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Accepted Manuscript Urinary calcium excretion and risk of chronic kidney disease in the general population Jacob M. Taylor, PhD, RD, Lyanne M. Kieneker, MSc, Martin H. de Borst, MD, PhD, Sipke T. Visser, MSc, Ido P. Kema, MD, PhD, Stephan JL. Bakker, MD, PhD, Ron T. Gansevoort, MD, PhD PII:

S2468-0249(16)30194-2

DOI:

10.1016/j.ekir.2016.12.007

Reference:

EKIR 88

To appear in:

Kidney International Reports

Received Date: 23 November 2016 Revised Date:

19 December 2016

Accepted Date: 22 December 2016

Please cite this article as: Taylor JM, Kieneker LM, de Borst MH, Visser ST, Kema IP, Bakker SJ, Gansevoort RT, for the PREVEND Study Group, Urinary calcium excretion and risk of chronic kidney disease in the general population, Kidney International Reports (2017), doi: 10.1016/j.ekir.2016.12.007. 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.

ACCEPTED MANUSCRIPT Title: Urinary calcium excretion and risk of chronic kidney disease in the general population

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Authors: Jacob M Taylor, PhD, RDa, Lyanne M Kieneker, MSca, Martin H de Borst, MD,

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PhDa, Sipke T Visser, MScb, Ido P Kema, MD, PhDc, Stephan JL Bakker, MD, PhDa, Ron T

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Gansevoort, MD, PhDa for the PREVEND Study Group

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Institutions and Affiliations:

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a

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Medicine, Division of Nephrology, Groningen, the Netherlands

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Pharmacoepidemiology and Pharmacoeconomics, Groningen, the Netherlands

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University of Groningen, University Medical Center Groningen, Department of Internal

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University of Groningen, University Medical Center Groningen, Department of

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Medicine, Groningen, the Netherlands

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Corresponding Author Information:

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Jacob M Taylor, PhD, RD

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University Medical Center Groningen, University of Groningen, PO box 30.001, 9700 RB

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Groningen, the Netherlands

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Phone: +31 503612688

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Running Head: Urinary calcium excretion and CKD

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Key Words: calcium, nutrition, chronic kidney disease, hypercalciuria

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Word Count

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University of Groningen, University Medical Center Groningen, Department of Laboratory

Fax: +31 503619067

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Email: [email protected]

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ACCEPTED MANUSCRIPT Abstract

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Background and objectives High urinary calcium excretion (UCaE) has been shown to lead

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to accelerated renal function decline in individuals with renal tubular diseases. It is not

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known whether this association also exists in the general population. Therefore, we

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investigated whether high UCaE is associated with risk of developing chronic kidney disease

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(CKD) in community-dwelling subjects.

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Design, setting, participants, & measurements Urine samples of 5,491 subjects who were

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free of CKD at baseline and participated in the PREVEND study (a prospective,

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observational, general population-based cohort of Dutch men and women aged 28-75 years),

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were examined for UCaE. UCa concentration was measured in two 24h urine samples at

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baseline (1997-1998) by indirect potentiometry. UCaE was treated as a continuous variable

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and a categorical variable grouped according to sex-specific quintiles for UCaE. UCaE was

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compared to de novo development of eGFR 30mg/24h.

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Results Baseline median UCaE was 4.13 mmol/24h for men and 3.52 mmol/24h for women.

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During a median follow-up of 10.3 years, 899 subjects developed CKD. After multivariable

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adjustment, every 1mmol/24h higher baseline UCaE was associated with a 6% lower risk for

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incident CKD during follow-up (HR:0.94 [0.88-0.99], p=0.02). The association showed to be

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significantly non-linear, with highest risk of CKD in the lowest quintile for UCaE (HR:1.28

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[0.97-1.68], p=0.09). There was no association between UCaE and mortality or

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cardiovascular health during follow-up, suggesting that this association was not a reflection

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poor nutritional intake due to bad health.

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Conclusion These findings indicate that high UCaE does not increase risk of CKD, but rather

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that low UCaE may be harmful.

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ACCEPTED MANUSCRIPT Introduction

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Calcium and vitamin D are essential nutrients for human health, playing a pivotal role in

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normal bone mineralization. Yet, data from Dutch and American cohorts show that less than

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50% of adults meet their daily recommended intake for calcium and are assumed to be at risk

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for bone fractures (1-3). To meet these recommendations, a substantial portion of the

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population must increase calcium intake through dietary interventions, such as by increasing

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the intake of dairy products, or by being prescribed daily calcium supplements. Recently,

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however, investigators have questioned whether increasing the intake of calcium is

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beneficial, since higher intakes of calcium were not associated with a reduction in bone

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fractures (4). The promotion of higher intakes of calcium has also come under scrutiny

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because this will likely lead to higher UCaE and kidneys may be susceptible to damage from

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high UCaE.

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It has been shown that specific renal tubular diseases that result in hypercalciuria lead

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to nephrocalcinosis and accelerated renal function loss. For instance, 30-80% of males

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suffering from Dent’s disease develop chronic kidney disease (CKD) between 30 and 50

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years of age, and familial hypomagnesemia with hypercalciuria results in CKD by age 30 in

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50-73% of cases (5-8). These findings suggest that high urinary calcium excretion (UCaE)

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may have deleterious renal effects. Cohort studies that investigated the impact of UCaE, such

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as the Nurses’ Health Study, have focused on the association between UCaE and kidney

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stones, leaving unknown whether high UCaE effects long-term kidney function in community

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dwelling subjects (9). Therefore, we investigated the association between high UCaE and risk

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of developing CKD in a general population cohort.

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ACCEPTED MANUSCRIPT Materials and Methods

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Study Design and Population

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The PREVEND study is designed to prospectively investigate the natural course of increased

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levels of UAE and its relation with renal and cardiovascular outcome in a large cohort drawn

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from the general population. Details of this study have been described elsewhere (10). In

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brief, from 1997 to 1998, all inhabitants of Groningen (the Netherlands), aged 28 to 75 years

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(n=85,421), were sent a short questionnaire on demographics and renal and cardiovascular

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morbidity and a vial to collect a first morning void urine sample. Altogether, 40,856 people

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(48%) responded and their urinary albumin concentration was assessed. Of these people,

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9,966 had a urinary albumin concentration of ≥10 mg/L. After exclusion of pregnant women

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and subjects with type 1 diabetes mellitus, 7,768 subjects were invited to participate, of

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whom 6,000 consented and were enrolled. In addition, of the 40,856 responders, there were

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30,890 people with a urinary albumin concentration 6 weeks. Hypertension was defined as

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systolic blood pressure of ≥140 mmHg, a diastolic blood pressure of ≥90 mmHg, or the use

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of antihypertensive agents as previously described (15,16). Urinary sodium, potassium,

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magnesium, urea and circulating levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D,

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calcium, phosphorus, PTH, magnesium, total cholesterol, HDL cholesterol, triglycerides, and

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glucose were determined as previously described (12,17-20). Hypercholesterolemia was

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defined as having a total cholesterol >6.2 mmol/L without a history of myocardial infarction,

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a total cholesterol >5.2 mmol/L with a history of myocardial infarction, or use of a lipid

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lowering drug. Diabetes was defined as a fasting plasma glucose ≥7.0 mmol/L (>126 mg/dL)

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or the use of glucose-lowering drugs (21). Information on calcium and vitamin D

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supplements, thiazide and loop diuretics, and bisphosphonates were obtained from the

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IADB.nl database, a database which contains pharmacy-dispensing data from community

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pharmacies in the northern part of the Netherlands (22).

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Statistical Analyses

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Baseline characteristics are presented according to sex-specific quintiles of UCaE. Ranges for

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the quintiles remained the same during sensitivity analyses to allow for ease comparing

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results. Continuous data are presented as mean ± SD or as median (IQR) in the case of

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skewed distribution. Categorical data are presented as percentages. Linear-by-linear

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associations were determined by χ2 test for categorical variables and linear regression for

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continuous variables. UCaE was analyzed as a continuous variable and in sex-specific quintiles. To study

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the prospective association between UCaE and risk of developing CKD, Cox proportional

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hazards regression analyses were used to calculate HRs and 95% CIs. Nonlinearity was tested

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by using the likelihood ratio test, comparing nested models with linear and cubic spline

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terms.

We first calculated HRs (95% CIs) for the crude model. Second, we adjusted for body

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size and non-modifiable factors associated with risk of kidney dysfunction, including age,

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sex, height, weight, race, and baseline eGFR and lnUAE. Third, we adjusted for renal disease

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risk factors, including smoking, alcohol, hypertension, diabetes, parental history of CKD, and

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hypercholesterolemia. Fourth, we adjusted for plasma markers and supplement/medication

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usage that may affect calcium uptake and excretion, including plasma magnesium, calcium,

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phosphorus, PTH, 1,25 dihydroxyvitamin D, albumin, use of loop diuretics, thiazide

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diuretics, calcium supplements, vitamin D supplements, and bisphosphonates. Finally, we

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additionally adjusted for dietary factors potentially associated with risk of CKD and UCaE,

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including urinary sodium, potassium, urea, and magnesium excretion. In secondary analyses,

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CKD incidence was defined by either impaired eGFR or albuminuria alone. We also

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evaluated potential effect modification by sex, plasma calcium, PTH, 25-hydroxyvitamin D,

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and 1,25-dihydroxyvitamin D, by fitting models containing both the main effects and their

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cross-product terms.

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Several sensitivity analyses were performed to examine the robustness of the

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associations between UCaE and risk of CKD. First, we excluded subjects at baseline with an

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ACCEPTED MANUSCRIPT eGFR 30) to

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assure a more pronounced decline in kidney function to define the primary outcome of

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incident CKD. Second, we analyzed the data excluding subjects with potential inadequate 24-

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hour urine collections. We defined potential inadequate 24-hour urine collections (i.e. over or

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under collection) as the upper and lower 2.5% of the difference between the estimated and

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measured volume of a subject’s 24-hour urine sample. The estimated 24-hour urine volume

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was derived from the formula: Creatinine clearance = ([urine creatinine]×24-hour urine

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volume)/[serum creatinine]), where creatinine clearance was estimated using the Cockcroft-

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Gault formula (23). Third, we addressed the oversampling of subjects with higher urinary

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albumin concentrations by analyzing the data in a subset of subjects from the cohort that are

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representative of the Netherlands population. This subset included all subjects with a urinary

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albumin concentration of 95% of the PREVEND cohort is Caucasian. Lastly, the

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PREVEND cohort oversampled individuals with elevated UAE. However, subjects with

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elevated albuminuria at baseline were excluded from these analyses, and when we

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additionally adjusted for sample design in one of the sensitivity analyses this rendered similar

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trends.

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Strengths of this study include that it is the first study to examine the associations of UCaE on risk of CKD in a population-based cohort, along with this study being conducted

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prospectively, collecting multiple 24-hour urine samples, and having a relatively large sample

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size. We also used a CKD end point that consisted of a creatinine-cystatin C-based eGFR and

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two consecutive 24-h UAE at each time point to determine CKD events. Lastly, several

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sensitivity analyses (some using alternative end points, such as decline in eGFR per year, risk

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of being a fast progressor to CKD, and risk of having ≥25% decline in kidney function during

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follow-up) were performed to confirm our findings.

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In conclusion, low UCaE, rather than high UCaE, was associated with an increased risk of developing CKD in this prospective, population-based cohort study. This effect

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remained even after adjustment for various confounders. While the effect of increasing

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calcium intake on bone health may be in question, one modifiable factor that may be

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renoprotective is the avoidance of low UCaE.

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Acknowledgements

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The PREVEND study has been made possible by grants from the Dutch Kidney Foundation.

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This work was supported by research grants CH001 and CH003 from the Top Institute (TI)

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Food and Nutrition, the Netherlands. The supporting agencies had no role in the design or

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ACCEPTED MANUSCRIPT conduct of the study, collection, analysis, or interpretation of the data, or the preparation and

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approval of the manuscript.

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Disclosures

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None of the authors reported a conflict of interest.

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Author Responsibility

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The authors’ responsibilities were as follows—SJLB and RTG created the concept and design

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of the study; SJLB, RTG, STV, and IPK acquired the data; JMT and LMK performed the

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statistical analyses and wrote the first draft of the manuscript; MHB, SJLB and RTG

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provided critical review, advice, and consultation throughout.

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Table 1. Baseline characteristics according to quintiles of urinary calcium excretion of 5,491 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study Sex-specific quintiles of urinary calcium excretion, mmol/24-hour Ptrend ♂ 5.80 Variables lineara N ♀ 5.14 Overall Participants, N 5491 1098 1098 1101 1097 1097 Women, % 5491 52.6 52.6 52.6 52.7 52.6 52.6 0.98 Age, y 5491 48.3 ± 11.7 47.9 ± 12.7 47.9 ± 12.2 48.2 ± 11.7 48.2 ± 11.2 49.4 ± 10.8 0.001 Race, whites, % 5454 95.9 91.8 95.4 96.7 97.3 98.3