University of Groningen Albuminuria: more than a renal risk marker? van den Belt, Sophie Mariëlle

Albuminuria: more than a renal risk marker?

van den Belt, Sophie Mariëlle

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Publication date: 2018

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van den Belt, S. M. (2018). Albuminuria: more than a renal risk marker? About the prevalence, measurement, and treatment of albuminuria in children. Rijksuniversiteit Groningen.

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518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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How to measure and monitor albuminuria in

healthy toddlers

Authors ^ŽƉŚŝĞD͘ǀĂŶĚĞŶĞůƚ1_{͕sĂůĞŶƟŶĂ'ƌĂĐĐŚŝ}2_{͕ŝĐŬĚĞĞĞƵǁ}1_, ,ŝĚĚŽ:͘>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ1 ĸůŝĂƟŽŶƐ 1_{ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůWŚĂƌŵĂĐLJĂŶĚWŚĂƌŵĂĐŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂů} ĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕dŚĞEĞƚŚĞƌůĂŶĚƐ 2_{ĞƉĂƌƚŵĞŶƚŽĨWĞĚŝĂƚƌŝĐƐ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕} dŚĞEĞƚŚĞƌůĂŶĚƐ ^ƵďŵŝƩĞĚ

4

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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Abstract

Background hƌŝŶĂƌLJĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ;h_ZͿŝŶĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚ;&DsͿƵƌŝŶĞƐĂŵƉůĞƐĐŽůůĞĐƚĞĚ ŽǀĞƌƚŚƌĞĞĚĂLJƐŝƐƚŚĞƌĞĐŽŵŵĞŶĚĞĚŵĞƚŚŽĚĨŽƌŵĞĂƐƵƌŝŶŐĂŶĚŵŽŶŝƚŽƌŝŶŐĂůďƵŵŝŶƵƌŝĂ ŝŶĂĚƵůƚƐŝŶƚŚĞĐůŝŶŝĐĂůƐĞƫŶŐ͘^ƵĐŚĂŐƵŝĚĞůŝŶĞŝƐŶŽƚĂǀĂŝůĂďůĞĨŽƌƚŽĚĚůĞƌƐĂŶĚLJŽƵŶŐ ĐŚŝůĚƌĞŶ͘tĞƚĞƐƚĞĚƐĞǀĞƌĂůƵƌŝŶĞĐŽůůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐĨŽƌĂůďƵŵŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚŝŶ ƚŽĚĚůĞƌƐŝŶĂƉƌŽƐƉĞĐƟǀĞŽďƐĞƌǀĂƟŽŶĂůƐƚƵĚLJ͘ Methods ŽƚŚĂ&DsĂŶĚĂƌĂŶĚŽŵĚĂLJƟŵĞƵƌŝŶĞƐĂŵƉůĞǁĞƌĞĐŽůůĞĐƚĞĚŽŶƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞ ĚĂLJƐĂƚǁĞĞŬϬ͕ϰ͕ĂŶĚϴŝŶƚŽĚĚůĞƌƐĂŐĞĚϭϮͲϰϴŵŽŶƚŚƐ͘/ŶƚƌĂͲŝŶĚŝǀŝĚƵĂůĐŽĞĸĐŝĞŶƚƐ ŽĨǀĂƌŝĂƟŽŶ;sͿŽĨƵƌŝŶĂƌLJĂůďƵŵŝŶ;h_ͿĂŶĚh_ZǁĞƌĞĐŽŵƉĂƌĞĚƵƐŝŶŐŽŶůLJƚŚĞĮƌƐƚ ŵĞĂƐƵƌĞŵĞŶƚĂŶĚƵƐŝŶŐĂůůƚŚƌĞĞŵĞĂƐƵƌĞŵĞŶƚƐƉĞƌƟŵĞƉŽŝŶƚ͘/ŶĂĚĚŝƟŽŶ͕ƚŚĞƐĞǁĞƌĞ ĐŽŵƉĂƌĞĚǁŝƚŚƉƵďůŝƐŚĞĚsŽĨĂĚƵůƚƐ͘ Results ƚŽƚĂůŽĨϴϬƚŽĚĚůĞƌƐ;ŵĞĂŶĂŐĞϮϳŵŽŶƚŚƐ͕ϱϯйŵĂůĞͿǁĞƌĞŝŶĐůƵĚĞĚ͘/ŶƚƌĂͲŝŶĚŝǀŝĚƵĂů sŽĨ&DsƐĂŵƉůĞƐĂƉƉĞĂƌĞĚůŽǁĞƌƚŚĂŶǁŝƚŚƌĂŶĚŽŵƐĂŵƉůĞƐ͘dŚĞŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůs ŝŶh_Žƌh_ZǁĂƐƐŵĂůůĞƌƵƐŝŶŐŵƵůƟƉůĞĐŽŵƉĂƌĞĚƚŽƐŝŶŐůĞƐĂŵƉůĞƐ͘dŚĞůŽǁĞƐƚŝŶƚƌĂͲ ŝŶĚŝǀŝĚƵĂůsǁĂƐŽďƐĞƌǀĞĚǁŚĞŶh_ǁĂƐŵĞĂƐƵƌĞĚŝŶ&DsŽǀĞƌƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞ ĚĂLJƐ;ϯϴ͘ϯйͿ͘sŽĨh_ǁĂƐƐŝŵŝůĂƌƚŽǀĂůƵĞƐƉƵďůŝƐŚĞĚĨŽƌĂĚƵůƚƐ͘,ŽǁĞǀĞƌ͕h_ZsǁĂƐ ĐŽŶƐŝĚĞƌĂďůLJŚŝŐŚĞƌŝŶƚŽĚĚůĞƌƐ͘ Conclusions dŚĞƐĞĚĂƚĂƐŚŽǁƚŚĂƚͲŝŶĂŶĂůŽŐLJǁŝƚŚĂĚƵůƚĚĂƚĂͲŵƵůƟƉůĞĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƵƌŝŶĞ ƐĂŵƉůĞƐƐŚŽƵůĚďĞƉƌĞĨĞƌƌĞĚƚŽƐŝŶŐůĞŽƌƌĂŶĚŽŵƵƌŝŶĞƐĂŵƉůĞƐĨŽƌĞƐƚĂďůŝƐŚŝŶŐĂŶĚ ŵŽŶŝƚŽƌŝŶŐĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐ͘&ƵƌƚŚĞƌƐƚƵĚŝĞƐĂƌĞŶĞĞĚĞĚ ƚŽŝŶǀĞƐƟŐĂƚĞǁŚLJ ĐƌĞĂƟŶŝŶĞĐŽƌƌĞĐƟŽŶĨŽƌĚŝīĞƌĞŶĐĞƐŝŶƵƌŝŶĞĚŝůƵƟŽŶŝƐůĞƐƐĞīĞĐƟǀĞŝŶĐŚŝůĚƌĞŶ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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Introduction

DĞĂƐƵƌĞŵĞŶƚ ŽĨ ƵƌŝŶĞ ĂůďƵŵŝŶ ŝƐ ŝŵƉŽƌƚĂŶƚ͕ ďŽƚŚ ŝŶ ĐůŝŶŝĐĂů ƉƌĂĐƚŝĐĞ ĂŶĚ ŝŶ ĞƉŝĚĞŵŝŽůŽŐŝĐĂůƐƚƵĚŝĞƐĂŶĚĐůŝŶŝĐĂůƚƌŝĂůƐ͘dŽĂĐĐƵƌĂƚĞůLJƋƵĂŶƟĨLJĂůďƵŵŝŶƵƌŝĂŝŶƚŚĞĂĚƵůƚ ƉŽƉƵůĂƟŽŶ͕ĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶŝƐĐŽŶƐŝĚĞƌĞĚƚŚĞŐŽůĚƐƚĂŶĚĂƌĚ͘dŚŝƐŵĞƚŚŽĚ ŝƐƌĂƚŚĞƌĐƵŵďĞƌƐŽŵĞĂŶĚŚĂƐƚŚƵƐďĞĞŶƌĞƉůĂĐĞĚŝŶĐůŝŶŝĐĂůƉƌĂĐƟĐĞďLJĂůƚĞƌŶĂƟǀĞƐ ƐƵĐŚĂƐĐŽůůĞĐƟŽŶŽĨĂĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚ;&DsͿŽƌĂƌĂŶĚŽŵĚĂLJƟŵĞƵƌŝŶĞƐĂŵƉůĞ͘dŽ ĐŽƌƌĞĐƚĨŽƌƵƌŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶŝŶƚŚĞƐĞƐĂŵƉůĞƐ͕ĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶŝƐĚŝǀŝĚĞĚďLJ ĐƌĞĂƟŶŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶ͕ǁŚĞƌĞƚŚĞůĂƩĞƌŝƐĂƐƐƵŵĞĚƚŽďĞĞdžĐƌĞƚĞĚĂƚĂĐŽŶƐƚĂŶƚƌĂƚĞ ŽǀĞƌϮϰŚŽƵƌƐ͘1 dŽǀĂůŝĚĂƚĞƚŚĞƐĞĂůƚĞƌŶĂƟǀĞĂůďƵŵŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚƐĂŐĂŝŶƐƚƚŚĞϮϰͲŚŽƵƌƵƌŝŶĞ ĂůďƵŵŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚ͕ƐĞǀĞƌĂůƐƚƵĚŝĞƐŚĂǀĞďĞĞŶƉĞƌĨŽƌŵĞĚ͘2,3 _{These studies} ƐŚŽǁĞĚƚŚĂƚŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJŝŶh_Z͕ƌĞƉƌĞƐĞŶƚĞĚďLJƚŚĞĐŽĞĸĐŝĞŶƚŽĨǀĂƌŝĂƟŽŶ ;sͿ͕ŝƐůŽǁĞƌŝŶ&DsƚŚĂŶŝŶƌĂŶĚŽŵƐĂŵƉůĞƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕&DsƉĞƌĨŽƌŵƐĂƚůĞĂƐƚĂƐ ŐŽŽĚĂƐĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶ͕ƐŽƚŚĂƚĂĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƵƌŝŶĞƐĂŵƉůĞĐŽŶƐƟƚƵƚĞƐ ĂŐŽŽĚĂůƚĞƌŶĂƟǀĞƚŽĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶ͘2 ,ŽǁĞǀĞƌ͕ƚŚĞƌĞŝƐƐƟůůŶŽĐŽŶƐĞŶƐƵƐŽŶŚŽǁƚŽŽƉƟŵĂůůLJŵĞĂƐƵƌĞĂŶĚŵŽŶŝƚŽƌ ĂůďƵŵŝŶƵƌŝĂŽǀĞƌƟŵĞŝŶƚŽĚĚůĞƌƐ͘ĞĐĂƵƐĞĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶŝƐĞǀĞŶŵŽƌĞ ĐƵŵďĞƌƐŽŵĞŝŶLJŽƵŶŐĐŚŝůĚƌĞŶƚŚĂŶŝŶĂĚƵůƚƐĂŶĚŝƐŶŽƚĨĞĂƐŝďůĞĨŽƌƌĞŐƵůĂƌĐŽŶƚƌŽůƐ͕ŝƚ ŝƐǀĞƌLJŝŵƉŽƌƚĂŶƚƚŽŚĂǀĞƌĞůŝĂďůĞĂůƚĞƌŶĂƟǀĞƐƚŚĂƚĐĂŶďĞĞĂƐŝůLJŝŵƉůĞŵĞŶƚĞĚŝŶĐůŝŶŝĐĂů ƉƌĂĐƟĐĞ͘ dŚĞƌĞĨŽƌĞ͕ŝŶƚŚŝƐƐƚƵĚLJǁĞŚĂǀĞĐŽŵƉĂƌĞĚǀĂƌŝŽƵƐƵƌŝŶĞĐŽůůĞĐƟŽŶƚĞĐŚŶŝƋƵĞƐƚŽ ŵĞĂƐƵƌĞĂŶĚŵŽŶŝƚŽƌĂůďƵŵŝŶƵƌŝĂŝŶŚĞĂůƚŚLJƚŽĚĚůĞƌƐ͘dŚĞƌĞƐƵůƚƐĂƌĞĐŽŵƉĂƌĞĚǁŝƚŚ ƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůs͛ƐŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚĐƌĞĂƟŶŝŶĞŵĞĂƐƵƌĞŵĞŶƚƐ ŝŶĂĚƵůƚƐ͘2

Materials and methods

^ƚƵĚLJƉŽƉƵůĂƟŽŶ /ŶƚŚŝƐŽďƐĞƌǀĂƟŽŶĂůƉƌŽƐƉĞĐƟǀĞĐŽŚŽƌƚƐƚƵĚLJ͕ŚĞĂůƚŚLJƚŽĚĚůĞƌƐ;ϭϮͲϰϴŵŽŶƚŚƐŽĨĂŐĞͿ ǁĞƌĞƌĞĐƌƵŝƚĞĚĨƌŽŵDĂLJϮϬϭϱƵŶƟůKĐƚŽďĞƌϮϬϭϲǀŝĂǁĞůůͲďĂďLJĐůŝŶŝĐƐĂŶĚĐŚŝůĚƌĞŶ͛Ɛ ĚĂLJĐĂƌĞĐĞŶƚĞƌƐŝŶ'ƌŽŶŝŶŐĞŶ͕ƌĞŶƚŚĞĂŶĚ&ƌŝĞƐůĂŶĚ;ƚŚƌĞĞEŽƌƚŚĞƌŶƉƌŽǀŝŶĐĞƐŝŶƚŚĞ EĞƚŚĞƌůĂŶĚƐͿ͘ŚŝůĚƌĞŶǁŝƚŚƉƌĞǀŝŽƵƐůLJĚŝĂŐŶŽƐĞĚŬŝĚŶĞLJĚŝƐĞĂƐĞǁĞƌĞĞdžĐůƵĚĞĚĨƌŽŵƚŚĞ ƐƚƵĚLJ͘ŽƚŚƉĂƌĞŶƚƐŽƌƚŚĞůĞŐĂůŐƵĂƌĚŝĂŶŽĨƚŚĞĐŚŝůĚƐŝŐŶĞĚĨŽƌŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚ͘dŚĞ ƐƚƵĚLJǁĂƐĂƉƉƌŽǀĞĚďLJƚŚĞŵĞĚŝĐĂůĞƚŚŝĐĂůĐŽŵŵŝƩĞĞŽĨƚŚĞhŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ ŽĨ'ƌŽŶŝŶŐĞŶ;hD'Ϳ;DdĐƌĞĨĞƌĞŶĐĞŶƵŵďĞƌϮϬϭϰͲϱϭϮͿĂŶĚǁĂƐĐŽŶĚƵĐƚĞĚĂĐĐŽƌĚŝŶŐ ƚŚĞƉƌŝŶĐŝƉůĞƐŽĨƚŚĞĚĞĐůĂƌĂƟŽŶŽĨ,ĞůƐŝŶŬŝ͘ ĂƚĂĐŽůůĞĐƟŽŶĂŶĚŵĞĂƐƵƌĞŵĞŶƚƐ ĂƚĂǁĂƐĐŽůůĞĐƚĞĚŽŶƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞĚĂLJƐĂƚƚŚƌĞĞĚŝīĞƌĞŶƚƟŵĞƉŽŝŶƚƐ͗Ϭ͕ϰĂŶĚ ϴǁĞĞŬƐ͘ĂƚĂĐŽŶƐŝƐƚĞĚŽĨƚŚƌĞĞĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƐ;&DsͿ͕ƚŚƌĞĞƌĂŶĚŽŵĚĂLJƟŵĞ

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518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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ƐĂŵƉůĞƐĂŶĚĂƋƵĞƐƟŽŶŶĂŝƌĞĂƚĞĂĐŚƟŵĞƉŽŝŶƚ;&ŝŐƵƌĞϭͿ͘ůůǁĞƌĞĐŽůůĞĐƚĞĚĂƚŚŽŵĞ͕ ĂŶĚƐĞŶƚďLJŵĂŝůƚŽƚŚĞĐĞŶƚƌĂůůĂďŽƌĂƚŽƌLJŽĨƚŚĞhD'͘dŚĞƋƵĞƐƟŽŶŶĂŝƌĞŝŶĐůƵĚĞĚ ŝƚĞŵƐƌĞŐĂƌĚŝŶŐĚĂƚĞĂŶĚƟŵĞŽĨƵƌŝŶĞĐŽůůĞĐƟŽŶ͕ƉŽƐƐŝďůĞƌĞĐĞŶƚĨĞďƌŝůĞĞƉŝƐŽĚĞƐŽĨ the child, anthropometric data of child and parents, prenatal and postnatal factors, and ŝŶĨŽƌŵĂƟŽŶŽŶĚŝĂďĞƚĞƐ͕ŚLJƉĞƌƚĞŶƐŝŽŶĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞŝŶƉĂƌĞŶƚƐ͘dŽĂǀŽŝĚ ĂŶĂůLJnjŝŶŐƐĂŵƉůĞƐǁŝƚŚƚƌĂŶƐŝĞŶƚƐƉƵƌŝŽƵƐŚŝŐŚĂůďƵŵŝŶƵƌŝĂĚƵƌŝŶŐĨĞďƌŝůĞĞƉŝƐŽĚĞƐ͕ƵƌŝŶĞ ƐĂŵƉůĞƐǁĞƌĞĚŝƐĐĂƌĚĞĚŝĨƚŚĞĐŚŝůĚŚĂĚĨĞǀĞƌĚƵƌŝŶŐƚŚĞĐŽůůĞĐƟŽŶƉĞƌŝŽĚ͘dŚŝƐŽĐĐƵƌƌĞĚ ĞŝŐŚƚƟŵĞƐ͘ Figure 1.6FKHGXOHRIGDWDFROOHFWLRQ hƌŝŶĞǁĂƐĐŽůůĞĐƚĞĚǁŝƚŚƚŚĞWĞĞ^ƉŽƚΠĚĞǀŝĐĞ͕ǁŚŝĐŚŝƐĂǀĂůŝĚĂƚĞĚƚŽŽůĨŽƌƵƌŝŶĞ ĐŽůůĞĐƟŽŶŝŶďŽƚŚĐŚŝůĚƌĞŶǁŚŽĂƌĞĐŽŶƟŶĞŶƚĨŽƌƵƌŝŶĞĂŶĚĐŚŝůĚƌĞŶǁŚŽĂƌĞŶŽƚ͘4_/ƚ ĐŽŶƐŝƐƚƐŽĨĂƵƌŝŶĞĂďƐŽƌƉƟŽŶƉĂĚ͕ĂŚŽůĚĞƌ͕ĂƚƵďĞĂŶĚĂůŝĚ;&ŝŐƵƌĞϮͿ͘/ŶĐŚŝůĚƌĞŶǁŚŽ ĂƌĞŶŽƚĐŽŶƟŶĞŶƚLJĞƚ͕ƚŚĞĂďƐŽƌƉƟŽŶƉĂĚĐĂŶďĞƉůĂĐĞĚŝŶƚŚĞĚŝĂƉĞƌĂŶĚƌĞŵŽǀĞĚ ĂŌĞƌŵŝĐƚƵƌŝƟŽŶ͘ŽŶƟŶĞŶƚĐŚŝůĚƌĞŶĐĂŶǀŽŝĚŽǀĞƌƚŚĞĂďƐŽƌƉƟŽŶƉĂĚǁŚŝůĞƉůĂĐĞĚŝŶ ƚŚĞŚŽůĚĞƌ͘ŌĞƌǀŽŝĚŝŶŐ͕ƚŚĞƉĂĚĂŶĚŚŽůĚĞƌĂƌĞƉůĂĐĞĚŝŶƚŚĞƚƵďĞ͕ĐůŽƐĞĚǁŝƚŚƚŚĞůŝĚ ĂŶĚŬĞƉƚŝŶƚŚĞƌĞĨƌŝŐĞƌĂƚŽƌƵŶƟůƐĞŶĚŝŶŐƚŽƚŚĞůĂďŽƌĂƚŽƌLJ͘ŌĞƌĐŽŵƉůĞƟŶŐƚŚĞƵƌŝŶĞ ĐŽůůĞĐƟŽŶƐ͕ƚŚĞWĞĞ^ƉŽƚƐǁĞƌĞƉůĂĐĞĚŝŶĂƐĂĨĞƚLJďĂŐĂŶĚƐĞŶƚƚŽƚŚĞĐĞŶƚƌĂůůĂďŽƌĂƚŽƌLJ ŝŶĂŶĞŶǀĞůŽƉĞĨŽƌďŝŽůŽŐŝĐĂůŵĂƚĞƌŝĂůƐ;WŽůLJDĞĚ͕ĂŬůĂWĂĐŬƵƌŽƉĞͿƚŽŐĞƚŚĞƌǁŝƚŚƚŚĞ ƋƵĞƐƟŽŶŶĂŝƌĞ͘hƉŽŶĂƌƌŝǀĂůĂƚƚŚĞůĂďŽƌĂƚŽƌLJ͕ƐĂŵƉůĞƐǁĞƌĞƉƌŽĐĞƐƐĞĚǁŝƚŚŝŶϮϰŚŽƵƌƐ͘ WƌĞǀŝŽƵƐƐƚƵĚŝĞƐŚĂǀĞƐŚŽǁŶƚŚĂƚĂůďƵŵŝŶƵƌŝĂƌĞŵĂŝŶƐƐƚĂďůĞĚƵƌŝŶŐƐƚŽƌĂŐĞŽŶƌŽŽŵ ƚĞŵƉĞƌĂƚƵƌĞƵƉƚŽƐĞǀĞŶĚĂLJƐ͘4,5_{dƵďĞƐǁĞƌĞĐĞŶƚƌŝĨƵŐĞĚĨŽƌϱŵŝŶƵƚĞƐŽŶϯϱϬ';ZŽƟŶĂ} ϯϱZͿ͘hƌŝŶĂƌLJĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶ;h_ͿǁĂƐŵĞĂƐƵƌĞĚǁŝƚŚƚŚĞZŽĐŚĞDŽĚƵůĂƌWƵƐŝŶŐ ƚŚĞŝŵŵƵŶŽƚƵƌďŝŵĞƚƌŝĐĂƐƐĂLJĂŶĚĞdžƉƌĞƐƐĞĚŝŶŵŐͬ>͘hƌŝŶĂƌLJĐƌĞĂƟŶŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶ

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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55 ;h_ZͿǁĂƐŵĞĂƐƵƌĞĚǁŝƚŚƚŚĞZŽĐŚĞDŽĚƵůĂƌWƵƐŝŶŐĐƌĞĂƟŶĂƐĞƚŽƐĂƌĐŽƐŝŶĞŽdžŝĚĂƐĞ ďĂƐĞĚĐŽůŽƌŝŵĞƚƌŝĐŵĞƚŚŽĚĂŶĚĞdžƉƌĞƐƐĞĚŝŶŐͬ>͘dŽĐŽƌƌĞĐƚh_ĨŽƌƵƌŝŶĞĚŝůƵƟŽŶ͕ƵƌŝŶĂƌLJ ĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ;h_ZͿǁĂƐĂƐƐĞƐƐĞĚ͘hƌŝŶĞƐĂŵƉůĞƐǁĞƌĞƚĞƐƚĞĚĨŽƌůĞƵŬŽĐLJƚĞƐ ǁŝƚŚƵƌŝŶĂƌLJĚŝƉƐƟĐŬƐ;ŽŵďƵƌͲƚĞƐƚΠƐƚƌŝƉƐͿ͕ŝŶŽƌĚĞƌƚŽĞdžĐůƵĚĞĂŶŝŶƚĞƌĐƵƌƌĞŶƚƵƌŝŶĂƌLJ ƚƌĂĐƚŝŶĨĞĐƟŽŶ͘ Figure 2. 7KH3HH6SRWV\VWHP ^ĂŵƉůĞƐŝnjĞĐĂůĐƵůĂƟŽŶ ĞĨŽƌĞƐƚĂƌƟŶŐƚŚĞƐƚƵĚLJ͕ǁĞĐĂůĐƵůĂƚĞĚƚŚĂƚĂƐƚƵĚLJƉŽƉƵůĂƟŽŶŽĨϭϬϬƐƵďũĞĐƚƐǁŽƵůĚ ƉƌŽǀŝĚĞϴϬйƉŽǁĞƌŝŶĚĞƚĞĐƟŶŐĂsďĞƚǁĞĞŶϭϰйĂŶĚϮϰй;ĚŝīĞƌĞŶĐĞŽĨϱйƌĞůĂƟǀĞ ƚŽϭϵйͿ͕ĂƐƐƵŵŝŶŐĂ^ŽĨƚŚĞǁŝƚŚŝŶƐƵďũĞĐƚsŽĨϮϬй͘,ŽǁĞǀĞƌ͕ŝŶĂŶŝŶƚĞƌŝŵĂŶĂůLJƐŝƐ ŚĂůĨǁĂLJƚŚĞƐƚƵĚLJ͕ǁĞĚŝƐĐŽǀĞƌĞĚƚŚĂƚƚŚĞ^ŽĨƚŚĞǁŝƚŚŝŶƐƵďũĞĐƚsǁĂƐĐŽŶƐŝĚĞƌĂďůLJ ůŽǁĞƌ͘dŚĞƌĞĨŽƌĞ͕ǁĞĚĞĐŝĚĞĚƚŽŝŶĐůƵĚĞϴϬƉĂƌƟĐŝƉĂŶƚƐ͘ ^ƚĂƟƐƟĐĂůĂŶĂůLJƐĞƐ ĞƐĐƌŝƉƟǀĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶǁĞƌĞƌĞƉŽƌƚĞĚĂƐŵĞĂŶцƐƚĂŶĚĂƌĚ ĚĞǀŝĂƟŽŶ͘h_ĂŶĚh_ZĂƌĞƌĞƉƌĞƐĞŶƚĞĚďLJŐĞŽŵĞƚƌŝĐŵĞĂŶĂŶĚƐƚĂŶĚĂƌĚĚĞǀŝĂƟŽŶ͘ /ŶŽƌĚĞƌƚŽĂƐƐĞƐƐƚŚĞŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJŽĨĂůďƵŵŝŶƵƌŝĂ͕ŝŶĚŝǀŝĚƵĂůƐƚĂŶĚĂƌĚ ĚĞǀŝĂƟŽŶ ĂŶĚ ŝŶĚŝǀŝĚƵĂů ŐĞŽŵĞƚƌŝĐ ŵĞĂŶ ǁĞƌĞ ĂƐƐĞƐƐĞĚ ƚŽ ĐĂůĐƵůĂƚĞ ĐŽĞĸĐŝĞŶƚƐ ŽĨǀĂƌŝĂƟŽŶ;sͿŽĨĂůďƵŵŝŶƵƌŝĂƉĞƌŝŶĚŝǀŝĚƵĂůǁŝƚŚƚŚĞĨŽůůŽǁŝŶŐĨŽƌŵƵůĂ͗;ƐƚĂŶĚĂƌĚ ĚĞǀŝĂƟŽŶͬŐĞŽŵĞƚƌŝĐŵĞĂŶͿΎϭϬϬй͘ŽĞĸĐŝĞŶƚƐŽĨǀĂƌŝĂƟŽŶǁĞƌĞĐĂůĐƵůĂƚĞĚƵƐŝŶŐĂƐŝŶŐůĞ ŵĞĂƐƵƌĞŵĞŶƚ;ĮƌƐƚĚĂLJͿƉĞƌƟŵĞƉŽŝŶƚĂŶĚƵƐŝŶŐĂůůƚŚƌĞĞŵĞĂƐƵƌĞŵĞŶƚƐƉĞƌƟŵĞƉŽŝŶƚ͘ dŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂǁĂƐĂƐƐĞƐƐĞĚƵƐŝŶŐƚŚĞĚĞĮŶŝƟŽŶƐƚŚĂƚĂƌĞĐƵƌƌĞŶƚůLJ ĂĚǀŽĐĂƚĞĚŝŶƚŚĞƉĂĞĚŝĂƚƌŝĐůŝƚĞƌĂƚƵƌĞ;h_шϮϬŵŐͬ>Žƌh_ZшϯϬŵŐͬŐͿ͘6_{ŝīĞƌĞŶĐĞƐ} ďĞƚǁĞĞŶs͛ƐǁĞƌĞƚĞƐƚĞĚƵƐŝŶŐtŝůĐŽdžŽŶŵĂƚĐŚĞĚͲƉĂŝƌƐƐŝŐŶĞĚͲƌĂŶŬƐƚĞƐƚ͘ƚǁŽͲƐŝĚĞĚ WͲǀĂůƵĞŽĨчϬ͘ϬϱǁĂƐĐŽŶƐŝĚĞƌĞĚƚŽŝŶĚŝĐĂƚĞƐƚĂƟƐƟĐĂůƐŝŐŶŝĮĐĂŶĐĞ͘ĂƚĂĂƌĞĞdžƉƌĞƐƐĞĚ ĂƐĞŝƚŚĞƌŵĞĂŶĂŶĚƐƚĂŶĚĂƌĚĚĞǀŝĂƟŽŶŽƌŵĞĚŝĂŶĂŶĚϮϱth_-75th_{ƉĞƌĐĞŶƟůĞĨŽƌĐŽŶƟŶƵŽƵƐ} ǀĂƌŝĂďůĞƐĂŶĚƉĞƌĐĞŶƚĂŐĞƐĂŶĚĐŽƵŶƚĨŽƌĐĂƚĞŐŽƌŝĐĂůǀĂƌŝĂďůĞƐ͘ĂƚĂǁĞƌĞĂŶĂůLJnjĞĚƵƐŝŶŐ ^ddǀĞƌƐŝŽŶϭϯ͘ϭ͘

4

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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Results

KĨƚŚĞϵϱĐŚŝůĚƌĞŶŽĨǁŚŽŵŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚǁĂƐƐŝŐŶĞĚ͕ĂƚŽƚĂůŽĨϴϬƚŽĚĚůĞƌƐ;ŵĞĂŶ ĂŐĞϮϲ͘ϲŵŽŶƚŚƐ;^ϭϬ͘ϴͿ͕ϱϯйŵĂůĞͿĐŽŵƉůĞƚĞĚĨŽůůŽǁͲƵƉĂŶĚǁĞƌĞŝŶĐůƵĚĞĚŝŶƚŚŝƐ ĂŶĂůLJƐŝƐ͘dŚĞƌĞŵĂŝŶŝŶŐϭϱĐŚŝůĚƌĞŶǁĞƌĞůŽƐƚƚŽĨŽůůŽǁͲƵƉ͘dŚĞŵĂŝŶĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨ ƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶĂƌĞƐŚŽǁŶŝŶdĂďůĞϭ͘ Variability in albuminuria dĂďůĞϮƐŚŽǁƐƚŚĂƚ&DsĐŽůůĞĐƟŽŶƐƉƌŽǀŝĚĞůŽǁĞƌs͛ƐŝŶĂůďƵŵŝŶƵƌŝĂ;ďŽƚŚĨŽƌh_ and h_ZͿƚŚĂŶƌĂŶĚŽŵƐĂŵƉůĞĐŽůůĞĐƟŽŶƐ͕ĂůƚŚŽƵŐŚƚŚĞĚŝīĞƌĞŶĐĞƐĚŝĚŶŽƚĂůǁĂLJƐƌĞĂĐŚ ƐƚĂƟƐƟĐĂůƐŝŐŶŝĮĐĂŶĐĞ͘/ŶĂĚĚŝƟŽŶ͕dĂďůĞϮƐŚŽǁƐƚŚĂƚƚŚƌĞĞƐĂŵƉůĞƐƉĞƌƟŵĞƉŽŝŶƚƐŚŽǁ ůŽǁĞƌs͛ƐŝŶĂůďƵŵŝŶƵƌŝĂ;ďŽƚŚh_ĂŶĚh_ZͿĐŽŵƉĂƌĞĚƚŽĂƐŝŶŐůĞĐŽůůĞĐƟŽŶƉĞƌƟŵĞ ƉŽŝŶƚ͘dŚĞůŽǁĞƐƚŵĞĚŝĂŶŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůsǁĂƐŽďƐĞƌǀĞĚǁŚĞŶh_ǁĂƐŵĞĂƐƵƌĞĚ ŝŶ &Ds ŽŶ ƚŚƌĞĞ ĐŽŶƐĞĐƵƟǀĞ ĚĂLJƐ ;ϯϴ͘ϯйͿ͘ tŚĞŶ ĐŽŵƉĂƌŝŶŐ ƚŚĞ s͛Ɛ ŽĨ ĂůďƵŵŝŶ ĐŽŶĐĞŶƚƌĂƟŽŶǁŝƚŚĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ͕h_ZĐŽŶƐŝƐƚĞŶƚůLJƐŚŽǁĞĚĂŚŝŐŚĞƌs͘dŚŝƐ ǁĂƐƚŚĞĐĂƐĞďŽƚŚǁŝƚŚĂƐŝŶŐůĞƵƌŝŶĞƐĂŵƉůĞƉĞƌƟŵĞƉŽŝŶƚŽƌƚŚƌĞĞƵƌŝŶĞƐĂŵƉůĞƐƉĞƌ ƟŵĞƉŽŝŶƚĂŶĚǁŝƚŚĞŝƚŚĞƌ&DsŽƌƌĂŶĚŽŵƐĂŵƉůĞƐ͘

Impact of albuminuria measurement on prevalence of microalbuminuria

/Ŷ ĐůŝŶŝĐĂů ƉƌĂĐƚŝĐĞ͕ ƵƌŝŶĞ ĂůďƵŵŝŶ ĞdžĐƌĞƚŝŽŶ ŝƐ ĐůĂƐƐŝĨŝĞĚ ŝŶ ŶŽƌŵŽͲ͕ ŵŝĐƌŽͲ͕ ĂŶĚ macroalbuminuria,6_{ŽƌƌĞĐĞŶƚůLJďLJŶŽƌŵĂůƚŽŵŝůĚůLJŝŶĐƌĞĂƐĞĚ͕ŵŽĚĞƌĂƚĞůLJŝŶĐƌĞĂƐĞĚ} ĂŶĚƐĞǀĞƌĞůLJŝŶĐƌĞĂƐĞĚ͘7_{/ŶĂĚƵůƚƐ͕ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĚŝĂŐŶŽƐĞĚǁŚĞŶĂƚůĞĂƐƚƚǁŽ} ŽƵƚŽĨƚŚƌĞĞ&DsƐĂŵƉůĞƐŚĂǀĞǀĂůƵĞƐŝŶƚŚĞŵŝĐƌŽĂůďƵŵŝŶƵƌŝĐƌĂŶŐĞ͘tĞĐĂůĐƵůĂƚĞĚ ƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂƵƐŝŶŐƚŚŝƐĂĚƵůƚŐƵŝĚĞůŝŶĞ;ĂƚůĞĂƐƚƚǁŽŽĨƚŚƌĞĞĮƌƐƚ ƐĂŵƉůĞƐƉĞƌƟŵĞƉŽŝŶƚh_шϮϬŵŐͬůŽƌh_ZшϯϬŵŐͬŐͿĂƐǁĞůůĂƐƵƐŝŶŐƚŚĞŐĞŽŵĞƚƌŝĐ ŵĞĂŶŽĨƚŚĞƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞƐĂŵƉůĞƐ;ŐĞŽŵĞƚƌŝĐŵĞĂŶŽĨϯĐŽŶƐĞĐƵƟǀĞƐĂŵƉůĞƐǁŝƚŚŝŶ ƟŵĞƉŽŝŶƚh_шϮϬŵŐͬůŽƌh_ZшϯϬŵŐͬŐͿ͘/ƚŝƐĐůĞĂƌĨƌŽŵƚŚĞƌĞƐƵůƚƐŝŶdĂďůĞϯƚŚĂƚ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂƉƌĞǀĂůĞŶĐĞ;ďĂƐĞĚŽŶh_ͿŝƐǀĞƌLJůŽǁ;ĂƌŽƵŶĚϮйͿƵƐŝŶŐƚŚĞĂĚƵůƚ ŐƵŝĚĞůŝŶĞ͕ĂŶĚŝƐŚŝŐŚĞƌ;ĂƌŽƵŶĚϱйͿƵƐŝŶŐƚŚĞŐĞŽŵĞƚƌŝĐŵĞĂŶ͘/ŶƚĞƌĞƐƟŶŐůLJ͕ĐƌĞĂƟŶŝŶĞ ĐŽƌƌĞĐƟŽŶŐŝǀĞƐǀĞƌLJŚŝŐŚƉƌĞǀĂůĞŶĐĞƐ;ϭϳ͘ϱƚŽϯϯ͘ϴйͿǁŚĞŶƵƐŝŶŐďŽƚŚƚŚĞĂĚƵůƚŐƵŝĚĞůŝŶĞ ĂŶĚƚŚĞŐĞŽŵĞƚƌŝĐŵĞĂŶ͘ ŽŵƉĂƌŝƐŽŶǁŝƚŚŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůĐŽĞĸĐŝĞŶƚƐŽĨǀĂƌŝĂƟŽŶŝŶĂĚƵůƚƐ tĞĐŽŵƉĂƌĞĚƚŚĞŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůsĨŽƵŶĚŝŶƚŚŝƐƐƚƵĚLJǁŝƚŚƌĞƐƵůƚƐĨƌŽŵĂƉƌĞǀŝŽƵƐ ƐƚƵĚLJŝŶĂĚƵůƚƐ͘2_{/ŶƚŚŝƐƐƚƵĚLJϮϰϭŚĞĂůƚŚLJĂĚƵůƚƐǁĞƌĞŝŶĐůƵĚĞĚĂŶĚĂ&DsĂŶĚƌĂŶĚŽŵ} ƐĂŵƉůĞǁĞƌĞĐŽůůĞĐƚĞĚĂǁĞĞŬϬ͕ǁĞĞŬϯĂŶĚǁĞĞŬϲ͘dĂďůĞϰƐŚŽǁƐƚŚĂƚŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂů sŝŶh_ĂŶĚh_ZŝŶƚŚŝƐƉŽƉƵůĂƟŽŶǁĞƌĞƐŝŵŝůĂƌ͘,ŽǁĞǀĞƌ͕h_ZsŝŶŽƵƌĐŽŚŽƌƚǁĂƐ ŵƵĐŚŚŝŐŚĞƌ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 57PDF page: 57PDF page: 57PDF page: 57

57 Table 1. &KDUDFWHULVWLFVRIWKHVWXG\SRSXODWLRQQ  Child ŐĞ͕ŵŽŶƚŚƐ;^Ϳ Ϯϲ͘ϲ;ϭϬ͘ϴͿ DĂůĞ͕Ŷ;йͿ ϰϮ;ϱϯͿ ŽĚLJǁĞŝŐŚƚ͕ŬŐ;^Ϳ ϭϯ͘ϲ;ϯ͘ϬͿ ,ĞŝŐŚƚ͕Đŵ;^Ϳ ϵϭ͘ϰ;ϵ͘ϳͿ D/͕ŬŐͬŵϮ;^Ϳ ϭϲ͘Ϯ;ϭ͘ϱͿ ůďƵŵŝŶƵƌŝĂĂƚĮƌƐƚƟŵĞƉŽŝŶƚ͖ - U_AC, ŵŐͬ>;Ϯ͘ϱth_-97.5th_{ƉĞƌĐĞŶƟůĞͿ} - U_ACR͕ŵŐͬŐ;Ϯ͘ϱth_-97.5th_{ƉĞƌĐĞŶƟůĞͿ} - U_CRŵŵŽůͬ>;Ϯ͘ϱth_-97.5th_{ƉĞƌĐĞŶƟůĞͿ} ϱ͘ϭ;ϯ͘Ϭʹϰϯ͘ϭͿ ϭϲ͘ϯ;ϰ͘Ϯʹϭϱϯ͘ϬͿ ϯ͘ϱ;Ϭ͘ϯʹϵ͘ϰͿ Microalbuminuria#_{ĂƚĮƌƐƚƟŵĞƉŽŝŶƚ;&DsͿ} - U_AC͕й - U_ACR͕й ϱ͘ϮйϮϴ͘ϲй

Antenatal and postnatal factors

ŝƌƚŚǁĞŝŐŚƚ͕Ő;^Ϳ ϯϱϭϴ;ϱϰϱͿ ^ŵŽŬŝŶŐĚƵƌŝŶŐƉƌĞŐŶĂŶĐLJ͕Ŷ;йͿ ϵ;ϭϭ͘ϯͿ 'ĞƐƚĂƟŽŶĂůĚŝĂďĞƚĞƐ͕Ŷ;йͿ ϯ;ϯ͘ϴͿ 'ĞƐƚĂƟŽŶĂůŚLJƉĞƌƚĞŶƐŝŽŶ͕Ŷ;йͿ ϯ;ϯ͘ϴͿ ƌĞĂƐƚĨĞĞĚŝŶŐ͕Ŷ;йͿ ϲϴ;ϴϱͿ Parental: mother ŝĂďĞƚĞƐ͕Ŷ;йͿ ϰ;ϱͿ ,LJƉĞƌƚĞŶƐŝŽŶ͕Ŷ;йͿ ϭ;ϭͿ ,ĞĂƌƚĚŝƐĞĂƐĞ͕Ŷ;йͿ Ϭ;ϬͿ Parental: father ŝĂďĞƚĞƐ͕Ŷ;йͿ ϭ;ϭͿ ,LJƉĞƌƚĞŶƐŝŽŶ͕Ŷ;йͿ Ϭ;ϬͿ ,ĞĂƌƚĚŝƐĞĂƐĞ͕Ŷ;йͿ Ϭ;ϬͿ #_{0LFURDOEXPLQXULDGHÀQHGDV8} AC•PJ/RU8ACR•PJJ

4

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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58

Table 2. ,QWUDLQGLYLGXDOFRHIÀFLHQWVRIYDULDWLRQE\QXPEHURIVDPSOHVDQGE\FROOHFWLRQ

time (median (25th_-75th_SHUFHQWLOH

^ŝŶŐůĞƵƌŝŶĞƐĂŵƉůĞƉĞƌƟŵĞƉŽŝŶƚ dŚƌĞĞƵƌŝŶĞƐĂŵƉůĞƐƉĞƌƟŵĞƉŽŝŶƚ

FMV Random P-value1 _{FMV Random P-value}2 _P-value3 _P-value4

U_AC ϰϱ͘ϴй ;ϭϳ͘ϱͲϵϵ͘ϴͿ ϰϰ͘ϳй ;ϭϭ͘ϴͲϴϱ͘ϲͿ 0.94 ϯϴ͘ϯй ;ϮϮ͘ϭͲϱϲ͘ϳͿ ϰϭ͘ϳй ;Ϯϯ͘ϰͲϲϰ͘ϭͿ 0.66 0.01 0.16 U_ACR ϱϰ͘ϯй ;Ϯϲ͘ϵͲϭϭϰ͘ϲͿ ϴϭ͘ϲй ;ϯϵ͘ϱͲϭϰϰ͘ϯͿ 0.05 ϰϰ͘ϱй ;Ϯϳ͘ϰͲϳϰ͘ϮͿ ϲϭ͘ϳй ;ϯϰ͘ϭͲϵϬ͘ϰͿ 0.10 0.06 0.002 U_CR ϰϮ͘ϯй ;ϮϬ͘ϰͲϳϳ͘ϲͿ ϱϴ͘ϰй ;ϯϱ͘ϲͲϴϳ͘ϳͿ 0.03 Ϯϳ͘ϴй ;ϭϱ͘ϴͲϱϳ͘ϯͿ ϰϲ͘ϰй ;Ϯϯ͘ϵͲϲϵ͘ϱͿ 0.03 0.001 <0.001 1_{)09VLQJOHVDPSOHSHUWLPHSHULRGYVUDQGRPVLQJOHVDPSOHSHUWLPHSHULRG} 2_{)09WKUHHVDPSOHVSHUWLPHSHULRGYVUDQGRPWKUHHVDPSOHVSHUWLPHSHULRG} 3_{)09VLQJOHVDPSOHSHUWLPHSHULRGYV)09WKUHHVDPSOHVSHUWLPHSHULRG} 4_{5DQGRPVLQJOHVDPSOHSHUWLPHSHULRGYVUDQGRPWKUHHVDPSOHVSHUWLPHSHULRG}

Table 3. Prevalence of microalbuminuria

“Adult - Guideline”

microalbuminuria1 “Geometric Mean” _{microalbuminuria}2

Week 0 Week 4 Week 8

U_AC &Ds Ϯ͘ϱй ϱ͘Ϯй ϱ͘ϲй ϰ͘ϯй Random sample ϭ͘ϯй ϲ͘ϰй Ϭй ϴ͘ϱй U_ACR &Ds Ϯϭ͘ϯй Ϯϴ͘ϲй Ϯϴ͘Ϯй Ϯϴ͘ϲй Random sample ϭϳ͘ϱй ϯϯ͘ϯй ϯϯ͘ϴй ϯϯ͘ϯй 1_{GHÀQHGDVDWOHDVWWZRRIWKUHHÀUVWVDPSOHVSHUWLPHSRLQW8} AC•PJORU8ACR•PJJ 2_{GHÀQHGDVJHRPHWULFPHDQRIFRQVHFXWLYHVDPSOHVZLWKLQWLPHSRLQW8} AC•PJORU U_ACR•PJJ Table 4. ,QWUDLQGLYLGXDOFRHIÀFLHQWVRIYDULDWLRQRIDOEXPLQXULDLQDGXOWV:LWWHHWDO-$61 EDVHGRQWKUHHXULQHFROOHFWLRQVPHGLDQth_-75th_SHUFHQWLOH FMV Random U_{AC ;ϭϵ͘ϰͲϰϳ͘ϴͿ}ϯϬ͘ϵй _{;Ϯϳ͘ϴͲϳϬ͘ϮͿ}ϰϬ͘ϵй U_{ACR ;ϭϭ͘ϲͲϮϴ͘ϰͿ}ϭϵ͘ϭй _{;ϭϳ͘ϲͲϱϱ͘ϲͿ}ϯϱ͘ϴй U_{CR ;ϭϯ͘ϴͲϲϲ͘ϳͿ}Ϯϯ͘ϱй _{;ϭϵ͘ϭͲϱϲ͘ϭͿ}ϯϭ͘ϯй

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 59PDF page: 59PDF page: 59PDF page: 59

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Discussion

/ŶƚŚŝƐƐƚƵĚLJǁĞĐŽŵƉĂƌĞĚĨŽƌƚŚĞĮƌƐƚƟŵĞǀĂƌŝŽƵƐƵƌŝŶĞĐŽůůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐƚŽŽƉƟŵĂůůLJ ŵĞĂƐƵƌĞĂŶĚŵŽŶŝƚŽƌĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐ͘ƐĞdžƉĞĐƚĞĚ͕ĂůďƵŵŝŶƵƌŝĂs͛ƐĂƌĞůŽǁĞƌ ǁŚĞŶŵĞĂƐƵƌĞĚŝŶĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚĐŽŵƉĂƌĞĚƚŽƌĂŶĚŽŵƐĂŵƉůĞƐ͕ĂŶĚǁŚĞŶĚŽŶĞǁŝƚŚ ϯĐŽŶƐĞĐƵƟǀĞƵƌŝŶĞĐŽůůĞĐƟŽŶƐǀĞƌƐƵƐŽŶĞĐŽůůĞĐƟŽŶ͘dŚŝƐƐƵƉƉŽƌƚƐŝŵƉůĞŵĞŶƚĂƟŽŶŽĨ ŵƵůƟƉůĞĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƵƌŝŶĞƐĂŵƉůĞƐĨŽƌĞƐƚĂďůŝƐŚŝŶŐĂŶĚŵŽŶŝƚŽƌŝŶŐĂůďƵŵŝŶƵƌŝĂ ŝŶƚŽĚĚůĞƌƐ͕ĐŽŶĨŽƌŵƚŽĂĚƵůƚŐƵŝĚĞůŝŶĞƐ͘ ,ŽǁĞǀĞƌ͕ǁĞĂůƐŽŝĚĞŶƟĮĞĚĚŝīĞƌĞŶĐĞƐǁŝƚŚƚŚĞĂĚƵůƚƉŽƉƵůĂƟŽŶ͘/ŶĂĚƵůƚƐ͕ƵƌŝŶĞ ĂůďƵŵŝŶĐŽƌƌĞĐƟŽŶĨŽƌƵƌŝŶĞĐƌĞĂƟŶŝŶĞ;ƵƌŝŶĂƌLJĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽͿŚĞůƉƐƚŽĐŽƌƌĞĐƚ ĨŽƌĚŝīĞƌĞŶĐĞƐŝŶƵƌŝŶĞĚŝůƵƟŽŶĂŶĚƌĞĚƵĐĞƐǀĂƌŝĂďŝůŝƚLJŝŶƚŚĞŵĞĂƐƵƌĞŵĞŶƚƐŝŶĮƌƐƚ ŵŽƌŶŝŶŐǀŽŝĚŽƌƌĂŶĚŽŵƵƌŝŶĞƐĂŵƉůĞƐ͘/ŶĂĚƵůƚƐƚŚŝƐŝŶĚĞĞĚůĞĂĚƐƚŽĂŵŽƌĞƉƌĞĐŝƐĞ ĂƐƐĞƐƐŵĞŶƚŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚĂƐŵĂůůĞƌŝŶƚƌĂͲŝŶĚŝǀŝĚƵĂůǀĂƌŝĂďŝůŝƚLJŝŶĂůďƵŵŝŶƵƌŝĂ͘ ^ƵƌƉƌŝƐŝŶŐůLJ͕ŝŶŽƵƌƐƚƵĚLJǁĞŽďƐĞƌǀĞĚŚŝŐŚĞƌs͛ƐǁŚĞŶh_ZǁĂƐƵƐĞĚĂƐĐŽŵƉĂƌĞĚ ƚŽh_͘dŚŝƐĐŽƵůĚďĞĚƵĞƚŽĂůĂƌŐĞƌǀĂƌŝĂďŝůŝƚLJŽĨƵƌŝŶĞĐƌĞĂƟŶŝŶĞŝŶĐŚŝůĚƌĞŶ͘,ŽǁĞǀĞƌ͕ ǁĞĚŝĚŶŽƚŽďƐĞƌǀĞĂĚŝīĞƌĞŶĐĞŝŶƵƌŝŶĂƌLJĐƌĞĂƟŶŝŶĞs͛ƐďĞƚǁĞĞŶĂĚƵůƚƐĂŶĚƚŽĚĚůĞƌƐ͘ tĞƚŚĞƌĞĨŽƌĞĚŽŶŽƚŚĂǀĞĂĐůĞĂƌĞdžƉůĂŶĂƟŽŶǁŚLJĐƌĞĂƟŶŝŶĞĐŽƌƌĞĐƟŽŶĚŽĞƐŶŽƚǁŽƌŬ ŝŶƚŽĚĚůĞƌƐ͕ŽƚŚĞƌƚŚĂŶƚŚĂƚƵƌŝŶĞĐƌĞĂƟŶŝŶĞŵĞĂƐƵƌĞŵĞŶƚŝƚƐĞůĨŝƐŇĂǁĞĚŝŶĐŚŝůĚƌĞŶ͘ ŶŽƚŚĞƌĚŝīĞƌĞŶĐĞǁĞĞŶĐŽƵŶƚĞƌĞĚǁŝƚŚƚŚĞĂĚƵůƚƉŽƉƵůĂƟŽŶŝƐƚŚĂƚǁŚĞŶƵƐŝŶŐ ƵƌŝŶĞĂůďƵŵŝŶĐŽƌƌĞĐƟŽŶĨŽƌĐƌĞĂƟŶŝŶĞŝŶĐŚŝůĚƌĞŶ͕ƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ;ĚĞĮŶĞĚĂƐh_ZшϯϬŵŐͬŐͿĂůƐŽŝŶĐƌĞĂƐĞƐƐƵďƐƚĂŶƟĂůůLJĂƐĐŽŵƉĂƌĞĚƚŽƚŚĞƉƌĞǀĂůĞŶĐĞ ĚĞĮŶĞĚŽŶƚŚĞďĂƐŝƐŽĨh_;шϮϬŵŐͬůͿ͘dŚĞŵŽƐƚůŝŬĞůLJĞdžƉůĂŶĂƟŽŶĨŽƌƚŚŝƐŝƐƚŚĞĨĂĐƚ ƚŚĂƚĐŚŝůĚƌĞŶŚĂǀĞĂůŽǁĞƌŵƵƐĐůĞŵĂƐƐ͕ǁŚŝĐŚĂĐĐŽƵŶƚƐĨŽƌĂŶŽǀĞƌĂůůůŽǁĞƌƵƌŝŶĂƌLJ ĐƌĞĂƟŶŝŶĞĞdžĐƌĞƟŽŶĂŶĚƚŚĞƌĞĨŽƌĞŚŝŐŚĞƌƉŚLJƐŝŽůŽŐŝĐǀĂůƵĞƐŽĨh_Z͘/ŶĚĞĞĚ͕ŵƵůƟƉůĞ ƐƚƵĚŝĞƐƌĞƉŽƌƚĞĚƚŚĂƚh_ZŝƐŚŝŐŚĞƌŝŶLJŽƵŶŐĞƌĐŚŝůĚƌĞŶ͘8,9_{dŽƐŽůǀĞƚŚĞƐĞŝƐƐƵĞƐ͕ĂůĂƌŐĞ} ĐŽŚŽƌƚƐƚƵĚLJŝŶĚŝīĞƌĞŶƚĂŐĞŐƌŽƵƉƐƐŚŽƵůĚďĞƉĞƌĨŽƌŵĞĚƚŽŝŶǀĞƐƟŐĂƚĞĚŝīĞƌĞŶĐĞƐ ŝŶh_ĂŶĚh_ZŝŶ&DsƐĂŵƉůĞƐĂŶĚĐŽŵƉĂƌĞƚŚĞƐĞƌĞƐƵůƚƐǁŝƚŚϮϰͲŚŽƵƌƵƌŝŶĞĂůďƵŵŝŶ ĞdžĐƌĞƟŽŶƚŽĞƐƚĂďůŝƐŚŽƉƟŵĂůĂŐĞͲĚĞƉĞŶĚĞŶƚƌĞĨĞƌĞŶĐĞǀĂůƵĞƐĨŽƌh_Z͘/ŶĂĚĚŝƟŽŶ͕ƚŚĞ ƵƌŝŶĞĐƌĞĂƟŶŝŶĞŵĞĂƐƵƌĞŵĞŶƚŝƚƐĞůĨŝŶĐŚŝůĚƌĞŶƐŚŽƵůĚďĞǀĂůŝĚĂƚĞĚĂŶĚĐŽŵƉĂƌĞĚǁŝƚŚ ĂĚƵůƚƐƚŽĮŶĚĂŶĞdžƉůĂŶĂƟŽŶǁŚLJh_ZĐŽƌƌĞĐƟŽŶĚŽĞƐŶŽƚǁŽƌŬŝŶĐŚŝůĚƌĞŶ͘ƚƚŚŝƐƐƚĂŐĞ͕ ǁĞƌĞĐŽŵŵĞŶĚƚŽŝŶƚĞƌƉƌĞƚh_ZŝŶLJŽƵŶŐĐŚŝůĚƌĞŶǁŝƚŚĞdžƚƌĞŵĞĐĂƵƟŽŶ͘ ĨĞǁƐƚƵĚŝĞƐŚĂǀĞƌĞƉŽƌƚĞĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶĐŚŝůĚƌĞŶŝŶƚŚĞ ŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͘8-12_{DŽƐƚŽĨƚŚĞƐĞƐƚƵĚŝĞƐƵƐĞĚƐŝŶŐůĞƵƌŝŶĞƐĂŵƉůĞƐĐŽůůĞĐƚĞĚĂƚĂ} ƐŝŶŐůĞƟŵĞƉŽŝŶƚ͘8,9,11,12_{,ŽǁĞǀĞƌ͕ŶŽŶĞŽĨƚŚĞƐĞƐƚƵĚŝĞƐŚĂǀĞƐLJƐƚĞŵĂƟĐĂůůLJĐŽŵƉĂƌĞĚ} ƚŚĞǁŝƚŚŝŶƉĞƌƐŽŶǀĂƌŝĂďŝůŝƚLJŽĨĂůďƵŵŝŶƵƌŝĂŝŶŚĞĂůƚŚLJƚŽĚĚůĞƌƐ͘dŚŝƐŝƐŝŵƉŽƌƚĂŶƚƐŝŶĐĞ ƚŚĞǁŝƚŚŝŶƉĞƌƐŽŶǀĂƌŝĂƟŽŶŝŶĂůďƵŵŝŶƵƌŝĂŽǀĞƌƟŵĞŵĂLJŝŵƉĂĐƚŽŶƚŚĞĂĐĐƵƌĂĐLJŽĨ ĞƉŝĚĞŵŝŽůŽŐŝĐĂůĚĂƚĂĂŶĚƚŚĞŵŽŶŝƚŽƌŝŶŐŽĨĂůďƵŵŝŶƵƌŝĂ͘ dŚŝƐƐƚƵĚLJŚĂƐƐĞǀĞƌĂůůŝŵŝƚĂƟŽŶƐ͘dŚĞŵŽƐƚŝŵƉŽƌƚĂŶƚŝƐƚŚĂƚƚŚĞĂůďƵŵŝŶŵĞĂƐƵƌĞĚŝŶ ƚŚĞƵƌŝŶĞƐĂŵƉůĞƐĐŽƵůĚŶŽƚďĞĐŽŵƉĂƌĞĚƚŽƚŚĞŐŽůĚƐƚĂŶĚĂƌĚŝŶĂƐƐĞƐƐŝŶŐĂůďƵŵŝŶƵƌŝĂ͕ ŝ͘Ğ͘ϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶ͘hŶĨŽƌƚƵŶĂƚĞůLJ͕ĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶŝŶŝŶĐŽŶƟŶĞŶƚ ĐŚŝůĚƌĞŶŝƐŽŶůLJƉŽƐƐŝďůĞďLJƉůĂĐŝŶŐĂƵƌŝŶĂƌLJĐĂƚŚĞƚĞƌ͘/ŶŽƵƌŽƉŝŶŝŽŶ͕ƚŚŝƐŝŶƚĞƌǀĞŶƟŽŶ

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518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 60PDF page: 60PDF page: 60PDF page: 60

60 ǁŽƵůĚŶŽƚŚĂǀĞďĞĞŶĞƚŚŝĐĂůůLJĂĐĐĞƉƚĂďůĞĨŽƌĂƉƌĞůŝŵŝŶĂƌLJƐƚƵĚLJŝŶŚĞĂůƚŚLJĐŚŝůĚƌĞŶ͕ƚŚĞ ƉŽƉƵůĂƟŽŶǁĞǁĞƌĞŝŶƚĞƌĞƐƚĞĚŝŶ͘&ƵƌƚŚĞƌŵŽƌĞ͕ďLJĐŽŵƉĂƌŝŶŐƚǁŽƐƚƌĂƚĞŐŝĞƐŽĨƵƌŝŶĞ ĐŽůůĞĐƟŽŶƚŚĂƚĐĂŶďĞĞĂƐŝůLJƉĞƌĨŽƌŵĞĚďLJƚŚĞƉĂƌĞŶƚƐĂƚŚŽŵĞ͕ǁĞŝŶƚĞŶĚĞĚƚŽƐĞĂƌĐŚ ĨŽƌďŽƚŚƚŚĞŵŽƐƚƌĞůŝĂďůĞĂŶĚƚŚĞŵŽƐƚƉƌĂĐƟĐĂůŵĞƚŚŽĚĨŽƌĂƐƐĞƐƐŝŶŐĂŶĚŵŽŶŝƚŽƌŝŶŐ ĂůďƵŵŝŶƵƌŝĂ͘ƐĞĐŽŶĚůŝŵŝƚĂƟŽŶŝƐƚŚĂƚĂůůƚŚĞƵƌŝŶĞƐĂŵƉůŝŶŐŚĂƐƚĂŬĞŶƉůĂĐĞĂƚŚŽŵĞ͕ ƐŽƚŚĞƌĞǁĂƐŶŽĐŽŶƚƌŽůŽŶǁŚĞƚŚĞƌƚŚĞĐŽůůĞĐƟŽŶƐǁĞƌĞƉĞƌĨŽƌŵĞĚŝŶƚŚĞƌŝŐŚƚǁĂLJ ĂŶĚŶŽĐŽŶƚƌŽůŽŶĐůŝŶŝĐĂůĐŽŶĚŝƟŽŶŽĨƚŚĞĐŚŝůĚ͘,ŽǁĞǀĞƌ͕ďLJƌĞĐŽƌĚŝŶŐĚĂƚĞ͕ƟŵĞŽĨ ĐŽůůĞĐƟŽŶƐ͕ŝŶĨŽƌŵĂƟŽŶĂďŽƵƚĐůŝŶŝĐĂůĐŽŶĚŝƟŽŶŽĨƚŚĞĐŚŝůĚ͕ƉŽƐƐŝďůĞĨĞďƌŝůĞĞƉŝƐŽĚĞƐ͕ ĂŶĚďLJƚĞƐƟŶŐĨŽƌƵƌŝŶĂƌLJůĞƵĐŽĐLJƚĞƐ͕ǁĞŝŶƚĞŶĚĞĚƚŽƐĐƌĞĞŶĨŽƌĨĂĐƚŽƌƐƚŚĂƚĐŽƵůĚďŝĂƐ ƚŚĞƌĞƐƵůƚƐ͘DŽƌĞŽǀĞƌ͕ĂůƐŽŝŶĐůŝŶŝĐĂůƉƌĂĐƟĐĞŵŽƐƚƵƌŝŶĞĐŽůůĞĐƟŽŶƐǁŝůůďĞƉĞƌĨŽƌŵĞĚ ĂƚŚŽŵĞ͕ĞƐƉĞĐŝĂůůLJǁŚĞŶ&DsƐĂŵƉůĞƐĂƌĞƌĞƋƵŝƌĞĚ͕ƐŽŽƵƌƐƚƵĚLJƉƌŽƚŽĐŽůĚŽĞƐŵŝŵŝĐ ĐůŝŶŝĐĂůƐŝƚƵĂƟŽŶƐ͘ĮŶĂůůŝŵŝƚĂƟŽŶŝƐƚŚĞƌĞůĂƟǀĞůŽǁŶƵŵďĞƌŽĨƐƵďũĞĐƚƐ͘dŚŝƐŚĂĚĂ ĐůĞĂƌŝŵƉĂĐƚŽŶƚŚĞůŽǁƉŽǁĞƌŽĨƐŽŵĞŽĨƚŚĞƉƌĞƐĞŶƚĞĚƌĞƐƵůƚƐƐƵĐŚĂƐƚŚĞĚŝīĞƌĞŶĐĞ ďĞƚǁĞĞŶs͛ƐŽĨ&DsĂŶĚƌĂŶĚŽŵƐĂŵƉůĞƐĂŶĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶƚŚĞ ƐƚƵĚLJƉŽƉƵůĂƟŽŶ͘DŽƌĞŽǀĞƌ͕ǁŚĞŶƚƌLJŝŶŐƚŽŵĞĂƐƵƌĞƚŚĞŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂƉƌĞǀĂůĞŶĐĞ ƵƐŝŶŐƚŚĞĂĚƵůƚŐƵŝĚĞůŝŶĞ͕ǁĞĨŽƵŶĚǀĞƌLJůŽǁƉƌĞǀĂůĞŶĐĞƐǁŚĞƌĞĂƐƚŚĞƉƌĞǀĂůĞŶĐĞƐŽĨ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŵĞĂƐƵƌĞĚǁŝƚŚŝŶƚŚĞƟŵĞƉŽŝŶƚƐĂƌĞĐŽŶƐŝĚĞƌĂďůLJŚŝŐŚĞƌĂŶĚĂƌĞ ƐŝŵŝůĂƌƚŽƚŚĞƉƌĞǀĂůĞŶĐĞǁĞƉƌĞǀŝŽƵƐůLJĚĞƐĐƌŝďĞĚŝŶĂĐŽŚŽƌƚŽĨƚŚĞƐĂŵĞĂŐĞ͘13_{dŚĞůŽǁ} ŶƵŵďĞƌŽĨƐƵďũĞĐƚƐŝŶƚŚŝƐƐƚƵĚLJŵŝŐŚƚďĞĂŶŝŵƉŽƌƚĂŶƚƌĞĂƐŽŶĨŽƌƚŚŝƐĮŶĚŝŶŐ͘ /Ŷ ĐŽŶĐůƵƐŝŽŶ͕ ŝŶ ƚŚŝƐ ƐƚƵĚLJ ǁĞ ŚĂǀĞ ĐŽŵƉĂƌĞĚ ĐůŝŶŝĐĂů ĨĞĂƐŝďůĞ ƐƚƌĂƚĞŐŝĞƐ ĨŽƌ ĞƐƚĂďůŝƐŚŝŶŐĂŶĚŵŽŶŝƚŽƌŝŶŐĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐ͘ĂƐĞĚŽŶŽƵƌĮŶĚŝŶŐƐ͕ƚŚĞŵŽƐƚ ŽƉƟŵĂůƐƚƌĂƚĞŐLJŝƐƚŽŵĞĂƐƵƌĞh_ŝŶ&DsƐĂŵƉůĞƐŽŶƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞĚĂLJƐ͕ĂŶĚ ƚŽƌĞƉĞĂƚŵĞĂƐƵƌĞŵĞŶƚƐŝŶƟŵĞ͘hŶůŝŬĞŝŶĂĚƵůƚƐ͕ƵƌŝŶĞĐƌĞĂƟŶŝŶĞĐŽƌƌĞĐƟŽŶƐĞĞŵƐ ŶŽƚƚŽŝŵƉƌŽǀĞƚŚĞĂĐĐƵƌĂĐLJŽĨƚŚĞŵĞĂƐƵƌĞŵĞŶƚ͘&ƵƌƚŚĞƌƐƚƵĚŝĞƐŝŶƚŽƚŚĞĐƌĞĂƟŶŝŶĞ ŵĞĂƐƵƌĞŵĞŶƚŝƚƐĞůĨĂƐǁĞůůĂƐŝŶƚŽƚŚĞŝŶŇƵĞŶĐĞŽĨŵƵƐĐůĞŵĂƐƐŽŶƚŚĞƵƐĞŽĨƵƌŝŶĞ ĐƌĞĂƟŶŝŶĞĐŽƌƌĞĐƟŽŶƐ͕ĂƌĞŶĞĞĚĞĚƚŽƐƚĂŶĚĂƌĚŝnjĞƚŚĞĂůďƵŵŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚƐĂŶĚ ĚĞĮŶŝƟŽŶƐďĞƚǁĞĞŶĐŚŝůĚƌĞŶĂŶĚĂĚƵůƚƐ͘

Disclosures

dŚĞƌĞĂƌĞŶŽĐŽŶŇŝĐƚƐŽĨŝŶƚĞƌĞƐƚƚŽĚŝƐĐůŽƐĞ͘

Acknowledgements

tĞǁŽƵůĚůŝŬĞƚŽƚŚĂŶŬ,ĞƐƐĞůƐн'ƌŽďĨŽƌƚŚĞƐƵƉƉŽƌƚǁŝƚŚƉƌŽǀŝƐŝŽŶŽĨƚŚĞWĞĞ^ƉŽƚƐ͘ tĞĂůƐŽĂĐŬŶŽǁůĞĚŐĞƚŚĞǁĞůůͲďĂďLJĐůŝŶŝĐƐŝŶ'ƌŽŶŝŶŐĞŶĂŶĚƐƐĞŶĨŽƌƚŚĞŝƌƐƵƉƉŽƌƚŝŶ ƌĞĐƌƵŝƟŶŐƉĂƌƟĐŝƉĂŶƚƐĨŽƌƚŚĞƐƚƵĚLJ͘&ŝŶĂůůLJ͕ǁĞƚŚĂŶŬĂůůƉĂƌƟĐŝƉĂŶƚƐĂŶĚƚŚĞŝƌƉĂƌĞŶƚƐͬ ŐƵĂƌĚŝĂŶƐĨŽƌƚŚĞŝƌĞīŽƌƚƐŝŶĐŽŽƉĞƌĂƟŶŐŝŶƚŚŝƐƐƚƵĚLJ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 61PDF page: 61PDF page: 61PDF page: 61

61

References

ϭ͘ sĞƐƚĞƌŐĂĂƌĚ W͕ >ĞǀĞƌĞƩ Z͘ ŽŶƐƚĂŶĐLJ ŽĨ ƵƌŝŶĂƌLJĐƌĞĂƟŶŝŶĞĞdžĐƌĞƟŽŶ͘:>ĂďůŝŶDĞĚ͘ ϭϵϱϴ͖ϱϭ;ϮͿ͗ϮϭϭͲϮϭϴ͘ Ϯ͘ tŝƩĞ͕>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ,:͕ĚĞĞĞƵǁ ͕ĂŬŬĞƌ^:͕ĚĞ:ŽŶŐW͕'ĂŶƐĞǀŽŽƌƚZ͘&ŝƌƐƚ ŵŽƌŶŝŶŐǀŽŝĚƐĂƌĞŵŽƌĞƌĞůŝĂďůĞƚŚĂŶƐƉŽƚ ƵƌŝŶĞƐĂŵƉůĞƐƚŽĂƐƐĞƐƐŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘ :ŵ^ŽĐEĞƉŚƌŽů͘ϮϬϬϵ͖ϮϬ;ϮͿ͗ϰϯϲͲϰϰϯ͘ ϯ͘ WĞƚƌLJŬŝǀ^/͕ĚĞĞĞƵǁ͕WĞƌƐƐŽŶ&͕ĞƚĂů͘ sĂƌŝĂďŝůŝƚLJ ŝŶ ƌĞƐƉŽŶƐĞ ƚŽ ĂůďƵŵŝŶƵƌŝĂͲ ůŽǁĞƌŝŶŐĚƌƵŐƐ͗dƌƵĞŽƌƌĂŶĚŽŵ͍ƌ:ůŝŶ WŚĂƌŵĂĐŽů͘ϮϬϭϲ͘ ϰ͘ ,ĞƌƌŝŶŐƚŽŶ t͕ /ůůŝŶŐǁŽƌƚŚ E͕ ^ƚĂƉůŝŶ E͕ Ğƚ Ăů͘ īĞĐƚ ŽĨ ƉƌŽĐĞƐƐŝŶŐ ĚĞůĂLJ ĂŶĚ ƐƚŽƌĂŐĞ ĐŽŶĚŝƟŽŶƐ ŽŶ ƵƌŝŶĞ ĂůďƵŵŝŶͲƚŽͲ ĐƌĞĂƟŶŝŶĞ ƌĂƟŽ͘ ůŝŶ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϭϲ͖ϭϭ;ϭϬͿ͗ϭϳϵϰͲϭϴϬϭ͘ ϱ͘ ǀĂŶ ĚĞŶ Ğůƚ ^D͕ 'ƌĂĐĐŚŝ s͕ ĚĞ ĞĞƵǁ ͕ ,ĞĞƌƐƉŝŶŬ ,:͘ ŽŵƉĂƌŝƐŽŶ ŽĨ ƵƌŝŶĞ collection methods for albuminuria ĂƐƐĞƐƐŵĞŶƚ ŝŶ LJŽƵŶŐ ĐŚŝůĚƌĞŶ͘ ůŝŶ Śŝŵ ĐƚĂ͘ϮϬϭϲ͖ϰϱϴ͗ϭϮϬͲϭϮϯ͘ ϲ͘ E&< <KY/ ĐůŝŶŝĐĂů ƉƌĂĐƚŝĐĞ ŐƵŝĚĞůŝŶĞƐ ĨŽƌ ĐŚƌŽŶŝĐ ŬŝĚŶĞLJ ĚŝƐĞĂƐĞ͗ ǀĂůƵĂƚŝŽŶ͕ ĐůĂƐƐŝĨŝĐĂƚŝŽŶ͕ ĂŶĚ ƐƚƌĂƚŝĨŝĐĂƚŝŽŶ͘ ŚƚƚƉ͗ͬͬ ǁǁǁϮ͘ŬŝĚŶĞLJ͘ŽƌŐͬƉƌŽĨĞƐƐŝŽŶĂůƐͬŬĚŽƋŝͬ ŐƵŝĚĞůŝŶĞƐͺĐŬĚͬƚŽĐ͘Śƚŵ͘ ĐĐĞƐƐĞĚ ϴͬϮ͕ ϮϬϭϳ͘ ϳ͘ </'K ϮϬϭϮ ůŝŶŝĐĂů ƉƌĂĐƚŝĐĞ ŐƵŝĚĞůŝŶĞ ĨŽƌ ƚŚĞ ĞǀĂůƵĂƚŝŽŶ ĂŶĚ ŵĂŶĂŐĞŵĞŶƚ ŽĨ ĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͘<ŝĚŶĞLJ/ŶƚĞƌŶĂƟŽŶĂů ^ƵƉƉůĞŵĞŶƚƐ͘ϮϬϭϯ͖ϯ;ϰͿ͘ ϴ͘ ^ĂŶĐŚĞnjͲĂLJůĞD͕ZŽĚƌŝŐƵĞnjͲŝŵĂĚĞǀŝůůĂ͕ ƐĞŶƐŝŽ͕ĞƚĂů͘hƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶ ŝŶ ^ƉĂŶŝƐŚ ĐŚŝůĚƌĞŶ͘ EŝŶŽ :ĞƐƵƐ ŐƌŽƵƉ͘ WĞĚŝĂƚƌEĞƉŚƌŽů͘ϭϵϵϱ͖ϵ;ϰͿ͗ϰϮϴͲϰϯϬ͘ ϵ͘ >ĞŚƌŶďĞĐŚĞƌ d͕ 'ƌĞŝƐƐŝŶŐĞƌ ^͕ EĂǀŝĚ &͕ WĨƵůůĞƌ,͕:ĞƐĐŚŬĞZ͘ůďƵŵŝŶ͕/Ő'͕ƌĞƟŶŽůͲ ďŝŶĚŝŶŐƉƌŽƚĞŝŶ͕ĂŶĚĂůƉŚĂϭͲŵŝĐƌŽŐůŽďƵůŝŶ ĞdžĐƌĞƟŽŶ ŝŶ ĐŚŝůĚŚŽŽĚ͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ ϭϵϵϴ͖ϭϮ;ϰͿ͗ϮϵϬͲϮϵϮ͘ ϭϬ͘ 'ŝďďD͕^ŚĂŚs͕WƌĞĞĐĞD͕ĂƌƌĂƩdD͘ sĂƌŝĂďŝůŝƚLJ ŽĨ ƵƌŝŶĞ ĂůďƵŵŝŶ ĞdžĐƌĞƚŝŽŶ ŝŶ ŶŽƌŵĂů ĂŶĚ ĚŝĂďĞƟĐ ĐŚŝůĚƌĞŶ͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ϭϵϴϵ͖ϯ;ϰͿ͗ϰϭϰͲϰϭϵ͘ ϭϭ͘ ĂǀŝĞƐ'͕WŽƐƚůĞƚŚǁĂŝƚĞZ:͕WƌŝĐĞ͕ƵƌŶ :>͕,ŽƵůƚŽŶ͕&ŝĞůĚŝŶŐ͘hƌŝŶĂƌLJĂůďƵŵŝŶ ĞdžĐƌĞƟŽŶŝŶƐĐŚŽŽůĐŚŝůĚƌĞŶ͘ƌĐŚŝƐŚŝůĚ͘ ϭϵϴϰ͖ϱϵ;ϳͿ͗ϲϮϱͲϲϯϬ͘ ϭϮ͘ >ĂƌŬŝŶƐ E͕ dĞŝdžĞŝƌĂͲWŝŶƚŽ ͕ ƌĂŝŐ :͘ dŚĞ ƉŽƉƵůĂƟŽŶͲďĂƐĞĚƉƌĞǀĂůĞŶĐĞŽĨĂůďƵŵŝŶƵƌŝĂ ŝŶĐŚŝůĚƌĞŶ͘WĞĚŝĂƚƌEĞƉŚƌŽů͘ϮϬϭϳ͘ ϭϯ͘ 'ƌĂĐĐŚŝ s͕ ǀĂŶ ĚĞŶ Ğůƚ ^D͕ <ƵƉĞƌƐ ><͕ ŽƌƉĞůĞŝũŶ ͕ ĚĞ ĞĞƵǁ ͕ ,ĞĞƌƐƉŝŶŬ ,:͘ WƌĞǀĂůĞŶĐĞ ĂŶĚ ĚŝƐƚƌŝďƵƚŝŽŶ ŽĨ ;ŵŝĐƌŽͿ ĂůďƵŵŝŶƵƌŝĂ ŝŶ ƚŽĚĚůĞƌƐ͘ EĞƉŚƌŽů ŝĂů dƌĂŶƐƉůĂŶƚ͘ϮϬϭϱ

4

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 63PDF page: 63PDF page: 63PDF page: 63

Part 2

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018