and

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suspected underlying cardiovascular or structural heart disease.40 Despite the high risk of cardiac disease in our population, a surprising minority of patients underwent cardiac investigations beyond an EKG such as an echocardiogram, a Holter monitor or a cardiology consultation. A further surprising observation is the frequency of these investigations did not seem to increase

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with lower levels of eGFR or higher ACR despite the higher risks. This may be because traditional syncope risk scores and previous studies looking at prognostic factors for syncope have failed to consider CKD as a potential adverse factor,41–43 making the need for further

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cardiac investigation more likely to be overlooked. We believe our study highlights a potential underutilization of appropriate cardiac investigations in seniors with CKD and syncope,

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particularly among those with lower eGFR or higher ACR levels. These patients have a much higher likelihood of having significant cardiovascular disease and are often treated with medications which can cause electrolyte imbalances leading to malignant arrhythmias. Future studies should specifically aim to examine the role for more extensive cardiac testing in seniors with CKD having sustained a syncopal event.

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The main strength of our study is its large size encompassing a diverse population throughout the most populous province in Canada. Our study examined a broad range of investigations, healthcare utilization, and clinical outcomes associated with syncope. There are

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limitations worth mentioning. As we focused on individuals with the highest CKD prevalence and risk of outcomes (seniors) our results may not be generalizable to younger patients. By

including patients with available measures of eGFR and ACR, we cover only individuals who

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seek medical attention or receive further evaluation for findings of abnormal kidney function since ACR testing is not part of routine health screening in Ontario. Also, there is a risk of

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misclassification with the use of single values of eGFR and ACR to define levels of CKD, and of ICD codes for identifying diagnoses. However, we did use, when available, validated diagnostic codes. The lack of clinical history on presentation means that the type of syncope cannot be determined with certainty. We did not account for time-varying confounders like changes in

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clinical status or medications that may alter the risk for syncopal events. Finally, the retrospective nature of our study prevents us from establishing a causal relationship between incident syncope in patients with renal impairment and adverse outcomes.

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In conclusion, older patients with CKD are at high risk for incident episodes of syncope.

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These events lead to a significant number of evaluations and healthcare utilization, and confer a significant risk for adverse outcomes. In this setting, it is likely that syncope is the manifestation of a potentially serious underlying cardiovascular disease and proper evaluation for this should be undertaken.

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Acknowledgements We thank IMS Brogan Inc. for use of their Drug Information Database to help link claims and

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prescription data, providing us with medication information for the study.

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Support

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This study was supported by the Institute for Clinical Evaluative Sciences (ICES) Western site. ICES is funded by an annual grant from the Ontario Ministry of Health and LongTerm Care (MOHLTC). Core funding for ICES Western is provided by the Academic Medical Organization of Southwestern Ontario (AMOSO), the Schulich School of Medicine and Dentistry (SSMD), Western University, and the Lawson Health Research Institute (LHRI). The

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research was conducted by members of the ICES Kidney, Dialysis and Transplantation team, at the ICES Western facility, who are supported by a grant from the Canadian Institutes of Health Research (CIHR). The opinions, results, and conclusions are those of the authors and are

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independent from the funding sources. The funders had no role in the design and conduct of the

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study, nor in the collection, management, analysis, and interpretation of the data, nor in the preparation, review, or approval of the manuscript. No endorsement by ICES, AMOSO, SSMD, LHRI, CIHR, or the MOHLTC is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI.

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Disclosures

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None

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Authors’ Contributions

MMS, DMA, MKM and JPK contributed to the study design and review of the

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manuscript. DMA and MMS drafted the first version of the manuscript. JPK conducted the data

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analysis. All authors read, critiqued, contributed to and approved the final manuscript.

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Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med. 2002;347(12):878-885. doi:10.1056/NEJMoa012407

2.

Colman N, Nahm K, Ganzeboom KS, et al. Epidemiology of reflex syncope. Clin Auton Res. 2004;14(SUPPL. 1). doi:10.1007/s10286-004-1003-3

3.

Sun BC, Emond JA, Camargo CA. Direct medical costs of syncope-related hospitalizations in the United States. Am J Cardiol. 2005;95(5):668-671. doi:10.1016/j.amjcard.2004.11.013

4.

D’Ascenzo F, Biondi-Zoccai G, Reed MJ, et al. Incidence, etiology and predictors of adverse outcomes in 43,315 patients presenting to the Emergency Department with syncope: An international meta-analysis. Int J Cardiol. 2013;167(1):57-62. doi:10.1016/j.ijcard.2011.11.083

5.

Del Rosso A, Alboni P, Brignole M, Menozzi C, Raviele A. Relation of clinical presentation of syncope to the age of patients. Am J Cardiol. 2005;96(10):1431-1435. doi:10.1016/j.amjcard.2005.07.047

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Coresh J, Astor BC, Greene T, Eknoyan G, Levey a S. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1-12. doi:10.1053/ajkd.2003.50007

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Coresh J, Byrd-Holt D, Astor BC, et al. Chronic Kidney Disease Awareness, Prevalence, and Trends among U.S. Adults, 1999 to 2000. J Am Soc Nephrol. 2005;16:180-188. doi:10.1681/ASN.2004070539

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Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298(17):2038-2047. doi:10.1001/jama.298.17.2038

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Hsu JY, Roy JA, Xie D, et al. Statistical methods for cohort studies of CKD: Survival analysis in the setting of competing risks. Clin J Am Soc Nephrol. 2017;12(7):1181-1189. doi:10.2215/CJN.10301016

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Roberts R, Jeffrey C, Carlisle G, Brierley E. Prospective investigation of the incidence of

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Baber U, Howard VJ, Halperin JL, et al. Association of chronic kidney disease with atrial fibrillation among adults in the United States REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Circ Arrhythmia Electrophysiol. 2011;4(1):2632. doi:10.1161/CIRCEP.110.957100

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Alboni P, Brignole M, Menozzi C, et al. Diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol. 2001;37(7):1921-1928. doi:10.1016/S0735-1097(01)01241-4

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Costantino G, Perego F, Dipaola F, et al. Short- and Long-Term Prognosis of Syncope, Risk Factors, and Role of Hospital Admission. Results From the STePS (Short-Term Prognosis of Syncope) Study. J Am Coll Cardiol. 2008;51(3):276-283. doi:10.1016/j.jacc.2007.08.059

AC C

EP

TE D

M AN U

SC

RI PT

39.

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Figure Legends

RI PT

Figure 1: Incidence rates of syncope based on renal function

Abbreviations: eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol)

SC

Figure 2: Frequency of investigations and evaluations received for first syncope episode, by eGFR and ACR

M AN U

Abbreviations: ECG electrocardiogram, CXR chest x-ray, CT computed tomography, TTE transthoracic echocardiogram, MRI magnetic resonance imaging, eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol), MI myocardial infarction

Figure 3: Incidence rates for outcomes in patients with syncope, by eGFR and ACR levels

TE D

Composite: MI, stroke, death

AC C

EP

Abbreviations: eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol), MI myocardial infarction

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Table 1a: Baseline characteristics by eGFR eGFR 60<90

eGFR 45<60

eGFR 30<45

eGFR <30

Total cohort

26,153 (9.61)

159,665 (58.67)

51,201 (18.81)

26,140 (9.61)

8,987 (3.3)

272,146 (100)

69.27 (3.41)

73.88 (5.91)

76.79 (6.62)

78.93 (6.93)

80.49 (7.14)

74.69 (6.56)

0.55

0.51

0.54

0.56

0.58

0.53

Quintile 1

0.19

0.19

0.20

0.21

0.23

0.19

Quintile 2

0.22

Quintile 3

0.21

Quintile 4

0.20

Quintile 5

0.18

Total, N (%) Age at index mean (SD)

female

0.22

0.22

0.23

0.23

0.22

0.20

0.20

0.20

0.20

0.20

0.20

0.19

0.18

0.18

0.20

0.19

0.18

0.17

0.16

0.19

0.91

0.91

0.90

0.90

0.91

75.77 (8.69)

53.18 (4.26)

38.45 (4.23)

23.77 (4.91)

67.92 (18.41)

4.99 (25.63)

9.48 (39.08)

17.85 (59.39)

42.05 (107.42)

8.26 (38.64)

0.35 (0.79)

0.37 (0.83)

0.45 (0.95)

0.57 (1.08)

0.75 (1.3)

0.42 (0.90)

0.44 (1.28)

0.43 (1.04)

0.54 (1.21)

0.71 (1.57)

0.99 (1.65)

0.49 (1.19)

8.39 (7.95)

8.59 (7.56)

9.68 (8.53)

11.1 (9.97)

12.45 (11.33)

9.14 (8.31)

Residential Status % 0.92

TE D

Urban Renal Fx. eGFR mean eGFR (SD)

EP

ACR mean (SD)

M AN U

Income quintile %

SC

Sex %

RI PT

eGFR ≥90

AC C

Hospitalizations in last year mean (SD)

ED visits in last year mean (SD)

GP/FP Visits in last year mean (SD) Nephrologist visits in last year

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mean (SD)

0.03 (0.35)

0.04 (0.42)

0.16 (0.71)

0.54 (1.36)

1.41 (2.69)

0.16 (0.84)

Diabetes

0.52

0.48

0.49

0.50

0.51

0.49

Hypertension

0.68

0.74

0.82

0.86

0.86

0.77

Ischemic stroke

0.01

0.01

0.02

Major hemorrhage

0.04

0.04

0.05

Congestive heart failure

0.05

0.07

0.13

MI

0.02

0.02

0.04

Coronary artery disease, excl angina

0.18

0.24

0.31

CABG

0.01

0.02

Peripheral vascular disease

0.01

COPD

0.02

Major Cancer

0.11

Arrhythmia

0.03

Atrial Fibrillation

0.02

Chronic Liver Disease

0.05

0.03

0.02

0.06

0.08

0.04

0.22

0.33

0.11

0.06

0.09

0.03

0.36

0.41

0.26

0.02

0.03

0.03

0.02

0.01

0.02

0.03

0.04

0.01

0.02

0.03

0.05

0.07

0.03

0.12

0.13

0.14

0.15

0.12

0.05

0.09

0.13

0.17

0.07

0.04

0.06

0.09

0.13

0.05

0.04

0.04

0.04

0.04

0.04

Statins

M AN U

SC

0.02

TE D

Medications %

RI PT

Comorbidities %

0.46

0.50

0.55

0.58

0.60

0.51

0.20

0.26

0.36

0.43

0.50

0.30

0.31

0.34

0.41

0.44

0.40

0.36

0.19

0.22

0.29

0.34

0.35

0.25

0.15

0.18

0.23

0.26

0.23

0.19

Calcium Channel Blockers

0.23

0.27

0.34

0.42

0.51

0.30

Antiarrhythmics

0.002

0.01

0.02

0.03

0.05

0.01

Clopidogrel

0.03

0.04

0.05

0.07

0.09

0.04

Glucose lowering agents

0.33

0.29

0.32

0.34

0.35

0.30

Antipsychotics

0.02

0.02

0.03

0.03

0.04

0.02

Antihypertensives

0.62

0.69

0.82

0.89

0.91

0.74

Beta Blockers

ARBs

AC C

Thiazide Diuretics

EP

ACE inhibitors

P-value for all variables between eGFR groups <0.001 Abbreviations: eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol), N number, % percentage, SD standard deviation, ED emergency department, GP/FP general practitioner/family physician, MI

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AC C

EP

TE D

M AN U

SC

RI PT

myocardial infarction, CABG coronary artery bypass graft, COPD chronic obstructive pulmonary disease, ACE angiotensin converting enzyme, ARB angiotensin II receptor blocker

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Table 1b: Baseline characteristics by ACR ACR <3

ACR 3-30

ACR >30

Total

196,585 (72.23)

62,206 (22.86)

13,355 (4.91)

272,146 (100)

74.02 (6.25)

76.42 (7.00)

76.53 (7.03)

74.69 (6.56)

0.54

0.50

0.44

0.53

Quintile 1

0.19

0.21

0.23

0.19

Quintile 2

0.22

0.23

0.24

0.22

Quintile 3

0.20

0.20

0.20

0.20

Quintile 4

0.20

Quintile 5

0.19

Total, N (%)

mean (SD) Sex % female

M AN U

SC

Income quintile %

RI PT

Age at index

0.19

0.18

0.20

0.17

0.15

0.19

0.92

0.92

0.91

63.48 (20.03)

53.46 (21.86)

67.92 (18.41)

1.02 (0.68)

8.76 (6.31)

112.55 (136.30)

8.26 (38.64)

0.37 (0.81)

0.51 (1.06)

0.65 (1.20)

0.42 (0.90)

0.43 (1.08)

0.62 (1.30)

0.82 (1.82)

0.49 (1.19)

8.66 (7.62)

10.21 (9.57)

11.31 (10.59)

9.14 (8.31)

0.09 (0.56)

0.26 (1.10)

0.69 (1.93)

0.16 (0.84)

Diabetes

0.45

0.58

0.67

0.49

Hypertension

0.75

0.80

0.83

0.77

Residential Status % Urban

0.91

eGFR

70.3 (16.84)

ACR mean (SD)

mean (SD) ED visits in last year

AC C

mean (SD)

EP

Hospitalizations in last year

TE D

mean eGFR (SD)

GP/FP Visits in last year mean (SD)

Nephrologist visits in last year mean (SD)

Comorbidities %

0.01

0.02

0.03

0.02

Major hemorrhage

0.04

0.05

0.06

0.04

Congestive heart failure

0.08

0.15

0.21

0.11

MI

0.03

0.04

0.06

0.03

Coronary artery disease, excl angina

0.24

0.31

0.35

0.26

CABG

0.02

0.02

0.03

0.02

Peripheral vascular disease

0.01

0.02

0.03

0.01

COPD

0.02

0.04

0.05

0.03

Major Cancer

0.12

0.13

0.14

0.12

Arrhythmia

0.05

0.10

0.12

0.07

Atrial Fibrillation

0.04

0.08

0.09

0.05

Chronic Liver Disease

0.04

SC

RI PT

Ischemic stroke

M AN U

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0.04

0.05

0.04

0.55

0.60

0.51

0.36

0.43

0.30

0.41

0.44

0.36

0.27

0.34

0.25

0.19

0.20

0.21

0.19

0.26

0.39

0.53

0.30

0.01

0.02

0.01

0.01

0.04

0.05

0.07

0.04

Glucose lowering agents

0.26

0.40

0.52

0.30

Antipsychotics

0.02

0.03

0.03

0.02

0.70

0.81

0.88

0.74

Medications % 0.50

Beta Blockers

0.27

ACE inhibitors

0.34

ARBs

0.23

Thiazide Diuretics Calcium Channel Blockers

AC C

Clopidogrel

EP

Antiarrhythmics

TE D

Statins

Antihypertensives

P-value for all variables between ACR groups <0.001 Abbreviations: eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol), N number, % percentage, SD standard deviation, ED emergency department, GP/FP general practitioner/family physician, MI myocardial infarction, CABG coronary artery bypass graft, COPD chronic obstructive pulmonary disease, ACE angiotensin converting enzyme, ARB angiotensin II receptor blocker

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Table 2: Hazard ratios and sub-hazard ratios of syncope by CKD eGFR and ACR stage Incidence rate / 100 person-years

Crude HR (95% CI) Cox model

Adjusted HR Adjusted (95% CI) sHR (95% Cox model CI) Fine and Grey model

0.62 eGFR ≥90

849 (3.25)

REF (0.58-0.66) 1.50

(0.91-0.95)

(1.39-1.60)

1.32

2.12

(1.27-1.36)

(1.97-2.28)

3,516 (6.87) 1.66

eGFR 30-<45

eGFR <30

1.17

1.24

(1.09-1.26)

(1.15-1.33)

1.37

1.45

(1.27-1.49)

(1.34-1.57)

2.69

1.49

1.49

(1.59-1.74)

(2.48-2.92)

(1.37-1.63)

(1.36-1.62)

2.09

3.44

1.67

1.40

(3.11-3.80)

(1.50-1.87)

(1.25-1.57)

REF

REF

REF

1.29

1.34

1.09

1.02

(1.25-1.33)

(1.29-1.39)

(1.05-1.13)

(0.98-1.06)

1.52

1.59

1.15

0.95

(1.42-1.63)

(1.48-1.70)

(1.07-1.24)

(0.88-1.02)

2,031 (7.77)

681 (7.58)

(1.93-2.25) 0.97 10,292 (5.24)

ACR <3

REF

SC

eGFR 45-<60

0.93 7,997 (5.01)

REF

M AN U

eGFR 60-<90

RI PT

# Syncope events (%)

ACR >30

3,919 (6.30)

EP

ACR 3-30

TE D

(0.95-0.99)

863 (6.46)

AC C

Cox Proportional Hazards Models adjusted for all baseline characteristics (demographics, co-morbidities, index year, healthcare utilization and medications). Fine and Grey sub-distribution hazards models account for the competing risk of death. Results for eGFR groups were adjusted for ACR and results for ACR groups were adjusted for eGFR Abbreviations: HR hazard ratio, sHR sub-hazard ratio, CI confidence interval, eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol), REF referent

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Table 3: Incidence rates and hazard ratios of composite outcome in patients with syncope, by CKD stage (ACR and eGFR) Adjusted HR (95% CI)

11.48

(36.16)

(11.08-11.89)

1692

18.44

1.57

(50.21)

(17.57-19.34)

(1.48-1.66)

(1.23-1.39)

458

25.36

2.12

1.77

(61.98)

(23.09-27.79)

177

7.91

REF

ACR >30

REF 1.31

(1.92-2.33)

(1.60-1.96)

REF

REF

(25.76)

(6.79-9.17)

eGFR

2425

11.70

1.46

1.05

60-<90

(36.19)

(11.24-12.17)

(1.26-1.71)

(0.90-1.22)

1337

14.99

1.86

1.12

45-<60

(44.43)

(14.20-15.81)

(1.59-2.18)

(0.96-1.32)

eGFR

TE D

eGFR ≥90

939

19.34

2.38

1.28

30-<45

(54.25)

(18.13-20.62)

(2.03-2.80)

(1.08-1.51)

eGFR <30

382

28.49

3.38

1.62

(65.52)

(25.71-31.50)

(2.83-4.04)

(1.34-1.96)

2467

8.36 REF

REF

(28.68)

(8.04-8.70)

1431

14.00

1.66

1.35

(42.46)

(13.29-14.75)

(1.55-1.77)

(1.26-1.44)

408

20.17

2.36

2.00

(55.21)

(18.26-22.23)

(2.13-2.62)

(1.79-2.23)

AC C

EP

eGFR

ACR <3 ACR 330

Adjusted sHR (95% CI) Competing Risk Model

RI PT

Crude HR (95% CI)

3110 ACR <3 ACR 330

Death

Incidence rate / 100 personyears (95% CI)

SC

Composite MI, stroke, death

Exposure # of events (%)

M AN U

Outcome

ACR >30

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eGFR ≥90

127

5.31

(18.49)

(4.43-6.32)

eGFR

1912

60-<90

REF

8.45

1.58

1.06

(28.54)

(8.08-8.84)

(1.32-1.90)

(0.89-1.28)

eGFR

1101

11.16

2.09

45-<60

(36.59)

(10.51-11.84)

(1.74-2.51)

eGFR

820

15.26

2.84

30-<45

(47.37)

(14.23-16.34)

(2.35-3.42)

eGFR <30

346

23.23

4.24

1.84

(59.35)

(20.85-25.81)

(3.46-5.19)

(1.48-2.28)

343 ACR <3

1.15

(0.95-1.39) 1.37

SC

(1.13-1.67)

1.19

REF

REF

REF

1.96

1.59

1.30

1.24

(3.99)

(1.07-1.33)

194 (5.76)

(1.69-2.25)

(1.33-1.89)

(1.08-1.55)

(1.03-1.48)

60 (8.12)

3.08

2.43

1.76

1.52

ACR >30

(1.84-3.19)

(1.32-2.34)

(1.14-2.03)

REF

REF

REF

TE D

ACR 330

(2.35-3.96)

23

0.98

(3.35)

(0.62-1.48)

288

1.30

1.32

1.15

1.15

60-<90

(4.30)

(1.16-1.46)

(0.86-2.01)

(0.74-1.77)

(0.75-1.78)

eGFR

152

1.59

1.59

1.22

1.23

45-<60

(5.05)

(1.35-1.86)

(1.02-2.46)

(0.78-1.93)

(0.78-1.94)

eGFR

99

1.90

1.88

1.32

1.27

30-<45

(5.72)

(1.54-2.31)

(1.19-2.96)

(0.82-2.13)

(0.79-2.04)

eGFR <30

35

2.44

2.27

1.49

1.31

(6.00)

(1.70-3.39)

(1.34-3.85)

(0.85-2.61)

(0.74-2.31)

ACR <3

870

3.14

REF

REF

REF

eGFR ≥90

AC C

EP

eGFR

Stroke

M AN U

MI

RI PT

REF

ACCEPTED MANUSCRIPT

(2.93-3.35)

414

4.38

1.34

1.20

1.14

(12.28)

(3.97-4.83)

(1.19-1.51)

(1.07-1.36)

(1.01-1.29)

94

5.02

1.49

1.34

1.16

(12.72)

(4.05-6.14)

(1.21-1.85)

ACR >30

RI PT

ACR 330

(10.12)

(1.07-1.67)

(0.93-1.45)

REF

REF

1.11

1.13

eGFR ≥90

53

2.32

(7.71)

(1.74-3.04)

eGFR

709

3.35

1.42

60-<90

(10.58)

(3.10-3.60)

(1.08-1.88)

(0.83-1.47)

(0.85-1.50)

eGFR

347

3.78

1.59

1.10

1.10

45-<60

(11.53)

(3.40-4.20)

(1.19-2.12)

(0.81-1.48)

(0.82-1.49)

eGFR

199

3.98

1.65

1.05

1.01

30-<45

(11.50)

(3.45-4.58)

(1.22-2.24)

(0.76-1.45)

(0.73-1.39)

eGFR <30

70

5.02

1.97

1.16

1.01

(3.92-6.35)

(1.38-2.81)

(0.79-1.69)

(0.69-1.49)

REF

REF

REF

ACR <3

SC

M AN U

2861

12.96

(33.26)

(12.49-13.44)

1360

19.14

1.32

1.15

1.12

(40.36)

(18.14-20.19)

(1.24-1.41)

(1.07-1.22)

(1.05-1.19)

292

20.64

1.34

1.15

1.07

(39.51)

(18.34-23.15)

(1.19-1.51)

(1.01-1.30)

(0.95-1.20)

REF

REF

REF

EP

ACR 330

(12.01)

TE D

Arrhythmia

REF

AC C

ACR >30 eGFR ≥90

172

8.88

(25.04)

(7.60-10.31)

eGFR

2221

13.13

1.40

1.13

1.15

60-<90

(33.15)

(12.59-13.68)

(1.20-1.63)

(0.97-1.33)

(0.98-1.34)

eGFR

1146

16.27

1.66

1.17

1.17

45-<60

(38.09)

(15.35-17.24)

(1.42-1.95)

(0.99-1.38)

(1.00-1.38)

ACCEPTED MANUSCRIPT

746

20.44

1.98

1.26

1.24

30-<45

(43.10)

(19.00-21.96)

(1.68-2.33)

(1.06-1.50)

(1.05-1.47)

eGFR <30

228

21.63

1.88

1.07

1.00

(39.11)

(18.91-24.63)

(1.54-2.29)

(0.87-1.32)

(0.81-1.23)

RI PT

eGFR

Cox Proportional Hazards Models adjusted for all baseline characteristics (demographics, co-morbidities, index year, healthcare utilization and medications). Fine and Grey sub-distribution hazards models account for the competing risk of death. Results for eGFR groups were adjusted for ACR and results for ACR groups were adjusted for eGFR

AC C

EP

TE D

M AN U

SC

Abbreviations: HR hazard ratio, sHR sub-hazard ratio, CI confidence interval, eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol), MI myocardial infarction, REF referent

ACCEPTED MANUSCRIPT

Table 4: Number of events and incidence rates of type of arrhythmia, by CKD stage (eGFR and ACR) # of events (%)

Supraventricular arrhythmia*

eGFR ≥90 eGFR 60-<90 eGFR 45-<60 eGFR 30-<45 eGFR <30 ACR <3 ACR 3-30 ACR >30 eGFR ≥90 eGFR 60-<90 eGFR 45-<60 eGFR 30-<45 eGFR <30 ACR <3 ACR 3-30 ACR >30 eGFR ≥90 eGFR 60-<90 eGFR 45-<60 eGFR 30-<45 eGFR <30 ACR <3 ACR 3-30 ACR >30

104 (15.14%) 1442 (21.52%) 773 (25.69%) 504 (29.12%) 152 (26.07%) 1864 (21.67%) 920 (27.30%) 191 (25.85%) 22 (3.20%) 211 (3.15%) 104 (3.46%) 54 (3.12%) 20 (3.43%) 260 (3.02%) 126 (3.74%) 25 (3.38%) 42 (6.11%) 764 (11.40%) 377 (12.53%) 257 (14.85%) 82 (14.07%) 958 (11.14%) 466 (13.83%) 98 (13.26%)

EP

Bradyarrhythmia±

M AN U

TE D

Ventricular arrhythmia+

Incidence Rate / 100 person-years (95% CI) 4.83 (3.90-5.76) 7.43 (7.05-7.82) 9.49 (8.82-10.16) 11.48 (10.48-12.49) 12.21 (10.27-14.15) 7.38 (7.04-7.71) 10.98 (10.27-11.69) 11.23 (9.64-12.82) 0.94 (0.55-1.33) 0.96 (0.83-1.09) 1.08 (0.87-1.29) 1.02 (0.75-1.29) 1.37 (0.77-1.98) 0.90 (0.79-1.01) 1.27 (1.05-1.49) 1.26 (0.77-1.76) 1.85 (.129-2.41) 3.74 (3.48-4.01) 4.28 (3.85-4.71) 5.57 (4.89-6.25) 6.31 (4.94-7.68) 3.59 (3.36-3.82) 5.21 (4.73-5.68) 5.52 (4.43-6.61)

RI PT

Exposure

SC

Outcome

AC C

Abbreviations: CI confidence interval, eGFR estimated glomerular filtration rate (ml/min/1.73m2), ACR albumin to creatinine ratio (mg/mmol) Other arrhythmias not classified as supraventricular, ventricular or bradyarrhythmias were not shown since these represented less than 2% of the cohort *Supraventricular arrhythmia includes atrial fibrillation/flutter, paroxysmal tachycardia, atrial premature depolarization and junctional premature depolarization + Ventricular arrhythmia includes ventricular tachycardia and ventricular fibrillation ± Bradyarrhythmia includes atrioventricular and left bundle branch block, other conduction disorders and bradycardia

ACCEPTED MANUSCRIPT

RI PT

2.5 2 1.5

SC

1

ACR > 30 ACR 3-30 ACR < 3

0 eGFR 60<90

eGFR 45<60

eGFR 30<45

EP

TE D

eGFR >90

M AN U

0.5

AC C

Incidence rates of syncope (100 person-years)

Figure 1

eGFR <30

ACCEPTED MANUSCRIPT

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CT

TTE

Holter

MRI

Internal Med consult

SC

CXR

eGFR ≥90

eGFR 60-<90 eGFR 45-<60 eGFR 30-<45

eGFR<30

ACR <3

ACR 3-30

ACR >30

AC C

EP

TE D

M AN U

ECG

RI PT

Figure 2

Cardio consult

Nephro consult

ACCEPTED MANUSCRIPT

30 25

RI PT

20 15 10 5 Composite

Death

MI

Stroke

SC

0 eGFR ≥90

eGFR 60-<90 eGFR 45-<60 eGFR 30-<45

eGFR<30

ACR <3

ACR 3-30

ACR >30

M AN U TE D EP AC C

Incidence per 100 person-years

Figure 3

Arrhythmia