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

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date: 2018

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

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.

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

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: 65PDF page: 65PDF page: 65PDF page: 65

Early proteinuria lowering by ACE inhibition

predicts renal survival in children with

chronic kidney disease

Authors ^ŽƉŚŝĞD͘ǀĂŶĚĞŶĞůƚ1_{͕,ŝĚĚŽ:͘>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ}1_{͕sĂůĞŶƟŶĂ'ƌĂĐĐŚŝ}2_, ŝĐŬĚĞĞĞƵǁ1_{͕ůŬĞtƺŚů}3_{͕&ƌĂŶnj^ĐŚĂĞĨĞƌ}3 ĸůŝĂƟŽŶƐ 1_{ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůWŚĂƌŵĂĐLJĂŶĚWŚĂƌŵĂĐŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂů} ĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕ƚŚĞEĞƚŚĞƌůĂŶĚƐ 2_{ĞƉĂƌƚŵĞŶƚŽĨWĞĚŝĂƚƌŝĐEĞƉŚƌŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ} 'ƌŽŶŝŶŐĞŶ͕ƚŚĞEĞƚŚĞƌůĂŶĚƐ 3_{ŝǀŝƐŝŽŶŽĨWĞĚŝĂƚƌŝĐEĞƉŚƌŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJ,ŽƐƉŝƚĂů} ,ĞŝĚĞůďĞƌŐ͕'ĞƌŵĂŶLJ ^ƵďŵŝƩĞĚ

5

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: 66PDF page: 66PDF page: 66PDF page: 66

66

Abstract

Background WƌŽƚĞŝŶƵƌŝĂƉƌĞĚŝĐƚƐƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨĂŝůƵƌĞŝŶĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ;<Ϳ͘tŚŝůĞ ƉŚĂƌŵĂĐŽƚŚĞƌĂƉĞƵƟĐƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐǁĂƐĨŽƵŶĚŶĞƉŚƌŽƉƌŽƚĞĐƟǀĞŝŶĂĚƵůƚƐ͕ƚŚĞ ƉƌĞĚŝĐƟǀĞǀĂůƵĞŽĨĞĂƌůLJĚƌƵŐͲŝŶĚƵĐĞĚƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶĨŽƌůŽŶŐͲƚĞƌŵƌĞŶĂůƐƵƌǀŝǀĂů ŝŶƉĞĚŝĂƚƌŝĐ<ŝƐƵŶŬŶŽǁŶ͘tĞĂŶĂůLJƐĞĚĚĂƚĂĨƌŽŵƚŚĞ^WdƌŝĂůĨŽƌĂƉŽƚĞŶƟĂů ĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƚŚĞŝŶŝƟĂůĂŶƟƉƌŽƚĞŝŶƵƌŝĐĞīĞĐƚŽĨƐƚĂŶĚĂƌĚŝnjĞĚŝŶŚŝďŝƟŽŶĂŶĚ ƐƵďƐĞƋƵĞŶƚƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘ Methods ϮϴϬĞůŝŐŝďůĞĐŚŝůĚƌĞŶǁŝƚŚ<ƐƚĂŐĞ//Ͳ/s;ŵĞĂŶĂŐĞϭϭ͘ϳLJĞĂƌƐ͕ŵĞĂŶĞ'&Zϰϯŵůͬ ŵŝŶͬϭ͘ϳϯŵ2_{͕ϳϭйĐŽŶŐĞŶŝƚĂůƌĞŶĂůŵĂůĨŽƌŵĂƟŽŶƐͿƌĞĐĞŝǀĞĚĂĮdžĞĚĚŽƐĞŽĨƌĂŵŝƉƌŝů;ϲŵŐͬ} m2_{ͬĚĂLJͿĂŶĚǁĞƌĞƐƵďƐĞƋƵĞŶƚůLJƌĂŶĚŽŵŝnjĞĚƚŽĐŽŶǀĞŶƟŽŶĂůŽƌŝŶƚĞŶƐŝĮĞĚďůŽŽĚƉƌĞƐƐƵƌĞ} ĐŽŶƚƌŽů͘/ŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐĂƐƐĞƐƐĞĚĨƌŽŵďĂƐĞůŝŶĞƚŽĮƌƐƚŵĞĂƐƵƌĞŵĞŶƚ ŽŶƌĂŵŝƉƌŝů;ĂƚϮ͘ϱцϭ͘ϯŵŽŶƚŚƐͿ͘DƵůƟǀĂƌŝĂďůĞŽdžŵŽĚĞůůŝŶŐǁĂƐƵƐĞĚƚŽĞƐƟŵĂƚĞƚŚĞ ĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶĂŶĚƚŚĞƌŝƐŬŽĨƌĞĂĐŚŝŶŐĂƌĞŶĂůĞŶĚ ƉŽŝŶƚ;ϱϬйĞ'&ZĚĞĐůŝŶĞŽƌĞŶĚͲƐƚĂŐĞƌĞŶĂůĚŝƐĞĂƐĞͿ͕ǁŚŝĐŚŽĐĐƵƌƌĞĚŝŶϴϬƉĂƟĞŶƚƐĚƵƌŝŶŐ ϱLJĞĂƌƐŽďƐĞƌǀĂƟŽŶ͘ Results ZĂŵŝƉƌŝůƚŚĞƌĂƉLJůŽǁĞƌĞĚƉƌŽƚĞŝŶƵƌŝĂďLJĂŵĞĂŶŽĨϰϯ͘ϱй;ϵϱй/ϯϲ͘ϯͲϰϵ͘ϵйͿ͘ZĞůĂƟǀĞ ƚŽƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶфϯϬй͕ϯϬͲϲϬйƌĞĚƵĐƟŽŶƌĞƐƵůƚĞĚŝŶĂ,ZŽĨϬ͘ϳϬ;ϵϱй/Ϭ͘ϰϬͲ ϭ͘ϮϮͿĂŶĚхϲϬйƌĞĚƵĐƟŽŶŝŶ,ZŽĨϬ͘ϰϮ;Ϭ͘ϮϮͲϬ͘ϳϵͿ͘dŚŝƐĂƐƐŽĐŝĂƟŽŶǁĂƐŝŶĚĞƉĞŶĚĞŶƚŽĨ ĂŐĞ͕ŐĞŶĚĞƌ͕<ĚŝĂŐŶŽƐŝƐ͕ďĂƐĞůŝŶĞĞ'&Z͕ďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂ͕ŝŶŝƟĂůďůŽŽĚƉƌĞƐƐƵƌĞ͕ ĂŶĚĐŽŶĐŽŵŝƚĂŶƚďůŽŽĚƉƌĞƐƐƵƌĞƌĞĚƵĐƟŽŶ͘ Conclusions dŚĞĞĂƌůLJĂŶƟƉƌŽƚĞŝŶƵƌŝĐĞīĞĐƚŽĨŝŶŚŝďŝƟŽŶŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚůŽŶŐͲƚĞƌŵƉƌĞƐĞƌǀĂƟŽŶ ŽĨƌĞŶĂůĨƵŶĐƟŽŶŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘WƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐƐŚŽƵůĚďĞĐŽŶƐŝĚĞƌĞĚĂŶ ŝŵƉŽƌƚĂŶƚƚĂƌŐĞƚŝŶƚŚĞŵĂŶĂŐĞŵĞŶƚŽĨƉĞĚŝĂƚƌŝĐ<͘

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: 67PDF page: 67PDF page: 67PDF page: 67

67

Introduction

/ŶƚŚĞŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶ͕ŝŶĐƌĞĂƐĞĚůĞǀĞůƐŽĨƵƌŝŶĂƌLJĂůďƵŵŝŶĂƌĞƉƌĞƐĞŶƚŝŶ ĂƉƉƌŽdžŝŵĂƚĞůLJϳйŽĨŝŶĚŝǀŝĚƵĂůƐĂŶĚĂƌĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŚŝŐŚĞƌƌŝƐŬŽĨƌĞŶĂůĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘1-3_{tĞƌĞĐĞŶƚůLJƐŚŽǁĞĚƚŚĂƚŝŶƚŚĞŐĞŶĞƌĂůƚŽĚĚůĞƌƉŽƉƵůĂƟŽŶ͕} ŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂŝƐƉƌĞƐĞŶƚŝŶĂƉƉƌŽdžŝŵĂƚĞůLJϳйŽĨƚŚĞĐŚŝůĚƌĞŶ͕ŝŶĂŶĂůŽŐLJƚŽƚŚĞ ĂĚƵůƚƉŽƉƵůĂƟŽŶ͘4_{ůƐŽŝŶĐŚŝůĚƌĞŶǁŝƚŚĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͕ŚŝŐŚĞƌƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůƐ} ĂƌĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŶŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĂŶĚƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͘5-7 ŶƚĂŐŽŶŝƐƚƐŽĨƚŚĞƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐLJƐƚĞŵ;Z^ͿĞĸĐŝĞŶƚůLJůŽǁĞƌƉƌŽƚĞŝŶƵƌŝĂ͘ ^ƚƵĚŝĞƐǁŝƚŚĂŶŐŝŽƚĞŶƐŝŶĐŽŶǀĞƌƟŶŐĞŶnjLJŵĞ;ͿŝŶŚŝďŝƚŽƌƐĂŶĚĂŶŐŝŽƚĞŶƐŝŶ//ƚLJƉĞ/ ƌĞĐĞƉƚŽƌďůŽĐŬĞƌƐ;ZƐͿŝŶĂĚƵůƚƐǁŝƚŚĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ;<ͿĚƵĞƚŽŐůŽŵĞƌƵůĂƌ ĚŝƐŽƌĚĞƌƐŚĂǀĞƐŚŽǁŶƚŚĂƚƚŚĞůĂƌŐĞƌƚŚĞƌĞĚƵĐƟŽŶŝŶĂůďƵŵŝŶƵƌŝĂŝŶĚƵĐĞĚďLJƚŚĞƐĞ ĂŐĞŶƚƐĚƵƌŝŶŐƚŚĞĮƌƐƚŵŽŶƚŚƐŽĨƚƌĞĂƚŵĞŶƚ͕ƚŚĞůĂƌŐĞƌƚŚĞƌĞĚƵĐƟŽŶŝŶƌĞŶĂůĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬĚƵƌŝŶŐƐƵďƐĞƋƵĞŶƚĨŽůůŽǁͲƵƉ͘8-10_{ůƐŽŝŶĐŚŝůĚƌĞŶ͕ŝŶǁŚŽŵ<ŝƐ} ŵŽƐƚŽŌĞŶĐĂƵƐĞĚďLJĂĐŽŶŐĞŶŝƚĂůŶĞƉŚƌŽŶĚĞĮĐŝƚĚƵĞƚŽŬŝĚŶĞLJŵĂůĚĞǀĞůŽƉŵĞŶƚ͕ ŝŶŚŝďŝƚŽƌƐĂŶĚZƐŚĂǀĞďĞĞŶƐŚŽǁŶƚŽƌĞĚƵĐĞĂůďƵŵŝŶƵƌŝĂ͘11,12_{,ŽǁĞǀĞƌ͕ƚŚĞĞīĞĐƚŽĨ} ƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐŽŶůŽŶŐͲƚĞƌŵƌĞŶĂůƐƵƌǀŝǀĂůŚĂƐŶŽƚďĞĞŶĞƐƚĂďůŝƐŚĞĚŝŶƚŚĞƉĞĚŝĂƚƌŝĐ <ƉŽƉƵůĂƟŽŶ͘ ,ĞƌĞ͕ǁĞŵĂĚĞƵƐĞŽĨƚŚĞůĂƌŐĞƐƚƉŚĂƌŵĂĐŽůŽŐŝĐĂůŶĞƉŚƌŽƉƌŽƚĞĐƟŽŶƚƌŝĂůƉĞƌĨŽƌŵĞĚ ƚŽ ĚĂƚĞ ŝŶ ĐŚŝůĚƌĞŶ ƚŽ ŝŶǀĞƐƟŐĂƚĞ Ă ƉŽƐƐŝďůĞ ƋƵĂŶƟƚĂƟǀĞ ĂƐƐŽĐŝĂƟŽŶ ďĞƚǁĞĞŶ ƚŚĞ ŝŶŝƟĂůĂŶƟƉƌŽƚĞŝŶƵƌŝĐĞīĞĐƚŽĨŝŶŚŝďŝƟŽŶĂŶĚƐƵďƐĞƋƵĞŶƚ<ƉƌŽŐƌĞƐƐŝŽŶ͘tĞ ĂůƐŽĚĞƚĞƌŵŝŶĞĚǁŚĞƚŚĞƌƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂ;ŝ͘Ğ͘ƚŚĞƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůĚƵƌŝŶŐ ŝŶŚŝďŝƟŽŶͿŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŚŝŐŚĞƌƌĞŶĂůƌŝƐŬ͕ĂƌŐƵŝŶŐƚŚĂƚƉŽƐŝƟǀĞĮŶĚŝŶŐƐĨŽƌƚŚĞƐĞ ƚǁŽĂƐƐŽĐŝĂƟŽŶƐǁŽƵůĚƐƚƌĞŶŐƚŚĞŶƚŚĞŚLJƉŽƚŚĞƐŝƐƚŚĂƚĂůďƵŵŝŶƵƌŝĂŝƐĂŶŝŵƉŽƌƚĂŶƚ ŵŽĚŝĮĂďůĞĚĞƚĞƌŵŝŶĂŶƚŽĨƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶĂůƐŽŝŶƉĞĚŝĂƚƌŝĐ<͘

Materials and methods

^ƚƵĚLJĚĞƐŝŐŶĂŶĚƉĂƟĞŶƚƐ &ŽƌƚŚŝƐƐƚƵĚLJǁĞƵƐĞĚĚĂƚĂĨƌŽŵƚŚĞīĞĐƚŽĨ^ƚƌŝĐƚůŽŽĚWƌĞƐƐƵƌĞŽŶƚƌŽůĂŶĚ ŝŶŚŝďŝƟŽŶŽŶƚŚĞWƌŽŐƌĞƐƐŝŽŶŽĨZ&ŝŶWĞĚŝĂƚƌŝĐWĂƟĞŶƚƐ;^WͿƚƌŝĂů͘ZĂƟŽŶĂůĞ͕ƐƚƵĚLJ ĚĞƐŝŐŶĂŶĚƌĞƐƵůƚƐŽĨƚŚŝƐƐƚƵĚLJŚĂǀĞďĞĞŶƉƵďůŝƐŚĞĚĞůƐĞǁŚĞƌĞ͘11_{/ŶƐŚŽƌƚ͕ƚŚĞ^W} ƚƌŝĂůǁĂƐĂŶŝŶǀĞƐƟŐĂƚŽƌͲŝŶŝƟĂƚĞĚ͕ƌĂŶĚŽŵŝnjĞĚ͕ĐŽŶƚƌŽůůĞĚƚƌŝĂůŝŶǀĞƐƟŐĂƟŶŐǁŚĞƚŚĞƌ ŝŶƚĞŶƐŝĮĞĚďůŽŽĚƉƌĞƐƐƵƌĞĐŽŶƚƌŽů;фϱϬth_{ƉĞƌĐĞŶƟůĞĨŽƌĂŐĞͿǁŽƵůĚĚĞůĂLJƚŚĞƉƌŽŐƌĞƐƐŝŽŶ} ŽĨƌĞŶĂůĚŝƐĞĂƐĞŝŶĐŚŝůĚƌĞŶǁŝƚŚ<ǁŚŽǁĞƌĞƌĞĐĞŝǀŝŶŐĂĮdžĞĚĚŽƐĞŽĨŝŶŚŝďŝƟŽŶ͘/Ŷ ƚŚŝƐƐƚƵĚLJ͕ϯϴϱĐŚŝůĚƌĞŶǁŝƚŚ<;ĂŐĞĚϯͲϭϴLJĞĂƌƐ͕Ğ'&ZŽĨϭϱͲϴϬŵůͬŵŝŶͬϭ͘ϳϯŵ2_ďŽĚLJͲ ƐƵƌĨĂĐĞĂƌĞĂͿ͕ǁŚŽƐĞϮϰͲŚŽƵƌŵĞĂŶĂƌƚĞƌŝĂůƉƌĞƐƐƵƌĞ;DWͿǁĂƐĞŝƚŚĞƌĞůĞǀĂƚĞĚ;хϵϱth ƉĞƌĐĞŶƟůĞͿŽƌĐŽŶƚƌŽůůĞĚǁŝƚŚĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞŵĞĚŝĐĂƟŽŶ͕ǁĞƌĞŝŶĐůƵĚĞĚ͘džĐůƵƐŝŽŶ ĐƌŝƚĞƌŝĂǁĞƌĞƌĞŶĂůͲĂƌƚĞƌLJƐƚĞŶŽƐŝƐ͕ĂŚŝƐƚŽƌLJŽĨŬŝĚŶĞLJƚƌĂŶƐƉůĂŶƚĂƟŽŶ͕ĂŶƵŶƐƚĂďůĞĐůŝŶŝĐĂů ĐŽŶĚŝƟŽŶ͕ƚƌĞĂƚŵĞŶƚǁŝƚŚŝŵŵƵŶŽƐƵƉƉƌĞƐƐŝǀĞĂŐĞŶƚƐ;ŝŶĐůƵĚŝŶŐŐůƵĐŽĐŽƌƟĐŽŝĚƐͿĂŶĚ ŵĂũŽƌƉƌŝŵĂƌLJĐĂƌĚŝĂĐ͕ŚĞƉĂƟĐŽƌŐĂƐƚƌŽŝŶƚĞƐƟŶĂůĚŝƐŽƌĚĞƌƐ͘dŚĞƐƚƵĚLJƉƌŽƚŽĐŽůǁĂƐ

5

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: 68PDF page: 68PDF page: 68PDF page: 68

68 ĂƉƉƌŽǀĞĚďLJƚŚĞĐĞŶƚƌĂůĞƚŚŝĐƐĐŽŵŵŝƩĞĞŽĨƚŚĞŵĞĚŝĐĂůĨĂĐƵůƚLJŽĨƚŚĞhŶŝǀĞƌƐŝƚLJŽĨ ,ĞŝĚĞůďĞƌŐĂŶĚďLJƚŚĞůŽĐĂůŝŶƐƟƚƵƟŽŶƌĞǀŝĞǁďŽĂƌĚŽĨĞĂĐŚƐŝƚĞ͘WĂƌĞŶƚƐŽĨĂůůĐŚŝůĚƌĞŶ ƉƌŽǀŝĚĞĚǁƌŝƩĞŶŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚ͘ ƚƐĐƌĞĞŶŝŶŐ͕ĞůŝŐŝďůĞƉĂƟĞŶƚƐƵŶĚĞƌǁĞŶƚĂŶĂŵďƵůĂƚŽƌLJďůŽŽĚƉƌĞƐƐƵƌĞŵŽŶŝƚŽƌŝŶŐ͘ ůŝŐŝďůĞƉĂƟĞŶƚƐƐƚĂƌƚĞĚĂƌƵŶͲŝŶƉĞƌŝŽĚŽĨƐŝdžŵŽŶƚŚƐ͕ĚƵƌŝŶŐǁŚŝĐŚƚŚĞLJĂƩĞŶĚĞĚĐůŝŶŝĐ ǀŝƐŝƚƐĞǀĞƌLJƚǁŽŵŽŶƚŚƐ͘ƚůĞĂƐƚƚǁŽŵŽŶƚŚƐďĞĨŽƌĞƚŚĞĞŶĚŽĨƚŚĞƌƵŶͲŝŶƉĞƌŝŽĚ͕ĂŶLJ ƚƌĞĂƚŵĞŶƚǁŝƚŚĂŶŝŶŚŝďŝƚŽƌŽĨƚŚĞƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐLJƐƚĞŵǁĂƐĚŝƐĐŽŶƟŶƵĞĚ͘ŌĞƌƚŚĞ ƌƵŶͲŝŶƉĞƌŝŽĚ͕ĂůůĐŚŝůĚƌĞŶƌĞĐĞŝǀĞĚƚŚĞƐĂŵĞĚŽƐĞŽĨƚŚĞŝŶŚŝďŝƚŽƌƌĂŵŝƉƌŝů;ϲŵŐͬ m2_{ďŽĚLJͲƐƵƌĨĂĐĞĂƌĞĂƉĞƌĚĂLJ͕ĞƋƵŝǀĂůĞŶƚƚŽƚŚĞŵĂdžŝŵƵŵĂƉƉƌŽǀĞĚĚŽƐĞŽĨϭϬŵŐͬ} ĚĂLJŝŶĂĚƵůƚƐͿ͘dŚĞĚŽƐĂŐĞǁĂƐŐƌĂĚƵĂůůLJƵƉƟƚƌĂƚĞĚŽǀĞƌƚŚĞĐŽƵƌƐĞŽĨƚǁŽŵŽŶƚŚƐ͘ ^ƵďƐĞƋƵĞŶƚůLJ͕ƉĂƟĞŶƚƐǁĞƌĞƐƚƌĂƟĮĞĚƚŽĞŝƚŚĞƌĂĐŽŶǀĞŶƟŽŶĂůďůŽŽĚͲƉƌĞƐƐƵƌĞƚĂƌŐĞƚ ;ϱϬth_-95th_{ƉĞƌĐĞŶƟůĞŽĨϮϰͲŚŽƵƌŵĞĂŶĂƌƚĞƌŝĂůƉƌĞƐƐƵƌĞ;DWͿͿŽƌĂŶŝŶƚĞŶƐŝĮĞĚďůŽŽĚͲ} ƉƌĞƐƐƵƌĞƚĂƌŐĞƚ;фϱϬth_{ƉĞƌĐĞŶƟůĞŽĨϮϰͲŚŽƵƌDWͿ͘dŽƌĞĂĐŚƚŚĞďůŽŽĚͲƉƌĞƐƐƵƌĞƚĂƌŐĞƚ͕} ĂŶLJĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞĂŐĞŶƚĐŽƵůĚďĞƉƌĞƐĐƌŝďĞĚĞdžĐĞƉƚĨŽƌŽƚŚĞƌŝŶŚŝďŝƚŽƌƐŽĨƚŚĞƌĞŶŝŶͲ ĂŶŐŝŽƚĞŶƐŝŶƐLJƐƚĞŵ͘ ƵƌŝŶŐƚŚĞϱͲLJĞĂƌƐƚƵĚLJƉĞƌŝŽĚ͕ďůŽŽĚͲƉƌĞƐƐƵƌĞ͕ƉƌŽƚĞŝŶƵƌŝĂĂŶĚĞ'&ZǁĞƌĞĂƐƐĞƐƐĞĚ ĞǀĞƌLJ ƚǁŽ ŵŽŶƚŚƐ͕ ĂŶĚ ϮϰͲŚŽƵƌ ĂŵďƵůĂƚŽƌLJ ďůŽŽĚ ƉƌĞƐƐƵƌĞ ŵĞĂƐƵƌĞŵĞŶƚƐ ǁĞƌĞ ƉĞƌĨŽƌŵĞĚĞǀĞƌLJƐŝdžŵŽŶƚŚƐ͘Ğ'&ZǁĂƐĂƐƐĞƐƐĞĚďLJŵĞĂŶƐŽĨƚŚĞ^ĐŚǁĂƌƚnjĨŽƌŵƵůĂ͕ ǁŝƚŚƚŚĞƵƐĞŽĨŵĞĂƐƵƌĞŵĞŶƚƐŽĨƐĞƌƵŵĐƌĞĂƟŶŝŶĞĂŶĚŚĞŝŐŚƚĂŶĚĂŬĐŽŶƐƚĂŶƚŽĨϬ͘ϱϱ͘13 /ͬŐĞŶŽƚLJƉĞǁĂƐŵĞĂƐƵƌĞĚŝŶďůŽŽĚĐŽůůĞĐƚĞĚĚƵƌŝŶŐƚŚĞƌƵŶͲŝŶƉĞƌŝŽĚ͕ƵƐŝŶŐƚŚĞ ŵĞƚŚŽĚƚŚĂƚŚĂƐďĞĞŶĞdžƚĞŶƐŝǀĞůLJĚĞƐĐƌŝďĞĚƉƌĞǀŝŽƵƐůLJ͘14 Proteinuria measurements hƌŝŶĞĐŽůůĞĐƟŽŶƐ;ǁŚĞƌĞƉŽƐƐŝďůĞĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶͿ͕ǁĞƌĞƉĞƌĨŽƌŵĞĚĞǀĞƌLJƚǁŽ ŵŽŶƚŚƐ͘/ĨĐŽůůĞĐƟŽŶŽĨĂϮϰͲŚŽƵƌƵƌŝŶĞƐĂŵƉůĞǁĂƐŶŽƚƉŽƐƐŝďůĞĚƵĞƚŽLJŽƵŶŐĂŐĞŽƌ ĞŶƵƌĞƐŝƐ͕ĂƌĂŶĚŽŵƵƌŝŶĞƐĂŵƉůĞǁĂƐĐŽůůĞĐƚĞĚĚƵƌŝŶŐƚŚĞĐůŝŶŝĐĂůǀŝƐŝƚ͘ƚƚŚĞďĂƐĞůŝŶĞ ǀŝƐŝƚ͕ĂƌĂŶĚŽŵƐĂŵƉůĞŝŶƐƚĞĂĚŽĨĂϮϰͲŚŽƵƌƵƌŝŶĞƐĂŵƉůĞǁĂƐĐŽůůĞĐƚĞĚŝŶϰϯŝŶĚŝǀŝĚƵĂůƐ͘ dŽƚĂůƉƌŽƚĞŝŶĂŶĚĐƌĞĂƟŶŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶǁĞƌĞŵĞĂƐƵƌĞĚŝŶƚŚĞƐĂŵƉůĞƐǁŝƚŚƚŚĞƵƐĞ ŽĨŽŽŵĂƐƐŝĞďůƵĞƐƚĂŝŶŝŶŐĂŶĚŵŽĚŝĮĞĚ:ĂīĞƌĞĂĐƟŽŶ͕ƌĞƐƉĞĐƟǀĞůLJ͘WƌŽƚĞŝŶƵƌŝĂǁĂƐ ŵĞĂƐƵƌĞĚĂƐƚŚĞƵƌŝŶĂƌLJƉƌŽƚĞŝŶͲƚŽͲĐƌĞĂƟŶŝŶĞƌĂƟŽ;WZͿŝŶŵŐͬŵŐ͘dŚƌŽƵŐŚŽƵƚƚŚĞ ĂƌƟĐůĞǁĞƵƐĞƚŚĞƚĞƌŵƉƌŽƚĞŝŶƵƌŝĂ͘ dŚĞŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐĚĞĮŶĞĚĂƐƚŚĞŶĂƚƵƌĂůůŽŐĂƌŝƚŚŵŽĨƚŚĞƌĞĚƵĐƟŽŶ ŝŶƉƌŽƚĞŝŶƵƌŝĂĨƌŽŵďĂƐĞůŝŶĞŵĞĂƐƵƌĞŵĞŶƚƚŽƚŚĞĮƌƐƚƉƌŽƚĞŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚĂŌĞƌ ĂƩĂŝŶŵĞŶƚŽĨƚŚĞĨƵůůĚŽƐĞŽĨƌĂŵŝƉƌŝů͕ĐĂůĐƵůĂƚĞĚĂƐĨŽůůŽǁƐ͗ůŶ;ĮƌƐƚŵĞĂƐƵƌĞŵĞŶƚĂŌĞƌ ĨƵůůĚŽƐĞŽĨƌĂŵŝƉƌŝůͬďĂƐĞůŝŶĞŵĞĂƐƵƌĞŵĞŶƚͿ͘tĞĚĞĮŶĞĚƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂĂƐƚŚĞůĞǀĞů ŽĨƉƌŽƚĞŝŶƵƌŝĂƉƌĞƐĞŶƚĚƵƌŝŶŐƚƌĞĂƚŵĞŶƚǁŝƚŚϲŵŐͬŵ2_{ƌĂŵŝƉƌŝů͘WƌŽƚĞŝŶƵƌŝĂĞdžƉŽƐƵƌĞŽǀĞƌ} ƟŵĞǁĂƐĐĂůĐƵůĂƚĞĚĂƐƚŚĞĂƌĞĂƵŶĚĞƌƚŚĞĐƵƌǀĞ;hͿŽĨĂůůƉƌŽƚĞŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚƐ ĨƌŽŵďĂƐĞůŝŶĞƵŶƟůĞŝƚŚĞƌƌĞĂĐŚŝŶŐƚŚĞĞŶĚƉŽŝŶƚŽƌĞŶĚŽĨƐƚƵĚLJ͘DĞĚŝĂŶŶƵŵďĞƌŽĨ ƉƌŽƚĞŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚƐƚŽĐĂůĐƵůĂƚĞƚŚĞhǁĂƐϭϱ;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞϴƚŽϮϰ} ŵĞĂƐƵƌĞŵĞŶƚƐͿ͘

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: 69PDF page: 69PDF page: 69PDF page: 69

69 /ŶƚŚŝƐƐƚƵĚLJ͕ǁĞŝŶĐůƵĚĞĚϮϴϬĐŚŝůĚƌĞŶŽĨƚŚĞŝŶŝƟĂů^WƐƚƵĚLJƉŽƉƵůĂƟŽŶ͘ŚŝůĚƌĞŶ ǁŝƚŚĂŵŝƐƐŝŶŐƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůĂƚďĂƐĞůŝŶĞ;ŶсϰϯͿ͕ŶŽĨŽůůŽǁͲƵƉŵĞĂƐƵƌĞŵĞŶƚǁŝƚŚŝŶϲ ŵŽŶƚŚƐĂŌĞƌƐƚĂƌƟŶŐƌĂŵŝƉƌŝů;ŶсϮϵͿ͕ĂŵŝƐƐŝŶŐĂŵďƵůĂƚŽƌLJďůŽŽĚƉƌĞƐƐƵƌĞŵĞĂƐƵƌĞŵĞŶƚ ĂƚďĂƐĞůŝŶĞ;ŶсϯͿŽƌĂŌĞƌϲŵŽŶƚŚƐ;ŶсϮϭͿ͕ŽƌǁŚŽǁĞƌĞůŽƐƚƚŽĨŽůůŽǁƵƉ;ŶсϵͿǁĞƌĞ ĞdžĐůƵĚĞĚ͘ Outcomes dŚĞƉƌĞͲƐƉĞĐŝĮĞĚƉƌŝŵĂƌLJĞĸĐĂĐLJŵĞĂƐƵƌĞŽĨ^WƐƚƵĚLJǁĂƐƟŵĞĨƌŽŵĂƩĂŝŶŵĞŶƚ ŽĨƚŚĞĨƵůůĚŽƐĞŽĨƌĂŵŝƉƌŝůƵŶƟůƚŚĞĮƌƐƚĞǀĞŶƚŽĨƚŚĞĐŽŵƉŽƐŝƚĞĞŶĚƉŽŝŶƚ͕ǁŚŝĐŚǁĂƐ ĚĞĮŶĞĚĂƐĂƐƵƐƚĂŝŶĞĚϱϬйƌĞĚƵĐƟŽŶŽĨĞ'&ZŽƌƉƌŽŐƌĞƐƐŝŽŶƚŽĞŶĚͲƐƚĂŐĞƌĞŶĂůĚŝƐĞĂƐĞ ;Ğ'&ZфϭϬŵůͬŵŝŶͬϭ͘ϳϯŵ2_{ŽƌƐƚĂƌƚŽĨƌĞŶĂůƌĞƉůĂĐĞŵĞŶƚƚŚĞƌĂƉLJͿ͘/ŶƚŚŝƐƐƚƵĚLJ͕ƚŚĞƐĂŵĞ} ĐŽŵƉŽƐŝƚĞĞŶĚƉŽŝŶƚǁĂƐƵƐĞĚ͘ ^ƚĂƟƐƟĐĂůĂŶĂůLJƐĞƐ dŚĞĐƵŵƵůĂƟǀĞĞǀĞŶƚƌĂƚĞĨŽƌƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚŝŶƐƵďŐƌŽƵƉƐŽĨƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶǁĂƐĂƐƐĞƐƐĞĚƵƐŝŶŐƚŚĞ<ĂƉůĂŶͲDĞŝĞƌƉƌŽĐĞĚƵƌĞ͘WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐ ƐƚƌĂƟĮĞĚŝŶƚŽƚŚƌĞĞƐƵďŐƌŽƵƉƐ͖хϲϬйƌĞĚƵĐƟŽŶ͕ϯϬͲϲϬйƌĞĚƵĐƟŽŶĂŶĚфϯϬйƌĞĚƵĐƟŽŶ͘ dŚĞƐĞŐƌŽƵƉƐǁĞƌĞĐŚŽƐĞŶƉŽƐƚŚŽĐ͕ŝŶŽƌĚĞƌƚŽƉƌŽǀŝĚĞĞĂƐŝůLJƵŶĚĞƌƐƚĂŶĚĂďůĞƚŚƌĞƐŚŽůĚƐ͕ ǁŚĞƌĞĂƐ ƚŚĞ ŶƵŵďĞƌ ŽĨ ƉĂƟĞŶƚƐ ǁŝƚŚŝŶ ƚŚĞ ŐƌŽƵƉƐ ƌĞŵĂŝŶƐ ƐŝŵŝůĂƌ͘ ŝīĞƌĞŶĐĞƐ ŝŶ ƉŽƉƵůĂƟŽŶĐŚĂƌĂĐƚĞƌŝƐƟĐƐďĞƚǁĞĞŶƚŚƌĞĞŐƌŽƵƉƐŽĨƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĞƌĞƚĞƐƚĞĚ ǁŝƚŚŚŝ2_{ƚĞƐƚ͕EKsŽƌ^ƉĞĂƌŵĂŶƌĂŶŬĐŽƌƌĞůĂƟŽŶƚĞƐƚ͕ǁŚĞƌĞĂƉƉƌŽƉƌŝĂƚĞ͘Ždž} ƉƌŽƉŽƌƟŽŶĂůŚĂnjĂƌĚƐŵŽĚĞůǁĂƐƵƐĞĚƚŽĞƐƟŵĂƚĞƚŚĞƌĞŶĂůƌŝƐŬĚŝīĞƌĞŶĐĞĂŵŽŶŐƚŚĞ ƚŚƌĞĞƐƵďŐƌŽƵƉƐŽĨƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͘dŚĞŽdžŵŽĚĞůǁĂƐĂĚũƵƐƚĞĚĨŽƌƚŚĞĨŽůůŽǁŝŶŐ ĐŽǀĂƌŝĂƚĞƐ͗ĂŐĞ͕ŐĞŶĚĞƌ͕<ĚŝĂŐŶŽƐŝƐ;ŐůŽŵĞƌƵůŽƉĂƚŚLJ͕ŽŶŐĞŶŝƚĂůŶŽŵĂůŝĞƐŽĨƚŚĞ <ŝĚŶĞLJĂŶĚhƌŝŶĂƌLJdƌĂĐƚ;<hdͿ͕ŽƌŽƚŚĞƌĚŝĂŐŶŽƐŝƐͿ͕ďĂƐĞůŝŶĞĞ'&Z͕ďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂ͕ ďĂƐĞůŝŶĞ ďůŽŽĚ ƉƌĞƐƐƵƌĞ͕ ĂŶĚ ďůŽŽĚ ƉƌĞƐƐƵƌĞ ƌĞĚƵĐƟŽŶ ĨƌŽŵ ďĂƐĞůŝŶĞ ƚŽ ŵŽŶƚŚ ϲ͘ DƵůƟǀĂƌŝĂďůĞůŝŶĞĂƌƌĞŐƌĞƐƐŝŽŶǁĂƐƉĞƌĨŽƌŵĞĚƚŽĂƐƐĞƐƐǁŚŝĐŚďĂƐĞůŝŶĞǀĂƌŝĂďůĞƐǁĞƌĞ ĂƐƐŽĐŝĂƚĞĚǁŝƚŚƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͘/ŶŽƌĚĞƌƚŽĂƐĐĞƌƚĂŝŶƚŚĂƚƚŚĞĞīĞĐƚŽĨƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶ ŽŶ ƚŚĞ ĐŽŵƉŽƐŝƚĞ ƌĞŶĂů ĞŶĚƉŽŝŶƚ ǁĂƐ ŶŽƚ ŵŽĚŝĮĞĚ ďLJ ĞŝƚŚĞƌ ďĂƐĞůŝŶĞ ƉƌŽƚĞŝŶƵƌŝĂŽƌďůŽŽĚƉƌĞƐƐƵƌĞƌĞĚƵĐƟŽŶ͕ǁĞƉĞƌĨŽƌŵĞĚƚǁŽƐĞƉĂƌĂƚĞŵƵůƟǀĂƌŝĂďůĞŽdž ŵŽĚĞůƐŝŶǁŚŝĐŚĂŶŝŶƚĞƌĂĐƟŽŶƚĞƌŵďĞƚǁĞĞŶĞŝƚŚĞƌďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂĂŶĚƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶŽƌďůŽŽĚƉƌĞƐƐƵƌĞƌĞĚƵĐƟŽŶĂŶĚƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐŝŶĐůƵĚĞĚ͘ dŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂĂŶĚƚŚĞƌĞŶĂůĞŶĚƉŽŝŶƚǁĂƐĞƐƟŵĂƚĞĚ ƵƐŝŶŐƚŚĞ<ĂƉůĂŶͲDĞŝĞƌƉƌŽĐĞĚƵƌĞ͕ǁŝƚŚƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂĐĂƚĞŐŽƌŝnjĞĚŝŶƚŽƚŚƌĞĞ ƐƵďŐƌŽƵƉƐ͖фϬ͘ϮŵŐͬŵŐ͕Ϭ͘ϮͲϭ͘ϬŵŐͬŵŐĂŶĚхϭ͘ϬŵŐͬŵŐ͘/ŶŽƌĚĞƌƚŽĂƐƐĞƐƐƚŚĞĞīĞĐƚ ŽĨƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂŽŶƚŚĞƌĞŶĂůĞŶĚƉŽŝŶƚ͕ĂŵƵůƟǀĂƌŝĂďůĞŽdžƉƌŽƉŽƌƟŽŶĂůŚĂnjĂƌĚƐ ŵŽĚĞůǁŝƚŚƚŚĞƚŚƌĞĞŐƌŽƵƉŽĨƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂǁĂƐƉĞƌĨŽƌŵĞĚ͕ĂĚũƵƐƚĞĚĨŽƌƚŚĞ ĐŽǀĂƌŝĂƚĞƐŵĞŶƟŽŶĞĚĞĂƌůŝĞƌ͘ƐƉƌŽƚĞŝŶƵƌŝĂŵĂLJĐŚĂŶŐĞŽǀĞƌƟŵĞĚƵƌŝŶŐƉƌŽůŽŶŐĞĚ ĞdžƉŽƐƵƌĞƚŽZ^ďůŽĐŬĂĚĞ͕ǁĞĂůƐŽĂƐƐĞƐƐĞĚƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƐƵďŐƌŽƵƉƐŽĨ ĞdžƉŽƐƵƌĞƚŽƉƌŽƚĞŝŶƵƌŝĂŽǀĞƌƟŵĞĂŶĚƌĞŶĂůƌŝƐŬƵƐŝŶŐďŽƚŚƚŚĞ<ĂƉůĂŶͲDĞŝĞƌĂŶĂůLJƐŝƐĂŶĚ

5

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: 70PDF page: 70PDF page: 70PDF page: 70

70 ĂŵƵůƟǀĂƌŝĂďůĞŽdžƉƌŽƉŽƌƟŽŶĂůŚĂnjĂƌĚƐŵŽĚĞů͕ĂĚũƵƐƚĞĚĨŽƌƚŚĞĐŽǀĂƌŝĂƚĞƐŵĞŶƟŽŶĞĚ ĂďŽǀĞ͘15_{džƉŽƐƵƌĞƚŽƉƌŽƚĞŝŶƵƌŝĂǁĂƐƐƚƌĂƟĮĞĚŝŶƚŽƚĞƌƟůĞƐ͘} /ŶŽƌĚĞƌƚŽĂƐƐĞƐƐǁŚĞƚŚĞƌƚŚĞĮŶĚŝŶŐƐŽĨƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶĂŶĚƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚǁĞƌĞƌŽďƵƐƚĂŶĚŶŽƚĚĞƉĞŶĚĞŶƚŽĨƚŚĞ ƐĞůĞĐƟŽŶŽĨƚŚĞƚŚƌĞƐŚŽůĚƐ͕ǁĞĂŶĂůLJƐĞĚƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ ĂƐĂĐŽŶƟŶƵŽƵƐŵĞĂƐƵƌĞĂŶĚƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚŝŶĂƐĞŶƐŝƟǀŝƚLJĂŶĂůLJƐŝƐ͘ ^ĞŶƐŝƟǀŝƚLJŽĨƚŚĞƉƌŽƚĞŝŶƵƌŝĂĂƐƐĂLJŝŶƚŚĞůŽǁͲŶŽƌŵĂůƉƌŽƚĞŝŶƵƌŝĂƌĂŶŐĞŝƐůŽǁĂŶĚ ŵĞĂƐƵƌĞŵĞŶƚƐďĞůŽǁƚŚĞůŝŵŝƚŽĨĚĞƚĞĐƟŽŶŵĂLJŝŶƚƌŽĚƵĐĞŵŝƐĐůĂƐƐŝĮĐĂƟŽŶƐŝŶƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶ͘dŚĞƌĞĨŽƌĞ͕ĂƐĞŶƐŝƟǀŝƚLJĂŶĂůLJƐŝƐǁĂƐƉĞƌĨŽƌŵĞĚ͕ŝŶǁŚŝĐŚĐŚŝůĚƌĞŶǁŝƚŚĂ ďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂфϬ͘ϭŵŐͬŵŐǁĞƌĞĞdžĐůƵĚĞĚ͘/ŶƚŚŝƐƐĞŶƐŝƟǀŝƚLJĂŶĂůLJƐŝƐǁĞƵƐĞĚĂŽdž ƉƌŽƉŽƌƟŽŶĂůŚĂnjĂƌĚƐŵŽĚĞůǁŝƚŚŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶĂŶĚƚŚĞƐĂŵĞĐŽǀĂƌŝĂƚĞƐĂƐ ĚĞƐĐƌŝďĞĚĞĂƌůŝĞƌ͘/ŶŽƌĚĞƌƚŽĂƐĐĞƌƚĂŝŶƚŚĂƚƚŚĞƌĞƐƵůƚƐĂƌĞŶŽƚĚƌŝǀĞŶďLJƚŚĞŝŶĚŝǀŝĚƵĂůƐ ǁŝƚŚƚŚĞŚŝŐŚĞƐƚďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂ͕ǁĞƉĞƌĨŽƌŵĞĚĂƐĞŶƐŝƟǀŝƚLJĂŶĂůLJƐŝƐŝŶǁŚŝĐŚ ƉĂƟĞŶƚƐǁŝƚŚĂďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂхϵϬth_{ƉĞƌĐĞŶƟůĞǁĞƌĞĞdžĐůƵĚĞĚ͘ĮŶĂůƐĞŶƐŝƟǀŝƚLJ} ĂŶĂůLJƐŝƐǁĂƐƉĞƌĨŽƌŵĞĚ͕ŝŶǁŚŝĐŚĐŚŝůĚƌĞŶǁŚŽƐƚĂƌƚĞĚĂĚĚŝƟŽŶĂůĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞ ŵĞĚŝĐĂƟŽŶƚŽƌĞĂĐŚƚŚĞďůŽŽĚƉƌĞƐƐƵƌĞƚĂƌŐĞƚǁĞƌĞĞdžĐůƵĚĞĚƚŽĂǀŽŝĚŝŶƚĞƌĨĞƌĞŶĐĞŽĨ ŽƚŚĞƌĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞƚŚĞƌĂƉLJŽŶƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƉƌŽƚĞŝŶƵƌŝĂĐŚĂŶŐĞĂŶĚƌĞŶĂů ŽƵƚĐŽŵĞ͘/ŶƚŚŝƐĂŶĂůLJƐŝƐ͕ƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐĂŶĂůLJƐĞĚĂƐĂĐŽŶƟŶƵŽƵƐŵĞĂƐƵƌĞ ĂƐǁĞĚŝĚŶŽƚŚĂǀĞĞŶŽƵŐŚƉŽǁĞƌƚŽƵƐĞƚŚƌĞĞƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶŐƌŽƵƉƐ͘ ĂƚĂĂƌĞĞdžƉƌĞƐƐĞĚĂƐĞŝƚŚĞƌŵĞĂŶĂŶĚƐƚĂŶĚĂƌĚĚĞǀŝĂƟŽŶŽƌŵĞĚŝĂŶĂŶĚŝŶƚĞƌƋƵĂƌƟůĞ ƌĂŶŐĞĨŽƌĐŽŶƟŶƵŽƵƐǀĂƌŝĂďůĞƐĂŶĚƉĞƌĐĞŶƚĂŐĞƐĂŶĚĐŽƵŶƚĨŽƌĐĂƚĞŐŽƌŝĐĂůǀĂƌŝĂďůĞƐ͘ůů ĂŶĂůLJƐĞƐǁĞƌĞƉĞƌĨŽƌŵĞĚƵƐŝŶŐ^ddǀĞƌƐŝŽŶϭϰ;^ƚĂƚĂĐŽƌƉ>WͿ͘

Results

DĞĂŶƉĂƟĞŶƚĂŐĞǁĂƐϭϭ͘ϳLJĞĂƌƐ;ƐƚĂŶĚĂƌĚĚĞǀŝĂƟŽŶ;^Ϳϯ͘ϵͿĂŶĚϲϬйǁĞƌĞŵĂůĞ͘dŚĞ ŵĞĂŶƟŵĞŝŶƚĞƌǀĂůďĞƚǁĞĞŶďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚĂŶĚĮƌƐƚŵĞĂƐƵƌĞŵĞŶƚŽŶ ĨƵůůͲĚŽƐĞƌĂŵŝƉƌŝůǁĂƐϮ͘ϱŵŽŶƚŚƐ;^ϭ͘ϯŵŽŶƚŚƐͿ͘dŚĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨƚŚĞƉŽƉƵůĂƟŽŶ ŝŶĐůƵĚĞĚŝŶƚŚĞĐƵƌƌĞŶƚƐƚƵĚLJǁĞƌĞƐŝŵŝůĂƌƚŽƚŚŽƐĞŽĨƚŚĞŽǀĞƌĂůů^WƚƌŝĂůƉŽƉƵůĂƟŽŶ ;dĂďůĞϭͿ͘ /ŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁŝƚŚŝŶƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶ dŚĞŵĞĂŶŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂĐŚĂŶŐĞǁĂƐʹϰϬ͘Ϯй;ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů΀/΁Ͳϰϵ͘ϭƚŽ ͲϮϵ͘ϲйͿŝŶƚŚĞĐŽŶǀĞŶƟŽŶĂůďůŽŽĚƉƌĞƐƐƵƌĞĐŽŶƚƌŽůŐƌŽƵƉĂŶĚͲϰϲ͘ϳй;ϵϱй/Ͳϱϱ͘ϱйƚŽ Ͳϯϲ͘ϮйͿŝŶƚŚĞŝŶƚĞŶƐŝĮĞĚďůŽŽĚƉƌĞƐƐƵƌĞĐŽŶƚƌŽůŐƌŽƵƉ;ƉсϬ͘ϯϱĨŽƌƚŚĞďĞƚǁĞĞŶŐƌŽƵƉ ĚŝīĞƌĞŶĐĞͿ;&ŝŐƵƌĞϭͿ͘ƵĞƚŽƚŚĞƐŝŵŝůĂƌŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂĐŚĂŶŐĞŝŶƚŚĞƚǁŽƐƚƵĚLJĂƌŵƐ ƚŚĞŐƌŽƵƉƐǁĞƌĞĐŽŵďŝŶĞĚĨŽƌĨƵƌƚŚĞƌĂŶĂůLJƐŝƐ͘/ŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂĐŚĂŶŐĞǁĂƐƐŝŵŝůĂƌ ďĞƚǁĞĞŶƚŚĞĚŝīĞƌĞŶƚƌĞŶĂůĚŝĂŐŶŽƐĞƐ͕ǁŝƚŚĂŵĞĂŶŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂĐŚĂŶŐĞŽĨͲϰϴ͘ϳй ;ϵϱй/Ͳϲϭ͘ϭйƚŽͲϯϮ͘ϭйͿŝŶƚŚĞĐŚŝůĚƌĞŶǁŝƚŚŐůŽŵĞƌƵůŽƉĂƚŚŝĞƐ͕Ͳϯϵ͘ϵй;ϵϱй/Ͳϰϳ͘ϳйƚŽ ͲϯϬ͘ϵйͿŝŶƚŚĞĐŚŝůĚƌĞŶǁŝƚŚ<hdĂŶĚͲϱϯ͘ϲй;ϵϱй/Ͳϲϴ͘ϯйƚŽͲϯϮ͘ϮйͿŝŶƚŚĞĐŚŝůĚƌĞŶ

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: 71PDF page: 71PDF page: 71PDF page: 71

71 ǁŝƚŚŽƚŚĞƌĚŝĂŐŶŽƐĞƐ;ƉсϬ͘ϮϲͿ͘/ŶƚŚĞƚŽƚĂůƐƚƵĚLJ ƉŽƉƵůĂƟŽŶ͕ ŝŶŝƟĂů ƉƌŽƚĞŝŶƵƌŝĂ ǁĂƐ ƌĞĚƵĐĞĚ ďLJ ĂŵĞĂŶŽĨϰϯ͘ϱй͕ǁŝƚŚĂůĂƌŐĞŝŶƚĞƌͲŝŶĚŝǀŝĚƵĂů ǀĂƌŝĂƟŽŶ;ƌĂŶŐĞͲϵϵ͘ϴйƚŽнϱϰϳй͖&ŝŐƵƌĞϭͿ͘Ŷ ŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶďLJŵŽƌĞƚŚĂŶϲϬй ǁĂƐŽďƐĞƌǀĞĚŝŶϯϯй͕ϯϬƚŽϲϬйƌĞĚƵĐƟŽŶŝŶ ϮϳйĂŶĚůĞƐƐƚŚĂŶϯϬйƌĞĚƵĐƟŽŶŝŶϰϬйŽĨƚŚĞ ƉĂƟĞŶƚƐ͘ĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂǁĂƐůŽǁĞƌŝŶƚŚĞ ŐƌŽƵƉǁŝƚŚƚŚĞůĞĂƐƚƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͕ĂŶĚ ĂŐĞ ǁĂƐ ĚŝīĞƌĞŶƚ ďĞƚǁĞĞŶ ƚŚĞ ƚŚƌĞĞ ŐƌŽƵƉƐ ŽĨ ƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƚŝŽŶ͘ KƚŚĞƌ ƉŽƉƵůĂƚŝŽŶ ĐŚĂƌĂĐƚĞƌŝƐƟĐƐǁĞƌĞƐŝŵŝůĂƌĂŵŽŶŐƚŚĞŐƌŽƵƉƐ ;dĂďůĞ ϭͿ͘ LJ ŵƵůƚŝǀĂƌŝĂďůĞ ůŝŶĞĂƌ ƌĞŐƌĞƐƐŝŽŶ ĂŶĂůLJƐŝƐ͕ŚŝŐŚĞƌƉƌŽƚĞŝŶƵƌŝĂ;ɴсϬ͘ϭϰƉĞƌϭŵŐͬ ŵŐ͖ƉфϬ͘ϬϬϭͿǁĂƐŝŶĚĞƉĞŶĚĞŶƚůLJĂƐƐŽĐŝĂƚĞĚǁŝƚŚ ĂůĂƌŐĞƌƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͕ǁŚĞƌĞĂƐƐĞdž͕ĂŐĞ͕ ƚƌĞĂƚŵĞŶƚĂƐƐŝŐŶŵĞŶƚ͕ƉƌŝŵĂƌLJƌĞŶĂůĚŝĂŐŶŽƐŝƐ͕ ďĂƐĞůŝŶĞĞ'&Z͕ďĂƐĞůŝŶĞďůŽŽĚƉƌĞƐƐƵƌĞ͕ďĂƐĞůŝŶĞ ƐĞƌƵŵ ƵƌĞĂ ĂŶĚ  /ͬ ŐĞŶŽƚLJƉĞ ǁĞƌĞ ŶŽƚ ŝŶĚĞƉĞŶĚĞŶƚůLJ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ƉƌŽƚĞŝŶƵƌŝĂ ůŽǁĞƌŝŶŐ;^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϭͿ͘ Figure 1.'LVWULEXWLRQRILQLWLDOSURWHLQXULDFKDQJHLQ WKHWRWDOVWXG\SRSXODWLRQ/HIWSDQHOER[ZKLVNHU SORWV RI SURWHLQXULD FKDQJH :KLVNHUV UHSUHVHQW th_th_{ SHUFHQWLOH 5LJKW SDQHO GLVWULEXWLRQ RI}

LQWUDLQGLYLGXDO SURWHLQXULD FKDQJH LQ WRWDO VWXG\ SRSXODWLRQ FRQYHQWLRQDO EORRG SUHVVXUH FRQWURO JURXSDQGLQWHQVLÀHGEORRGSUHVVXUHFRQWUROJURXS

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: 72PDF page: 72PDF page: 72PDF page: 72

72 /ŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶĂƐĂƉƌĞĚŝĐƚŽƌŽĨƌĞŶĂůŽƵƚĐŽŵĞƐ >ĂƌŐĞƌŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂůĂƌŐĞƌƌŝƐŬƌĞĚƵĐƟŽŶĨŽƌƚŚĞ ƉƌŝŵĂƌLJƌĞŶĂůĞŶĚƉŽŝŶƚ;&ŝŐƵƌĞϮͿ͘dĂŬŝŶŐƚŚĞĚŝīĞƌĞŶĐĞƐŝŶďĂƐĞůŝŶĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐŝŶƚŽ ĂĐĐŽƵŶƚŝŶĂŵƵůƟǀĂƌŝĂďůĞŽdžŵŽĚĞů͕ƚŚĞƐƵďŐƌŽƵƉǁŝƚŚƚŚĞůĂƌŐĞƐƚŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶ;хϲϬйͿƌĞŵĂŝŶĞĚĂƚůŽǁĞƐƚƌŝƐŬ;ŚĂnjĂƌĚƌĂƟŽϬ͘ϰϮ;ϵϱй/Ϭ͘ϮϮʹϬ͘ϳϵͿƌĞůĂƟǀĞ ƚŽƚŚĞƉĂƟĞŶƚƐǁŝƚŚфϯϬйƌĞĚƵĐƟŽŶ͘dŚĞŝŶƚĞƌŵĞĚŝĂƚĞƉƌŽƚĞŝŶƵƌŝĂƌĞƐƉŽŶĚĞƌƐ;ϯϬͲϲϬй ƌĞĚƵĐƟŽŶͿƐŚŽǁĞĚĂŶŝŶƐŝŐŶŝĮĐĂŶƚƌĞůĂƟǀĞƌŝƐŬƌĞĚƵĐƟŽŶ;ŚĂnjĂƌĚƌĂƟŽϬ͘ϳϬ;ϵϱй/Ϭ͘ϰϬ ʹϭ͘ϮϮͿ;&ŝŐƵƌĞϮĂŶĚdĂďůĞϮͿ͘dŚĞĞīĞĐƚŽĨƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐŶŽƚŵŽĚŝĮĞĚďLJ ĞŝƚŚĞƌďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂŽƌďůŽŽĚƉƌĞƐƐƵƌĞƌĞĚƵĐƟŽŶĂƐĞǀŝĚĞŶĐĞĚďLJŝŶƐŝŐŶŝĮĐĂŶƚ ŝŶƚĞƌĂĐƟŽŶƚĞƌŵƐƌĞƉƌĞƐĞŶƚĞĚŝŶ^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϮĂŶĚϯ͘ZĞƐƵůƚƐǁĞƌĞƐŝŵŝůĂƌǁŚĞŶ ƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĂƐĂŶĂůLJƐĞĚĂƐĂĐŽŶƟŶƵŽƵƐǀĂƌŝĂďůĞ;^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϰͿ͘ ƐĞŶƐŝƟǀŝƚLJĂŶĂůLJƐŝƐƚŚĂƚĞdžĐůƵĚĞĚϮϲŝŶĚŝǀŝĚƵĂůƐǁŝƚŚďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂďĞůŽǁ Ϭ͘ϭŵŐͬŵŐƐŚŽǁĞĚĂƐŝŵŝůĂƌƉĂƩĞƌŶŝŶƚŚĂƚƉĂƟĞŶƚƐǁŝƚŚĂůĂƌŐĞƌŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶŚĂĚĂůŽǁĞƌƌŝƐŬŽĨƚŚĞĐŽŵƉŽƐŝƚĞĞŶĚƉŽŝŶƚǁŝƚŚ,Z͛ƐŽĨϬ͘ϰϯ;ϵϱй/Ϭ͘Ϯϯ ƚŽϬ͘ϴϯͿĨŽƌƚŚĞхϲϬйƌĞĚƵĐƟŽŶŐƌŽƵƉĂŶĚϬ͘ϳϱ;ϵϱй/Ϭ͘ϰϯƚŽϭ͘ϯϯͿĨŽƌƚŚĞϯϬͲϲϬй ƌĞĚƵĐƟŽŶŐƌŽƵƉĐŽŵƉĂƌĞĚƚŽƚŚĞфϯϬйƌĞĚƵĐƟŽŶŐƌŽƵƉ;^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϱͿ͘dŚĞ ƐĂŵĞƌĞƐƵůƚƐǁĞƌĞƐĞĞŶǁŚĞŶƉĂƟĞŶƚƐǁŝƚŚĂďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂхϵϬth_{ƉĞƌĐĞŶƟůĞǁĞƌĞ} ĞdžĐůƵĚĞĚ;^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϲͿ͘ZĞƐƵůƚƐǁĞƌĞĂůƐŽĐŽŶĮƌŵĞĚǁŚĞŶϭϯϴƉĂƟĞŶƚƐǁŝƚŚ ĂĚĚŝƟŽŶĂůĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞŵĞĚŝĐĂƟŽŶĚƵƌŝŶŐƚŚĞƐƚƵĚLJǁĞƌĞĞdžĐůƵĚĞĚ͕ǁŝƚŚůĂƌŐĞƌŝŶŝƟĂů ƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶƌĞŵĂŝŶŝŶŐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂůŽǁĞƌƌĞŶĂůƌŝƐŬ͕ǁŝƚŚĂŚĂnjĂƌĚƌĂƟŽ ŽĨϬ͘ϰϭ;ϵϱй/Ϭ͘ϮϮƚŽϬ͘ϳϳͿ;^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϳͿ͘

Residual proteinuria as a predictor of renal outcomes

ŌĞƌĂƩĂŝŶŝŶŐƚŚĞĨƵůůĚŽƐĞŽĨƌĂŵŝƉƌŝů͕ƚŚĞŵĞĚŝĂŶƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂǁĂƐϬ͘ϰϰŵŐͬŵŐ ;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞϬ͘ϭϰʹϭ͘ϬϰŵŐͬŵŐͿ͘ZĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂǁĂƐфϬ͘ϮŵŐͬŵŐŝŶϯϮй͕} ďĞƚǁĞĞŶϬ͘ϮĂŶĚϭ͘ϬŵŐͬŵŐŝŶϰϮйĂŶĚхϭ͘ϬŵŐͬŵŐŝŶϮϲйŽĨƉĂƟĞŶƚƐ͘<ĂƉůĂŶͲDĞŝĞƌ ĂŶĂůLJƐŝƐĂŶĚŽdžŵŽĚĞůůŝŶŐƌĞǀĞĂůĞĚƚŚĂƚĐŚŝůĚƌĞŶǁŝƚŚĂŚŝŐŚĞƌƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂ ůĞǀĞůĐĂƌƌLJĂŚŝŐŚĞƌƌŝƐŬŽĨƌĞĂĐŚŝŶŐƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚ;&ŝŐƵƌĞϮͿ͕ǁŝƚŚ,Z͛Ɛ ĐĂůĐƵůĂƚĞĚǁŝƚŚƚŚĞŵƵůƟǀĂƌŝĂďůĞŽdžŵŽĚĞůŽĨϯ͘ϵϭ;ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů;/Ϳϭ͘ϲϰ ʹϵ͘ϯϯͿĨŽƌƚŚĞƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂхϮ͘ϬŵŐͬŵŐŐƌŽƵƉĂŶĚϭ͘ϲϯ;ϵϱй/Ϭ͘ϳϬʹϯ͘ϴϭͿĨŽƌ ƚŚĞƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂϬ͘ϮʹϮ͘ϬŵŐͬŵŐŐƌŽƵƉĐŽŵƉĂƌĞĚƚŽƚŚĞƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂ фϬ͘ϮŵŐͬŵŐŐƌŽƵƉ dŚĞŵĞĚŝĂŶĞdžƉŽƐƵƌĞƚŽƉƌŽƚĞŝŶƵƌŝĂŽǀĞƌƟŵĞĚƵƌŝŶŐƚŚĞĞŶƟƌĞƐƚƵĚLJƉĞƌŝŽĚĂƐ ĐĂůĐƵůĂƚĞĚǁŝƚŚƚŚĞhŽĨĂůůƉƌŽƚĞŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚƐĨƌŽŵďĂƐĞůŝŶĞƵŶƟůĞŝƚŚĞƌ ƌĞĂĐŚŝŶŐƚŚĞĞŶĚƉŽŝŶƚŽƌĞŶĚŽĨƐƚƵĚLJǁĂƐϬ͘ϭ;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞϬ͘ϭʹϬ͘ϮͿŵŐͬŵŐŝŶ} ƚŚĞŐƌŽƵƉǁŝƚŚƚŚĞůŽǁĞƐƚĞdžƉŽƐƵƌĞ͕Ϭ͘ϲ;Ϭ͘ϰʹϬ͘ϵͿŵŐͬŵŐŝŶƚŚĞŵĞĚŝƵŵƉƌŽƚĞŝŶƵƌŝĂ ĞdžƉŽƐƵƌĞ ŐƌŽƵƉ͕ ĂŶĚ Ϯ͘ϭ ;ϭ͘ϱ ʹ ϯ͘ϮͿ ŵŐͬŵŐ ŝŶ ƚŚĞ ŚŝŐŚĞƐƚ ĞdžƉŽƐƵƌĞ ŐƌŽƵƉ͘ ,ŝŐŚĞƌ ƉƌŽƚĞŝŶƵƌŝĂĞdžƉŽƐƵƌĞŽǀĞƌƟŵĞǁĂƐĂŶŝŶĚĞƉĞŶĚĞŶƚƉƌĞĚŝĐƚŽƌĨŽƌƌĞĂĐŚŝŶŐƚŚĞƌĞŶĂů ĞŶĚƉŽŝŶƚ;&ŝŐƵƌĞϮ͖^ƵƉƉůĞŵĞŶƚĂƌLJƚĂďůĞϴͿ͘

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: 73PDF page: 73PDF page: 73PDF page: 73

73 Figure 2.5LVNRQFRPSRVLWHUHQDOHQGSRLQWZLWK.DSODQ0HLHUDQDO\VLVDQGKD]DUGUDWLRV

FDOFXODWHGZLWKFR[SURSRUWLRQDOKD]DUGPRGHO1_{IRULQLWLDOSURWHLQXULDUHGXFWLRQ$UHVLGXDO}

SURWHLQXULD%DQGH[SRVXUHWRSURWHLQXULDRYHUWLPH&

1_{Initial proteinuria reduction adjusted for: DJHJHQGHU&.'GLDJQRVLVEDVHOLQHDPEXODWRU\}

0$3EDVHOLQHH*)5EDVHOLQHSURWHLQXULDFKDQJHLQDPEXODWRU\0$3

Residual proteinuria adjusted for: DJHJHQGHU&.'GLDJQRVLVEDVHOLQHDPEXODWRU\0$3 EDVHOLQHH*)5FKDQJHLQDPEXODWRU\0$3

Long term exposure to proteinuria adjusted for: DJHJHQGHU&.'GLDJQRVLVEDVHOLQH DPEXODWRU\0$3EDVHOLQHH*)5FKDQJHLQDPEXODWRU\0$3

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: 74PDF page: 74PDF page: 74PDF page: 74

74 Ta b le 1. 3 RS XO D WLR Q FK D UD FW H ULV WLF V E D VH G R Q S UR WH LQ XU LD UH G XF WLR Q G LY LG HG LQW RW KUH HFD WH J R ULH V dŽƚ Ăů ^W ƉŽ ƉƵ ůĂ ƟŽ Ŷ (n=385) WŽƉƵůĂ ƟŽŶƐĞůĞĐƚ ĞĚĨ ŽƌĐƵƌƌ ĞŶ ƚĂŶĂůLJ ƐŝƐ;ŶсϮϴϬͿ Tot al s tudy ƉŽƉƵůĂƟŽŶ;ŶсϮϴϬͿ WƌŽƚ ĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ хϲϬй;ŶсϵϮͿ WƌŽƚ ĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ _{ϯϬͲϲϬй;ŶсϳϲͿ} WƌŽƚ ĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ _{фϯϬй;ŶсϭϭϮͿ} P-value M al e se x, n ϮϯϬ;ϲϬͿ ϭϲϳ;ϲϬͿ ϱϰ;ϱϵͿ ϰϵ;ϲϰͿ ϲϰ;ϱϳͿ 0.588 Ag e, y ear s ϭϭ͘ϲ;ϰ͘ϬͿ ϭϭ͘ϳ;ϯ͘ϵͿ ϭϬ͘ϵ;ϯ͘ϴͿ ϭϮ͘ϰ;ϯ͘ϵͿ ϭϭ͘ϱ;ϯ͘ϴͿ 0.042 ŽŶ ǀĞŶ ƟŽŶĂůƚƌ ĞĂ ƚŵĞŶ ƚĂƌŵ͕Ŷ ϭϵϱ;ϱϭͿ ϭϰϬ;ϱϬͿ ϰϭ;ϰϱͿ ϰϬ;ϱϯͿ ϱϵ;ϱ ϯͿ 0.445 Re na l d ia gn os is -Glomerulopa thies, n -< hd ͕Ŷ -Other , n ϱϭ;ϭϯͿ _{Ϯϲϳ;ϳϬͿ} ϲϲ;ϭϳͿ ϯϲ;ϭϯͿ _{ϭϵϵ;ϳϭͿ} ϰϱ;ϭϲͿ ϭϰ;ϭϱͿ ϲϬ;ϲϱͿ ϭϴ;ϮϬͿ ϭϬ;ϭϯͿ ϱϴ;ϳϲͿ ϴ;ϭϭͿ ϭϮ;ϭϭͿ ϴϭ;ϳϮͿ ϭϵ;ϭϳͿ 0.437 ACE polymorphism -II g enotype, n -ID g enotype, n -DD g enotype, n ϳϬ;ϮϬͿ _{ϭϴϰ;ϱϵͿ ϭϬϯ;ϮϵͿ} ϱϮ;ϭϵͿ _{ϭϯϵ;ϱϮͿ} ϳϵ;ϮϵͿ Ϯϯ;ϮϱͿ ϰϰ;ϰϴͿ Ϯϱ;ϮϳͿ ϭϮ;ϭϲͿ ϰϯ;ϱϴͿ ϭϵ;ϮϲͿ ϭϳ;ϭϲͿ ϱϮ;ϱϱͿ ϯϱ;ϯϰͿ 0.289 Re ac he d en d po in t, n ϭϯϯ;ϯϲͿ ϴϬ;ϮϵͿ ϭϳ;ϭϴͿ ϮϮ;ϮϵͿ ϰϭ;ϯϳͿ 0.267 ĂƐĞůŝŶĞĞ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵϮ ϰϰ;ϮϵʹϱϵͿ ϰϲ;ϯϯʹϱϵͿ ϱϬ;ϯϳʹϲϭͿ ϰϯ ;ϮϴʹϱϱͿ ϰϱ;ϯϭʹϲϬͿ 0.171 Ba se lin e ur in ar y pr ot ei n/ Đƌ ĞĂ ƟŶŝŶĞƌ ĂƟŽ ͕ŵŐ ͬŵŐ Ϭ͘ϵ;Ϭ͘ϯʹϮ͘ϬͿ Ϭ͘ϴ;Ϭ͘ϯʹϭ͘ϴͿ ϭ͘Ϭ;Ϭ͘ϰʹϮ͘ϯͿ ϭ͘Ϭ;Ϭ͘ϰʹϭ͘ϴͿ Ϭ͘ϲ ;Ϭ͘Ϯʹϭ͘ϱͿ 0.001 Baseline serum ur ea, mmol/L ϭϯ͘ϭ;ϲ͘ϱͿ ϭϮ͘ϴ;ϲ͘ϭͿ ϭϮ͘ϭ;ϱ͘ϳͿ ϭϯ͘ϱ;ϲ͘ϭͿ ϭϯ͘Ϭ;ϲ͘ϱͿ 0.443 Baseline ambula tor y MAP , SDS ϭ͘Ϯ;Ϭ͘ϮʹϮ͘ϯͿ ϭ͘Ϯ;Ϭ͘ϮʹϮ͘ϯͿ ϭ͘ϯ;Ϭ͘ϰʹϮ͘ϭͿ ϭ͘Ϭ;Ϭ͘ϮʹϮ͘ϮͿ ϭ͘ϭ ;Ϭ͘ϮʹϮ͘ϰͿ 0.757 ŵďƵůĂ ƚŽƌ LJDWƌ ĞĚƵĐƟŽŶ͕^^ ϭ͘Ϯ;Ϭ͘ϯʹϮ͘ϭͿ ϭ͘Ϯ;Ϭ͘ϰʹϮ͘ϭͿ ϭ͘ϰ ;Ϭ͘ϱʹϮ͘ϮͿ ϭ͘Ϯ;Ϭ͘ϲʹϮ͘ϬͿ ϭ͘ϭ;Ϭ͘ϭʹϮ͘ϭͿ 0.007 9D OX HV IR UFR QW LQ XR XV YD ULD E OH V D UH G HV FU LE HG D V P HD Q “ 6' R UP HG LD Q   th-75 thS H UFH QW LOH  YD OX HV IR UF D WH J R ULF D OY D ULD E OH V D V QX P E H S H UFH QW D J H  13 YD OX HI R UG LIIH UH QFHD P RQ JW KHW KU HHV WUD WDR IS UR WH LQ XU LDUH G XF WLR Q

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: 75PDF page: 75PDF page: 75PDF page: 75

75 Table 2. $GMXVWHG FR[ SURSRUWLRQDO KD]DUGV PRGHO ZLWK DVVRFLDWLRQ EHWZHHQ LQLWLDO

SURWHLQXULDUHGXFWLRQDQGFRPSRVLWHUHQDOHQGSRLQW ,ĂnjĂƌĚƌĂƟŽ ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů P-value WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ - фϯϬй - ϯϬͲϲϬй - хϲϬй ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.70 0.42 Ϭ͘ϰϬʹϭ͘ϮϮ Ϭ͘ϮϮʹϬ͘ϳϵ 0.206 0.007 Male sex 0.77 Ϭ͘ϰϳʹϭ͘Ϯϱ 0.290 Age, years 1.08 ϭ͘ϬϮʹϭ͘ϭϱ 0.014

Baseline ambulatory MAP, SDS 1.18 ϭ͘ϬϬʹϭ͘ϯϴ 0.049

Diagnosis group - Glomerulopathies - <hd - Other ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.57 0.85 Ϭ͘ϯϭʹϭ͘Ϭϱ Ϭ͘ϯϴʹϭ͘ϴϵ 0.070 0.692 ĂƐĞůŝŶĞĞ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2 _{0.93 Ϭ͘ϵϭʹϬ͘ϵϰ <0.001}

Baseline Urinary protein/

ĐƌĞĂƟŶŝŶĞƌĂƟŽ͕ŵŐͬŵŐ 1.21 ϭ͘Ϭϵʹϭ͘ϯϰ <0.001 ŵďƵůĂƚŽƌLJDWƌĞĚƵĐƟŽŶ͕^^ 0.92 Ϭ͘ϳϳʹϭ͘ϭϬ 0.385 1RLQWHUDFWLRQZDVGHWHFWHGEHWZHHQSURWHLQXULDUHGXFWLRQDQGEDVHOLQHSURWHLQXULDZKHQ DGGHGWRWKHPRGHOS $OOPRGHOSDUDPHWHUVDUHVKRZQLQ6XSSOHPHQWDU\WDEOH 1RLQWHUDFWLRQZDVGHWHFWHGEHWZHHQSURWHLQXULDUHGXFWLRQDQGEORRGSUHVVXUHUHGXFWLRQ ZKHQDGGHGWRWKHPRGHOS $OOPRGHOSDUDPHWHUVDUHVKRZQLQ6XSSOHPHQWDU\ WDEOH

Discussion

/ŶƚŚŝƐƉŽƐƚͲŚŽĐĂŶĂůLJƐŝƐŽĨĂůĂƌŐĞŝŶƚĞƌǀĞŶƟŽŶĂůƚƌŝĂů͕ǁĞŚĂǀĞƐƚƵĚŝĞĚƚŚĞĞīĞĐƚŽĨ ƉƌŽƚĞŝŶƵƌŝĂͲůŽǁĞƌŝŶŐǁŝƚŚƐƚĂŶĚĂƌĚŝnjĞĚŝŶŚŝďŝƟŽŶŽŶƌĞŶĂůƐƵƌǀŝǀĂůŝŶĐŚŝůĚƌĞŶǁŝƚŚ <͘ŚŝŐŚĞƌĚĞŐƌĞĞŽĨƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐĚƵƌŝŶŐƚŚĞĮƌƐƚŵŽŶƚŚƐŽĨƚƌĞĂƚŵĞŶƚǁĂƐ ŝŶĚĞƉĞŶĚĞŶƚůLJĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂůŽǁĞƌƌŝƐŬŽĨ<ƉƌŽŐƌĞƐƐŝŽŶ͘/ŶĂĚĚŝƟŽŶ͕ďŽƚŚĂŚŝŐŚĞƌ ƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůĂŌĞƌĂƩĂŝŶŝŶŐƚŚĞĨƵůůĚŽƐĞŽĨƌĂŵŝƉƌŝůĂŶĚƚŚĞƚŽƚĂůĞdžƉŽƐƵƌĞ ƚŽƉƌŽƚĞŝŶƵƌŝĂĚƵƌŝŶŐĨŽůůŽǁͲƵƉĂĐĐŽƵŶƚĞĚĨŽƌĂŚŝŐŚĞƌƌŝƐŬŽĨ<ƉƌŽŐƌĞƐƐŝŽŶ͘dŚĞƐĞ ĮŶĚŝŶŐƐǁĞƌĞŝŶĚĞƉĞŶĚĞŶƚŽĨƚŚĞƵŶĚĞƌůLJŝŶŐĚŝƐĞĂƐĞ͕ďĂƐĞůŝŶĞƉƌŽƚĞŝŶƵƌŝĂĂŶĚďůŽŽĚ ƉƌĞƐƐƵƌĞĐŽŶƚƌŽů͘ŽůůĞĐƟǀĞůLJ͕ƚŚĞƐĞĚĂƚĂĞdžƚĞŶĚƉƌĞǀŝŽƵƐƐƚƵĚŝĞƐŝŶĂĚƵůƚƉŽƉƵůĂƟŽŶƐ ĂŶĚŚŝŐŚůŝŐŚƚƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨƉƌŽƚĞŝŶƵƌŝĂĂƐĂƌŝƐŬĨĂĐƚŽƌĨŽƌƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ ŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘ tŚĞƌĞĂƐƚŚĞĚĞŐƌĞĞŽĨƉƌŽƚĞŝŶƵƌŝĂŚĂƐďĞĞŶĚĞƐĐƌŝďĞĚĂƐĂƌŝƐŬĨĂĐƚŽƌĨŽƌƉƌŽŐƌĞƐƐŝŽŶ ŽĨƌĞŶĂůĚŝƐĞĂƐĞŝŶĐŚŝůĚƌĞŶ͕ƚŚĞůŽŶŐͲƚĞƌŵĞīĞĐƚŽĨĚƌƵŐŝŶĚƵĐĞĚƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐ ŽŶƌĞŶĂůƐƵƌǀŝǀĂůŚĂƐŶŽƚďĞĞŶǁĞůůĞƐƚĂďůŝƐŚĞĚŝŶĐŚŝůĚƌĞŶ͘/ŶĂĚƵůƚƐ͕ƐĞǀĞƌĂůƉŽƐƚͲŚŽĐ ƚƌŝĂůĂŶĂůLJƐĞƐŚĂǀĞƐŚŽǁŶĂƉŽƐŝƟǀĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶŝŶŝƟĂůƌĞĚƵĐƟŽŶŽĨƉƌŽƚĞŝŶƵƌŝĂ ŽƌĂůďƵŵŝŶƵƌŝĂĂŶĚƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͘dŚĞƐĞƐƚƵĚŝĞƐŚĂǀĞďĞĞŶƉĞƌĨŽƌŵĞĚŝŶ ĚŝīĞƌĞŶƚƉĂƟĞŶƚƉŽƉƵůĂƟŽŶƐǁŝƚŚĚŝīĞƌĞŶƚĚŝƐŽƌĚĞƌƐ;Ğ͘Ő͕͘ĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚŝĞƐ͕ŶŽŶͲ

5

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: 76PDF page: 76PDF page: 76PDF page: 76

76 ĚŝĂďĞƟĐŚLJƉĞƌƚĞŶƐŝǀĞŬŝĚŶĞLJĚŝƐĞĂƐĞ͕ĂŶĚƉƌŽƚĞŝŶƵƌŝĐĐŚƌŽŶŝĐŶĞƉŚƌŽƉĂƚŚLJͿĂŶĚŚĂǀĞ ƵƐĞĚĚƌƵŐƐŝŶƚĞƌǀĞŶŝŶŐŽŶƚŚĞƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐLJƐƚĞŵ͘8-10,16,17_{KŶĞŽďƐĞƌǀĂƟŽŶĂůƐƚƵĚLJ} ŝŶϮϬĐŚŝůĚƌĞŶǁŝƚŚĐŚƌŽŶŝĐŶĞƉŚƌŽƉĂƚŚŝĞƐŝŶǀĞƐƟŐĂƚĞĚƚŚĞĞīĞĐƚŽĨĐŽŵďŝŶĞĚƚƌĞĂƚŵĞŶƚ ŽĨƌĂŵŝƉƌŝůĂŶĚůŽƐĂƌƚĂŶŽŶĞ'&ZƐůŽƉĞƐ͘ŚŝůĚƌĞŶǁŚŽĂĐŚŝĞǀĞĚƌĞŵŝƐƐŝŽŶŽĨƉƌŽƚĞŝŶƵƌŝĂ ;ĚĞĮŶĞĚĂƐхϱϬйƌĞĚƵĐƟŽŶŝŶƉƌŽƚĞŝŶƵƌŝĂƚŽфϮϬϬŵŐƉĞƌĚĂLJͿŚĂĚŝŵƉƌŽǀĞĚĞ'&ZƐůŽƉĞƐ ĐŽŵƉĂƌĞĚƚŽĐŚŝůĚƌĞŶǁŚŽĚŝĚŶŽƚĂĐŚŝĞǀĞƌĞŵŝƐƐŝŽŶ͘12_{,ŽǁĞǀĞƌ͕ƚŚĂƚƐƚƵĚLJĚŝĚŶŽƚĂƐƐĞƐƐ} ƚŚĞĞīĞĐƚŽĨƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶĚƵƌŝŶŐZ^ďůŽĐŬĂĚĞŽŶĐůŝŶŝĐĂůŽƵƚĐŽŵĞƐ͘,ĞƌĞ͕ ǁĞĚĞŵŽŶƐƚƌĂƚĞŝŶĂůĂƌŐĞƉƌŽƐƉĞĐƟǀĞůLJĨŽůůŽǁĞĚƉĞĚŝĂƚƌŝĐĐŽŚŽƌƚƚŚĂƚŵŽƌĞĞĸĐŝĞŶƚ ƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐĚƵƌŝŶŐƚŚĞĮƌƐƚĨĞǁŵŽŶƚŚƐŽĨŝŶŚŝďŝƚŽƌƚŚĞƌĂƉLJŝƐĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚĂƌĞĚƵĐĞĚƌŝƐŬŽĨƌĞŶĂůĨĂŝůƵƌĞƉƌŽŐƌĞƐƐŝŽŶ͘/ŶŬĞĞƉŝŶŐǁŝƚŚƉƌĞǀŝŽƵƐĮŶĚŝŶŐƐŝŶ ĂĚƵůƚƐ͕ŽƵƌƌĞƐƵůƚƐĞŵƉŚĂƐŝnjĞƚŚĞƉŽƚĞŶƟĂůŝŵƉŽƌƚĂŶĐĞŽĨƉƌŽƚĞŝŶƵƌŝĂĂƐĂƚŚĞƌĂƉĞƵƟĐ ƚĂƌŐĞƚŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘ dŚĞŝŶŝƟĂůƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐĞīĞĐƚǀĂƌŝĞĚǁŝĚĞůLJďĞƚǁĞĞŶŝŶĚŝǀŝĚƵĂůƐ͕ŝŶŬĞĞƉŝŶŐ ǁŝƚŚŽďƐĞƌǀĂƟŽŶƐŝŶĂĚƵůƚƐ͘18,19_{tĞĨŽƵŶĚŶŽĐůĞĂƌŝŶĚŝĐĂƚŽƌƐƚŚĂƚĐŽƵůĚĞdžƉůĂŝŶƚŚĞůĂƌŐĞ} ǀĂƌŝĂƟŽŶŽĨƉƌŽƚĞŝŶƵƌŝĂƌĞƐƉŽŶƐĞƚŽĂĚĞĮŶĞĚŝŶŚŝďŝƚŽƌĚŽƐĞ͘/ŶĂĚƵůƚƐ͕ĚĞƚĞƌŵŝŶĂŶƚƐ ŽĨƚŚĞŝŶĚŝǀŝĚƵĂůƌĞƐƉŽŶƐĞƚŽĂŶŝŶŚŝďŝƚŽƌŝŶĐůƵĚĞĚŝĞƚĂƌLJĐŽŶƐƵŵƉƟŽŶŽĨƐĂůƚĂŶĚ ƉƌŽƚĞŝŶƐĂŶĚƚŚĞ/ͬƉŽůLJŵŽƌƉŚŝƐŵ͘20-23_{/ŶƚŚŝƐƐƚƵĚLJ͕ƚŚĞ/ͬŐĞŶŽƚLJƉĞĚŝĚŶŽƚ} ĞdžƉůĂŝŶƚŚĞǀĂƌŝĂďŝůŝƚLJŽĨƚŚĞƉƌŽƚĞŝŶƵƌŝĂƌĞƐƉŽŶƐĞƚŽƌĂŵŝƉƌŝů͘ /ŶŽƌĚĞƌƚŽĨƵƌƚŚĞƌŝŶǀĞƐƟŐĂƚĞƚŚĞƌŽůĞŽĨƉƌŽƚĞŝŶƵƌŝĂĂƐĂƌŝƐŬƉƌĞĚŝĐƚŽƌŽĨƌĞŶĂů ŽƵƚĐŽŵĞƐĚƵƌŝŶŐĐŽŶƟŶƵĞĚŝŶŚŝďŝƟŽŶ͕ǁĞĂůƐŽĂƐƐĞƐƐĞĚƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶ ƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂĂŶĚƌĞŶĂůŽƵƚĐŽŵĞ͘^ĞǀĞƌĂůĂĚƵůƚƐƚƵĚŝĞƐŚĂǀĞƐŚŽǁŶƚŚĂƚĞdžƉŽƐƵƌĞ ƚŽƉƌŽƚĞŝŶƵƌŝĂŽǀĞƌƟŵĞŝƐĂǀĞƌLJŝŵƉŽƌƚĂŶƚ͕ŝĨŶŽƚƚŚĞŵŽƐƚŝŵƉŽƌƚĂŶƚ͕ƉƌĞĚŝĐƚŽƌŽĨ ƌĞŶĂůŽƵƚĐŽŵĞƐŝŶĂĚƵůƚƐ͘24-26_{dŽŽƵƌŬŶŽǁůĞĚŐĞ͕ŶŽƐƚƵĚLJŝŶĐŚŝůĚƌĞŶŚĂƐŝŶǀĞƐƟŐĂƚĞĚƚŚĞ} ƉƌĞĚŝĐƟǀĞǀĂůƵĞŽĨůŽŶŐƚĞƌŵĞdžƉŽƐƵƌĞƚŽƉƌŽƚĞŝŶƵƌŝĂ͘ŽƚŚŚŝŐŚĞƌƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂ ĂŶĚŚŝŐŚĞƌƉƌŽƚĞŝŶƵƌŝĂĞdžƉŽƐƵƌĞŽǀĞƌƟŵĞĂĐĐŽƵŶƚĞĚĨŽƌĂŚŝŐŚĞƌƌĞŶĂůƌŝƐŬŝŶƚŚŝƐƐƚƵĚLJ ƉŽƉƵůĂƟŽŶ͕ĨƵƌƚŚĞƌƐƵŐŐĞƐƟŶŐƚŚĂƚƉƌŽƚĞŝŶƵƌŝĂŵŝŐŚƚďĞĂǀĞƌLJŝŵƉŽƌƚĂŶƚƉĂƌĂŵĞƚĞƌŝŶ ƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘/ƚƐŚŽƵůĚďĞĞŵƉŚĂƐŝnjĞĚƚŚŽƵŐŚƚŚĂƚƚŚĞ ĞĂƌůLJƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶƉƌĞĚŝĐƚĞĚƌĞŶĂůƐƵƌǀŝǀĂůĂƐǁĞůůĂƐƚŚĞůŽŶŐͲƚĞƌŵĞǀŽůƵƟŽŶ ŽĨƉƌŽƚĞŝŶƵƌŝĂ͕ŚŝŐŚůŝŐŚƟŶŐƚŚĞƚƌƵĞƉƌĞĚŝĐƟǀĞǀĂůƵĞŽĨƚŚŝƐĞĂƌůLJĞīĞĐƚ͘ dŚĞŽďƐĞƌǀĂƟŽŶƚŚĂƚƉĂƟĞŶƚƐǁŝƚŚƚŚĞůĞĂƐƚƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶǁĞƌĞĂƚŚŝŐŚĞƐƚ ƌŝƐŬŽĨ<ƉƌŽŐƌĞƐƐŝŽŶǁĂƌƌĂŶƚƐĂĚĚŝƟŽŶĂůƐƚƌĂƚĞŐŝĞƐƚŽĨƵƌƚŚĞƌůŽǁĞƌƉƌŽƚĞŝŶƵƌŝĂŝŶ ƚŚĞƐĞƉĂƟĞŶƚƐ͘dŚĞƐĞŝŶĐůƵĚĞƚŚĞĂĚĚŝƟŽŶŽĨŚLJĚƌŽĐŚůŽƌŽƚŚŝĂnjŝĚĞƚŽƚŚĞƚƌĞĂƚŵĞŶƚ ƉƌŽƚŽĐŽůƐ͕ĚŝĞƚĂƌLJŝŶƚĞƌǀĞŶƟŽŶƐƐƵĐŚĂƐĂŵŽĚĞƌĂƟŽŶŽĨĚŝĞƚĂƌLJƐŽĚŝƵŵŽƌƉƌŽƚĞŝŶ ŝŶƚĂŬĞ͕ŽƌƉŽƐƐŝďůLJŶŽǀĞůƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐƚŚĞƌĂƉŝĞƐŽƚŚĞƌƚŚĂŶZ^ŝŶŚŝďŝƟŽŶ;Ğ͘Ő͘ ^'>dͲϮŝŶŚŝďŝƚŽƌƐͿ6,27-31_{͘&ŝŶĂůůLJ͕ŵŽŶŝƚŽƌŝŶŐďůŽŽĚƉƌĞƐƐƵƌĞĂŶĚƚƌĞĂƟŶŐŚLJƉĞƌƚĞŶƐŝŽŶŝƐ} ĂůƐŽŝŵƉŽƌƚĂŶƚŝŶƚŚĞƐĞƉĂƟĞŶƚƐ͕ĂƐďůŽŽĚƉƌĞƐƐƵƌĞĐŽŶƚƌŽůŝƐƚŚĞŽŶůLJŽƚŚĞƌŝŶƚĞƌǀĞŶƟŽŶ ƚŚĂƚŚĂƐďĞĞŶƉƌŽǀĞŶƚŽďĞŶĞƉŚƌŽƉƌŽƚĞĐƟǀĞŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘11 tĞƌĞĐŽŐŶŝnjĞƐĞǀĞƌĂůůŝŵŝƚĂƟŽŶƐƚŽŽƵƌƐƚƵĚLJ͘&ŝƌƐƚ͕ŝƚƐŚŽƵůĚďĞŶŽƚĞĚƚŚĂƚƚŚŝƐƐƚƵĚLJ ŝƐĂƉŽƐƚͲŚŽĐĂŶĂůLJƐŝƐŽĨĂĐůŝŶŝĐĂůƚƌŝĂůƚŚĂƚǁĂƐŶŽƚĚĞƐŝŐŶĞĚƚŽŝŶǀĞƐƟŐĂƚĞƚŚĞĂƐƐŽĐŝĂƟŽŶ ďĞƚǁĞĞŶŝŶŚŝďŝƟŽŶŝŶĚƵĐĞĚƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐĂŶĚƌĞŶĂůĞŶĚƉŽŝŶƚƐĂŶĚƚŚĂƚ

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: 77PDF page: 77PDF page: 77PDF page: 77

77 ƌĞƐƵůƚƐŵƵƐƚďĞŝŶƚĞƌƉƌĞƚĞĚĂĐĐŽƌĚŝŶŐůLJ͘ƉƌŽƐƉĞĐƟǀĞƐƚƵĚLJĂŝŵĞĚĂƚŝŶǀĞƐƟŐĂƟŶŐ ƚŚĞĞīĞĐƚŽĨƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐŽŶƌĞŶĂůƐƵƌǀŝǀĂůŝŶĐŚŝůĚƌĞŶǁŝƚŚ<ǁŽƵůĚďĞ ƌĞƋƵŝƌĞĚƚŽƵŶĞƋƵŝǀŽĐĂůůLJĐŽŶĮƌŵƚŚĞĮŶĚŝŶŐƐĚĞƐĐƌŝďĞĚŝŶƚŚŝƐƉĂƉĞƌ͘&ƵƌƚŚĞƌŵŽƌĞ͕ ĂĚĚŝƟŽŶĂůĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞŵĞĚŝĐĂƟŽŶŝŶŝƟĂƚĞĚĚƵƌŝŶŐƚŚĞƚƌŝĂůŝŶĂƉƉƌŽdžŝŵĂƚĞůLJŚĂůĨ ŽĨƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶƚŽƌĞĂĐŚƚŚĞďůŽŽĚƉƌĞƐƐƵƌĞƚĂƌŐĞƚĐŽƵůĚŚĂǀĞŝŶƚĞƌĨĞƌĞĚǁŝƚŚ <ƉƌŽŐƌĞƐƐŝŽŶ͘ƐĞŶƐŝƟǀŝƚLJĂŶĂůLJƐŝƐƚŚĂƚĞdžĐůƵĚĞĚƉĂƟĞŶƚƐǁŚŽƌĞĐĞŝǀĞĚĂĚĚŝƟŽŶĂů ĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞŵĞĚŝĐĂƟŽŶƐŚŽǁĞĚƐŝŵŝůĂƌƌĞƐƵůƚƐĂƐŽƵƌŵĂŝŶĂŶĂůLJƐĞƐ͕ƐƵŐŐĞƐƟŶŐ ŵŝŶŝŵĂůŝŵƉĂĐƚŽĨĂĚĚŝƟŽŶĂůĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞŵĞĚŝĐĂƟŽŶƵƐĞŽŶŽƵƌĮŶĚŝŶŐƐ͘ĮŶĂů ĐĂǀĞĂƚƌĞůĂƚĞƐƚŽƚŚĞĚŝĸĐƵůƚLJŽĨƐĞƉĂƌĂƟŶŐŽƵƚƚŚĞƌĞůĂƟǀĞďĞŶĞĮƚƐŽĨƉƌŽƚĞŝŶƵƌŝĂĂŶĚ ďůŽŽĚƉƌĞƐƐƵƌĞƌĞĚƵĐƟŽŶ͘,ŽǁĞǀĞƌ͕ĂƐďůŽŽĚƉƌĞƐƐƵƌĞůŽǁĞƌŝŶŐǁĂƐƚĂŬĞŶŝŶƚŽĂĐĐŽƵŶƚĂƐ ĂĐŽǀĂƌŝĂƚĞŝŶƚŚĞŵƵůƟǀĂƌŝĂďůĞŽdžŵŽĚĞůƐ͕ŝƚŝƐƐƵŐŐĞƐƚĞĚƚŚĂƚƚŚĞĞīĞĐƚŽĨƉƌŽƚĞŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶǁĂƐůĂƌŐĞůLJŝŶĚĞƉĞŶĚĞŶƚŽĨƚŚĞĞīĞĐƚŽĨďůŽŽĚƉƌĞƐƐƵƌĞůŽǁĞƌŝŶŐ͘DŽƌĞŽǀĞƌ͕ ƚŚĞ ƐƚĂƟƐƟĐĂůůLJ ŶŽŶͲƐŝŐŶŝĮĐĂŶƚ ŝŶƚĞƌĂĐƟŽŶ ďĞƚǁĞĞŶ ďůŽŽĚ ƉƌĞƐƐƵƌĞ ƌĞĚƵĐƟŽŶ ĂŶĚ ƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶƐƵŐŐĞƐƚƐƚŚĂƚƚŚĞĞīĞĐƚŽĨƉƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶŝƐŶŽƚŵŽĚŝĮĞĚ ďLJďůŽŽĚƉƌĞƐƐƵƌĞƌĞĚƵĐƟŽŶ͘ /ŶĐŽŶĐůƵƐŝŽŶ͕ƚŚŝƐƉŽƐƚͲŚŽĐĂŶĂůLJƐŝƐƐŚŽǁƐƚŚĂƚƚŚĞĞĂƌůLJĂŶƟƉƌŽƚĞŝŶƵƌŝĐĞīĞĐƚ ŽĨŝŶŚŝďŝƟŽŶŝŶĚĞƉĞŶĚĞŶƚůLJƉƌĞĚŝĐƚƐůŽŶŐͲƚĞƌŵƉƌĞƐĞƌǀĂƟŽŶŽĨƌĞŶĂůĨƵŶĐƟŽŶŝŶ ĐŚŝůĚƌĞŶǁŝƚŚ<͘DŽƌĞŽǀĞƌ͕ŚŝŐŚĞƌƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂĂŶĚŚŝŐŚĞƌůŽŶŐƚĞƌŵƉƌŽƚĞŝŶƵƌŝĂ ĞdžƉŽƐƵƌĞĂĐĐŽƵŶƚĨŽƌǁŽƌƐĞƌĞŶĂůƐƵƌǀŝǀĂů͘dŚĞƐĞĮŶĚŝŶŐƐŝŶĚŝĐĂƚĞƚŚĂƚƉƌŽƚĞŝŶƵƌŝĂ ůŽǁĞƌŝŶŐŝƐĂŶŝŵƉŽƌƚĂŶƚƚĂƌŐĞƚŝŶƚŚĞŵĂŶĂŐĞŵĞŶƚŽĨĐŚŝůĚƌĞŶǁŝƚŚ<͘

Acknowledgements and disclosures

dŚĞ^WƐƚƵĚLJǁĂƐƐƵƉƉŽƌƚĞĚďLJŐƌĂŶƚƐŽĨƚŚĞŽĞŚƌŝŶŐĞƌ/ŶŐĞůŚĞŝŵ^ƟŌƵŶŐ͕ƚŚĞ ƵƌŽƉĞĂŶŽŵŵŝƐƐŝŽŶ;ϱƚŚ&ƌĂŵĞǁŽƌŬWƌŽŐƌĂŵŵĞY>ZdͲϮϬϬϭͲϬϬϵϬϴ͕ƚŚĞ<ƵƌĂƚŽƌŝƵŵ ĨƺƌŝĂůLJƐĞƵŶĚEŝĞƌĞŶƚƌĂŶƐƉůĂŶƚĂƟŽŶĞ͘s͕͘EĞƵͲ/ƐĞŶďƵƌŐ͕ĂŶĚƚŚĞĂdžƚĞƌdžƚƌĂŵƵƌĂů 'ƌĂŶƚWƌŽŐƌĂŵ͘dŚĞƐƚƵĚLJƉƌŽƚŽĐŽůǁĂƐĚĞǀĞůŽƉĞĚĞdžĐůƵƐŝǀĞůLJďLJƚŚĞƉĂƌƟĐŝƉĂŶƚƐ͘KŶƐŝƚĞ ŵŽŶŝƚŽƌŝŶŐŽĨƐƚƵĚLJĚĂƚĂĐŽůůĞĐƟŽŶǁĂƐƉĞƌĨŽƌŵĞĚďLJĂŶŝŶĚĞƉĞŶĚĞŶƚĐůŝŶŝĐĂůƌĞƐĞĂƌĐŚ ŽƌŐĂŶŝnjĂƟŽŶ;KŵŶŝĐĂƌĞůŝŶŝĐĂůZĞƐĞĂƌĐŚͿ͘ǀĞŶƟƐWŚĂƌŵĂĐĞƵƟĐĂůƐƐƵƉƉůŝĞĚƌĂŵŝƉƌŝů ĂŶĚĮŶĂŶĐĞĚƚŚĞ'WĂƵĚŝƚ͘ ƌ͘^ĐŚĂĞĨĞƌƌĞƉŽƌƚƐƐĞƌǀŝŶŐĂƐĂƉĂŝĚĂĚǀŝƐŽƌĨŽƌďďǀŝĞ͕ƐƚĞůůĂƐ͕ĂŶĚĂLJĞƌ͘EŽŽƚŚĞƌ ƉŽƚĞŶƟĂůĐŽŶŇŝĐƚƐŽĨŝŶƚĞƌĞƐƚƌĞůĞǀĂŶƚƚŽƚŚŝƐĂƌƟĐůĞǁĞƌĞƌĞƉŽƌƚĞĚ͘

5

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: 78PDF page: 78PDF page: 78PDF page: 78

78

References

ϭ͘ ,ŝůůĞŐĞ,>͕&ŝĚůĞƌs͕ŝĞƌĐŬƐ'&͕ĞƚĂů͘hƌŝŶĂƌLJ ĂůďƵŵŝŶĞdžĐƌĞƟŽŶƉƌĞĚŝĐƚƐĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĂŶĚŶŽŶĐĂƌĚŝŽǀĂƐĐƵůĂƌŵŽƌƚĂůŝƚLJŝŶŐĞŶĞƌĂů ƉŽƉƵůĂƟŽŶ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϮ͖ϭϬϲ;ϭϰͿ͗ϭϳϳϳͲ ϭϳϴϮ͘ Ϯ͘ DĂƚƐƵƐŚŝƚĂ <͕ ŽƌĞƐŚ :͕ ^ĂŶŐ z͕ Ğƚ Ăů͘ ƐƟŵĂƚĞĚ ŐůŽŵĞƌƵůĂƌ ĮůƚƌĂƟŽŶ ƌĂƚĞ ĂŶĚ ĂůďƵŵŝŶƵƌŝĂĨŽƌƉƌĞĚŝĐƟŽŶŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌ ŽƵƚĐŽŵĞƐ͗ĐŽůůĂďŽƌĂƟǀĞŵĞƚĂͲĂŶĂůLJƐŝƐŽĨ ŝŶĚŝǀŝĚƵĂůƉĂƌƟĐŝƉĂŶƚĚĂƚĂ͘>ĂŶĐĞƚŝĂďĞƚĞƐ ŶĚŽĐƌŝŶŽů͘ϮϬϭϱ͖ϯ;ϳͿ͗ϱϭϰͲϱϮϱ͘ ϯ͘ ǀĂŶĚĞƌsĞůĚĞD͕,ĂůďĞƐŵĂE͕ĚĞŚĂƌƌŽ&d͕ ĞƚĂů͘^ĐƌĞĞŶŝŶŐĨŽƌĂůďƵŵŝŶƵƌŝĂŝĚĞŶƟĮĞƐ ŝŶĚŝǀŝĚƵĂůƐĂƚŝŶĐƌĞĂƐĞĚƌĞŶĂůƌŝƐŬ͘:ŵ^ŽĐ EĞƉŚƌŽů͘ϮϬϬϵ͖ϮϬ;ϰͿ͗ϴϱϮͲϴϲϮ͘ ϰ͘ 'ƌĂĐĐŚŝ s͕ ǀĂŶ ĚĞŶ Ğůƚ ^D͕ <ƵƉĞƌƐ ><͕ ŽƌƉĞůĞŝũŶ ͕ ĚĞ ĞĞƵǁ ͕ ,ĞĞƌƐƉŝŶŬ ,:͘ WƌĞǀĂůĞŶĐĞ ĂŶĚ ĚŝƐƚƌŝďƵƚŝŽŶ ŽĨ ;ŵŝĐƌŽͿ ĂůďƵŵŝŶƵƌŝĂ ŝŶ ƚŽĚĚůĞƌƐ͘ EĞƉŚƌŽů ŝĂů dƌĂŶƐƉůĂŶƚ͘ϮϬϭϱ͘ ϱ͘ <ĂǀĞLJ Z͕ ůůĂĚĂ s͕ ĂŶŝĞůƐ ^Z͕ Ğƚ Ăů͘ ĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬƌĞĚƵĐƟŽŶŝŶŚŝŐŚͲƌŝƐŬ ƉĞĚŝĂƚƌŝĐ ƉĂƟĞŶƚƐ͗  ƐĐŝĞŶƟĮĐ ƐƚĂƚĞŵĞŶƚ from the american heart association ĞdžƉĞƌƚƉĂŶĞůŽŶƉŽƉƵůĂƟŽŶĂŶĚƉƌĞǀĞŶƟŽŶ ƐĐŝĞŶĐĞ͖ ƚŚĞ ĐŽƵŶĐŝůƐ ŽŶ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞ ŝŶ ƚŚĞ LJŽƵŶŐ͕ ĞƉŝĚĞŵŝŽůŽŐLJ ĂŶĚ ƉƌĞǀĞŶƟŽŶ͕ŶƵƚƌŝƟŽŶ͕ƉŚLJƐŝĐĂůĂĐƟǀŝƚLJĂŶĚ ŵĞƚĂďŽůŝƐŵ͕ŚŝŐŚďůŽŽĚƉƌĞƐƐƵƌĞƌĞƐĞĂƌĐŚ͕ ĐĂƌĚŝŽǀĂƐĐƵůĂƌŶƵƌƐŝŶŐ͕ĂŶĚƚŚĞŬŝĚŶĞLJŝŶ ŚĞĂƌƚ ĚŝƐĞĂƐĞ͖ ĂŶĚ ƚŚĞ ŝŶƚĞƌĚŝƐĐŝƉůŝŶĂƌLJ ǁŽƌŬŝŶŐ ŐƌŽƵƉ ŽŶ ƋƵĂůŝƚLJ ŽĨ ĐĂƌĞ ĂŶĚ ŽƵƚĐŽŵĞƐ ƌĞƐĞĂƌĐŚ͗ ŶĚŽƌƐĞĚ ďLJ ƚŚĞ ĂŵĞƌŝĐĂŶĂĐĂĚĞŵLJŽĨƉĞĚŝĂƚƌŝĐƐ͘ŝƌĐƵůĂƟŽŶ͘ ϮϬϬϲ͖ϭϭϰ;ϮϰͿ͗ϮϳϭϬͲϮϳϯϴ͘ ϲ͘ tŝŶŐĞŶ D͕ &ĂďŝĂŶͲĂĐŚ ͕ ^ĐŚĂĞĨĞƌ &͕ DĞŚůƐ K͘ ZĂŶĚŽŵŝƐĞĚ ŵƵůƟĐĞŶƚƌĞ ƐƚƵĚLJ ŽĨĂůŽǁͲƉƌŽƚĞŝŶĚŝĞƚŽŶƚŚĞƉƌŽŐƌĞƐƐŝŽŶŽĨ ĐŚƌŽŶŝĐƌĞŶĂůĨĂŝůƵƌĞŝŶĐŚŝůĚƌĞŶ͘ĞƵƌŽƉĞĂŶ ƐƚƵĚLJ ŐƌŽƵƉ ŽĨ ŶƵƚƌŝƟŽŶĂů ƚƌĞĂƚŵĞŶƚ ŽĨ ĐŚƌŽŶŝĐƌĞŶĂůĨĂŝůƵƌĞŝŶĐŚŝůĚŚŽŽĚ͘>ĂŶĐĞƚ͘ ϭϵϵϳ͖ϯϰϵ;ϵϬϱϵͿ͗ϭϭϭϳͲϭϭϮϯ͘ ϳ͘ tĂƌĂĚLJ ͕ ďƌĂŚĂŵ '͕ ^ĐŚǁĂƌƚnj ':͕ Ğƚ Ăů͘ WƌĞĚŝĐƚŽƌƐ ŽĨ ƌĂƉŝĚ ƉƌŽŐƌĞƐƐŝŽŶ ŽĨ ŐůŽŵĞƌƵůĂƌ ĂŶĚ ŶŽŶŐůŽŵĞƌƵůĂƌ ŬŝĚŶĞLJ disease in children and adolescents: The ĐŚƌŽŶŝĐ ŬŝĚŶĞLJ ĚŝƐĞĂƐĞ ŝŶ ĐŚŝůĚƌĞŶ ;<ŝͿ ĐŽŚŽƌƚ͘ŵ:<ŝĚŶĞLJŝƐ͘ϮϬϭϱ͖ϲϱ;ϲͿ͗ϴϳϴͲ ϴϴϴ͘ ϴ͘ ĚĞ ĞĞƵǁ ͕ ZĞŵƵnjnjŝ '͕ WĂƌǀŝŶŐ ,,͕ Ğƚ Ăů͘ ůďƵŵŝŶƵƌŝĂ͕ Ă ƚŚĞƌĂƉĞƵƟĐ ƚĂƌŐĞƚ ĨŽƌ ĐĂƌĚŝŽǀĂƐĐƵůĂƌƉƌŽƚĞĐƟŽŶŝŶƚLJƉĞϮĚŝĂďĞƟĐ ƉĂƚŝĞŶƚƐ ǁŝƚŚ ŶĞƉŚƌŽƉĂƚŚLJ͘ ŝƌĐƵůĂƚŝŽŶ͘ ϮϬϬϰ͖ϭϭϬ;ϴͿ͗ϵϮϭͲϵϮϳ͘ ϵ͘ >ĞĂ :͕ 'ƌĞĞŶĞ d͕ ,ĞďĞƌƚ >͕ Ğƚ Ăů͘ dŚĞ ƌĞůĂƚŝŽŶƐŚŝƉ ďĞƚǁĞĞŶ ŵĂŐŶŝƚƵĚĞ ŽĨ proteinuria reduction and risk of end-ƐƚĂŐĞ ƌĞŶĂů ĚŝƐĞĂƐĞ͗ ZĞƐƵůƚƐ ŽĨ ƚŚĞ ĂĨƌŝĐĂŶĂŵĞƌŝĐĂŶƐƚƵĚLJŽĨŬŝĚŶĞLJĚŝƐĞĂƐĞ ĂŶĚ ŚLJƉĞƌƚĞŶƐŝŽŶ͘ ƌĐŚ /ŶƚĞƌŶ DĞĚ͘ ϮϬϬϱ͖ϭϲϱ;ϴͿ͗ϵϰϳͲϵϱϯ͘ ϭϬ͘ ŝũŬĞůŬĂŵƉt͕ŚĂŶŐ͕ZĞŵƵnjnjŝ'͕ĞƚĂů͘ ůďƵŵŝŶƵƌŝĂŝƐĂƚĂƌŐĞƚĨŽƌƌĞŶŽƉƌŽƚĞĐƟǀĞ ƚŚĞƌĂƉLJŝŶĚĞƉĞŶĚĞŶƚĨƌŽŵďůŽŽĚƉƌĞƐƐƵƌĞŝŶ ƉĂƟĞŶƚƐǁŝƚŚƚLJƉĞϮĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͗ WŽƐƚ ŚŽĐ ĂŶĂůLJƐŝƐ ĨƌŽŵ ƚŚĞ ƌĞĚƵĐƟŽŶ ŽĨ ĞŶĚƉŽŝŶƚƐŝŶE/DǁŝƚŚƚŚĞĂŶŐŝŽƚĞŶƐŝŶ //ĂŶƚĂŐŽŶŝƐƚůŽƐĂƌƚĂŶ;ZE>ͿƚƌŝĂů͘:ŵ ^ŽĐEĞƉŚƌŽů͘ϮϬϬϳ͖ϭϴ;ϱͿ͗ϭϱϰϬͲϭϱϰϲ͘ ϭϭ͘ ^W dƌŝĂů 'ƌŽƵƉ͕ tƵŚů ͕ dƌŝǀĞůůŝ ͕ Ğƚ Ăů͘ ^ƚƌŝĐƚ ďůŽŽĚͲƉƌĞƐƐƵƌĞ ĐŽŶƚƌŽů ĂŶĚ ƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨĂŝůƵƌĞŝŶĐŚŝůĚƌĞŶ͘E ŶŐů:DĞĚ͘ϮϬϬϵ͖ϯϲϭ;ϭϳͿ͗ϭϲϯϵͲϭϲϱϬ͘ ϭϮ͘ ZƵŐŐĞŶĞŶƟW͕ƌĂǀĞĚŝW͕ŚŝĂŶĐĂ͕ĂƌƵƐŽ D͕ ZĞŵƵnjnjŝ '͘ ĐŚŝĞǀŝŶŐ ƌĞŵŝƐƐŝŽŶ ŽĨ ƉƌŽƚĞŝŶƵƌŝĂ ŝŶ ĐŚŝůĚŚŽŽĚ <͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ϮϬϭϳ͖ϯϮ;ϮͿ͗ϯϮϭͲϯϯϬ͘ ϭϯ͘ ^ĐŚǁĂƌƚnj':͕ƌŝŽŶ>W͕^ƉŝƚnjĞƌ͘dŚĞƵƐĞ of plasma creatinine concentration for ĞƐƚŝŵĂƚŝŶŐ ŐůŽŵĞƌƵůĂƌ ĨŝůƚƌĂƚŝŽŶ ƌĂƚĞ ŝŶ ŝŶĨĂŶƚƐ͕ĐŚŝůĚƌĞŶ͕ĂŶĚĂĚŽůĞƐĐĞŶƚƐ͘WĞĚŝĂƚƌ ůŝŶEŽƌƚŚŵ͘ϭϵϴϳ͖ϯϰ;ϯͿ͗ϱϳϭͲϱϵϬ͘

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: 79PDF page: 79PDF page: 79PDF page: 79

79 ϭϰ͘ ,ŽŚĞŶĨĞůůŶĞƌ <͕ tŝŶŐĞŶ D͕ EĂƵƌŽƚŚ K͕ tƵŚů ͕ DĞŚůƐ K͕ ^ĐŚĂĞĨĞƌ &͘ /ŵƉĂĐƚ ŽĨ /ͬŐĞŶĞƉŽůLJŵŽƌƉŚŝƐŵŽŶĐŽŶŐĞŶŝƚĂů ƌĞŶĂů ŵĂůĨŽƌŵĂƚŝŽŶƐ͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ ϮϬϬϭ͖ϭϲ;ϰͿ͗ϯϱϲͲϯϲϭ͘ ϭϱ͘ &Ğůŝdž<ƌŽƉĞůŝŶd͕ĚĞĞĞƵǁ͕,ŽůƚŬĂŵƉ&͕ WĂĐŬŚĂŵ <͕ > ,ĞĞƌƐƉŝŶŬ ,:͘ /ŶĚŝǀŝĚƵĂů ůŽŶŐͲƚĞƌŵ ĂůďƵŵŝŶƵƌŝĂ ĞdžƉŽƐƵƌĞ ĚƵƌŝŶŐ ĂŶŐŝŽƚĞŶƐŝŶ ƌĞĐĞƉƚŽƌ ďůŽĐŬĞƌ ƚŚĞƌĂƉLJ ŝƐ ƚŚĞŽƉƟŵĂůƉƌĞĚŝĐƚŽƌĨŽƌƌĞŶĂůŽƵƚĐŽŵĞ͘ EĞƉŚƌŽůŝĂůdƌĂŶƐƉůĂŶƚ͘ϮϬϭϲ͖ϯϭ;ϵͿ͗ϭϰϳϭͲ ϭϰϳϳ͘ ϭϲ͘ ZƵŐŐĞŶĞŶƟW͕WĞƌŶĂ͕ZĞŵƵnjnjŝ'͕'/^E 'ƌŽƵƉ/ŶǀĞƐƟŐĂƚŽƌƐ͘ZĞƚĂƌĚŝŶŐƉƌŽŐƌĞƐƐŝŽŶ ŽĨ ĐŚƌŽŶŝĐ ƌĞŶĂů ĚŝƐĞĂƐĞ͗ dŚĞ ŶĞŐůĞĐƚĞĚ ŝƐƐƵĞ ŽĨ ƌĞƐŝĚƵĂů ƉƌŽƚĞŝŶƵƌŝĂ͘ <ŝĚŶĞLJ /Ŷƚ͘ ϮϬϬϯ͖ϲϯ;ϲͿ͗ϮϮϱϰͲϮϮϲϭ͘ ϭϳ͘ ,ĞůůĞŵŽŶƐ D͕ WĞƌƐƐŽŶ &͕ ĂŬŬĞƌ ^:͕ Ğƚ Ăů͘ /ŶŝƟĂů ĂŶŐŝŽƚĞŶƐŝŶ ƌĞĐĞƉƚŽƌ ďůŽĐŬĂĚĞͲ induced decrease in albuminuria ŝƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ůŽŶŐͲƚĞƌŵ ƌĞŶĂů ŽƵƚĐŽŵĞŝŶƚLJƉĞϮĚŝĂďĞƟĐƉĂƟĞŶƚƐǁŝƚŚ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͗  ƉŽƐƚ ŚŽĐ ĂŶĂůLJƐŝƐ ŽĨ ƚŚĞ /ZDͲϮ ƚƌŝĂů͘ ŝĂďĞƚĞƐ ĂƌĞ͘ ϮϬϭϭ͖ϯϰ;ϵͿ͗ϮϬϳϴͲϮϬϴϯ͘ ϭϴ͘ ĚĞĞĞƵǁ͕ZĞŵƵnjnjŝ'͕WĂƌǀŝŶŐ,,͕ĞƚĂů͘ WƌŽƚĞŝŶƵƌŝĂ͕ĂƚĂƌŐĞƚĨŽƌƌĞŶŽƉƌŽƚĞĐƟŽŶŝŶ ƉĂƟĞŶƚƐǁŝƚŚƚLJƉĞϮĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͗ >ĞƐƐŽŶƐ ĨƌŽŵ ZE>͘ <ŝĚŶĞLJ /Ŷƚ͘ ϮϬϬϰ͖ϲϱ;ϲͿ͗ϮϯϬϵͲϮϯϮϬ͘ ϭϵ͘ ^ĐŚŝĞǀŝŶŬ ͕ ĚĞ ĞĞƵǁ ͕ WĂƌǀŝŶŐ ,,͕ ZŽƐƐŝŶŐW͕>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ,:͘dŚĞƌĞŶĂů ƉƌŽƚĞĐƟǀĞ ĞīĞĐƚ ŽĨ ĂŶŐŝŽƚĞŶƐŝŶ ƌĞĐĞƉƚŽƌ blockers depends on intra-individual ƌĞƐƉŽŶƐĞǀĂƌŝĂƟŽŶŝŶŵƵůƟƉůĞƌŝƐŬŵĂƌŬĞƌƐ͘ ƌ:ůŝŶWŚĂƌŵĂĐŽů͘ϮϬϭϱ͖ϴϬ;ϰͿ͗ϲϳϴͲϲϴϲ͘ ϮϬ͘ WĂƌǀŝŶŐ ,,͕ ĚĞ ĞĞƵǁ ͕ ŽŽƉĞƌ D͕ Ğƚ Ăů͘ŐĞŶĞƉŽůLJŵŽƌƉŚŝƐŵĂŶĚůŽƐĂƌƚĂŶ ƚƌĞĂƚŵĞŶƚ ŝŶ ƚLJƉĞ Ϯ ĚŝĂďĞƚŝĐ ƉĂƚŝĞŶƚƐ ǁŝƚŚ ŶĞƉŚƌŽƉĂƚŚLJ͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϬϴ͖ϭϵ;ϰͿ͗ϳϳϭͲϳϳϵ͘ Ϯϭ͘ WĞƌŶĂ͕ZƵŐŐĞŶĞŶƟW͕dĞƐƚĂ͕ĞƚĂů͘ ŐĞŶŽƚLJƉĞ ĂŶĚ  ŝŶŚŝďŝƚŽƌƐ ŝŶĚƵĐĞĚ renoprotection in chronic proteinuric ŶĞƉŚƌŽƉĂƚŚŝĞƐϭ͘<ŝĚŶĞLJ/Ŷƚ͘ϮϬϬϬ͖ϱϳ;ϭͿ͗ϮϳϰͲ Ϯϴϭ͘ ϮϮ͘ >ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ,:͕,ŽůƚŬĂŵƉ&͕WĂƌǀŝŶŐ ,,͕ Ğƚ Ăů͘ DŽĚĞƌĂƟŽŶ ŽĨ ĚŝĞƚĂƌLJ ƐŽĚŝƵŵ ƉŽƚĞŶƟĂƚĞƐ ƚŚĞ ƌĞŶĂů ĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ƉƌŽƚĞĐƟǀĞĞīĞĐƚƐŽĨĂŶŐŝŽƚĞŶƐŝŶƌĞĐĞƉƚŽƌ ďůŽĐŬĞƌƐ͘<ŝĚŶĞLJ/Ŷƚ͘ϮϬϭϮ͖ϴϮ;ϯͿ͗ϯϯϬͲϯϯϳ͘ Ϯϯ͘ sĞŐƚĞƌ ^͕ WĞƌŶĂ ͕ WŽƐƚŵĂ D:͕ EĂǀŝƐ '͕ ZĞŵƵnjnjŝ'͕ZƵŐŐĞŶĞŶƟW͘^ŽĚŝƵŵŝŶƚĂŬĞ͕ ŝŶŚŝďŝƟŽŶ͕ĂŶĚƉƌŽŐƌĞƐƐŝŽŶƚŽ^Z͘: ŵ^ŽĐEĞƉŚƌŽů͘ϮϬϭϮ͖Ϯϯ;ϭͿ͗ϭϲϱͲϭϳϯ͘ Ϯϰ͘ >ŝ W<͕ ,Ž <<͕ ^njĞƚŽ ͕ zƵ >͕ >Ăŝ &D͘ WƌŽŐŶŽƐƟĐŝŶĚŝĐĂƚŽƌƐŽĨ/ŐŶĞƉŚƌŽƉĂƚŚLJ ŝŶ ƚŚĞ ĐŚŝŶĞƐĞͲͲĐůŝŶŝĐĂů ĂŶĚ ƉĂƚŚŽůŽŐŝĐĂů ƉĞƌƐƉĞĐƚŝǀĞƐ͘ EĞƉŚƌŽů ŝĂů dƌĂŶƐƉůĂŶƚ͘ ϮϬϬϮ͖ϭϳ;ϭͿ͗ϲϰͲϲϵ͘ Ϯϱ͘ ZĞŝĐŚ,E͕dƌŽLJĂŶŽǀ^͕^ĐŚŽůĞLJ:t͕ĂƩƌĂŶ ͕dŽƌŽŶƚŽ'ůŽŵĞƌƵůŽŶĞƉŚƌŝƟƐZĞŐŝƐƚƌLJ͘ Remission of proteinuria improves ƉƌŽŐŶŽƐŝƐ ŝŶ /Ő ŶĞƉŚƌŽƉĂƚŚLJ͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ϮϬϬϳ͖ϭϴ;ϭϮͿ͗ϯϭϳϳͲϯϭϴϯ͘

Ϯϲ͘ ĞůůŽ͕dŚŽŵƉƐŽŶ^͕>ůŽLJĚ͕ĞƚĂů͘DƵůƟƉůĞ ǀĞƌƐƵƐƐŝŶŐůĞĂŶĚŽƚŚĞƌĞƐƟŵĂƚĞƐŽĨďĂƐĞůŝŶĞ proteinuria status as predictors of adverse ŽƵƚĐŽŵĞƐŝŶƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͘ŵ: <ŝĚŶĞLJŝƐ͘ϮϬϭϮ͖ϱϵ;ϯͿ͗ϯϲϰͲϯϳϭ͘ Ϯϳ͘ ,ĞĞŐ:͕ĚĞ:ŽŶŐW͕ǀĂŶĚĞƌ,Ğŵ'<͕ĚĞ ĞĞƵǁ ͘ ĸĐĂĐLJ ĂŶĚ ǀĂƌŝĂďŝůŝƚLJ ŽĨ ƚŚĞ ĂŶƟƉƌŽƚĞŝŶƵƌŝĐĞīĞĐƚŽĨŝŶŚŝďŝƟŽŶďLJ ůŝƐŝŶŽƉƌŝů͘<ŝĚŶĞLJ/Ŷƚ͘ϭϵϴϵ͖ϯϲ;ϮͿ͗ϮϳϮͲϮϳϵ͘ Ϯϴ͘ ďĞD͕KŬĂĚĂ<͕DĂƌƵLJĂŵĂd͕DĂƚƐƵŵŽƚŽ <͘ ŶƚŝƉƌŽƚĞŝŶƵƌŝĐ ĂŶĚ ďůŽŽĚ ƉƌĞƐƐƵƌĞͲ ůŽǁĞƌŝŶŐĞīĞĐƚƐŽĨĂĮdžĞĚͲĚŽƐĞĐŽŵďŝŶĂƟŽŶ ŽĨ ůŽƐĂƌƚĂŶ ĂŶĚ ŚLJĚƌŽĐŚůŽƌŽƚŚŝĂnjŝĚĞ ŝŶ ŚLJƉĞƌƚĞŶƐŝǀĞ ƉĂƚŝĞŶƚƐ ǁŝƚŚ ƐƚĂŐĞ ϯ ĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͘WŚĂƌŵĂĐŽƚŚĞƌĂƉLJ͘ ϮϬϬϵ͖Ϯϵ;ϵͿ͗ϭϬϲϭͲϭϬϳϮ͘ Ϯϵ͘ ,ĂůďĞƐŵĂ E͕ ĂŬŬĞƌ ^:͕ :ĂŶƐĞŶ &͕ Ğƚ Ăů͘ ,ŝŐŚ ƉƌŽƚĞŝŶ ŝŶƚĂŬĞ ĂƐƐŽĐŝĂƚĞƐ ǁŝƚŚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ ďƵƚ ŶŽƚ ǁŝƚŚ ůŽƐƐ ŽĨ ƌĞŶĂů ĨƵŶĐƚŝŽŶ͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϬϵ͖ϮϬ;ϴͿ͗ϭϳϵϳͲϭϴϬϰ͘

5

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: 80PDF page: 80PDF page: 80PDF page: 80

80 ϯϬ͘ sŽŐƚ>͕tĂĂŶĚĞƌƐ&͕ŽŽŵƐŵĂ&͕ĚĞĞĞƵǁ ͕EĂǀŝƐ'͘īĞĐƚƐŽĨĚŝĞƚĂƌLJƐŽĚŝƵŵĂŶĚ ŚLJĚƌŽĐŚůŽƌŽƚŚŝĂnjŝĚĞŽŶƚŚĞĂŶƟƉƌŽƚĞŝŶƵƌŝĐ ĞĨĨŝĐĂĐLJ ŽĨ ůŽƐĂƌƚĂŶ͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϬϴ͖ϭϵ;ϱͿ͗ϵϵϵͲϭϬϬϳ͘ ϯϭ͘ ŚŝŶ,:͕<ŝŵ<͕WĂƌŬ:,͕ĞƚĂů͘īĞĐƚŽĨƵƌŝŶĞ ƵƌĞĂŶŝƚƌŽŐĞŶĂŶĚƉƌŽƚĞŝŶŝŶƚĂŬĞĂĚũƵƐƚĞĚ ďLJ ƵƐŝŶŐ ƚŚĞ ĞƐƟŵĂƚĞĚ ƵƌŝŶĞ ĐƌĞĂƟŶŝŶĞ ĞdžĐƌĞƟŽŶƌĂƚĞŽŶƚŚĞĂŶƟƉƌŽƚĞŝŶƵƌŝĐĞīĞĐƚ ŽĨĂŶŐŝŽƚĞŶƐŝŶ//ƚLJƉĞ/ƌĞĐĞƉƚŽƌďůŽĐŬĞƌƐ͘ EƵƚƌŝƟŽŶ͘ϮϬϭϱ͖ϯϭ;ϭϭͲϭϮͿ͗ϭϯϯϯͲϭϯϯϴ͘

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: 81PDF page: 81PDF page: 81PDF page: 81

81 Supplementary table 1. Multivariable linear regression analysis of association between

SURWHLQXULDUHGXFWLRQDQGEDVHOLQHYDULDEOHV ŽĞĸĐŝĞŶƚ P-value Male sex -0.24 0.086 Age, years 0.03 0.078 ŽŶǀĞŶƟŽŶĂůďůŽŽĚƉƌĞƐƐƵƌĞĐŽŶƚƌŽů 0.06 0.618 Diagnosis group - Glomerulopathies - <hd - Other Ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.00 -0.28 0.990 0.307 ĂƐĞůŝŶĞĞ'&Z͕ϭϬŵůͬŵŝŶͬϭ͘ϳϯŵ2 _{-0.05 0.407}

Baseline ambulatory MAP, SDS 0.04 0.323

ĂƐĞůŝŶĞƵƌŝŶĂƌLJƉƌŽƚĞŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ͕ŵŐͬŵŐ -0.14 <0.001

Baseline serum urea, mmol/L 0.01 0.457

ACE I/D genotype - II genotype - ID genotype - DD genotype Ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.15 0.22 0.3750.262

Supplementary table 2.0XOWLYDULDEOH&R[SURSRUWLRQDOKD]DUGVPRGHOZLWKDVVRFLDWLRQ

EHWZHHQLQWHUDFWLRQEHWZHHQSURWHLQXULDUHGXFWLRQDQGEDVHOLQHSURWHLQXULDDQGWKH FRPSRVLWHUHQDOHQGSRLQW

,ĂnjĂƌĚƌĂƟŽ ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů P-value

WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͕ƉĞƌϭϬй

ƌĞĚƵĐƟŽŶ 0.93 Ϭ͘ϴϴʹϬ͘ϵϴ 0.012

Baseline Urinary protein/

ĐƌĞĂƟŶŝŶĞƌĂƟŽ͕ŵŐͬŵŐ 1.35 ϭ͘ϭϵʹϭ͘ϱϰ <0.001

WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶΎďĂƐĞůŝŶĞ

proteinuria 1.15 Ϭ͘ϵϳʹϭ͘ϯϴ 0.115

Male sex 0.91 Ϭ͘ϱϱʹϭ͘ϱϭ 0.708

Age, years 1.08 ϭ͘Ϭϭʹϭ͘ϭϱ 0.019

Baseline ambulatory MAP, SDS 1.21 ϭ͘Ϭϯʹϭ͘ϰϭ 0.018

Diagnosis group - Glomerulopathies - <hd - Other ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.58 0.85 Ϭ͘ϯϭʹϭ͘ϬϱϬ͘ϯϴʹϭ͘ϴϴ 0.0740.690 ĂƐĞůŝŶĞĞ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2 _{0.93 Ϭ͘ϵϭʹϬ͘ϵϰ <0.001} ŵďƵůĂƚŽƌLJDWƌĞĚƵĐƟŽŶ͕^^ 0.89 Ϭ͘ϳϰʹϭ͘Ϭϲ 0.185

5

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: 82PDF page: 82PDF page: 82PDF page: 82

82

Supplementary table 3.0XOWLYDULDEOH&R[SURSRUWLRQDOKD]DUGVPRGHOZLWKDVVRFLDWLRQ

EHWZHHQLQWHUDFWLRQEHWZHHQSURWHLQXULDUHGXFWLRQDQGEORRGSUHVVXUHUHGXFWLRQDQG WKHFRPSRVLWHUHQDOHQGSRLQW ,ĂnjĂƌĚƌĂƟŽ ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů P-value WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͕ƉĞƌϭϬй ƌĞĚƵĐƟŽŶ 0.90 Ϭ͘ϴϲʹϬ͘ϵϱ <0.001 ŵďƵůĂƚŽƌLJDWƌĞĚƵĐƟŽŶ͕^^ 0.84 Ϭ͘ϳϬʹϭ͘Ϭϭ 0.064 WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶΎDW ƌĞĚƵĐƟŽŶ 0.83 Ϭ͘ϲϲʹϭ͘Ϭϰ 0.104 Male sex 0.90 Ϭ͘ϱϰʹϭ͘ϰϵ 0.684 Age, years 1.08 ϭ͘Ϭϭʹϭ͘ϭϱ 0.025

Baseline ambulatory MAP, SDS 1.20 ϭ͘ϬϮʹϭ͘ϰϬ 0.024

Diagnosis group - Glomerulopathies - <hd - Other ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.56 0.80 Ϭ͘ϯϬʹϭ͘ϬϮ Ϭ͘ϯϲʹϭ͘ϳϳ 0.057 0.580 ĂƐĞůŝŶĞĞ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2 _{0.92 Ϭ͘ϵϭʹϬ͘ϵϰ <0.001} Baseline urinary ƉƌŽƚĞŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ͕ŵŐͬŵŐ 1.24 ϭ͘ϭϮʹϭ͘ϯϴ <0.001

Supplementary table 4. 6HQVLWLYLW\DQDO\VLV$GMXVWHGFR[SURSRUWLRQDOKD]DUGVPRGHOZLWK

DVVRFLDWLRQEHWZHHQLQLWLDOSURWHLQXULDUHGXFWLRQDQGFRPSRVLWHUHQDOHQGSRLQWSURWHLQXULD UHGXFWLRQDQDO\VHGDVFRQWLQXRXVPHDVXUH ,ĂnjĂƌĚƌĂƟŽ ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů P-value WƌŽƚĞŝŶƵƌŝĂƌĞĚƵĐƟŽŶ͕ƉĞƌϭϬй ƌĞĚƵĐƟŽŶ 0.93 Ϭ͘ϵϬʹϬ͘ϵϲ <0.001 Male sex 0.89 Ϭ͘ϱϰʹϭ͘ϰϳ 0.649 Age, years 1.07 ϭ͘ϬϬʹϭ͘ϭϰ 0.040

Baseline ambulatory MAP, SDS 1.22 ϭ͘Ϭϰʹϭ͘ϰϮ 0.014

Diagnosis group - Glomerulopathies - <hd - Other ϭ͘ϬϬ;ƌĞĨĞƌĞŶĐĞŐƌŽƵƉͿ 0.58 0.82 Ϭ͘ϯϮʹϭ͘Ϭϱ Ϭ͘ϯϳʹϭ͘ϳϵ 0.072 0.614 ĂƐĞůŝŶĞĞ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2 _{0.93 Ϭ͘ϵϭʹϬ͘ϵϰ <0.001}

Baseline urinary protein/

ĐƌĞĂƟŶŝŶĞƌĂƟŽ͕ŵŐͬŵŐ 1.24 ϭ͘ϭϮʹϭ͘ϯϳ <0.001