Analysis Plan Submission Form

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1 Analysis Plan Submission Form DMHT : Analysis Plan # Date submitted: 19 November 2018 at 13:16:20 Date approved: Analysis Plan Title: The Association between Serum Uric Acid and Chronic Kidney Disease in Patients with Hypertension: A Multicenter Nationwide Cross-sectional Study Investigator s Name: Wisit Kaewput (wisit_nephro@hotmail.com) Contact Address: Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand Rationale/Background: The prevalence of hypertension and its related complications has rapidly risen worldwide, resulting in significantly increased morbidity and mortality (1, 2). One of these hypertensive related progressive end-organ injury effects consists of chronic kidney disease (CKD). CKD has a high health burden and healthcare expenditure and combined with hypertension can substantially accelerate vascular disease (3). Laterally related, hyperuricemia is also a common finding that has been associated with multiple vascular complications (1, 4-13), especially in patients with gouty arthritis. Serum uric acid has been utilized to monitor for the occurrence of cardiovascular complications (1, 14). Prior studies have also shown that serum uric acid levels are an independent risk factor for the progression of a variety of kidney diseases (4, 15-23). A prospective cohort study by Bellomo et al. showed an association between serum uric acid and a decline in renal function in healthy normotensive individuals (24). Another prospective controlled trial had examined the effects of decreasing serum uric acid with allopurinol in CKD patients with hyperuricemia and the clinical outcomes (25-27). The intervention group showed a slower decrease in kidney function, suggesting a role of uric acid in the pathogenesis of CKD. Other previous studies have also demonstrated that hyperuricemia in gout patients is associated with CKD (28-32). However, other studies had failed to demonstrate this association between kidney dysfunction and hyperuricemia (30, 33-39). There are also no reports that demonstrate the pattern and magnitude for the association between uric acid and CKD between patients with and without gouty arthritis. Consequently, it is unclear whether hyperuricemia is a risk factor that accelerates CKD in hypertensive patients or if the kidney function deteriorations are from hypertension itself. Furthermore, there is a lack of data showing the magnitude and pattern of association between uric acid and CKD in hypertensive patients. The present study sought to determine whether there

2 exists an association of uric acid and CKD in hypertensive patients, and then to identify the pattern and magnitude of such an association between hypertensive patients with and without gouty arthritis. Objective: The Association between Serum Uric Acid and Chronic Kidney Disease in Patients with Hypertension: A Multicenter Nationwide Cross-sectional Study Dataset to be used: Primary outcome descriptions: serum uric acid level range was selected as the reference group for outcome comparison Primary outcome variable: Materials and Methods: Study Design and Population This was a nationwide, multi-center, cross-sectional study. Secondary analysis was performed using the DM/HT dataset in 2014 (40). Data Collection Clinical characteristics, demographic information, medication, and laboratory data were collected using manual data retrieval from the medical record as described above. The most recent uric acid within 12 months prior to the consent process was collected. GFR was estimated based on age, sex, race and the most recent creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (41). Primary outcome was chronic kidney disease, defined as egfr of 60 ml/min/1.73 m 2 based on KDIGO guideline for chronic kidney disease (42). Statistical Analysis Continuous variables were presented as mean ± standard deviation. Categorical variables were presented as count with percentage. Baseline demographics and clinical characteristics were compared among serum uric acid group, using analysis of variance (ANOVA) for continuous variables and the chi-square test for categorical variables. Serum uric acid was categorized into 5 groups, based on its quintile distribution. The most common serum uric acid level range was selected as the reference group for outcome comparison. Univariable and then multivariable logistic regression analysis, adjusting for priori-defined variables, was performed to assess the independent association between serum uric acid and chronic kidney disease. Odd ratio (OR) with 95% confidence interval (CI) was reported. The adjusted variables were age, sex, smoking, waist circumference, duration of hypertension, the number of antihypertensive medication, comorbidities and medications. Comorbidities were diabetes mellitus (DM), dyslipidemia, gout, coronary artery disease (CAD) and cerebrovascular disease (CVD). Medications were renin-angiotensin-aldosterone system (RAAS) blockade use, diuretics, beta-blockers, calcium channel blockers (CCB), direct vasodilators, statin, fibrates, and antiplatelet medications. We further evaluated the pattern and magnitude of associations between serum uric acid and chronic kidney

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