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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Should RAAS inhibition be discontinued in

children with advanced chronic kidney

disease? Results of the 4C study

Authors ^ŽƉŚŝĞD͘ǀĂŶĚĞŶĞůƚ1_{͕,ŝĚĚŽ:͘>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ}1_{͕DĂƌŝĞƩĂ<ŝƌĐŚŶĞƌ}2_,

sĂůĞŶƟŶĂ'ƌĂĐĐŚŝ1_{͕ĂŶŝĞůĂdŚƵƌŶͲsĂůƐĂƐƐŝŶĂ}3_{͕LJƐƵŶ<͘ĂLJĂnjŝƚ}3_{, Anna} EŝŵŝĞƌƐŬĂ3_{͕EƵƌĂŶƉŽůĂƚ}3_{͕/ƉĞŬ<ĂƉůĂŶƵůƵƚ}3_{͕<ĂƌŽůŝƐnjƵŬĂŝƟƐ}3_{, Ali} ƵnjŽǀĂ3_{͕:ƵƐƟŶĞĂĐĐŚĞƩĂ}3_{͕ZƵŬƐŚĂŶĂ^ŚƌŽī}3_{, Dusan Paripovic}3_{͕ĞLJŶĞƉ} ŝƌƐŝŶPnjĕĂŬĂƌ3_{͕<ŝďƌŝLJĂ&ŝĚĂŶ}3_{͕,ĂŬĂŶƌĚŽŐĂŶ}3_{͕:ƵƩĂ'ĞůůĞƌŵĂŶŶ}3_͕ůŬĞ tƺŚů3,4_{͕ŝĐŬĚĞĞĞƵǁ}1_{͕ŶĞƩĞDĞůŬ}3_{͕hǁĞYƵĞƌĨĞůĚ}3_{͕&ƌĂŶnj^ĐŚĂĞĨĞƌ}3,4 ĸůŝĂƟŽŶƐ 1_{ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůWŚĂƌŵĂĐLJĂŶĚWŚĂƌŵĂĐŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂů} ĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕dŚĞEĞƚŚĞƌůĂŶĚƐ 2_{/ŶƐƟƚƵƚĞŽĨDĞĚŝĐĂůŝŽŵĞƚƌLJĂŶĚ/ŶĨŽƌŵĂƟĐƐ͕hŶŝǀĞƌƐŝƚLJŽĨ,ĞŝĚĞůďĞƌŐ͕} 'ĞƌŵĂŶLJ 3_{ϰƐƚƵĚLJŐƌŽƵƉ} 4_{ŝǀŝƐŝŽŶŽĨWĞĚŝĂƚƌŝĐEĞƉŚƌŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJ,ŽƐƉŝƚĂů,ĞŝĚĞůďĞƌŐ͕} 'ĞƌŵĂŶLJ ^ƵďŵŝƩĞĚ

6

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 ůƚŚŽƵŐŚZĞŶŝŶŶŐŝŽƚĞŶƐŝŶůĚŽƐƚĞƌŽŶĞ^LJƐƚĞŵŝŶŚŝďŝƟŽŶ;Z^ŝͿŝƐĂĐŽƌŶĞƌƐƚŽŶĞŝŶ ƚŚĞƚƌĞĂƚŵĞŶƚŽĨƌĞŶĂůĐŽŵƉůŝĐĂƟŽŶƐŝŶĐŚŝůĚƌĞŶǁŝƚŚŚƌŽŶŝĐ<ŝĚŶĞLJŝƐĞĂƐĞ;<Ϳ͕ŝƚŝƐ ƐŽŵĞƟŵĞƐĚŝƐĐŽŶƟŶƵĞĚǁŚĞŶƌĞŶĂůĨƵŶĐƟŽŶĚĞĐůŝŶĞƐĨƵƌƚŚĞƌ͘tĞƐƚƵĚŝĞĚƚŚĞƌĞĂƐŽŶƐ ĂŶĚŝŵƉĂĐƚŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŽŶŝŵƉŽƌƚĂŶƚƌŝƐŬŵĂƌŬĞƌƐŽĨ<ƉƌŽŐƌĞƐƐŝŽŶ ĂŶĚŽŶĞ'&ZĚĞĐůŝŶĞŝŶƚŚĞŽďƐĞƌǀĂƟŽŶĂůĂƌĚŝŽǀĂƐĐƵůĂƌŽŵŽƌďŝĚŝƚLJŝŶŚŝůĚƌĞŶǁŝƚŚ <;ϰͿƐƚƵĚLJ͘ Methods ŚŝůĚƌĞŶǁŝƚŚ<ǁŚŽĚŝƐĐŽŶƟŶƵĞĚZ^ŝĚƵƌŝŶŐƉƌŽƐƉĞĐƟǀĞĨŽůůŽǁͲƵƉǁĞƌĞŝŶĐůƵĚĞĚ͘ /ŶŝƟĂůĐŚĂŶŐĞŝŶďůŽŽĚƉƌĞƐƐƵƌĞ͕ĂůďƵŵŝŶƵƌŝĂĂŶĚƉŽƚĂƐƐŝƵŵĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞ ĂƐƐĞƐƐĞĚ;ŵĞĚŝĂŶƟŵĞϲŵŽŶƚŚƐͿ͘ZĂƚĞŽĨĞ'&ZĚĞĐůŝŶĞ;Ğ'&ZƐůŽƉĞͿĚƵƌŝŶŐĂŵĞĚŝĂŶŽĨ ϭ͘ϵLJĞĂƌƐďĞĨŽƌĞĂŶĚϭ͘ϮLJĞĂƌƐĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞĞƐƟŵĂƚĞĚƵƐŝŶŐĂůŝŶĞĂƌŵŝdžĞĚ ĞīĞĐƚƐŵŽĚĞů͘ Results ϲϵĐŚŝůĚƌĞŶǁĞƌĞŝŶĐůƵĚĞĚŝŶƚŚĞƐƚƵĚLJ;ϲϳйŵĂůĞ͕ŵĞĂŶĂŐĞϭϯ͘ϳLJĞĂƌƐ͕ŵĞĂŶĞ'&ZϮϳ ŵůͬŵŝŶͬϭ͘ϳϯŵ2_{Ϳ͘WŚLJƐŝĐŝĂŶͲƌĞƉŽƌƚĞĚƌĞĂƐŽŶƐĨŽƌZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞŝŶĐƌĞĂƐĞŝŶ} ƐĞƌƵŵĐƌĞĂƟŶŝŶĞ͕ŚLJƉĞƌŬĂůĞŵŝĂ͕ĂŶĚƐLJŵƉƚŽŵĂƟĐŚLJƉŽƚĞŶƐŝŽŶ͘ŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨ Z^ŝ͕ďůŽŽĚƉƌĞƐƐƵƌĞĂŶĚĂůďƵŵŝŶƵƌŝĂŝŶĐƌĞĂƐĞĚǁŚĞƌĞĂƐƉŽƚĂƐƐŝƵŵĚĞĐƌĞĂƐĞĚ͘Ğ'&Z ĚĞĐůŝŶĞĚŵŽƌĞƌĂƉŝĚůLJĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝ;Ͳϯ͘ϵŵůͬŵŝŶͬϭ͘ϳϯŵϮͬLJĞĂƌ;ϵϱй/ Ͳϱ͘ϭƚŽͲϮ͘ϲͿͿĐŽŵƉĂƌĞĚƚŽƚŚĞƐůŽƉĞĚƵƌŝŶŐZ^ŝƚƌĞĂƚŵĞŶƚ;Ͳϭ͘ϱŵůͬŵŝŶͬϭ͘ϳϯŵ2_ͬLJĞĂƌ ;ϵϱй/ͲϮ͘ϰƚŽͲϬ͘ϲͿ͖WсϬ͘ϬϬϱͿ͘ Conclusions ŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŝŶĐŚŝůĚƌĞŶǁŝƚŚ<ŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŶĂĐĐĞůĞƌĂƟŽŶŽĨƌĞŶĂů ĨƵŶĐƟŽŶĚĞĐůŝŶĞ͘dŚĞƐĞƌĞƐƵůƚƐŝŶĚŝĐĂƚĞƚŚĂƚZ^ŝŝƐŝŵƉŽƌƚĂŶƚĨŽƌƌĞŶĂůƉƌŽƚĞĐƟŽŶĞǀĞŶ ŝŶĂĚǀĂŶĐĞĚ<ĂŶĚƚŚĂƚƐƚŽƉƉŝŶŐƚŚŝƐƚŚĞƌĂƉLJ͕ĞǀĞŶĨŽƌŐŽŽĚĐůŝŶŝĐĂůƌĞĂƐŽŶƐ͕ƐŚŽƵůĚ ďĞǁĞŝŐŚĞĚĂŐĂŝŶƐƚƚŚĞŶĞŐĂƟǀĞŝŵƉĂĐƚŽŶůŽŶŐƚĞƌŵƌĞŶĂůĨƵŶĐƟŽŶ͘

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

ZĞŶŝŶ ŶŐŝŽƚĞŶƐŝŶ ůĚŽƐƚĞƌŽŶĞ ^LJƐƚĞŵ Z^ ŝŶŚŝďŝƟŽŶ ;Z^ŝͿ ǁŝƚŚ ŶŐŝŽƚĞŶƐŝŶ ŽŶǀĞƌƟŶŐŶnjLJŵĞ;ͿŝŶŚŝďŝƟŽŶŽƌŶŐŝŽƚĞŶƐŝŶZĞĐĞƉƚŽƌůŽĐŬĂĚĞ;ZͿŝƐĂŵĂŝŶƐƚĂLJ ƚŚĞƌĂƉLJĨŽƌƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƉƌŽƚĞĐƟŽŶŝŶĂĚƵůƚƐ͕ĂŶĚĂůƐŽŝŶĐŚŝůĚƌĞŶ͕ǁŝƚŚĐŚƌŽŶŝĐ ŬŝĚŶĞLJĚŝƐĞĂƐĞ;<Ϳ͘1_{Z^ŝŚĂƐďĞĞŶƐŚŽǁŶƚŽďĞƌĞŶŽƉƌŽƚĞĐƟǀĞŝŶĞĂƌůLJĂƐǁĞůůĂƐŝŶ} ĂĚǀĂŶĐĞĚƐƚĂŐĞƐŽĨ<ŝŶƉĂƟĞŶƚƐǁŝƚŚďŽƚŚĚŝĂďĞƟĐĂŶĚŶŽŶͲĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚŝĞƐ͘2-6 ĞƐƉŝƚĞŽǀĞƌǁŚĞůŵŝŶŐƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůůĞĚĐůŝŶŝĐĂůƚƌŝĂůĞǀŝĚĞŶĐĞĚĞŵŽŶƐƚƌĂƟŶŐ ƚŚĂƚZ^ŝĚĞůĂLJƐƚŚĞƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨƵŶĐƟŽŶĚĞĐůŝŶĞ͕ĐůŝŶŝĐŝĂŶƐĨƌĞƋƵĞŶƚůLJĚĞĐŝĚĞ ƚŽĚŝƐĐŽŶƟŶƵĞZ^ŝŝŶƚŚĞĐŽƵƌƐĞŽĨƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͘ZĞĂƐŽŶƐĨŽƌƐƚŽƉƉŝŶŐ ŝŶĐůƵĚĞƐLJŵƉƚŽŵĂƟĐƐŝĚĞĞīĞĐƚƐƐƵĐŚĂƐŚLJƉŽƚĞŶƐŝŽŶŽƌĐŽƵŐŚ;ŝŶƚŚĞĐĂƐĞŽĨ ŝŶŚŝďŝƚŽƌƵƐĞͿ͕ŚLJƉĞƌŬĂůĂĞŵŝĂ͕ŽƌƚŽƌĞŐĂŝŶƌĞŶĂůĨƵŶĐƟŽŶĂŶĚĚĞůĂLJĚŝĂůLJƐŝƐ͘7-9 ůƚŚŽƵŐŚ ƚŚĞ ŝŶƚĞŶƟŽŶ ŽĨ ƚŚĞ ĐůŝŶŝĐŝĂŶ ŝƐ ƚŽ ƉƌĞǀĞŶƚ ŚĂƌŵ ƚŽ ƚŚĞ ƉĂƟĞŶƚ ďLJ ĚŝƐĐŽŶƟŶƵŝŶŐZ^ŝ͕ŝƚŝƐƵŶŬŶŽǁŶǁŚĞƚŚĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝǁŝůůĂīĞĐƚƌŝƐŬ ŵĂƌŬĞƌƐĂŶĚƉŽƐƐŝďůLJĂĐĐĞůĞƌĂƚĞƌĞŶĂůĨƵŶĐƟŽŶĚĞĐůŝŶĞ͘,ĞƌĞ͕ǁĞƐƚƵĚŝĞĚƚŚĞĨƌĞƋƵĞŶĐLJ ŽĨĂŶĚƌĞĂƐŽŶƐĨŽƌZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŝŶĂůĂƌŐĞĐŽŚŽƌƚŽĨƉĞĚŝĂƚƌŝĐƉĂƟĞŶƚƐǁŝƚŚ ĂĚǀĂŶĐĞĚ<͕ĂŶĚĞdžƉůŽƌĞĚƚŚĞŝŵƉĂĐƚŽŶƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͘

Materials and Methods

Study design &ŽƌƚŚŝƐƐƚƵĚLJ͕ĚĂƚĂĨƌŽŵƚŚĞĂƌĚŝŽǀĂƐĐƵůĂƌŽŵŽƌďŝĚŝƚLJŝŶŚŝůĚƌĞŶǁŝƚŚŚƌŽŶŝĐŬŝĚŶĞLJ ĚŝƐĞĂƐĞ;ϰͿƐƚƵĚLJǁĞƌĞĂŶĂůLJƐĞĚ͘dŚĞϰƐƚƵĚLJŝƐĂŶŽŶŐŽŝŶŐŵƵůƟĐĞŶƚƌĞƉƌŽƐƉĞĐƟǀĞ ŽďƐĞƌǀĂƟŽŶĂů ƐƚƵĚLJ ĚĞƐŝŐŶĞĚ ƚŽ ĞdžƉůŽƌĞ ƚŚĞ ƉƌĞǀĂůĞŶĐĞ͕ ĚĞŐƌĞĞ ĂŶĚ ƉƌŽŐƌĞƐƐŝŽŶ ŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĐŽŵŽƌďŝĚŝƚLJĂƐǁĞůůĂƐŝƚƐĂƐƐŽĐŝĂƟŽŶǁŝƚŚ<ƉƌŽŐƌĞƐƐŝŽŶĚƵƌŝŶŐ ůŽŶŐŝƚƵĚŝŶĂů ĨŽůůŽǁͲƵƉ͘ dŚĞ ĚĞƚĂŝůĞĚ ƐƚƵĚLJ ĚĞƐŝŐŶ ŚĂƐ ďĞĞŶ ĚĞƐĐƌŝďĞĚ ĞůƐĞǁŚĞƌĞ͘10 ŚŝůĚƌĞŶĂŐĞĚϲƚŽϭϳLJĞĂƌƐǁŝƚŚĂŶĞƐƟŵĂƚĞĚ'&ZŽĨϭϬͲϲϬŵůͬŵŝŶͬϭ͘ϳϯŵ2_{ǁĞƌĞŝŶĐůƵĚĞĚ͘} džĐůƵƐŝŽŶĐƌŝƚĞƌŝĂǁĞƌĞƚŚĞƉƌĞƐĞŶĐĞŽĨĂĐƟǀĞƐLJƐƚĞŵŝĐǀĂƐĐƵůŝƟƐ͕ƌĞŶĂůǀĂƐĐƵůĂƌĂŶŽŵĂůŝĞƐ͕ ĐŽĞdžŝƐƟŶŐƉƌŝŵĂƌLJĐĂƌĚŝŽǀĂƐĐƵůĂƌĂŶŽŵĂůŝĞƐĂŶĚĂŶŽŵĂůŝĞƐŽĨƚŚĞůŝŵďƐƉƌĞǀĞŶƟŶŐ ĚŝĂŐŶŽƐƟĐƉƌŽĐĞĚƵƌĞƐ͘^ƚƵĚLJǀŝƐŝƚƐǁŝƚŚŵĞĂƐƵƌĞŵĞŶƚƐŽĨĞ'&Z͕ĂůďƵŵŝŶƵƌŝĂ͕ƉŽƚĂƐƐŝƵŵ ĂŶĚďůŽŽĚƉƌĞƐƐƵƌĞǁĞƌĞƉĞƌĨŽƌŵĞĚĞǀĞƌLJƐŝdžŵŽŶƚŚƐ͘ůůƉƌĞƐĐƌŝďĞĚŵĞĚŝĐĂƟŽŶƐ͕ĂŶĚ ƚŚĞĚĂƚĞƐŽĨĂŶLJƉƌĞƐĐƌŝƉƟŽŶĐŚĂŶŐĞƐƐŝŶĐĞƚŚĞƉƌĞǀŝŽƵƐǀŝƐŝƚǁĞƌĞƌĞĐŽƌĚĞĚĂƚĞǀĞƌLJ ƐƚƵĚLJǀŝƐŝƚ͘/ŶƚŚĞĂďƐĞŶĐĞŽĨĂŶLJĐŚĂŶŐĞƐŝŶƉƌĞƐĐƌŝƉƟŽŶ͕ƚŚĞƵƐĞŽĨŝŶŚŝďŝƚŽƌƐĂŶĚ ZƐǁĂƐĂƐƐƵŵĞĚƚŽďĞĐŽŶƐŝƐƚĞŶƚďĞƚǁĞĞŶƚŚĞǀŝƐŝƚƐ͘ŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝǁĂƐ ĚĞĮŶĞĚĂƐƚŚĞƌĞŵŽǀĂůŽĨĂŶŝŶŚŝďŝƚŽƌŽƌZĨƌŽŵƚŚĞƌĞĐŽƌĚĞĚŵĞĚŝĐĂƟŽŶƐƐŝŶĐĞ ƚŚĞƉƌĞǀŝŽƵƐǀŝƐŝƚ͘ WĂƟĞŶƚƐĞůĞĐƟŽŶ ŚŝůĚƌĞŶǁŚŽĚŝƐĐŽŶƟŶƵĞĚZ^ŝĚƵƌŝŶŐĨŽůůŽǁͲƵƉŝŶƚŚĞϰƐƚƵĚLJ͕ĂŶĚǁŚŽŚĂĚĂƚ ůĞĂƐƚŽŶĞƌĞĐŽƌĚĞĚĞ'&ZŵĞĂƐƵƌĞŵĞŶƚďĞĨŽƌĞĂŶĚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨƚŚĞƌĂƉLJǁĞƌĞ ŝŶĐůƵĚĞĚŝŶƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶĨŽƌƚŚŝƐĂŶĂůLJƐŝƐ͘ŚŝůĚƌĞŶǁŚŽĚŝƐĐŽŶƟŶƵĞĚZ^ŝĂŌĞƌ

6

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: 90PDF page: 90PDF page: 90PDF page: 90

90 ƌĞĂĐŚŝŶŐƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚǁĞƌĞĞdžĐůƵĚĞĚĨƌŽŵƚŚĞĂŶĂůLJƐĞƐ͘ĂƚĂŽĨĂůů ĂǀĂŝůĂďůĞǀŝƐŝƚƐďĞĨŽƌĞĂŶĚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞŝŶĐůƵĚĞĚŝŶƚŚĞĂŶĂůLJƐĞƐ͕ĞdžĐĞƉƚ ĨŽƌƉĂƟĞŶƚƐŝŶƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶǁŚŽŚĂĚƉƌĞǀŝŽƵƐůLJƐƚĂƌƚĞĚZ^ŝĚƵƌŝŶŐĨŽůůŽǁƵƉ ŽĨƚŚĞϰƐƚƵĚLJ͘/ŶƚŚŝƐĐĂƐĞ͕ĚĂƚĂŽĨƚŚĞǀŝƐŝƚƐďĞĨŽƌĞƐƚĂƌƟŶŐZ^ŝǁĞƌĞĞdžĐůƵĚĞĚĨƌŽŵ ƚŚĞĂŶĂůLJƐĞƐ͘ Measurements ^ƉŽƚƵƌŝŶĞƐĂŵƉůĞƐǁĞƌĞĐŽůůĞĐƚĞĚĂƚĞǀĞƌLJǀŝƐŝƚ͘ůďƵŵŝŶĂŶĚĐƌĞĂƟŶŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶ ŽĨƚŚĞƵƌŝŶĞƐĂŵƉůĞƐǁĞƌĞŵĞĂƐƵƌĞĚĐĞŶƚƌĂůůLJ;^LJŶůĂď,ĞŝĚĞůďĞƌŐͿďLJƚƵƌďŝĚŝŵĞƚƌLJ ĂŶĚƉŚŽƚŽŵĞƚƌLJƌĞƐƉĞĐƟǀĞůLJ͘ƐƟŵĂƚĞĚ'&ZǁĂƐĂƐƐĞƐƐĞĚƵƐŝŶŐƚŚĞϮϬϬϵĐLJƐƚĂƟŶͬ ĐƌĞĂƟŶŝŶĞͲďĂƐĞĚĨŽƌŵƵůĂ͘11_{^ĞƌƵŵĐƌĞĂƟŶŝŶĞǁĂƐŵĞĂƐƵƌĞĚĞŶnjLJŵĂƟĐĂůůLJ͕ĂŶĚƐĞƌƵŵ} ĐLJƐƚĂƟŶƵƐŝŶŐƚŚĞƚƵƌďŝĚŝŵĞƚƌŝĐĂƐƐĂLJŽĨZŽĐŚĞ͘^ĞƌƵŵƉŽƚĂƐƐŝƵŵǁĂƐĂŶĂůLJnjĞĚůŽĐĂůůLJ͕ ƚŽƉƌĞǀĞŶƚĨĂůƐĞůLJŝŶĐƌĞĂƐĞĚƉŽƚĂƐƐŝƵŵůĞǀĞůƐĚƵĞƚŽŚĞŵŽůLJƐŝƐ͘dŚĞƌĞǁĞƌĞŶŽƐƉĞĐŝĮĐ ƌĞĐŽŵŵĞŶĚĂƟŽŶƐŝŶƚŚĞϰƐƚƵĚLJƉƌŽƚŽĐŽůŽŶŚŽǁƚŽŵĞĂƐƵƌĞďůŽŽĚƉƌĞƐƐƵƌĞ͘,ŽǁĞǀĞƌ͕ ŝŶŐĞŶĞƌĂů͕ŽĸĐŝĂůƌĞĐŽŵŵĞŶĚĂƟŽŶƐŽĨƚŚĞϰƚŚƌĞƉŽƌƚŽŶƚŚĞŝĂŐŶŽƐŝƐ͕ǀĂůƵĂƟŽŶ͕ ĂŶĚdƌĞĂƚŵĞŶƚŽĨ,ŝŐŚůŽŽĚWƌĞƐƐƵƌĞŝŶŚŝůĚƌĞŶĂŶĚĚŽůĞƐĐĞŶƚƐǁĞƌĞĨŽůůŽǁĞĚĂŶĚ ŽƐĐŝůůŽŵĞƚƌŝĐĚĞǀŝĐĞƐǁĞƌĞƵƐĞĚŝŶŵŽƐƚĐĞŶƚĞƌƐ͘12 Outcomes tĞƚĞƐƚĞĚƐĞǀĞƌĂůĞĸĐĂĐLJŵĞĂƐƵƌĞƐŝŶƚŚĞƐƚƵĚLJ͘&ŝƌƐƚ͕ǁĞĞǀĂůƵĂƚĞĚŝŶŝƟĂůĐŚĂŶŐĞŝŶ ƐLJƐƚŽůŝĐďůŽŽĚƉƌĞƐƐƵƌĞ͕ĂůďƵŵŝŶƵƌŝĂ͕ƉŽƚĂƐƐŝƵŵĂŶĚĞ'&ZĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝ͘ ^ĞĐŽŶĚůLJ͕Ğ'&ZƐůŽƉĞƐďĞĨŽƌĞĂŶĚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝǁĞƌĞĂƐƐĞƐƐĞĚ͘&ŝŶĂůůLJ͕ ǁĞŵĞĂƐƵƌĞĚƟŵĞĨƌŽŵĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝƚŽƚŚĞĮƌƐƚĞǀĞŶƚŽĨĂĐŽŵƉŽƐŝƚĞƌĞŶĂů ĞŶĚƉŽŝŶƚ͕ǁŚŝĐŚǁĂƐĚĞĮŶĞĚĂƐĂƐƵƐƚĂŝŶĞĚϱϬйƌĞĚƵĐƟŽŶŝŶĞ'&ZŽƌƉƌŽŐƌĞƐƐŝŽŶƚŽ ĞŶĚͲƐƚĂŐĞƌĞŶĂůĚŝƐĞĂƐĞ;Ğ'&ZфϭϬŵůͬŵŝŶͬϭ͘ϳϯŵ2_{ŽƌƐƚĂƌƚŽĨƌĞŶĂůƌĞƉůĂĐĞŵĞŶƚƚŚĞƌĂƉLJͿ͘} ^ƚĂƟƐƟĐĂůĂŶĂůLJƐŝƐ dŚĞŝŶŝƟĂůĐŚĂŶŐĞŝŶƐLJƐƚŽůŝĐďůŽŽĚƉƌĞƐƐƵƌĞ͕ƉŽƚĂƐƐŝƵŵĂŶĚĞ'&ZǁĂƐĚĞƚĞƌŵŝŶĞĚĂƐ ƚŚĞĂďƐŽůƵƚĞĚŝīĞƌĞŶĐĞďĞƚǁĞĞŶƚŚĞĮƌƐƚŵĞĂƐƵƌĞŵĞŶƚĂŌĞƌĂŶĚůĂƐƚŵĞĂƐƵƌĞŵĞŶƚ ďĞĨŽƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨƚŚĞZ^ŝ͘ůďƵŵŝŶƵƌŝĂǁĂƐůŽŐͲƚƌĂŶƐĨŽƌŵĞĚĚƵĞƚŽŝƚƐƐŬĞǁĞĚ ĚŝƐƚƌŝďƵƟŽŶ͘dͲƚĞƐƚƐǁĞƌĞƵƐĞĚƚŽƚĞƐƚƚŚĞĚŝīĞƌĞŶĐĞŝŶƌĞŶĂůƉĂƌĂŵĞƚĞƌƐďĞĨŽƌĞĂŶĚĂŌĞƌ ĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝ͘ Ğ'&ZƐůŽƉĞƐďĞĨŽƌĞĂŶĚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞĂƐƐĞƐƐĞĚƵƐŝŶŐĂůŝŶĞĂƌŵŝdžĞĚĞīĞĐƚƐ ŵŽĚĞůǁŝƚŚĂƌĂŶĚŽŵƐůŽƉĞĂŶĚƌĂŶĚŽŵŝŶƚĞƌĐĞƉƚ͘ƐƉůŝŶĞĂƚƟŵĞŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶǁĂƐ ŵŽĚĞůůĞĚƚŽĂƐƐĞƐƐƚŚĞĚŝīĞƌĞŶĐĞŝŶƐůŽƉĞďĞĨŽƌĞĂŶĚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶ͘Ğ'&ZƐůŽƉĞƐ ǁĞƌĞƌĞƉƌĞƐĞŶƚĞĚĂƐŵĞĂŶǁŝƚŚϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů;/ͿĂŶĚĂƐƐĞƐƐĞĚĨŽƌĚŝīĞƌĞŶƚ ƐƵďŐƌŽƵƉƐ͘ŝīĞƌĞŶĐĞƐŝŶĞ'&ZƐůŽƉĞƐďĞĨŽƌĞĂŶĚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞĐŽŵƉĂƌĞĚ ǁŝƚŚŝŶƚŚĞŵŽĚĞůƵƐŝŶŐůŝŶĞĂƌĐŽŵďŝŶĂƟŽŶƐŽĨĞƐƟŵĂƟŽŶƐ͘ /ŶŝƟĂůĐŚĂŶŐĞƐŝŶďůŽŽĚƉƌĞƐƐƵƌĞĂŶĚĂůďƵŵŝŶƵƌŝĂŚĂǀĞďĞĞŶĨŽƵŶĚƚŽƉƌĞĚŝĐƚĞĸĐĂĐLJ ŽĨZ^ŝŝŶĞĂƌůŝĞƌƐƚƵĚŝĞƐ͘13-16_{tĞƚĞƐƚĞĚǁŚĞƚŚĞƌƚŚĞƐĞĐŚĂŶŐĞƐĚƵƌŝŶŐĚŝƐĐŽŶƟŶƵĂƟŽŶ}

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: 91PDF page: 91PDF page: 91PDF page: 91

91 ŽĨZ^ŝĂƌĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚ͕ƵƐŝŶŐĂŽdžƉƌŽƉŽƌƟŽŶĂů ŚĂnjĂƌĚƐŵŽĚĞů͕ĂĚũƵƐƚĞĚĨŽƌĐŽǀĂƌŝĂƚĞƐĂƚƚŚĞůĂƐƚŵĞĂƐƵƌĞŵĞŶƚďĞĨŽƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶ ;ŐĞŶĚĞƌ͕ĂŐĞ͕Ğ'&Z͕ĂůďƵŵŝŶƵƌŝĂ͕ƐLJƐƚŽůŝĐďůŽŽĚƉƌĞƐƐƵƌĞͿ͘ ĂƚĂĂƌĞĞdžƉƌĞƐƐĞĚĂƐĞŝƚŚĞƌŵĞĂŶĂŶĚƐƚĂŶĚĂƌĚĚĞǀŝĂƟŽŶ;^ͿŽƌŵĞĚŝĂŶĂŶĚϮϱth -75th_{ƉĞƌĐĞŶƟůĞĨŽƌĐŽŶƟŶƵŽƵƐǀĂƌŝĂďůĞƐĂŶĚƉĞƌĐĞŶƚĂŐĞƐĂŶĚĐŽƵŶƚƐ;йͿĨŽƌĐĂƚĞŐŽƌŝĐĂů} ǀĂƌŝĂďůĞƐ͘ůůĂŶĂůLJƐĞƐǁĞƌĞƉĞƌĨŽƌŵĞĚƵƐŝŶŐ^ddǀĞƌƐŝŽŶϭϰ͘Ϯ;^ƚĂƚĂĐŽƌƉ>WͿ͘

Results

KĨƚŚĞϳϬϰĐŚŝůĚƌĞŶƚŚĂƚǁĞƌĞŝŶĐůƵĚĞĚŝŶƚŚĞϰĐŽŚŽƌƚ͕Ϯϵϴ;ϰϮйͿƵƐĞĚĂŶLJĨŽƌŵŽĨ Z^ŝĂƚĞŶƚƌLJŝŶƚŽƚŚĞƐƚƵĚLJ͘ŶĂĚĚŝƟŽŶĂůϴϮ;ϭϮйͿƐƚĂƌƚĞĚZ^ŝĚƵƌŝŶŐĨŽůůŽǁͲƵƉŽĨ ƚŚĞƐƚƵĚLJ͘KĨƚŚĞƐĞϯϴϬĐŚŝůĚƌĞŶ͕ϳϯĐŚŝůĚƌĞŶ;ϭϵйͿĚŝƐĐŽŶƟŶƵĞĚZ^ŝďĞĨŽƌĞƌĞĂĐŚŝŶŐ ƚŚĞĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚ͘KĨƚŚĞƐĞ͕ϲϵǁĞƌĞĞůŝŐŝďůĞĨŽƌƚŚŝƐĂŶĂůLJƐŝƐ͕ǁŚĞƌĞĂƐϰǁĞƌĞ ĞdžĐůƵĚĞĚĚƵĞƚŽŵŝƐƐŝŶŐĞ'&ZŵĞĂƐƵƌĞŵĞŶƚƐďĞĨŽƌĞŽƌĂŌĞƌZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶ͘ ƵƌŝŶŐƚŚĞůĂƐƚǀŝƐŝƚďĞĨŽƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶ͕ŵĞĂŶĂŐĞǁĂƐϭϯ͘ϳ;^ϯ͘ϮͿLJĞĂƌƐĂŶĚŵĞĂŶ Ğ'&ZǁĂƐϮϳ͘ϯ;ϭϭ͘ϴͿŵůͬŵŝŶͬϭ͘ϳϯŵϮ͘DŽƐƚĐŚŝůĚƌĞŶ;ϳϰйͿŚĂĚĂĐŽŶŐĞŶŝƚĂůĂŶŽŵĂůLJŽĨƚŚĞ ŬŝĚŶĞLJŽƌƵƌŝŶĂƌLJƚƌĂĐƚ;<hdͿĂƐƉƌŝŵĂƌLJƌĞŶĂůĚŝĂŐŶŽƐŝƐ͘dŚĞŵĂũŽƌŝƚLJŽĨƚŚĞĐŚŝůĚƌĞŶ ĚŝƐĐŽŶƟŶƵĞĚĂŶŝŶŚŝďŝƚŽƌ͗ĨŽƌƚLJĐŚŝůĚƌĞŶĚŝƐĐŽŶƟŶƵĞĚĞŶĂůĂƉƌŝů͕ϮϮĐŚŝůĚƌĞŶƌĂŵŝƉƌŝů ĂŶĚŽŶĞĐŚŝůĚĐĂƉƚŽƉƌŝů͘dŚĞŽƚŚĞƌƐŝdžĐŚŝůĚƌĞŶĚŝƐĐŽŶƟŶƵĞĚĂŶZ͗ĨŽƵƌĚŝƐĐŽŶƟŶƵĞĚ ůŽƐĂƌƚĂŶĂŶĚƚǁŽĐĂŶĚĞƐĂƌƚĂŶ͘&ŽƵƌƚĞĞŶ;ϮϬйͿĐŚŝůĚƌĞŶƐƚĂƌƚĞĚŽƚŚĞƌĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞ ƚŚĞƌĂƉLJĚŝƌĞĐƚůLJĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝ͗ĂĐĂůĐŝƵŵĐŚĂŶŶĞůďůŽĐŬĞƌǁĂƐƐƚĂƌƚĞĚŝŶ ĞŝŐŚƚĐŚŝůĚƌĞŶ͕ĂďĞƚĂďůŽĐŬĞƌŝŶƚŚƌĞĞĐŚŝůĚƌĞŶ͕ĂƉĞƌŝƉŚĞƌĂůĂůƉŚĂďůŽĐŬĞƌŝŶƚǁŽĐŚŝůĚƌĞŶ ĂŶĚŽŶĞĐŚŝůĚƐƚĂƌƚĞĚĂĚŝƵƌĞƟĐ͘ĚĚŝƟŽŶĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶĂƚƚŚĞ ůĂƐƚǀŝƐŝƚďĞĨŽƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶĂŶĚĂƚĞŶƌŽůŵĞŶƚŝŶƚŚĞϰƐƚƵĚLJŽĨZ^ŝĂƌĞƉƌĞƐĞŶƚĞĚ ŝŶdĂďůĞϭ͘DĞĚŝĂŶĨŽůůŽǁͲƵƉƟŵĞǁĂƐϭ͘ϵLJĞĂƌƐ;ϭ͘Ϭʹϯ͘ϱLJĞĂƌƐͿďĞĨŽƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶ ĂŶĚϭ͘ϮLJĞĂƌƐ;Ϭ͘ϲʹϮ͘ϯLJĞĂƌƐͿĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝ͘

6

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: 92PDF page: 92PDF page: 92PDF page: 92

92 Table 1.&KDUDFWHULVWLFVRIWKHVWXG\SRSXODWLRQEHIRUHGLVFRQWLQXDWLRQRI5$$6LQKLELWLRQ RAASi use at baseline or start during follow-up (n=380) ^ĞůĞĐƚĞĚƉŽƉƵůĂƟŽŶĨŽƌĐƵƌƌĞŶƚ analysis (n=69) ŚĂƌĂĐƚĞƌŝƐƟĐƐĂƚ ĞŶƌŽůŵĞŶƚŝŶϰ ŚĂƌĂĐƚĞƌŝƐƟĐƐĂƚĞŶƌŽůŵĞŶƚŝŶϰ ŚĂƌĂĐƚĞƌŝƐƟĐƐ at last visit before RAASi ĚŝƐĐŽŶƟŶƵĂƟŽŶ Age, years ϭϮ͘ϱ;ϯ͘ϯͿ ϭϭ͘ϱ;ϯ͘ϮͿ ϭϯ͘ϳ;ϯ͘ϮͿ &ĞŵĂůĞ͕Ŷ ϭϯϮ;ϯϱͿ Ϯϯ;ϯϯͿ Ϯϯ;ϯϯͿ Diagnosis, n - <hd - Other Ϯϰϰ;ϲϰͿϭϯϲ;ϯϲͿ ϱϭ;ϳϰͿϭϴ;ϮϲͿ ϱϭ;ϳϰͿϭϴ;ϮϲͿ

Systolic blood pressure, mmHg ϭϭϮ;ϭϱͿ ϭϭϬ;ϭϰͿ ϭϭϮ;ϭϲͿ

Ğ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2 _{ϯϬ͘ϰ;ϭϭ͘ϯͿ ϯϬ͘Ϯ;ϴ͘ϵͿ Ϯϳ͘ϯ;ϭϭ͘ϴͿ}

Ğ'&ZƐůŽƉĞ͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2_{/year N/A N/A Ͳϭ͘ϱ;ϯ͘ϳͿ}

Albuminuria, mg/g ϯϮϳ;ϴϰʹϭϭϮϴͿ ϯϵϱ;ϭϭϭʹϭϭϴϰͿ ϰϬϱ;ϭϱϭʹϭϰϲϰͿ

Serum potassium, mmol/L ϰ͘ϲ;Ϭ͘ϲͿ ϰ͘ϲ;Ϭ͘ϱͿ ϰ͘ϲ;Ϭ͘ϲͿ

Z^ŝŶŚŝďŝƟŽŶƵƐĞ͕Ŷ - ACE inhibitor - ARB Ϯϲϴ;ϳϭͿϱϱ;ϭϰͿ ϲϯ;ϵϭͿ ϲ;ϵͿ ϲϯ;ϵϭͿ ϲ;ϵͿ 9DOXHVIRUFRQWLQXRXVYDULDEOHVDUHGHVFULEHGDVPHDQ“6'RUPHGLDQth_-75th_{SHUFHQWLOH} YDOXHVIRUFDWHJRULFDOYDULDEOHVDVQXPEHUSHUFHQWDJH 1$QRWDSSOLFDEOHQRH*)5GDWDZHUHDYDLODEOHSULRUWRHQUROPHQWLQWRWKH&VWXG\ ĞƚĞƌŵŝŶĂŶƚƐĨŽƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŶŚŝďŝƟŽŶ dŽ ĞƐƚĂďůŝƐŚ ǁŚLJ ĐůŝŶŝĐŝĂŶƐ ĚŝƐĐŽŶƚŝŶƵĞĚ Z^ŝ͕ ƚŚĞ ƉƌŝŵĂƌLJ ƌĞĂƐŽŶƐ ĨŽƌ Z^ŝ ĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞĂƐƐĞƐƐĞĚ͘dŚĞŵŽƐƚŝŵƉŽƌƚĂŶƚƌĞĂƐŽŶƐĨŽƌZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶ ǁĞƌĞŝŶĐƌĞĂƐĞŝŶƐĞƌƵŵĐƌĞĂƟŶŝŶĞ͕ŚLJƉĞƌŬĂůĞŵŝĂ͕ĂŶĚƐLJŵƉƚŽŵĂƟĐŚLJƉŽƚĞŶƐŝŽŶ;dĂďůĞ ϮͿ͘EŽŵĂũŽƌĚŝīĞƌĞŶĐĞƐŝŶďĂƐĞůŝŶĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐďĞƚǁĞĞŶĐƵƌƌĞŶƚĂŶĚĨƵƚƵƌĞZ^ŝ ƵƐĞƌƐĂŶĚZ^ŝĚŝƐĐŽŶƟŶƵĞƌƐǁĞƌĞŽďƐĞƌǀĞĚ;dĂďůĞϭͿ͘ ƚƚŚĞƟŵĞŽĨZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŵĞĂŶĞ'&ZǁĂƐůŽǁĞƌŝŶƚŚŽƐĞĐŚŝůĚƌĞŶǁŚŽ ǁĞƌĞĚŝƐĐŽŶƟŶƵĞĚĚƵĞƚŽĂŶŝŶĐƌĞĂƐĞŝŶƐĞƌƵŵĐƌĞĂƟŶŝŶĞ;Ϯϯ͘ϰ;ϱ͘ϲͿŵůͬŵŝŶͬϭ͘ϳϯŵ2_Ϳ Žƌ ŚLJƉĞƌŬĂůĞŵŝĂ ;Ϯϱ͘Ϯ ;ϭϬ͘ϮͿ ŵůͬŵŝŶͬϭ͘ϳϯŵ2_{Ϳ ĐŽŵƉĂƌĞĚ ƚŽ ĚŝƐĐŽŶƟŶƵĂƟŽŶ ĚƵĞ ƚŽ} ƐLJŵƉƚŽŵĂƟĐŚLJƉŽƚĞŶƐŝŽŶ;ϯϴ͘ϲ;ϭϱ͘ϴͿŵůͬŵŝŶͬϭ͘ϳϯŵ2_{͖WфϬ͘ϬϬϭͿ͘dŚĞĂĐĐĞůĞƌĂƟŽŶŽĨ} Ğ'&ZĚĞĐůŝŶĞĨŽůůŽǁŝŶŐZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŽĐĐƵƌƌĞĚŝƌƌĞƐƉĞĐƟǀĞůLJŽĨƚŚĞƌĞĂƐŽŶĨŽƌ Z^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶ;dĂďůĞϯͿ͘ /ŶŝƟĂůĞīĞĐƚŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŽŶƌĞŶĂůƉĂƌĂŵĞƚĞƌƐĂŶĚĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ dŚĞŵĞĚŝĂŶƟŵĞďĞƚǁĞĞŶƚŚĞůĂƐƚǀŝƐŝƚďĞĨŽƌĞĂŶĚƚŚĞĮƌƐƚǀŝƐŝƚĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶ ŽĨZ^ŝǁĂƐϲ͘ϰ;ϱ͘ϳʹϳ͘ϬͿŵŽŶƚŚƐ͘dŚĞŝŶŝƟĂůĐŚĂŶŐĞƐŝŶ<ƌŝƐŬŵĂƌŬĞƌƐĂŌĞƌZ^ŝ

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: 93PDF page: 93PDF page: 93PDF page: 93

93 ĚŝƐĐŽŶƟŶƵĂƟŽŶĂƌĞĚĞƐĐƌŝďĞĚŝŶ&ŝŐƵƌĞϭ͘ůďƵŵŝŶƵƌŝĂŝŶĐƌĞĂƐĞĚďLJϭϭϱй;WфϬ͘ϬϬϭͿ ĂŶĚƐLJƐƚŽůŝĐďůŽŽĚƉƌĞƐƐƵƌĞďLJϮ͘ϴŵŵ,Ő;WсϬ͘ϬϴͿǁŚĞƌĞĂƐĞ'&ZĚĞĐƌĞĂƐĞĚďLJϭ͘ϯŵůͬ ŵŝŶͬϭ͘ϳϯŵ2_{;WсϬ͘ϬϴͿĂŶĚƉŽƚĂƐƐŝƵŵďLJϬ͘ϭϳŵŵŽůͬ>;WсϬ͘ϬϯͿ͘&ŽƌĂůůƉĂƌĂŵĞƚĞƌƐ͕ůĂƌŐĞ} ďĞƚǁĞĞŶͲƉĂƟĞŶƚǀĂƌŝĂďŝůŝƚLJǁĂƐŽďƐĞƌǀĞĚ;&ŝŐƵƌĞϭƌŝŐŚƚƉĂŶĞůͿ͘ Figure 1.,QLWLDOFKDQJHVREVHUYHGLQSDUDPHWHUVRILQWHUHVWH[SUHVVHGDVPHDQDQG FRQÀGHQFHLQWHUYDOVOHIWSDQHODQGGLVWULEXWLRQRILQWUDLQGLYLGXDOFKDQJHULJKWSDQHO

6

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: 94PDF page: 94PDF page: 94PDF page: 94

94

tĞŵŽĚĞůůĞĚƚŚĞĞīĞĐƚŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŽŶĞ'&ZƐůŽƉĞƐĂƐƐŚŽǁŶŝŶ&ŝŐƵƌĞ Ϯ͘ŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂĨĂƐƚĞƌĚĞĐůŝŶŝŶŐƐůŽƉĞŽĨͲϯ͘ϵ;ϵϱй/ Ͳϱ͘ϭƚŽͲϮ͘ϲͿŵůͬŵŝŶͬϭ͘ϳϯͬŵ2_{ͬLJĞĂƌĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶĐŽŵƉĂƌĞĚƚŽͲϭ͘ϱ;ϵϱй/ͲϮ͘ϰƚŽ} ͲϬ͘ϲͿŵůͬŵŝŶͬϭ͘ϳϯŵ2_{ͬLJĞĂƌďĞĨŽƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶ;WсϬ͘ϬϬϱͿ͘}

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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: 95PDF page: 95PDF page: 95PDF page: 95

95 Table 2.3K\VLFLDQUHSRUWHGUHDVRQVIRUGLVFRQWLQXDWLRQRI5$$6LQKLELWLRQLQWKHVWXG\ SRSXODWLRQ Reason Number (%) /ŶĐƌĞĂƐĞŽĨƐĞƌƵŵĐƌĞĂƟŶŝŶĞ Ϯϯ;ϯϯͿ Hyperkalemia ϭϲ;ϮϯͿ ŝĂůLJƐŝƐͬƚƌĂŶƐƉůĂŶƚĂƟŽŶ Ϭ;ϬͿ ^LJŵƉƚŽŵĂƟĐƐŝĚĞĞīĞĐƚƐ͗ - Hypotension - Cough - Other ϭϮ;ϭϳͿ Ϭ;ϬͿ Ϯ;ϯͿ Non-compliance ϭ;ϭͿ WĂƟĞŶƚƐǁŝƐŚ ϭ;ϭͿ Other ϲ;ϵͿ Unknown ϴ;ϭϮͿ Table 3. H*)5VORSHVEHIRUHDQGDIWHUGLVFRQWLQXDWLRQ'DWDDUHPHDQ&,H*)5VORSH POPLQP2_SHU\HDU

WŽƉƵůĂƟŽŶ Number eGFR slope before _{ĚŝƐĐŽŶƟŶƵĂƟŽŶ} Ğ'&ZƐůŽƉĞĂŌĞƌ_{ĚŝƐĐŽŶƟŶƵĂƟŽŶ P-value}

dŽƚĂůƐƚƵĚLJƉŽƉƵůĂƟŽŶ 69 Ͳϭ͘ϱ;ͲϮ͘ϰ͕ͲϬ͘ϲͿ Ͳϯ͘ϵ;Ͳϱ͘ϭ͕ͲϮ͘ϲͿ 0.005 ^ƚƵĚLJƉŽƉƵůĂƟŽŶǁŝƚŚŬŶŽǁŶ ƌĞĂƐŽŶŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶ 61 Ͳϭ͘ϲ;ͲϮ͘ϱ͕ͲϬ͘ϳͿ Ͳϰ͘Ϭ;Ͳϱ͘Ϯ͕ͲϮ͘ϳͿ 0.006 ZĞĂƐŽŶƐŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶ͗ Ͳ/ŶĐƌĞĂƐĞŝŶƐĞƌƵŵĐƌĞĂƟŶŝŶĞ - Hyperkalemia Ͳ^LJŵƉƚŽŵĂƟĐŚLJƉŽƚĞŶƐŝŽŶ 23 16 12 ͲϮ͘ϯ;Ͳϯ͘Ϭ͕Ͳϭ͘ϱͿ Ͳϭ͘ϯ;ͲϮ͘ϱ͕ͲϬ͘ϬͿ Ͳϭ͘ϱ;Ͳϰ͘ϵ͕ϭ͘ϴͿ Ͳϯ͘ϲ;Ͳϱ͘Ϯ͕ͲϮ͘ϬͿ Ͳϯ͘ϴ;Ͳϲ͘ϰ͕Ͳϭ͘ϮͿ Ͳϲ͘ϴ;Ͳϭϭ͘ϵ͕Ͳϭ͘ϴͿ 0.176 0.116 0.109 Table 4.&R[SURSRUWLRQDOKD]DUGVPRGHOLQGLVFRQWLQXDWLRQSRSXODWLRQ Variable ,ĂnjĂƌĚƌĂƟŽ ϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů P-value

Systolic blood pressure change, mmHg 0.99 Ϭ͘ϵϱʹϭ͘Ϭϰ 0.755

Log-transformed albuminuria change 2.15 ϭ͘ϭϬʹϰ͘ϮϮ 0.025

&ĞŵĂůĞ͕Ŷ 1.00 Ϭ͘ϰϭʹϮ͘ϰϬ 0.996

Age, years 0.92 Ϭ͘ϳϲʹϭ͘Ϭϴ 0.268

Ğ'&Z͕ŵůͬŵŝŶͬϭ͘ϳϯŵ2† _{0.92 Ϭ͘ϴϲʹϬ͘ϵϴ 0.009}

Albuminuria, 100 mg/g† _{1.11 ϭ͘Ϭϰʹϭ͘ϭϴ 0.001}

Systolic blood pressure, mmHg† _{1.00 Ϭ͘ϵϳʹϭ͘Ϭϱ 0.625}

†measurement at last visit before discontinuation

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: 96PDF page: 96PDF page: 96PDF page: 96

96

Discussion

dŚŝƐƉƌŽƐƉĞĐƟǀĞƐƚƵĚLJĂŝŵĞĚƚŽĂƐƐĞƐƐƚŚĞŝŵƉĂĐƚŽĨZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŽŶƌĞŶĂů ĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘dŽŽƵƌŬŶŽǁůĞĚŐĞŶŽƉƵďůŝƐŚĞĚƐƚƵĚŝĞƐŚĂǀĞ ĞdžƉůŽƌĞĚƚŚĞĐĂƵƐĞƐĂŶĚĐŽŶƐĞƋƵĞŶĐĞƐŽĨZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŝŶĐŚŝůĚƌĞŶŝŶĂĐůŝŶŝĐĂů ƉƌĂĐƟĐĞƐĞƫŶŐ͘/ŶĂĚĚŝƟŽŶƚŽĚĞƐĐƌŝďŝŶŐƚŚĞƐŚŽƌƚͲƚĞƌŵĞīĞĐƚƐŽĨZ^ŝǁŝƚŚĚƌĂǁĂů͕ ŽƵƌƐƚƵĚLJƉƌŽǀŝĚĞƐĞǀŝĚĞŶĐĞĨŽƌĂŶĂĚǀĞƌƐĞŝŵƉĂĐƚŽĨZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŽŶƚŚĞ ƉƌĞƐĞƌǀĂƟŽŶŽĨƌĞŶĂůĨƵŶĐƟŽŶŝŶĐŚŝůĚƌĞŶǁŝƚŚ<͘ ůŽŽĚƉƌĞƐƐƵƌĞĂŶĚĂůďƵŵŝŶƵƌŝĂ͕ƚŚĞǁĞůůͲĞƐƚĂďůŝƐŚĞĚƌĞŶĂů;ĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌͿƌŝƐŬ ŵĂƌŬĞƌƐŝŵƉĂĐƚĞĚƵƉŽŶďLJZ^ŝŶŚŝďŝƟŽŶ͕ŝŶĐƌĞĂƐĞĚĂŌĞƌƐƚŽƉƉŝŶŐZ^ŝ͘dŚĞƌŝƐĞŝŶ ĂůďƵŵŝŶƵƌŝĂďLJϭϭϱйǁĂƐŚŝŐŚůLJƐŝŐŶŝĮĐĂŶƚĂŶĚǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚƉƌŽŐƌĞƐƐŝŽŶƚŽƚŚĞ ĐŽŵƉŽƐŝƚĞƌĞŶĂůĞŶĚƉŽŝŶƚ͘KƵƌƌĞƐƵůƚƐĐŽŶƚƌĂƐƚĂŶĂĚƵůƚƐƚƵĚLJƚŚĂƚƌĞƉŽƌƚĞĚŶŽĞīĞĐƚŽĨ Z^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶŽŶƉƌŽƚĞŝŶƵƌŝĂ͘7_{dŚĞƐƵďƐƚĂŶƟĂůŝŶĐƌĞĂƐĞŝŶĂůďƵŵŝŶƵƌŝĂŽďƐĞƌǀĞĚ} ĂŌĞƌZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶƐƵŐŐĞƐƚƐĂƐƚƌŽŶŐĂŶĚƉĞƌƐŝƐƚĞŶƚĂůďƵŵŝŶƵƌŝĂůŽǁĞƌŝŶŐĞīĞĐƚ ƵƉŽŶZ^ŝŝŶŝƟĂƟŽŶŝŶƚŚŝƐƉĞĚŝĂƚƌŝĐĂĚǀĂŶĐĞĚ<ƉŽƉƵůĂƟŽŶ͘dŚŝƐŶŽƟŽŶŝƐƐƵƉƉŽƌƚĞĚ ďLJĚĂƚĂĨƌŽŵƚŚĞ^WƚƌŝĂůĚĞŵŽŶƐƚƌĂƟŶŐĂϱϬйƌĞĚƵĐƟŽŶŝŶƉƌŽƚĞŝŶƵƌŝĂĂŌĞƌƐƚĂƌƚŽĨ ĂŶŝŶŚŝďŝƚŽƌŝŶĂƉĞĚŝĂƚƌŝĐ<ƉŽƉƵůĂƟŽŶ͕ǁŝƚŚĂŶĞǀĞŶŵŽƌĞƉƌŽĨŽƵŶĚĂůďƵŵŝŶƵƌŝĂ ƌĞĚƵĐƟŽŶŽďƐĞƌǀĞĚŝŶĐŚŝůĚƌĞŶǁŝƚŚŵŽƌĞĂĚǀĂŶĐĞĚ<ƐƚĂŐĞƐ͘17_{dŚƵƐ͕ƚŚĞƐƚƌŽŶŐĞƌ} ĞīĞĐƚŽĨZ^ŝŝŶŚŝŐŚĞƌ<ƐƚĂŐĞƐŵŝŐŚƚĞdžƉůĂŝŶƚŚĞůĂƌŐĞŝŶĐƌĞĂƐĞŝŶĂůďƵŵŝŶƵƌŝĂĂŌĞƌ ĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨƚŚĞĚƌƵŐŝŶƚŚŝƐƐƚƵĚLJ͘ dŚĞďůŽŽĚƉƌĞƐƐƵƌĞƌŝƐĞŽĨĂƉƉƌŽdžŝŵĂƚĞůLJϯŵŵ,ŐǁĂƐŵŽĚĞƐƚ͖ŚŽǁĞǀĞƌŝƚŵƵƐƚ ďĞƚĂŬĞŶŝŶƚŽĂĐĐŽƵŶƚƚŚĂƚZ^ŝǁĂƐŝŵŵĞĚŝĂƚĞůLJƌĞƉůĂĐĞĚďLJŽƚŚĞƌĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞ ŵĞĚŝĐĂƟŽŶƐŝŶĂƐƵďƐĞƚŽĨƚŚĞĐŚŝůĚƌĞŶ͘/ŶĐŽŵƉĂƌŝƐŽŶ͕ŝŶĂĚƵůƚ<ƉĂƟĞŶƚƐĂƐŝŐŶŝĮĐĂŶƚ ŝŶĐƌĞĂƐĞŝŶŵĞĂŶĂƌƚĞƌŝĂůƉƌĞƐƐƵƌĞŽĨϰŵŵ,ŐϭϮŵŽŶƚŚƐĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝ ŚĂƐ ďĞĞŶ ƌĞƉŽƌƚĞĚ͘7_{ EŽƚĂďůLJ͕ ƚŚĞ ŽďƐĞƌǀĞĚ ďůŽŽĚ ƉƌĞƐƐƵƌĞ ŝŶĐƌĞĂƐĞ ǁĂƐ ŽĨ ƐŝŵŝůĂƌ} ŵĂŐŶŝƚƵĚĞĂƐĂĐŚŝĞǀĞĚďLJŝŶƚĞŶƐŝĮĞĚǀƐ͘ĐŽŶǀĞŶƟŽŶĂůĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞŵĂŶĂŐĞŵĞŶƚŝŶ ƚŚĞ^WƚƌŝĂů͕ǁŚĞƌĞƉĂƟĞŶƚƐŝŶƚŚĞŚŝŐŚĞƌďůŽŽĚƉƌĞƐƐƵƌĞĂƌŵƐŚŽǁĞĚƐŝŐŶŝĮĐĂŶƚůLJ ĨĂƐƚĞƌůŽŶŐͲƚĞƌŵ<ƉƌŽŐƌĞƐƐŝŽŶ͘17_{,ŽǁĞǀĞƌ͕ĂĐĐŽƌĚŝŶŐƚŽŵƵůƟǀĂƌŝĂƚĞŽdžƌĞŐƌĞƐƐŝŽŶ} ĂŶĂůLJƐŝƐƚŚĞƌŝƐŬŽĨ<ƉƌŽŐƌĞƐƐŝŽŶŽĨƚŚĞƉĂƟĞŶƚƐŝŶŽƵƌƐƚƵĚLJǁĂƐƉƌĞĚŽŵŝŶĂŶƚůLJ ĂƐƐŽĐŝĂƚĞĚǁŝƚŚƌĞďŽƵŶĚĂůďƵŵŝŶƵƌŝĂƌĂƚŚĞƌǁŝƚŚƚŚĞŝŶĐƌĞĂƐĞŝŶďůŽŽĚƉƌĞƐƐƵƌĞĨŽůůŽǁŝŶŐ Z^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶ͘ ĂƌůŝĞƌƐƚƵĚŝĞƐŚĂǀĞĚĞƐĐƌŝďĞĚƚŚĂƚĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŶ ŝŶĐƌĞĂƐĞŝŶĞ'&Z͘7,8_{dŚŝƐŝƐĂƌĞĂƐŽŶĨŽƌĐůŝŶŝĐŝĂŶƐƚŽƐƚŽƉZ^ŝǁŝƚŚƚŚĞŝŶƚĞŶƚƚŽĚĞůĂLJ} ƚŚĞƐƚĂƌƚŽĨĚŝĂůLJƐŝƐ͘7_{tŚŝůĞĂŶĞĂƌůLJŝŶĐƌĞĂƐĞŝŶĞ'&ZǁĂƐŶŽƚŽďƐĞƌǀĞĚŝŶŽƵƌƐƚƵĚLJ͕ƚŚĞ} ƟŵĞŝŶƚĞƌǀĂůďĞƚǁĞĞŶĞ'&ZŵĞĂƐƵƌĞŵĞŶƚƐŵĂLJŚĂǀĞďĞĞŶƚŽŽůŽŶŐ͕ĂŶĚĂŶLJƚƌĂŶƐŝĞŶƚ ƌŝƐĞŵĂLJŚĂǀĞďĞĞŶŵĂƐŬĞĚďLJƚŚĞƉƌŽŐƌĞƐƐŝǀĞůŽƐƐŽĨƌĞŶĂůĨƵŶĐƟŽŶ͘dŚĞĂĐĐĞůĞƌĂƟŽŶŽĨ ůŽŶŐƚĞƌŵƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶŝƐŝŶĐŽŶƚƌĂƐƚƚŽĮŶĚŝŶŐƐŽĨĂƉƌĞǀŝŽƵƐƐƚƵĚLJŝŶĂĚƵůƚ ƉĂƟĞŶƚƐ͕ǁŚĞƌĞĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝǁĂƐĨŽůůŽǁĞĚďLJŝŵƉƌŽǀĞŵĞŶƚŽĨƌĞŶĂůĨƵŶĐƟŽŶ ĚĞĐůŝŶĞ͘7_{dŚĞĚŝīĞƌĞŶĐĞƐďĞƚǁĞĞŶŽƵƌƌĞƐƵůƚƐĂŶĚƚŚĞĞĂƌůŝĞƌĮŶĚŝŶŐƐŵĂLJďĞƌĞůĂƚĞĚƚŽ} ĚŝīĞƌĞŶĐĞƐŝŶĞ'&Z͕ƉƌŽƚĞŝŶƵƌŝĂĂŶĚďůŽŽĚƉƌĞƐƐƵƌĞĂƚƟŵĞŽĨZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶ ĂŶĚͬŽƌŝŶƚŚĞƵŶĚĞƌůLJŝŶŐĚŝƐĞĂƐĞƐƉĞĐƚƌƵŵ͘

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: 97PDF page: 97PDF page: 97PDF page: 97

97 &ŽƌƚLJͲƚǁŽƉĞƌĐĞŶƚŽĨƚŚĞĐŚŝůĚƌĞŶƉĂƌƟĐŝƉĂƟŶŐŝŶƚŚĞϰƐƚƵĚLJƵƐĞĚZ^ŝĂƚŝŶĐůƵƐŝŽŶ ŝŶƚŚĞƐƚƵĚLJ͕ĂƐůŝŐŚƚůLJůŽǁĞƌƉƌĞǀĂůĞŶĐĞĂƐĐŽŵƉĂƌĞĚƚŽƚŚĞEŽƌƚŚŵĞƌŝĐĂŶŚƌŽŶŝĐ <ŝĚŶĞLJŝƐĞĂƐĞŝŶŚŝůĚƌĞŶ;</ͿĐŽŚŽƌƚǁŚĞƌĞϱϱйŽĨϴϱϭĐŚŝůĚƌĞŶƵƐĞĚZ^ŝĂƚƟŵĞ ŽĨĞŶƌŽůŵĞŶƚ͘18,19_{dƌĞĂƚŵĞŶƚǁŝƚŚZ^ŝŝƐƌĞĐŽŵŵĞŶĚĞĚŝŶĂůůĐŚŝůĚƌĞŶǁŝƚŚ<ĂŶĚ} ĞŝƚŚĞƌĂĐŽŶƐŝƐƚĞŶƚůLJĞůĞǀĂƚĞĚďůŽŽĚƉƌĞƐƐƵƌĞ;хϵϬth_{ƉĞƌĐĞŶƟůĞĨŽƌĂŐĞ͕ƐĞdžĂŶĚŚĞŝŐŚƚͿŽƌ} ŵĂĐƌŽĂůďƵŵŝŶƵƌŝĂ͘20_{dŚĞƐĞĐƌŝƚĞƌŝĂǁĞƌĞŵĞƚŝŶϲϳйŽĨƚŚĞĐŚŝůĚƌĞŶ͕ŝŶĚŝĐĂƟŶŐƐŝŐŶŝĮĐĂŶƚ} ƵŶĚĞƌƉƌĞƐĐƌŝƉƟŽŶŽĨZ^ŝŝŶƵƌŽƉĞĂŶĐŚŝůĚƌĞŶǁŝƚŚ<͘ dŚĞŵĂũŽƌůŝŵŝƚĂƟŽŶŽĨŽƵƌƐƚƵĚLJǁĂƐŝƚƐŽďƐĞƌǀĂƟŽŶĂůĚĞƐŝŐŶ͕ǁŝƚŚƉŽƚĞŶƟĂůďŝĂƐďLJ ŝŶĚŝĐĂƟŽŶƚŚĂƚǁŽƵůĚŶŽƚŚĂǀĞďĞĞŶƉƌĞƐĞŶƚŝŶĂƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůůĞĚƚƌŝĂů͘,ŽǁĞǀĞƌ͕ ƌĂŶĚŽŵĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨŶĞƉŚƌŽƉƌŽƚĞĐƟǀĞZ^ŝŶŚŝďŝƟŽŶŝŶĂĐŽŶƚƌŽůůĞĚƚƌŝĂůǁŽƵůĚ ŶŽƚŚĂǀĞďĞĞŶĞƚŚŝĐĂůůLJũƵƐƟĮĞĚ͘DŽƌĞŽǀĞƌ͕ĞdžƚĞŶĚĞĚůŽŶŐŝƚƵĚŝŶĂůĞ'&ZĚĂƚĂďĞĨŽƌĞ ĂŶĚĂŌĞƌZ^ŝĚŝƐĐŽŶƟŶƵĂƟŽŶǁĞƌĞĂŶĂůLJnjĞĚ͕ƵƐŝŶŐƚŚĞƉĂƟĞŶƚƐĂƐƚŚĞŝƌŽǁŶĐŽŶƚƌŽůƐ͘ ŶŽƚŚĞƌĂĚǀĂŶƚĂŐĞŽĨƚŚĞŽďƐĞƌǀĂƟŽŶĂůƐƚƵĚLJĚĞƐŝŐŶŽĨƚŚĞϰƐƚƵĚLJǁĂƐƚŚĞƉŽƐƐŝďŝůŝƚLJ ƚŽĂƐƐĞƐƐƚŚĞĨƌĞƋƵĞŶĐLJĂŶĚƌĞĂƐŽŶƐŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶ͘ /ŶĐŽŶĐůƵƐŝŽŶ͕ŝŶƚŚŝƐƐƚƵĚLJǁĞĂƐƐĞƐƐĞĚƚŚĞĨƌĞƋƵĞŶĐLJĂŶĚƌĞĂƐŽŶƐĂƐǁĞůůĂƐƚŚĞ ŝŵƉĂĐƚŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŽŶĞ'&ZĚĞĐůŝŶĞŝŶĂŶŽďƐĞƌǀĂƟŽŶĂůĐŽŚŽƌƚŽĨĐŚŝůĚƌĞŶ ǁŝƚŚ<͘ŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŝŶĐŚŝůĚƌĞŶǁŝƚŚ<ŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŶĂĐĐĞůĞƌĂƟŽŶ ŽĨƌĞŶĂůĨƵŶĐƟŽŶĚĞĐůŝŶĞ͘dŚĞƐĞƌĞƐƵůƚƐŝŶĚŝĐĂƚĞƚŚĂƚŝŶŚŝďŝƚŽƌŽƌZƚŚĞƌĂƉLJŝƐ ŝŵƉŽƌƚĂŶƚĨŽƌƌĞŶĂůƉƌŽƚĞĐƟŽŶĂŶĚƚŚĂƚƐƚŽƉƉŝŶŐƚŚŝƐƚŚĞƌĂƉLJĞǀĞŶĨŽƌŐŽŽĚĐůŝŶŝĐĂů ƌĞĂƐŽŶƐĂŶĚĞǀĞŶŝŶĂĚǀĂŶĐĞĚ<ƐŚŽƵůĚďĞǁĞŝŐŚĞĚĂŐĂŝŶƐƚƚŚĞŶĞŐĂƟǀĞŝŵƉĂĐƚŽŶ ůŽŶŐƚĞƌŵƌĞŶĂůĨƵŶĐƟŽŶ͘

Acknowledgements and disclosures

^ƵƉƉŽƌƚĨŽƌƚŚĞϰ^ƚƵĚLJǁĂƐƌĞĐĞŝǀĞĚĨƌŽŵƚŚĞZͲdZĞƐĞĂƌĐŚWƌŽŐƌĂŵŵĞ͕ƚŚĞ <Ĩ,&ŽƵŶĚĂƟŽŶĨŽƌWƌĞǀĞŶƟǀĞDĞĚŝĐŝŶĞĂŶĚƚŚĞ'ĞƌŵĂŶ&ĞĚĞƌĂůDŝŶŝƐƚƌLJŽĨĚƵĐĂƟŽŶ ĂŶĚZĞƐĞĂƌĐŚ;ƌĞĨĞƌĞŶĐĞŶƵŵďĞƌ͗ϬϭKϬϴϬϮͿ͘dŚĞĂƵƚŚŽƌƐƌĞƉŽƌƚŶŽĐŽŶŇŝĐƚŽĨŝŶƚĞƌĞƐƚ͘

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: 98PDF page: 98PDF page: 98PDF page: 98

98

References

ϭ͘ 'ĂƌĂďĞĚ͕>ĂŵĞŝƌĞE͘</'KϮϬϭϮĐůŝŶŝĐĂů ƉƌĂĐƟĐĞŐƵŝĚĞůŝŶĞĨŽƌƚŚĞĞǀĂůƵĂƟŽŶĂŶĚ ŵĂŶĂŐĞŵĞŶƚŽĨĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͘͘ ϮϬϭϮ͘ Ϯ͘ DĂŶŶ :&͕ ^ĐŚŵŝĞĚĞƌ Z͕ LJĂů >͕ Ğƚ Ăů͘ īĞĐƚ ŽĨ ƚĞůŵŝƐĂƌƚĂŶ ŽŶ ƌĞŶĂů ŽƵƚĐŽŵĞƐ͗  ƌĂŶĚŽŵŝnjĞĚ ƚƌŝĂů͘ ŶŶ /ŶƚĞƌŶ DĞĚ͘ ϮϬϬϵ͖ϭϱϭ;ϭͿ͗ϭͲϭϬ͕tϭͲϮ͘ ϯ͘ DĂŬŝŶŽ ,͕ ,ĂŶĞĚĂ D͕ ĂďĂnjŽŶŽ d͕ Ğƚ Ăů͘ Prevention of transition from incipient ƚŽŽǀĞƌƚŶĞƉŚƌŽƉĂƚŚLJǁŝƚŚƚĞůŵŝƐĂƌƚĂŶŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ƚLJƉĞ Ϯ ĚŝĂďĞƚĞƐ͘ ŝĂďĞƚĞƐ ĂƌĞ͘ϮϬϬϳ͖ϯϬ;ϲͿ͗ϭϱϳϳͲϭϱϳϴ͘ ϰ͘ ,ŽƵ&&͕ŚĂŶŐy͕ŚĂŶŐ',͕ĞƚĂů͘ĸĐĂĐLJ ĂŶĚ ƐĂĨĞƚLJ ŽĨ ďĞŶĂnjĞƉƌŝů ĨŽƌ ĂĚǀĂŶĐĞĚ ĐŚƌŽŶŝĐƌĞŶĂůŝŶƐƵĸĐŝĞŶĐLJ͘EŶŐů:DĞĚ͘ ϮϬϬϲ͖ϯϱϰ;ϮͿ͗ϭϯϭͲϭϰϬ͘ ϱ͘ ƌĞŶŶĞƌ D͕ ŽŽƉĞƌ D͕ ĚĞ ĞĞƵǁ ͕ Ğƚ Ăů͘ ĨĨĞĐƚƐ ŽĨ ůŽƐĂƌƚĂŶ ŽŶ ƌĞŶĂů ĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞƐŝŶƉĂƟĞŶƚƐǁŝƚŚ ƚLJƉĞϮĚŝĂďĞƚĞƐĂŶĚŶĞƉŚƌŽƉĂƚŚLJ͘EŶŐů: DĞĚ͘ϮϬϬϭ͖ϯϰϱ;ϭϮͿ͗ϴϲϭͲϴϲϵ͘ ϲ͘ >ĞǁŝƐ:͕,ƵŶƐŝĐŬĞƌ>'͕ůĂƌŬĞtZ͕ĞƚĂů͘ ZĞŶŽƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨƚŚĞĂŶŐŝŽƚĞŶƐŝŶͲ ƌĞĐĞƉƚŽƌĂŶƚĂŐŽŶŝƐƚŝƌďĞƐĂƌƚĂŶŝŶƉĂƟĞŶƚƐ ǁŝƚŚŶĞƉŚƌŽƉĂƚŚLJĚƵĞƚŽƚLJƉĞϮĚŝĂďĞƚĞƐ͘ EŶŐů:DĞĚ͘ϮϬϬϭ͖ϯϰϱ;ϭϮͿ͗ϴϱϭͲϴϲϬ͘ ϳ͘ ŚŵĞĚ<͕<ĂŵĂƚŚE^͕ů<ŽƐƐŝD͕ůEĂŚĂƐ D͘dŚĞŝŵƉĂĐƚŽĨƐƚŽƉƉŝŶŐŝŶŚŝďŝƚŽƌƐŽĨƚŚĞ ƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐLJƐƚĞŵŝŶƉĂƟĞŶƚƐǁŝƚŚ ĂĚǀĂŶĐĞĚĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͘EĞƉŚƌŽů ŝĂůdƌĂŶƐƉůĂŶƚ͘ϮϬϭϬ͖Ϯϱ;ϭϮͿ͗ϯϵϳϳͲϯϵϴϮ͘ ϴ͘ ,ĂŶƐĞŶ ,W͕ ZŽƐƐŝŶŐ W͕ dĂƌŶŽǁ >͕ EŝĞůƐĞŶ &^͕ :ĞŶƐĞŶ Z͕ WĂƌǀŝŶŐ ,,͘ /ŶĐƌĞĂƐĞĚ ŐůŽŵĞƌƵůĂƌĮůƚƌĂƟŽŶƌĂƚĞĂŌĞƌǁŝƚŚĚƌĂǁĂů ŽĨ ůŽŶŐͲƚĞƌŵ ĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞ ƚƌĞĂƚŵĞŶƚ ŝŶ ĚŝĂďĞƚŝĐ ŶĞƉŚƌŽƉĂƚŚLJ͘ <ŝĚŶĞLJ /Ŷƚ͘ ϭϵϵϱ͖ϰϳ;ϲͿ͗ϭϳϮϲͲϭϳϯϭ͘ ϵ͘ ŚĂŶĚĂƌŝ ^͕ /ǀĞƐ E͕ ƌĞƚƚĞůů ͕ Ğƚ Ăů͘ DƵůƟĐĞŶƚƌĞƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůůĞĚƚƌŝĂůŽĨ ĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐĞŶnjLJŵĞŝŶŚŝďŝƚŽƌͬ ĂŶŐŝŽƚĞŶƐŝŶƌĞĐĞƉƚŽƌďůŽĐŬĞƌǁŝƚŚĚƌĂǁĂůŝŶ ĂĚǀĂŶĐĞĚƌĞŶĂůĚŝƐĞĂƐĞ͗dŚĞ^dKWͲŝƚƌŝĂů͘ EĞƉŚƌŽů ŝĂů dƌĂŶƐƉůĂŶƚ͘ ϮϬϭϲ͖ϯϭ;ϮͿ͗ϮϱϱͲ Ϯϲϭ͘ ϭϬ͘ YƵĞƌĨĞůĚ h͕ ŶĂƌĂƚ ͕ ĂLJĂnjŝƚ <͕ Ğƚ Ăů͘ dŚĞĐĂƌĚŝŽǀĂƐĐƵůĂƌĐŽŵŽƌďŝĚŝƚLJŝŶĐŚŝůĚƌĞŶ ǁŝƚŚ ĐŚƌŽŶŝĐ ŬŝĚŶĞLJ ĚŝƐĞĂƐĞ ;ϰͿ ƐƚƵĚLJ͗ KďũĞĐƟǀĞƐ͕ĚĞƐŝŐŶ͕ĂŶĚŵĞƚŚŽĚŽůŽŐLJ͘ůŝŶ :ŵ^ŽĐEĞƉŚƌŽů͘ϮϬϭϬ͖ϱ;ϵͿ͗ϭϲϰϮͲϭϲϰϴ͘ ϭϭ͘ ^ĐŚǁĂƌƚnj ':͕ DƵŶŽnj ͕ ^ĐŚŶĞŝĚĞƌ D&͕ Ğƚ Ăů͘ EĞǁ ĞƋƵĂƚŝŽŶƐ ƚŽ ĞƐƚŝŵĂƚĞ '&Z ŝŶ ĐŚŝůĚƌĞŶ ǁŝƚŚ <͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϬϵ͖ϮϬ;ϯͿ͗ϲϮϵͲϲϯϳ͘ ϭϮ͘ EĂƟŽŶĂů ,ŝŐŚ ůŽŽĚ WƌĞƐƐƵƌĞ ĚƵĐĂƟŽŶ WƌŽŐƌĂŵ tŽƌŬŝŶŐ 'ƌŽƵƉ ŽŶ ,ŝŐŚ ůŽŽĚ WƌĞƐƐƵƌĞŝŶŚŝůĚƌĞŶĂŶĚĚŽůĞƐĐĞŶƚƐ͘dŚĞ ĨŽƵƌƚŚƌĞƉŽƌƚŽŶƚŚĞĚŝĂŐŶŽƐŝƐ͕ĞǀĂůƵĂƟŽŶ͕ ĂŶĚ ƚƌĞĂƚŵĞŶƚ ŽĨ ŚŝŐŚ ďůŽŽĚ ƉƌĞƐƐƵƌĞ ŝŶ ĐŚŝůĚƌĞŶ ĂŶĚ ĂĚŽůĞƐĐĞŶƚƐ͘ WĞĚŝĂƚƌŝĐƐ͘ ϮϬϬϰ͖ϭϭϰ;Ϯ^ƵƉƉůϰƚŚZĞƉŽƌƚͿ͗ϱϱϱͲϱϳϲ͘ ϭϯ͘ ĂƐĂƐ:W͕ŚƵĂt͕>ŽƵŬŽŐĞŽƌŐĂŬŝƐ^͕ĞƚĂů͘ īĞĐƚŽĨŝŶŚŝďŝƚŽƌƐŽĨƚŚĞƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶ ƐLJƐƚĞŵ ĂŶĚ ŽƚŚĞƌ ĂŶƚŝŚLJƉĞƌƚĞŶƐŝǀĞ ĚƌƵŐƐ ŽŶ ƌĞŶĂů ŽƵƚĐŽŵĞƐ͗ ^LJƐƚĞŵĂƚŝĐ ƌĞǀŝĞǁ ĂŶĚ ŵĞƚĂͲĂŶĂůLJƐŝƐ͘ >ĂŶĐĞƚ͘ ϮϬϬϱ͖ϯϲϲ;ϵϱϬϮͿ͗ϮϬϮϲͲϮϬϯϯ͘ ϭϰ͘ ĚĞĞĞƵǁ͕ZĞŵƵnjnjŝ'͕WĂƌǀŝŶŐ,,͕ĞƚĂů͘ WƌŽƚĞŝŶƵƌŝĂ͕ĂƚĂƌŐĞƚĨŽƌƌĞŶŽƉƌŽƚĞĐƟŽŶŝŶ ƉĂƟĞŶƚƐǁŝƚŚƚLJƉĞϮĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͗ >ĞƐƐŽŶƐ ĨƌŽŵ ZE>͘ <ŝĚŶĞLJ /Ŷƚ͘ ϮϬϬϰ͖ϲϱ;ϲͿ͗ϮϯϬϵͲϮϯϮϬ͘ ϭϱ͘ >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

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: 99PDF page: 99PDF page: 99PDF page: 99

99 ϭϲ͘ ŝũŬĞůŬĂŵƉt͕ŚĂŶŐ͕ZĞŵƵnjnjŝ'͕ĞƚĂů͘ ůďƵŵŝŶƵƌŝĂŝƐĂƚĂƌŐĞƚĨŽƌƌĞŶŽƉƌŽƚĞĐƟǀĞ ƚŚĞƌĂƉLJŝŶĚĞƉĞŶĚĞŶƚĨƌŽŵďůŽŽĚƉƌĞƐƐƵƌĞŝŶ ƉĂƟĞŶƚƐǁŝƚŚƚLJƉĞϮĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͗ WŽƐƚ ŚŽĐ ĂŶĂůLJƐŝƐ ĨƌŽŵ ƚŚĞ ƌĞĚƵĐƟŽŶ ŽĨ ĞŶĚƉŽŝŶƚƐŝŶE/DǁŝƚŚƚŚĞĂŶŐŝŽƚĞŶƐŝŶ //ĂŶƚĂŐŽŶŝƐƚůŽƐĂƌƚĂŶ;ZE>ͿƚƌŝĂů͘:ŵ ^ŽĐEĞƉŚƌŽů͘ϮϬϬϳ͖ϭϴ;ϱͿ͗ϭϱϰϬͲϭϱϰϲ͘ ϭϳ͘ ^W dƌŝĂů 'ƌŽƵƉ͕ tƵŚů ͕ dƌŝǀĞůůŝ ͕ Ğƚ Ăů͘ ^ƚƌŝĐƚ ďůŽŽĚͲƉƌĞƐƐƵƌĞ ĐŽŶƚƌŽů ĂŶĚ ƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨĂŝůƵƌĞŝŶĐŚŝůĚƌĞŶ͘E ŶŐů:DĞĚ͘ϮϬϬϵ͖ϯϲϭ;ϭϳͿ͗ϭϲϯϵͲϭϲϱϬ͘ ϭϴ͘ ďƌĂŚĂŵ'͕ĞƚŽŬŽ͕&ĂĚƌŽǁƐŬŝ::͕ĞƚĂů͘ ZĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶ //ͲĂůĚŽƐƚĞƌŽŶĞ ƐLJƐƚĞŵ ďůŽĐŬĞƌƐ ĂŶĚ ƟŵĞ ƚŽ ƌĞŶĂů ƌĞƉůĂĐĞŵĞŶƚ ƚŚĞƌĂƉLJ ŝŶ ĐŚŝůĚƌĞŶ ǁŝƚŚ <͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ϮϬϭϳ͖ϯϮ;ϰͿ͗ϲϰϯͲϲϰϵ͘ ϭϵ͘ ^ĐŚĂĞĨĞƌ &͕ ŽLJŽŶ ͕ njƵŬĂŝƟƐ <͕ Ğƚ Ăů͘ ĂƌĚŝŽǀĂƐĐƵůĂƌƉŚĞŶŽƚLJƉĞƐŝŶĐŚŝůĚƌĞŶǁŝƚŚ <͗dŚĞϰƐƚƵĚLJ͘ůŝŶ:ŵ^ŽĐEĞƉŚƌŽů͘ ϮϬϭϳ͖ϭϮ;ϭͿ͗ϭϵͲϮϴ͘ ϮϬ͘ </'KϮϬϭϮĐůŝŶŝĐĂůƉƌĂĐƟĐĞŐƵŝĚĞůŝŶĞĨŽƌ ƚŚĞĞǀĂůƵĂƟŽŶĂŶĚŵĂŶĂŐĞŵĞŶƚŽĨĐŚƌŽŶŝĐ ŬŝĚŶĞLJ ĚŝƐĞĂƐĞ͘ <ŝĚŶĞLJ /ŶƚĞƌŶĂƚŝŽŶĂů ^ƵƉƉůĞŵĞŶƚƐ͘ϮϬϭϯ͖ϯ;ϰͿ͘

6

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