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: 1PDF page: 1PDF page: 1PDF page: 1

About the prevalence, measurement and treatment of albuminuria in children

door

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: 2PDF page: 2PDF page: 2PDF page: 2 treatment of albuminuria in children

WŚĚŝƐƐĞƌƚĂƟŽŶ͕hŶŝǀĞƌƐŝƚLJŽĨ'ƌŽŶŝŶŐĞŶ͕ƚŚĞEĞƚŚĞƌůĂŶĚƐ &ŝŶĂŶĐŝĂůƐƵƉƉŽƌƚĨŽƌƚŚĞƉƵďůŝĐĂƟŽŶŽĨƚŚŝƐƚŚĞƐŝƐďLJƚŚĞhŶŝǀĞƌƐŝƚLJŽĨ'ƌŽŶŝŶŐĞŶ͕ hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕'ƌĂĚƵĂƚĞ^ĐŚŽŽůĨŽƌƌƵŐdžƉůŽƌĂƟŽŶ;'h/Ϳ͕ƚŚĞ ƵƚĐŚ<ŝĚŶĞLJ&ŽƵŶĚĂƟŽŶĂŶĚƵŝƚƐůĂŶĚ/ŶƐƟƚƵƵƚŵƐƚĞƌĚĂŵŝƐŐƌĂƚĞĨƵůůLJĂĐŬŶŽǁůĞĚŐĞĚ͘ ISBN ϵϳϴͲϵϰͲϬϯϰͲϬϲϰϲͲϲ;ƉƌŝŶƚĞĚǀĞƌƐŝŽŶͿ ϵϳϴͲϵϰͲϬϯϰͲϬϲϰϱͲϵ;ĚŝŐŝƚĂůǀĞƌƐŝŽŶͿ Cover design ƐƚŚĞƌ^ĐŚĞŝĚĞ͕ǁǁǁ͘ƉƌŽĞĨƐĐŚƌŝŌŽŵƐůĂŐ͘Ŷů Layout ŶŽƵŬtĞƐƚĞƌĚŝũŬ͕ƉĞƌƐŽŽŶůŝũŬƉƌŽĞĨƐĐŚƌŝŌ͘Ŷů Printed by /ƉƐŬĂŵƉƐƌƵŬŬĞƌƐ͕ŶƐĐŚĞĚĞ ΞϮϬϭϴ͕^͘D͘ǀĂŶĚĞŶĞůƚ͕'ƌŽŶŝŶŐĞŶ͕ƚŚĞEĞƚŚĞƌůĂŶĚƐ ůůƌŝŐŚƚƐƌĞƐĞƌǀĞĚ͘EŽƉĂƌƚŽĨƚŚŝƐƉƵďůŝĐĂƟŽŶŵĂLJďĞƌĞƉƌŽĚƵĐĞĚ͕ĐŽƉŝĞĚ͕ŵŽĚŝĮĞĚ͕ƐƚŽƌĞĚŝŶĂ ƌĞƚƌŝĞǀĂůƐLJƐƚĞŵ͕ŽƌƚƌĂŶƐŵŝƩĞĚŝŶĂŶLJĨŽƌŵǁŝƚŚŽƵƚƉĞƌŵŝƐƐŝŽŶŽĨƚŚĞĂƵƚŚŽƌ͘

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: 3PDF page: 3PDF page: 3PDF page: 3

About the prevalence, measurement and treatment of albuminuria in children

WƌŽĞĨƐĐŚƌŝŌ

ƚĞƌǀĞƌŬƌŝũŐŝŶŐǀĂŶĚĞŐƌĂĂĚǀĂŶĚŽĐƚŽƌĂĂŶĚĞ ZŝũŬƐƵŶŝǀĞƌƐŝƚĞŝƚ'ƌŽŶŝŶŐĞŶ ŽƉŐĞnjĂŐǀĂŶĚĞ ƌĞĐƚŽƌŵĂŐŶŝĮĐƵƐƉƌŽĨ͘Ěƌ͘͘^ƚĞƌŬĞŶ ĞŶǀŽůŐĞŶƐďĞƐůƵŝƚǀĂŶŚĞƚŽůůĞŐĞǀŽŽƌWƌŽŵŽƟĞƐ͘ ĞŽƉĞŶďĂƌĞǀĞƌĚĞĚŝŐŝŶŐnjĂůƉůĂĂƚƐǀŝŶĚĞŶŽƉ ĚŝŶƐĚĂŐϮϮŵĞŝϮϬϭϴŽŵϭϭ͘ϬϬƵƵƌ door

Sophie Mariëlle van den Belt

ŐĞďŽƌĞŶŽƉϭϱĂƵŐƵƐƚƵƐϭϵϵϬ ƚĞ'ƌŽŶŝŶŐĞŶ

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: 4PDF page: 4PDF page: 4PDF page: 4 WƌŽĨ͘Ěƌ͘,͘:͘>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ

Beoordelingscommissie

WƌŽĨ͘Ěƌ͘,͘:͘sĞƌŬĂĚĞ WƌŽĨ͘Ěƌ͘^͘W͘ĞƌŐĞƌ WƌŽĨ͘Ěƌ͘Z͘ŽǁĂƌĚ

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: 5PDF page: 5PDF page: 5PDF page: 5 ^ŝĞƚĂĚĞsƌŝĞƐ

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: 7PDF page: 7PDF page: 7PDF page: 7

ŚĂƉƚĞƌϭ /ŶƚƌŽĚƵĐƟŽŶĂŶĚŝŵƐŽĨdŚĞƐŝƐ 9

Part 1: The prevalence and measurement of albuminuria in children

ŚĂƉƚĞƌϮ WƌĞǀĂůĞŶĐĞĂŶĚĚŝƐƚƌŝďƵƟŽŶŽĨ;ŵŝĐƌŽͿĂůďƵŵŝŶƵƌŝĂŝŶ

toddlers 23

ŚĂƉƚĞƌϯ ŽŵƉĂƌŝƐŽŶŽĨƵƌŝŶĞĐŽůůĞĐƟŽŶŵĞƚŚŽĚƐĨŽƌ

albuminuria assessment in young children 39

ŚĂƉƚĞƌϰ How to measure and monitor albuminuria in healthy

toddlers 51

Part 2: The treatment of albuminuria in children

ŚĂƉƚĞƌϱ ĂƌůLJƉƌŽƚĞŝŶƵƌŝĂůŽǁĞƌŝŶŐďLJŝŶŚŝďŝƟŽŶƉƌĞĚŝĐƚƐ

renal survival in children with chronic kidney disease 65 ŚĂƉƚĞƌϲ ^ŚŽƵůĚZ^ŝŶŚŝďŝƟŽŶďĞĚŝƐĐŽŶƟŶƵĞĚŝŶĐŚŝůĚƌĞŶǁŝƚŚ

advanced chronic kidney disease? Results of the 4C study 87 ŚĂƉƚĞƌϳ ^ƵŵŵĂƌLJĂŶĚĨƵƚƵƌĞƉĞƌƐƉĞĐƟǀĞƐ 101 Appendices EĞĚĞƌůĂŶĚƐĞƐĂŵĞŶǀĂƫŶŐ Dankwoord

About the author

111 119 125

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: 9PDF page: 9PDF page: 9PDF page: 9

/ŶƚƌŽĚƵĐƟŽŶĂŶĚŝŵƐŽĨdŚĞƐŝƐ

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: 10PDF page: 10PDF page: 10PDF page: 10 10

Albuminuria, more than a marker of renal damage?

ůďƵŵŝŶƵƌŝĂŝƐƚŚĞĞdžĐƌĞƟŽŶŽĨƚŚĞƉůĂƐŵĂƉƌŽƚĞŝŶĂůďƵŵŝŶŝŶƵƌŝŶĞ͘hƌŝŶĂƌLJĂůďƵŵŝŶ ŝƐĂďƐĞŶƚŽƌůŽǁŝŶŚĞĂůƚŚLJĐŽŶĚŝƟŽŶƐ͘/ŶƚŚĞůĂƐƚĚĞĐĂĚĞƐ͕ůĂƌŐĞĐŽŚŽƌƚƐƚƵĚŝĞƐŚĂǀĞ ƐŚŽǁŶƚŚĂƚŵŝůĚůLJŝŶĐƌĞĂƐĞĚůĞǀĞůƐŽĨĂůďƵŵŝŶƵƌŝĂ;ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͖ƵƌŝŶĂƌLJĂůďƵŵŝŶ ĐŽŶĐĞŶƚƌĂƟŽŶхϮϬŵŐͬ>ŽƌϮϰͲŚƌĞdžĐƌĞƟŽŶхϯϬŵŐͿĂƌĞƉƌĞƐĞŶƚŝŶŚĞĂůƚŚLJƐƵďũĞĐƚƐ ;ϱͲϴйͿĂŶĚŚŝŐŚůLJƉƌĞǀĂůĞŶƚŝŶƉĂƟĞŶƚƐǁŝƚŚĚŝĂďĞƚĞƐ;ϭϴͲϯϵйͿĂŶĚŚLJƉĞƌƚĞŶƐŝŽŶ;ϭϭͲ ϮϯйͿ͘1-8 /ŶƚĞƌĞƐƚŝŶŐůLJ͕ ĂůďƵŵŝŶƵƌŝĂ ŚĂƐ ďĞĞŶ ƌĞƉŽƌƚĞĚ ĂƐ Ă ƌŝƐŬ ŵĂƌŬĞƌ ĨŽƌ ƌĞŶĂů ĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͗ƚŚĞŚŝŐŚĞƌƚŚĞĂůďƵŵŝŶŝŶƵƌŝŶĞ͕ƚŚĞŚŝŐŚĞƌƚŚĞƌŝƐŬĨŽƌƌĞŶĂůĂŶĚͬ ŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘9-15_{dŚŝƐŝŵŵĞĚŝĂƚĞůLJƌĂŝƐĞƐƚŚĞƋƵĞƐƟŽŶǁŚĞƚŚĞƌǁĞƐŚŽƵůĚ} ůŽǁĞƌĂůďƵŵŝŶƵƌŝĂƚŽƉƌĞƐĞƌǀĞĨƵŶĐƟŽŶŽĨƚŚĞƐĞŽƌŐĂŶƐ͘,ŽǁĞǀĞƌ͕ƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨ ĂůďƵŵŝŶƵƌŝĂĂƐĂƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚŝŶƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞŝƐƵŶĚĞƌĚŝƐĐƵƐƐŝŽŶ͘ /ŶŽƌĚĞƌƚŽĂĐĐĞƉƚĂďŝŽŵĂƌŬĞƌ͕ŝŶƚŚŝƐĐĂƐĞĂůďƵŵŝŶƵƌŝĂ͕ĂƐĂŶĂƉƉƌŽƉƌŝĂƚĞƚŚĞƌĂƉĞƵƟĐ ƚĂƌŐĞƚ͕ƚŚƌĞĞŝŵƉŽƌƚĂŶƚĐƌŝƚĞƌŝĂƐŚŽƵůĚďĞŵĞƚ͘16,17 _{First, evidence of a consistent and} ŝŶĚĞƉĞŶĚĞŶƚĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶůĞǀĞůƐŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚƌĞŶĂůͬĐĂƌĚŝŽǀĂƐĐƵůĂƌĞŶĚ ƉŽŝŶƚƐĚƵƌŝŶŐĨŽůůŽǁͲƵƉŵƵƐƚďĞĂǀĂŝůĂďůĞ͘^ĞĐŽŶĚ͕ĐůŝŶŝĐĂůƚƌŝĂůĞǀŝĚĞŶĐĞŶĞĞĚƐƚŽƐŚŽǁ ĂŶĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƚŚĞĞīĞĐƚƐŽĨĚŝīĞƌĞŶƚŝŶƚĞƌǀĞŶƟŽŶƐƚŚĂƚůŽǁĞƌĂůďƵŵŝŶƵƌŝĂ ĂŶĚƚŚĞƐƵďƐĞƋƵĞŶƚƌĞĚƵĐƟŽŶŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬ͘ŶĚƚŚŝƌĚ͕ĂďŝŽůŽŐŝĐĂů ŵĞĐŚĂŶŝƐŵƐŚŽƵůĚďĞĂǀĂŝůĂďůĞƚŽĞdžƉůĂŝŶŚŽǁĂůďƵŵŝŶƵƌŝĂĐĂƵƐĞƐƌĞŶĂůĚĂŵĂŐĞ͘ /ŶĚĞĞĚ͕ĐŽŚŽƌƚƐƚƵĚŝĞƐŚĂǀĞƐŚŽǁŶĂƐƚƌŽŶŐ͕ĐŽŶƐŝƐƚĞŶƚĂŶĚŝŶĚĞƉĞŶĚĞŶƚĂƐƐŽĐŝĂƟŽŶ ďĞƚǁĞĞŶƚŚĞĂŵŽƵŶƚŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚƌŝƐŬŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͕ďŽƚŚŝŶ ŚĞĂůƚŚLJƐƵďũĞĐƚƐĂŶĚŝŶƉĂƟĞŶƚƐǁŝƚŚĚŝĂďĞƚĞƐŽƌŚLJƉĞƌƚĞŶƐŝŽŶ͕ŵĞĞƟŶŐƚŚĞĮƌƐƚĐƌŝƚĞƌŝŽŶ ĨŽƌƚŚĞĂĐĐĞƉƚĂŶĐĞŽĨĂůďƵŵŝŶƵƌŝĂĂƐĂƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚ͘9-15_{DŽƌĞŽǀĞƌ͕ůŽǁĞƌŝŶŐŽĨ} ĂůďƵŵŝŶƵƌŝĂŚĂƐďĞĞŶƐŚŽǁŶƚŽƐůŽǁĚŽǁŶƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͘dŚŝƐŚĂƐďĞĞŶ ŝŶǀĞƐƟŐĂƚĞĚŝŶŵƵůƟƉůĞƉŽƐƚͲŚŽĐĂŶĂůLJƐĞƐ͕ĂŶĚĨŽƌĂůůƚŚĞƐĞƐƚƵĚŝĞƐƚŚĞƐĂŵĞƉĂƌĂĚŝŐŵ ŚŽůĚƐ͗ƚŚĞŐƌĞĂƚĞƌƚŚĞƌĞĚƵĐƟŽŶŝŶĂůďƵŵŝŶƵƌŝĂĚƵƌŝŶŐƚŚĞĮƌƐƚŵŽŶƚŚƐŽĨƚŚĞƌĂƉLJ͕ ƚŚĞůĂƌŐĞƌƚŚĞƌĞĚƵĐƟŽŶŽĨƌĞŶĂůŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬĚƵƌŝŶŐƐƵďƐĞƋƵĞŶƚĨŽůůŽǁͲƵƉ͘ 18-22_{dŚĞďŝŽůŽŐŝĐĂůŵĞĐŚĂŶŝƐŵƚŚĂƚĞdžƉůĂŝŶƐƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶĂůďƵŵŝŶƵƌŝĂĂŶĚ} ƌĞŶĂůĚĂŵĂŐĞŚĂƐďĞĞŶŵƵĐŚĚĞďĂƚĞĚ͘/ŶŝƟĂůůLJ͕ŝƚǁĂƐŚLJƉŽƚŚĞƐŝnjĞĚƚŚĂƚĂůďƵŵŝŶƵƌŝĂ ŝƐĂĐŽŶƐĞƋƵĞŶĐĞŽĨƌĞŶĂůĚĂŵĂŐĞ͘/ŶĚĞĞĚ͕ǁŚĞŶƚŚĞŐůŽŵĞƌƵůĂƌĮůƚĞƌŝŶƚŚĞŬŝĚŶĞLJ ŝƐĚĂŵĂŐĞĚ͕ŝŶĐƌĞĂƐĞĚĂŵŽƵŶƚƐŽĨĂůďƵŵŝŶĐŽƵůĚƉĂƐƐƚŚĞŐůŽŵĞƌƵůŝĂŶĚůĞĂŬŝŶƚŽƚŚĞ ƵƌŝŶĞ͘,ŽǁĞǀĞƌ͕ƌĞĐĞŶƚůLJĞǀŝĚĞŶĐĞŚĂƐďĞĞŶƉƌŽǀŝĚĞĚƚŚĂƚĂůďƵŵŝŶƵƌŝĂŵĂLJďĞŵŽƌĞƚŚĂŶ ŽŶůLJĂŵĂƌŬĞƌŽĨŬŝĚŶĞLJĚĂŵĂŐĞ͕ĂŶĚĐŽƵůĚďĞĂĐĂƵƐĞŽĨŬŝĚŶĞLJĚĂŵĂŐĞ͘dŚĞƌĞůĂƟǀĞůLJ ƌĞĐĞŶƚůLJĚŝƐĐŽǀĞƌĞĚŐůLJĐŽĐĂůLJdž;ĂůĂLJĞƌĐŽǀĞƌŝŶŐƚŚĞĞŶĚŽƚŚĞůŝƵŵͿĂƉƉĞĂƌƐƚŽďĞĂďĂƌƌŝĞƌ ĨŽƌĂůďƵŵŝŶƚŽůĞĂŬŽƵƚŽĨƚŚĞǀĂƐĐƵůĂƚƵƌĞ͕ŝŶĐůƵĚŝŶŐƚŚĞŐůŽŵĞƌƵůƵƐ;&ŝŐƵƌĞϭͿ͘23 _This ƐŚĞĚƐĂĚŝīĞƌĞŶƚůŝŐŚƚŽŶƚŚĞŵĞĐŚĂŶŝƐŵŽĨŝŶĐƌĞĂƐĞĚƌĞŶĂůůĞĂŬĂŐĞŽĨĂůďƵŵŝŶ͕ƐŝŶĐĞ ƚŚĞĮƌƐƚďĂƌƌŝĞƌĂƉƉĞĂƌƐƚŽďĞŶŽƚƚŚĞŐůŽŵĞƌƵůĂƌďĂƐĞŵĞŶƚŵĞŵďƌĂŶĞĂŶĚƐůŝƚƉŽƌĞƐ͕ ďƵƚƚŚĞǀĞƐƐĞůǁĂůůŝƚƐĞůĨ͘^ĞĐŽŶĚ͕ŝĨĂůďƵŵŝŶůĞĂŬƐŝŶƚŽƚŚĞƉƌŝŵĂƌLJƵƌŝŶĞ͕ƚŚĞƉŽĚŽĐLJƚĞƐ͕ ŵĞƐĂŶŐŝƵŵĂŶĚƚƵďƵůĞƐĂƌĞĞdžƉŽƐĞĚƚŽŚŝŐŚĐŽŶĐĞŶƚƌĂƟŽŶƐŽĨĂůďƵŵŝŶ͘WƌŽdžŝŵĂůƚƵďƵůĞƐ ĂƌĞĞƋƵŝƉƉĞĚǁŝƚŚƉƌŽƚĞŝŶƌĞĂďƐŽƌƉƟŽŶƚƌĂŶƐƉŽƌƚĞƌƐ͕ƚŚƌŽƵŐŚǁŚŝĐŚĂůƐŽĂůďƵŵŝŶŝƐ

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: 11PDF page: 11PDF page: 11PDF page: 11 11 ƌĞƚƌŝĞǀĞĚ͕ƌĞĂďƐŽƌďĞĚĂŶĚƚŚĞŶĚĞŐƌĂĚĞĚŝŶƚŚĞƉƌŽdžŝŵĂůƚƵďƵůĂƌĐĞůů͘/ŶƉŚLJƐŝŽůŽŐŝĐĂů ĐŝƌĐƵŵƐƚĂŶĐĞƐ͕ůŽǁƋƵĂŶƟƟĞƐŽĨĂůďƵŵŝŶŵĂLJďĞƌĞĂďƐŽƌďĞĚĂŶĚĚĞŐƌĂĚĞĚ͘,ŽǁĞǀĞƌ͕ ǁŚĞŶŚŝŐŚƋƵĂŶƟƟĞƐĂƉƉĞĂƌŝŶƚŚĞƉƌŝŵĂƌLJƵƌŝŶĞ͕ĂůďƵŵŝŶƌĞĂďƐŽƌƉƟŽŶŵĂLJĂĐƟǀĂƚĞƉƌŽͲ ŝŶŇĂŵŵĂƚŽƌLJƐƵďƐƚĂŶĐĞƐŝŶƚŚĞƚƵďƵůĂƌĐĞůůĐŚĂŶŐŝŶŐƚŚĞƚƵďƵůĞ͛ƐƉŚĞŶŽƚLJƉĞĂŶĚůĞĂĚŝŶŐ ƚŽŝŶƚĞƌƐƟƟĂůĚĂŵĂŐĞ͕ĮďƌŽƐŝƐ͕ĂŶĚƵůƟŵĂƚĞůLJƌĞĚƵĐĞĚŶĞƉŚƌŽŶĨƵŶĐƟŽŶ;&ŝŐƵƌĞϮͿ͘24-33 ŶĞdžƉůĂŶĂƟŽŶĨŽƌƚŚĞƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶĂůďƵŵŝŶƵƌŝĂĂŶĚƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞŚĂƐďĞĞŶƉƌŽƉŽƐĞĚďLJƚŚĞ^ƚĞŶŽŚLJƉŽƚŚĞƐŝƐ͕ǁŚŝĐŚƐƚĂƚĞƐƚŚĂƚĞdžĐĞƐƐŝǀĞƵƌŝŶĂƌLJ ĂůďƵŵŝŶůŽƐƐŝƐƚŚĞƌĞƐƵůƚŽĨǁŝĚĞƐƉƌĞĂĚƉĞƌŝƉŚĞƌĂůǀĂƐĐƵůĂƌĚĂŵĂŐĞŽƌĞŶĚŽƚŚĞůŝĂů ĚLJƐĨƵŶĐƟŽŶ͘34_{ĐĐŽƌĚŝŶŐƚŽƚŚŝƐŚLJƉŽƚŚĞƐŝƐĂůďƵŵŝŶůĞĂŬĂŐĞŝƐŶŽƚĐŽŶĮŶĞĚƚŽƚŚĞŬŝĚŶĞLJ͕} ďƵƚŝƐƉƌĞƐĞŶƚƚŚƌŽƵŐŚŽƵƚƚŚĞƉĞƌŝƉŚĞƌĂůǀĂƐĐƵůĂƚƵƌĞ͘^ĞǀĞƌĂůƐƚƵĚŝĞƐƵƐŝŶŐƌĂĚŝŽĂĐƟǀĞůLJ ůĂďĞůĞĚ ĂůďƵŵŝŶ͕ ŝŶĚĞĞĚ ĚĞŵŽŶƐƚƌĂƚĞ ƚŚĂƚ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ĂŶ ŝŶĐƌĞĂƐĞĚƉĞƌŵĞĂďŝůŝƚLJŽĨƚŚĞƉĞƌŝƉŚĞƌĂůǀĂƐĐƵůĂƌďĞĚƐƚŽŵĂĐƌŽŵŽůĞĐƵůĞƐ͘35-37_{ŐĂŝŶ͕ƚŚŝƐ} ŝƐůŝŶŬĞĚƚŽƚŚĞŐůLJĐŽĐĂůLJdž͕ǁŚŝĐŚŝƐƉƌĞƐĞŶƚŝŶǀĂƐĐƵůĂƚƵƌĞƚŚƌŽƵŐŚŽƵƚƚŚĞǁŚŽůĞďŽĚLJ͘

Figure 1. Link between vascular and renal mechanisms causing vascular and renal disease

/ĨŝŶĚĞĞĚĂůďƵŵŝŶƵƌŝĂŝƐĂĐĂƵƐĞŽĨƌĞŶĂůĂŶĚͬŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͕ƚŚĞƋƵĞƐƟŽŶ ĂƌŝƐĞƐ͗͞ǁŚĂƚĐĂƵƐĞƐĂůďƵŵŝŶƵƌŝĂƚŽŝŶĐƌĞĂƐĞ͍͟/ƐŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂĂĐŽŶĚŝƟŽŶĂĐƋƵŝƌĞĚ ĚƵƌŝŶŐůŝĨĞ͕ĂƐĂƌĞƐƵůƚŽĨǁĞƐƚĞƌŶůŝĨĞƐƚLJůĞ;Ğ͘Ő͘ŚŝŐŚƐĂůƚĂŶĚƉƌŽƚĞŝŶŝŶƚĂŬĞͿ͕ƐŵŽŬŝŶŐ͕ ŚLJƉĞƌƚĞŶƐŝŽŶŽƌĚŝĂďĞƚĞƐ͕ůĞĂĚŝŶŐƚŽǀĂƐĐƵůĂƌǁĂůůĚĂŵĂŐĞ͍KƌŝƐĂůďƵŵŝŶƵƌŝĂĂĐŽŶŐĞŶŝƚĂů ĐŽŶĚŝƟŽŶ͍ůŝŶŝĐĂůƐƚƵĚŝĞƐŚĂǀĞƐŚŽǁŶƚŚĂƚŚŝŐŚĂůďƵŵŝŶƵƌŝĂůĞǀĞůƐƉƌĞĐĞĚĞĂŶĚƉƌĞĚŝĐƚ ŶĞǁͲŽŶƐĞƚŚLJƉĞƌƚĞŶƐŝŽŶĂŶĚĚŝĂďĞƚĞƐ͕ƌĞŶĚĞƌŝŶŐƚŚĞĮƌƐƚƉŽƐƐŝďŝůŝƚLJůĞƐƐůŝŬĞůLJ͘dŚŝƐǁŽƵůĚ ŵĞĂŶƚŚĂƚĞůĞǀĂƚĞĚůĞǀĞůƐŽĨĂůďƵŵŝŶƵƌŝĂŵŝŐŚƚďĞĂŶŝŶďŽƌŶĐŚĂƌĂĐƚĞƌŝƐƟĐ͘ŵĞĐŚĂŶŝƐŵ ĞdžƉůĂŝŶŝŶŐǁŚLJĂůďƵŵŝŶƵƌŝĂǁŽƵůĚĂůƌĞĂĚLJďĞƉƌĞƐĞŶƚĂƚďŝƌƚŚŚĂƐďĞĞŶĚĞĮŶĞĚŝŶƚŚĞ ĂƌŬĞƌŚLJƉŽƚŚĞƐŝƐ͘dŚŝƐŚLJƉŽƚŚĞƐŝƐƐƚĂƚĞƐƚŚĂƚĂůƌĞĂĚLJŝŶƚŚĞǁŽŵď͕ĨĞƚƵƐĞƐŵĂLJďĞ ŚĂƌŵĞĚĚƵĞƚŽŐĞŶĞƟĐĨĂĐƚŽƌƐ͕ŵĂůŶƵƚƌŝƟŽŶĂŶĚŽƚŚĞƌŝŶƐƵůƚƐƚŽƚŚĞŵŽƚŚĞƌĚƵƌŝŶŐ ƉƌĞŐŶĂŶĐLJ͘38

1

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: 12PDF page: 12PDF page: 12PDF page: 12 12 /ĨĂůďƵŵŝŶƵƌŝĂŝƐĂůƌĞĂĚLJƉƌĞƐĞŶƚĂƚďŝƌƚŚ͕ƚŚŝƐǁŽƵůĚŵĂŬĞƚŚĞƵƐĞŽĨĂůďƵŵŝŶƵƌŝĂĂƐĂ ƚĂƌŐĞƚĞǀĞŶŵŽƌĞŝŵƉŽƌƚĂŶƚĂƐŝƚǁŽƵůĚĨĂĐŝůŝƚĂƚĞĞĂƌůLJŝĚĞŶƟĮĐĂƟŽŶŽĨŝŶĚŝǀŝĚƵĂůƐĂƚƌŝƐŬ ŽĨŽƌŐĂŶĨƵŶĐƟŽŶůŽƐƐĂŶĚŝƚǁŽƵůĚĐƌĞĂƚĞƚŚĞƉŽƐƐŝďŝůŝƚLJƚŽŝŶƚĞƌǀĞŶĞĞĂƌůLJŝŶƚŚĞĚŝƐĞĂƐĞ ƉƌŽĐĞƐƐ͘ƐŚŝŌĐŽƵůĚƚĂŬĞƉůĂĐĞĨƌŽŵŝŶƚĞƌǀĞŶƟŽŶƚŽƉƌĞǀĞŶƟŽŶŽĨĚŝƐĞĂƐĞ͘,ŽǁĞǀĞƌ͕ ƚŚĞƌĞŝƐĂƉĂƵĐŝƚLJŽĨĚĂƚĂŽŶĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐĂŶĚLJŽƵŶŐĐŚŝůĚƌĞŶ͕ĞŵƉŚĂƐŝnjŝŶŐ ƚŚĞ ŝŵƉŽƌƚĂŶĐĞ ŽĨ ĨƵƌƚŚĞƌ ƌĞƐĞĂƌĐŚ ŝŶ ƚŚŝƐ ĂƌĞĂ͘ ĂƚĂ ŽŶ ƚŚĞ ĂƐƐŽĐŝĂƟŽŶ ďĞƚǁĞĞŶ ĂůďƵŵŝŶƵƌŝĂĂŶĚƌĞŶĂůĞŶĚƉŽŝŶƚƐĂŶĚƚŚĞĞīĞĐƚŽĨƚƌĞĂƟŶŐĂůďƵŵŝŶƵƌŝĂŝŶĐŚŝůĚƌĞŶĂƌĞ ůĂĐŬŝŶŐ͘DŽƌĞŽǀĞƌ͕ŐƵŝĚĞůŝŶĞƐĨŽƌƚŚĞŽƉƟŵĂůŵĞƚŚŽĚƐĨŽƌŵĞĂƐƵƌŝŶŐĂŶĚŵŽŶŝƚŽƌŝŶŐ ĂůďƵŵŝŶƵƌŝĂŝŶĐŚŝůĚƌĞŶĂƌĞĂďƐĞŶƚ͘dŚĞƌĞĨŽƌĞ͕ŵŽƌĞƌĞƐĞĂƌĐŚŝŶƚŽĚŝīĞƌĞŶƚĂƐƉĞĐƚƐŽĨ ĂůďƵŵŝŶƵƌŝĂŝŶĐŚŝůĚƌĞŶŝƐŶĞĞĚĞĚ͘ Measurement of albuminuria /ŶŽƌĚĞƌƚŽĐŽƌƌĞĐƚůLJŝĚĞŶƟĨLJĂŶĚŵŽŶŝƚŽƌƚŚĞůĞǀĞůŽĨĂůďƵŵŝŶƵƌŝĂŝŶĂŶŝŶĚŝǀŝĚƵĂů͕ŽŶĞ ŚĂƐƚŽŵĞĂƐƵƌĞĂůďƵŵŝŶƵƌŝĂŝŶƚŚĞŵŽƐƚŽƉƟŵĂůǁĂLJ͘/ŶĐůŝŶŝĐĂůƉƌĂĐƟĐĞ͕ĂǁŝĚĞǀĂƌŝĞƚLJ ŽĨƵƌŝŶĞĐŽůůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐĂƌĞďĞŝŶŐƵƐĞĚ͘KŶĞĐĂŶƉĞƌĨŽƌŵĂϮϰͲŚŽƵƌƵƌŝŶĞĐŽůůĞĐƟŽŶ͕ ĐŽůůĞĐƚĂĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƵƌŝŶĞƐĂŵƉůĞŽƌĂƌĂŶĚŽŵƵƌŝŶĞƐĂŵƉůĞ;ĂŶLJƟŵĞĚƵƌŝŶŐĚĂLJ ŽƌŶŝŐŚƚͿ͘ƐŝŶŐůĞƐĂŵƉůĞ;ŽŶĂƐŝŶŐůĞĚĂLJͿŽƌŵƵůƟƉůĞƐĂŵƉůĞƐ;ŵƵůƟƉůĞƐƵďƐĞƋƵĞŶƚŽƌ Figure 2.0HFKDQLVPVXQGHUO\LQJWKHDFWLYDWLRQRILQÁDPPDWRU\DQGÀEURJHQLFSDWKZD\V LQSUR[LPDOWXEXODUHSLWKHOLDOFHOOVE\XOWUDÀOWHUHGSURWHLQORDG26-33_{$GDSWHGIURP$EEDWH} HWDO-$61

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: 13PDF page: 13PDF page: 13PDF page: 13 13 ƐĞƉĂƌĂƚĞĚĂLJƐͿĐĂŶďĞƵƐĞĚĂŶĚŽŶĞĐĂŶŵĞĂƐƵƌĞĞŝƚŚĞƌƚŚĞĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶ͕Žƌ ƵƐĞƚŚĞĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽƚŽĐŽƌƌĞĐƚĨŽƌŚLJĚƌĂƟŽŶƐƚĂƚƵƐ͘/ŶĂĚƵůƚƐ͕ŵƵůƟƉůĞƐƚƵĚŝĞƐ ŚĂǀĞŝŶǀĞƐƟŐĂƚĞĚĂŶĚĐŽŵƉĂƌĞĚĚŝīĞƌĞŶƚƵƌŝŶĞĐŽůůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐŝŶŽƌĚĞƌƚŽĮŶĚƚŚĞ ŽƉƟŵĂůƐƚƌĂƚĞŐLJƚŚĂƚŝŶƚƌŽĚƵĐĞƐƚŚĞůĞĂƐƚďŝĂƐ͘39-43_{ƵƌƌĞŶƚůLJ͕ƚŚĞŐŽůĚƐƚĂŶĚĂƌĚŝŶĂĚƵůƚƐŝƐ} ƐƟůůƚŚĞϮϰͲŚŽƵƌƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶƌĂƚĞ͕ĂůƚŚŽƵŐŚĂŐŽŽĚĂŶĚƉƌĂĐƟĐĂůĂůƚĞƌŶĂƟǀĞ ŝƐƚŚĞŵĞĂƐƵƌĞŵĞŶƚŽĨƚŚĞĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽŝŶĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƐĂŵƉůĞƐ;ĂǀĞƌĂŐĞ ŽĨƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞĚĂLJƐͿ͘44_{dŚĞƌĞĂƌĞŶŽĐůĞĂƌŐƵŝĚĞůŝŶĞƐĂǀĂŝůĂďůĞŝŶĐŚŝůĚƌĞŶ͕ƐŝŶĐĞ} ŶŽĞdžŚĂƵƐƟǀĞƐƚƵĚŝĞƐŽŶŽƉƟŵĂůƵƌŝŶĞĐŽůůĞĐƟŽŶƐĂŶĚŵĞĂƐƵƌĞŵĞŶƚƐŝŶĐŚŝůĚƌĞŶŚĂǀĞ ďĞĞŶĐŽŶĚƵĐƚĞĚ͘ ƉƌŽďůĞŵŝŶĂƐƐĞƐƐŝŶŐƚŚĞůĞǀĞůŽĨĂůďƵŵŝŶƵƌŝĂŝŶLJŽƵŶŐĐŚŝůĚƌĞŶŝƐƚŚĞĐŚŽŝĐĞ ŽĨƚŚĞƵƌŝŶĞĐŽůůĞĐƟŽŶŵĞƚŚŽĚŝƚƐĞůĨ͘ĂďŝĞƐĂŶĚƚŽĚĚůĞƌƐĂƌĞŝŶĐŽŶƟŶĞŶƚĨŽƌƵƌŝŶĞ͘ dŚŝƐŵĂŬĞƐƚŚĞĐŽůůĞĐƟŽŶŽĨƵƌŝŶĞĨŽƌĂůďƵŵŝŶŵĞĂƐƵƌĞŵĞŶƚƐĐƵŵďĞƌƐŽŵĞ͘DŽĚĞƌŶ ĚŝĂƉĞƌƐĂƌĞĞdžƚƌĞŵĞůLJĞĸĐŝĞŶƚŝŶƌĞƚĂŝŶŝŶŐƵƌŝŶĞ͕ƚŚƵƐŽůĚĨĂƐŚŝŽŶĞĚĐŽƩŽŶǁŽŽůŽƌ ŵŽĚĞƌŶƉĂŶƚLJůŝŶĞƌƐĐĂŶďĞƵƐĞĚƚŽŚĞůƉƌĞĐŽǀĞƌŝŶŐƵƌŝŶĞ͘dŚŝƐƚĞĐŚŶŝƋƵĞŝƐŶŽƚŽŶůLJ ƵŶŚĂŶĚLJŝŶƵƐĞďƵƚĂůƐŽŝƌƌĞƉƌŽĚƵĐŝďůĞ͘45,46_{dĂƉĞĚƉůĂƐƟĐďĂŐƐĂƌĞĨƌĞƋƵĞŶƚůLJƵƐĞĚĂƐĂŶ} ĂůƚĞƌŶĂƟǀĞŝŶĐůŝŶŝĐĂůƉƌĂĐƟĐĞ͕ďƵƚƚŚĞƐĞŚĂǀĞƚŚĞĚŝƐĂĚǀĂŶƚĂŐĞƚŚĂƚƚŚĞLJĚĞƚĂĐŚĞĂƐŝůLJ ĨƌŽŵƚŚĞƐŬŝŶĂŶĚĂƉƉĞĂƌƚŽďĞƵŶĐŽŵĨŽƌƚĂďůĞ͘45_{tŚĂƚŝƐƚŚĞŽƉƟŵĂůƵƌŝŶĞĐŽůůĞĐƟŽŶ} ŵĞƚŚŽĚĨŽƌĂůďƵŵŝŶƵƌŝĂĂƐƐĞƐƐŵĞŶƚŝŶLJŽƵŶŐĐŚŝůĚƌĞŶ͕ǁŚŝĐŚŝƐƉƌĂĐƟĐĂůŝŶƵƐĞ͕ƌĞůŝĂďůĞ ĂŶĚĐŽŵĨŽƌƚĂďůĞƐƟůůŶĞĞĚƐƚŽďĞĞƐƚĂďůŝƐŚĞĚ͘dŚŝƐŽƉƟŵĂůƵƌŝŶĞĐŽůůĞĐƟŽŶŵĞƚŚŽĚ͕ ŝŶĐŽŵďŝŶĂƟŽŶǁŝƚŚďĞƩĞƌŐƵŝĚĞůŝŶĞƐŽŶƵƌŝŶĞĐŽůůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐĨŽƌĂůďƵŵŝŶƵƌŝĂ ĂƐƐĞƐƐŵĞŶƚŝŶĐŚŝůĚƌĞŶǁŽƵůĚŝŵƉƌŽǀĞƚŚĞƋƵĂůŝƚLJŽĨĨƵƌƚŚĞƌƌĞƐĞĂƌĐŚŽŶƚŚĞŝŵƉŽƌƚĂŶĐĞ ŽĨĂůďƵŵŝŶƵƌŝĂĂƐĂƉŽƚĞŶƟĂůƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬŵĂƌŬĞƌŝŶĐŚŝůĚƌĞŶ͘ Treatment of albuminuria ĂƐĞĚ ŽŶ ƚŚĞ ĞdžƉĞƌŝŵĞŶƚĂů ĂŶĚ ĐůŝŶŝĐĂů ĚĂƚĂ ƐŚŽǁŝŶŐ ƚŚĂƚ ĂůďƵŵŝŶƵƌŝĂ ŵŝŐŚƚ ďĞ Ă causal factor in renal and cardiovascular disease development, albuminuria seems an ŝŶĚĞƉĞŶĚĞŶƚƚĂƌŐĞƚĨŽƌƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƉƌŽƚĞĐƟǀĞƚŚĞƌĂƉLJ͘dŚŝƐŝƐŝŵƉŽƌƚĂŶƚ ŝŶƚŚĞĐŽŶƚĞdžƚŽĨŶĞǁŝŶƚĞƌǀĞŶƟŽŶƐƚƌĂƚĞŐŝĞƐƚŽŚĂůƚƚŚĞƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĚŝƐĞĂƐĞ͘ ƵƌƌĞŶƚůLJ͕ƐĞǀĞƌĂůƚŚĞƌĂƉŝĞƐĨŽƌƚŚĞƌĞĚƵĐƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂĂƌĞĂǀĂŝůĂďůĞ͘ dŚĞŵŽƐƚŝŵƉŽƌƚĂŶƚƚŚĞƌĂƉLJƵƐĞĚŝŶĐƵƌƌĞŶƚĐůŝŶŝĐĂůƉƌĂĐƟĐĞ͕ǁŚŝĐŚŚĂƐďĞĞŶĐůĞĂƌůLJ ƐŚŽǁŶƚŽĚĞůĂLJƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͕ŝƐZĞŶŝŶͲŶŐŝŽƚĞŶƐŝŶͲůĚŽƐƚĞƌŽŶĞͲ^LJƐƚĞŵ ;Z^ͿŝŶŚŝďŝƟŽŶǁŝƚŚŶŐŝŽƚĞŶƐŝŶŽŶǀĞƌƟŶŐŶnjLJŵĞ;ͿŝŶŚŝďŝƟŽŶŽƌŶŐŝŽƚĞŶƐŝŶ ZĞĐĞƉƚŽƌ ůŽĐŬĂĚĞ ;ZͿ͘ dŚĞ ĞdžĂĐƚ ŵĞĐŚĂŶŝƐŵ ďLJ ǁŚŝĐŚ Z^ ŝŶŚŝďŝƟŽŶ ůŽǁĞƌƐ ĂůďƵŵŝŶƵƌŝĂŝƐƐƟůůƵŶŬŶŽǁŶ͘/ŶŚŝďŝƟŽŶŽĨƚŚĞZ^ƐLJƐƚĞŵ;Z^ŝͿůŽǁĞƌƐƚŚĞƉƌĞƐƐƵƌĞ ŽĨƚŚĞĞīĞƌĞŶƚĂƌƚĞƌŝŽůĞŽĨƚŚĞŐůŽŵĞƌƵůŝ͕ƚŚĞƌĞďLJƌĞĚƵĐŝŶŐƚŚĞŝŶƚƌĂŐůŽŵĞƌƵůĂƌƉƌĞƐƐƵƌĞ ĂŶĚƚŚĞŐůŽŵĞƌƵůĂƌĮůƚƌĂƟŽŶƌĂƚĞ͘dŚŝƐĐŽƵůĚůĞĂĚƚŽĐŚĂŶŐĞƐŝŶƚŚĞǀĂƐĐƵůĂƌďĂƌƌŝĞƌĂŶĚ ĂƌĞĚƵĐƟŽŶŽĨƚŚĞĮůƚƌĂƟŽŶŽĨŵŽůĞĐƵůĞƐůŝŬĞĂůďƵŵŝŶŽǀĞƌƚŚĞŐůŽŵĞƌƵůĂƌŵĞŵďƌĂŶĞ͘ ,ŽǁĞǀĞƌ͕ƚŚĞŚĂĞŵŽĚLJŶĂŵŝĐĞīĞĐƚƐŽĨZ^ŝĂƌĞŶĞĂƌůLJŝŶƐƚĂŶƚĂŶĞŽƵƐĂŶĚƐƚĂLJƐƚĂďůĞ ĂŌĞƌ ƚŚĂƚ ŝŶŝƟĂů ĞīĞĐƚ͕ ǁŚĞƌĞĂƐ ĂůďƵŵŝŶƵƌŝĂ ůŽǁĞƌŝŶŐ ƚĂŬĞƐ ǁĞĞŬƐ ƚŽ ƐƚĂďŝůŝnjĞ͘47,48 ^ĞĐŽŶĚĂƌLJĞīĞĐƚƐŽĨƚŚŝƐŝŶƚƌĂŐůŽŵĞƌƵůĂƌƉƌĞƐƐƵƌĞĨĂůůŽŶƚŚĞŝŶƚĞŐƌŝƚLJŽĨƚŚĞŐůŽŵĞƌƵůĂƌ

1

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: 14PDF page: 14PDF page: 14PDF page: 14 14 ďĂƌƌŝĞƌĨƵŶĐƟŽŶŵĂLJĂƉƉůLJ͘ůƐŽĞīĞĐƚƐŽĨZ^ŝŽŶƚŚĞŐůLJĐŽĐĂůLJdžĐĂŶƉůĂLJĂƌŽůĞ͘49,50 tŚĂƚĞǀĞƌƚŚĞƌĞůĂƟŽŶďĞƚǁĞĞŶZ^ŝĂŶĚĂůďƵŵŝŶƵƌŝĂůŽǁĞƌŝŶŐŝƐ͕ŝƚŝƐĐůĞĂƌƚŚĂƚZ^ŝ ƉƌŽƚĞĐƚƐƚŚĞŬŝĚŶĞLJĂŶĚƚŚĂƚƚŚŝƐƉƌŽƚĞĐƟŽŶĂƉƉĞĂƌƐƚŽďĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚƚŚĞůŽǁĞƌŝŶŐ ŽĨƌŝƐŬĨĂĐƚŽƌƐĂŵŽŶŐǁŚŝĐŚĂůďƵŵŝŶƵƌŝĂ͘ ůƚŚŽƵŐŚƚŚĞƌĞŝƐŽǀĞƌǁŚĞůŵŝŶŐƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůůĞĚĐůŝŶŝĐĂůƚƌŝĂůĞǀŝĚĞŶĐĞĂǀĂŝůĂďůĞ ŝŶĂĚƵůƚƐĚĞŵŽŶƐƚƌĂƟŶŐƚŚĂƚZ^ŝŶŚŝďŝƟŽŶĚĞůĂLJƐƚŚĞƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨƵŶĐƟŽŶ ĚĞĐůŝŶĞ͕ĂĚĞďĂƚĞĐŽŶƟŶƵĞƐĂƌŐƵŝŶŐƚŚĂƚŝŶĐĞƌƚĂŝŶƐĞƫŶŐƐZ^ŝŝƐŶŽƚĞĸĐĂĐŝŽƵƐĂŶĚ ĞǀĞŶƵŶƐĂĨĞ͘51-57_{ŶĞdžĂŵƉůĞŝƐĂƌĞĐĞŶƚƉƵďůŝĐĂƟŽŶƚŚĂƚĂĚǀŽĐĂƚĞƐƚŽƐƚŽƉZ^ŝŝŶ} ƉĂƟĞŶƚƐǁŝƚŚĂĚǀĂŶĐĞĚƌĞŶĂůĚŝƐĞĂƐĞ͘dŚĞŚĂĞŵŽĚLJŶĂŵŝĐĨĂůůŝŶĞ'&ZĂŌĞƌŝŶŝƟĂƟŽŶŽĨ Z^ŝŚĂƐďĞĞŶƐŚŽǁŶƚŽďĞƌĞǀĞƌƐŝďůĞĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶ͘58 _{With this in mind, it has} ďĞĞŶĂĚǀŽĐĂƚĞĚƚŽĚŝƐĐŽŶƟŶƵĞZ^ŝŝŶƉĂƟĞŶƚƐǁŝƚŚůĂƚĞƐƚĂŐĞĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ ŝŶŽƌĚĞƌƚŽƌĞŐĂŝŶƌĞŶĂůĨƵŶĐƟŽŶĂŶĚĚĞůĂLJĚŝĂůLJƐŝƐ͘56_{,ŽǁĞǀĞƌ͕ƚŚĞĐŽŶƐĞƋƵĞŶĐĞŽĨƚŚŝƐ} ĚŝƐĐŽŶƟŶƵĂƟŽŶŚĂƐŶŽƚďĞĞŶƉƌŽƉĞƌůLJƐƚƵĚŝĞĚ͘ /ŶĐŽŶƚƌĂƐƚƚŽƚŚĞůĂƌŐĞĂŵŽƵŶƚŽĨĚĂƚĂŽŶƚŚĞƌĞŶĂůƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨZ^ ŝŶŚŝďŝƟŽŶŝŶĂĚƵůƚƐ͕ƌĂŶĚŽŵŝnjĞĚƐƚƵĚŝĞƐŝŶĐŚŝůĚƌĞŶĂƌĞůĂĐŬŝŶŐ͘dŚĞ^WƐƚƵĚLJ͕ ŝŶǁŚŝĐŚĂůůĐŚŝůĚƌĞŶǁĞƌĞƚƌĞĂƚĞĚǁŝƚŚƐƚĂŶĚĂƌĚŝnjĞĚŝŶŚŝďŝƟŽŶƐŚŽǁĞĚƚŚĂƚ ŝŶŚŝďŝƟŽŶǁĂƐĞīĞĐƟǀĞŝŶůŽǁĞƌŝŶŐŽĨƉƌŽƚĞŝŶƵƌŝĂǁŝƚŚĂŶĂǀĞƌĂŐĞŝŶŝƟĂůƌĞĚƵĐƟŽŶŝŶ ƉƌŽƚĞŝŶƵƌŝĂŽĨϱϬй͘59_{/ŶƚŚĞŽďƐĞƌǀĂƟŽŶĂů<ŝƐƚƵĚLJ͕ŝŶŚŝďŝƚŽƌƵƐĞǁĂƐĂƐƐŽĐŝĂƚĞĚ} ǁŝƚŚůŽǁĞƌƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůƐ͘60_{hƐĞŽĨĂŶZǁĂƐƐŚŽǁŶƚŽďĞŵŽƌĞĞīĞĐƟǀĞŝŶůŽǁĞƌŝŶŐ} ŽĨƉƌŽƚĞŝŶƵƌŝĂƚŚĂŶĂĐĂůĐŝƵŵĐŚĂŶŶĞůďůŽĐŬĞƌŝŶĂƐŵĂůůƌĂŶĚŽŵŝnjĞĚŽƉĞŶͲůĂďĞůƐƚƵĚLJ͘61 dǁŽƐŵĂůůƵŶĐŽŶƚƌŽůůĞĚƐƚƵĚŝĞƐĚĞŵŽŶƐƚƌĂƚĞĚƐƚĂďŝůŝƐĂƟŽŶŽĨŬŝĚŶĞLJĨƵŶĐƟŽŶŝŶĐŚŝůĚƌĞŶ ǁŝƚŚ<ƚŚĂƚǁĞƌĞƚƌĞĂƚĞĚǁŝƚŚĂŶŝŶŚŝďŝƚŽƌƐŽƌZ͘62,63 _{&ŝŶĂůůLJ͕ŽŶĞŽďƐĞƌǀĂƟŽŶĂů} ƐƚƵĚLJĨĂŝůĞĚƚŽƐŚŽǁĞǀŝĚĞŶĐĞƚŚĂƚŝŶŚŝďŝƟŽŶƐůŽǁĞĚƚŚĞƉƌŽŐƌĞƐƐŝŽŶŽĨ<͘64_ŽƚŚ ƚŚĞĞīĞĐƚŽĨZ^ŝŶŚŝďŝƟŽŶĂŶĚƚŚĞĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨƚŚŝƐƚƌĞĂƚŵĞŶƚŽŶƌĞŶĂůĚŝƐĞĂƐĞ ƉƌŽŐƌĞƐƐŝŽŶĂƌĞƵŶŬŶŽǁŶĂŶĚŶĞĞĚƚŽďĞĨƵƌƚŚĞƌĞƐƚĂďůŝƐŚĞĚ͘

Aims of this thesis

dŚŝƐƚŚĞƐŝƐĂŝŵƐƚŽŝŶǀĞƐƟŐĂƚĞĚŝīĞƌĞŶƚĂƐƉĞĐƚƐŽĨĂůďƵŵŝŶƵƌŝĂŝŶĐŚŝůĚƌĞŶ͕ŝŶŽƌĚĞƌƚŽ ŝŶĐƌĞĂƐĞƚŚĞŬŶŽǁůĞĚŐĞŽŶƚŚŝƐƐƵďũĞĐƚĂŶĚĞŶĂďůĞĨƵƚƵƌĞƌĞƐĞĂƌĐŚŝŶƚŚŝƐĂƌĞĂ͘/ƚĨŽĐƵƐĞƐ ŽŶƚŚĞƉƌĞǀĂůĞŶĐĞ͕ŵĞĂƐƵƌĞŵĞŶƚĂŶĚƚƌĞĂƚŵĞŶƚŽĨĂůďƵŵŝŶƵƌŝĂ͘

Part 1. Prevalence and measurement of albuminuria in children.

WĂƌƚϭďĞŐŝŶƐďLJŝŶǀĞƐƟŐĂƟŶŐǁŚĞƚŚĞƌŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĂůƌĞĂĚLJƉƌĞƐĞŶƚŝŶLJŽƵŶŐ ĐŚŝůĚƌĞŶǁŝƚŚŽƵƚŬŝĚŶĞLJĚŝƐĞĂƐĞ͘Chapter 2 describes the prevalence of microalbuminuria

ŝŶƚŽĚĚůĞƌƐĨƌŽŵĂŶŽďƐĞƌǀĂƟŽŶĂůĐŽŚŽƌƚƐƚƵĚLJŝŶƚŚĞEŽƌƚŚĞƌŶƉĂƌƚŽĨƚŚĞEĞƚŚĞƌůĂŶĚƐ͕ ĂŶĚĐŽŵƉĂƌĞƐƚŚĞĚŝƐƚƌŝďƵƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂůĞǀĞůƐǁŝƚŚĂŶĂĚƵůƚĐŽŚŽƌƚŽĨƚŚĞŐĞŶĞƌĂů ƉŽƉƵůĂƟŽŶ ĨƌŽŵ ƚŚĞ ƐĂŵĞ ĂƌĞĂ͘ DŽƌĞŽǀĞƌ͕ ĂƐƐŽĐŝĂƟŽŶƐ ďĞƚǁĞĞŶ ƚŚĞ ƉƌĞƐĞŶĐĞ ŽĨ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂĂŶĚĚŝīĞƌĞŶƚĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐĂƌĞƚĞƐƚĞĚ͘

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: 15PDF page: 15PDF page: 15PDF page: 15 15 /ŶChapter 3, ƚŚĞŽƉƟŵĂůƵƌŝŶĞĐŽůůĞĐƟŽŶŵĞƚŚŽĚĨŽƌĂƐƐĞƐƐŵĞŶƚŽĨĂůďƵŵŝŶƵƌŝĂŝŶ ƚŽĚĚůĞƌƐŚĂƐďĞĞŶŝŶǀĞƐƟŐĂƚĞĚ͘ƐǀĞƌLJLJŽƵŶŐĐŚŝůĚƌĞŶĂƌĞŶŽƚĐŽŶƟŶĞŶƚĨŽƌƵƌŝŶĞ͕ƵƌŝŶĞ ĐŽůůĞĐƟŽŶŝŶƚŚŝƐƉŽƉƵůĂƟŽŶŝƐĂŶŝƐƐƵĞ͘dŚĞŵĞƚŚŽĚƵƐĞĚŝŶĐŚĂƉƚĞƌϮŝƐĐŽŵƉĂƌĞĚǁŝƚŚ ĂŶĞǁůLJĚĞǀĞůŽƉŵĞŶƚŵĞƚŚŽĚ͕ƚŚĞWĞĞ^ƉŽƚĂŶĚĂƌĞĨĞƌĞŶĐĞŵĞƚŚŽĚ͕ŝ͘Ğ͘ĂŶƵŶƉƌŽĐĞƐƐĞĚ ƵƌŝŶĞƐĂŵƉůĞǁŚŝĐŚŝƐƐƚŽƌĞĚĂƚϰΣ͘ Chapter 4 ƐƚƵĚŝĞƐ ƚŚĞ ŵŽƐƚ ŽƉƚŝŵĂů ƐƚƌĂƚĞŐLJ ĨŽƌ ŵĞĂƐƵƌŝŶŐ ĂŶĚ ŵŽŶŝƚŽƌŝŶŐ ĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐŝŶĂŶŽďƐĞƌǀĂƟŽŶĂůƉƌŽƐƉĞĐƟǀĞĐŽŚŽƌƚƐƚƵĚLJ͘ŝīĞƌĞŶƚƵƌŝŶĞ ĐŽůůĞĐƟŽŶƐƚƌĂƚĞŐŝĞƐĂƌĞƚĞƐƚĞĚĂŶĚĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞŐŽůĚƐƚĂŶĚĂƌĚŝŶĂĚƵůƚƐ͕ǁŚŝĐŚŝƐ ƚŚĞŵĞĂƐƵƌĞŵĞŶƚŽĨƵƌŝŶĂƌLJĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽŝŶƚŚƌĞĞĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƐĂŵƉůĞƐ͕ ĐŽůůĞĐƚĞĚŽǀĞƌƟŵĞ͘

Part 2: Treatment of albuminuria in children

WĂƌƚϮŽĨƚŚŝƐƚŚĞƐŝƐĨŽĐƵƐĞƐŽŶƚŚĞƚƌĞĂƚŵĞŶƚŽĨĂůďƵŵŝŶƵƌŝĂŝŶĐŚŝůĚƌĞŶ͘/ŶChapter 5, ƚŚĞŝŶŝƟĂůĞīĞĐƚŽĨƚŚĞŝŶŚŝďŝƚŽƌƌĂŵŝƉƌŝůŽŶƉƌŽƚĞŝŶƵƌŝĂĂŶĚŝƚƐĂƐƐŽĐŝĂƟŽŶǁŝƚŚ ƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶĂƌĞƚĞƐƚĞĚŝŶϮϴϬĐŚŝůĚƌĞŶǁŝƚŚŚƌŽŶŝĐ<ŝĚŶĞLJŝƐĞĂƐĞ;<Ϳ ŝŶĂƉŽƐƚͲŚŽĐĂŶĂůLJƐŝƐŽĨƚŚĞīĞĐƚŽĨ^ƚƌŝĐƚůŽŽĚWƌĞƐƐƵƌĞŽŶƚƌŽůĂŶĚŝŶŚŝďŝƟŽŶ ŽŶƚŚĞWƌŽŐƌĞƐƐŝŽŶŽĨŚƌŽŶŝĐZĞŶĂů&ĂŝůƵƌĞŝŶWĞĚŝĂƚƌŝĐWĂƟĞŶƚƐ;^WͿƚƌŝĂů͘/ƚǁĂƐ ĂůƐŽĚĞƚĞƌŵŝŶĞĚǁŚĞƚŚĞƌƌĞƐŝĚƵĂůƉƌŽƚĞŝŶƵƌŝĂ;ŝ͘Ğ͘ƚŚĞƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůĚƵƌŝŶŐ ŝŶŚŝďŝƟŽŶͿŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŚŝŐŚĞƌƌĞŶĂůƌŝƐŬ͘ŽŵďŝŶĞĚ͕ƚŚĞƐĞŵĞĂƐƵƌĞŵĞŶƚƐƐƚƵĚLJ ƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨƉƌŽƚĞŝŶƵƌŝĂĂƐĂƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚŝŶƚŚĞŵĂŶĂŐĞŵĞŶƚŽĨĐŚŝůĚƌĞŶ ǁŝƚŚ<͘ Chapter 6ĂƐƐĞƐƐĞƐƚŚĞĞīĞĐƚŽĨĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŶŚŝďŝƟŽŶƚŚĞƌĂƉLJŽŶ ŝŵƉŽƌƚĂŶƚƌĞŶĂůŵĂƌŬĞƌƐĂŶĚƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶŝŶĂŶŽďƐĞƌǀĂƟŽŶĂůĐŽŚŽƌƚƐƚƵĚLJ ŽĨĐŚŝůĚƌĞŶǁŝƚŚ<͕ŝŶŽƌĚĞƌƚŽŝŶǀĞƐƟŐĂƚĞǁŚĞƚŚĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŶŚŝďŝƟŽŶ ĨŽƌĐůŝŶŝĐĂůƌĞĂƐŽŶƐŝƐŝŶĚĞĞĚŝŶĚŝĐĂƚĞĚ͘DŽƌĞŽǀĞƌ͕ŝƚĞǀĂůƵĂƚĞƐƚŚĞŵŽƐƚŝŵƉŽƌƚĂŶƚ ƌĞĂƐŽŶƐĨŽƌĚŝƐĐŽŶƟŶƵĂƟŽŶŽĨZ^ŝŶŚŝďŝƟŽŶŝŶĂĐůŝŶŝĐĂůƉƌĂĐƟĐĞƐĞƫŶŐ͘ dŚŝƐƚŚĞƐŝƐĞŶĚƐǁŝƚŚĂƐƵŵŵĂƌLJŽĨƚŚĞƌĞƐƵůƚƐŽĨƚŚĞĐŽŶĚƵĐƚĞĚƐƚƵĚŝĞƐĂŶĚĂŶ ŽǀĞƌǀŝĞǁŽĨĨƵƚƵƌĞƉĞƌƐƉĞĐƟǀĞƐ͘

1

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: 16PDF page: 16PDF page: 16PDF page: 16 16

References

ϭ͘ ,ĞůůĞŵŽŶƐ D͕ ĞŶŝŐ W͕ ĚĞ ĞĞƵǁ ͕ sŽŽƌŚĂŵ :͕ >ĂŵďĞƌƐ ,ĞĞƌƐƉŝŶŬ ,:͘ /Ɛ ĂůďƵŵŝŶƵƌŝĂ ƐĐƌĞĞŶŝŶŐ ĂŶĚ ƚƌĞĂƚŵĞŶƚ ŽƉƟŵĂů ŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ƚLJƉĞ Ϯ ĚŝĂďĞƚĞƐ ŝŶƉƌŝŵĂƌLJĐĂƌĞ͍ŽďƐĞƌǀĂƟŽŶĂůĚĂƚĂŽĨƚŚĞ '/Edd ĐŽŚŽƌƚ͘ Nephrol Dial Transplant͘ ϮϬϭϯ͖Ϯϴ;ϯͿ͗ϳϬϲͲϳϭϱ͘

Ϯ͘ WĂƌǀŝŶŐ ,,͕ >ĞǁŝƐ :͕ ZĂǀŝĚ D͕ ZĞŵƵnjnjŝ '͕ ,ƵŶƐŝĐŬĞƌ >'͕ DE ŝŶǀĞƐƟŐĂƚŽƌƐ͘ Prevalence and risk factors for microalbuminuria in a referred cohort ŽĨ ƚLJƉĞ // ĚŝĂďĞƚŝĐ ƉĂƚŝĞŶƚƐ͗  ŐůŽďĂů ƉĞƌƐƉĞĐƟǀĞ͘Kidney Int͘ϮϬϬϲ͖ϲϵ;ϭϭͿ͗ϮϬϱϳͲ ϮϬϲϯ͘

ϯ͘ dĂƉƉ Z:͕ ^ŚĂǁ :͕ ŝŵŵĞƚ W͕ Ğƚ Ăů͘ ůďƵŵŝŶƵƌŝĂŝƐĞǀŝĚĞŶƚŝŶƚŚĞĞĂƌůLJƐƚĂŐĞƐŽĨ diabetes onset: Results from the australian ĚŝĂďĞƚĞƐ͕ ŽďĞƐŝƚLJ͕ ĂŶĚ ůŝĨĞƐƚLJůĞ ƐƚƵĚLJ ;ƵƐŝĂďͿ͘Am J Kidney Dis͘ϮϬϬϰ͖ϰϰ;ϱͿ͗ϳϵϮͲ ϳϵϴ͘ ϰ͘ tĂĐŚƚĞůů <͕ WĂůŵŝĞƌŝ s͕ KůƐĞŶ D,͕ Ğƚ Ăů͘ hƌŝŶĞ ĂůďƵŵŝŶͬĐƌĞĂƚŝŶŝŶĞ ƌĂƚŝŽ ĂŶĚ ĞĐŚŽĐĂƌĚŝŽŐƌĂƉŚŝĐůĞŌǀĞŶƚƌŝĐƵůĂƌƐƚƌƵĐƚƵƌĞ ĂŶĚ ĨƵŶĐƚŝŽŶ ŝŶ ŚLJƉĞƌƚĞŶƐŝǀĞ ƉĂƚŝĞŶƚƐ ǁŝƚŚĞůĞĐƚƌŽĐĂƌĚŝŽŐƌĂƉŚŝĐůĞŌǀĞŶƚƌŝĐƵůĂƌ ŚLJƉĞƌƚƌŽƉŚLJ͗ dŚĞ >/& ƐƚƵĚLJ͘ ůŽƐĂƌƚĂŶ ŝŶƚĞƌǀĞŶƟŽŶ ĨŽƌ ĞŶĚƉŽŝŶƚ ƌĞĚƵĐƟŽŶ͘ Am Heart J͘ϮϬϬϮ͖ϭϰϯ;ϮͿ͗ϯϭϵͲϯϮϲ͘ ϱ͘ ,ŝůůĞŐĞ ,>͕ :ĂŶƐƐĞŶ tD͕ ĂŬ ͕ Ğƚ Ăů͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝƐ ĐŽŵŵŽŶ͕ ĂůƐŽ ŝŶ Ă ŶŽŶĚŝĂďĞƚŝĐ͕ ŶŽŶŚLJƉĞƌƚĞŶƐŝǀĞ ƉŽƉƵůĂƟŽŶ͕ĂŶĚĂŶŝŶĚĞƉĞŶĚĞŶƚŝŶĚŝĐĂƚŽƌ of cardiovascular risk factors and ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ŵŽƌďŝĚŝƚLJ͘ J Intern Med͘ ϮϬϬϭ͖Ϯϰϵ;ϲͿ͗ϱϭϵͲϱϮϲ͘ ϲ͘ 'ĂƌŐ y͕ <ŝďĞƌĚ ͕ ůĂƌŬ t&͕ ,ĂLJŶĞƐ Z͕ ůĂƐĞ D͘ ůďƵŵŝŶƵƌŝĂ ĂŶĚ ƌĞŶĂů ŝŶƐƵĸĐŝĞŶĐLJƉƌĞǀĂůĞŶĐĞŐƵŝĚĞƐƉŽƉƵůĂƟŽŶ ƐĐƌĞĞŶŝŶŐ͗ ZĞƐƵůƚƐ ĨƌŽŵ ƚŚĞ E,E^ ///͘ Kidney Int͘ϮϬϬϮ͖ϲϭ;ϲͿ͗ϮϭϲϱͲϮϭϳϱ͘ ϳ͘ ZŽŵƵŶĚƐƚĂĚ^͕,ŽůŵĞŶ:͕,ĂůůĂŶ,͕<ǀĞŶŝůĚ <͕<ƌƵŐĞƌK͕DŝĚƚŚũĞůů<͘DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͕ cardiovascular disease and risk factors ŝŶ Ă ŶŽŶĚŝĂďĞƚŝĐͬŶŽŶŚLJƉĞƌƚĞŶƐŝǀĞ ƉŽƉƵůĂƟŽŶ͘ƚŚĞŶŽƌĚͲƚƌŽŶĚĞůĂŐŚĞĂůƚŚƐƚƵĚLJ ;,hEd͕ ϭϵϵϱͲϵϳͿ͕ ŶŽƌǁĂLJ͘ J Intern Med͘ ϮϬϬϮ͖ϮϱϮ;ϮͿ͗ϭϲϰͲϭϳϮ͘

ϴ͘ ƚŬŝŶƐ Z͕ WŽůŬŝŶŐŚŽƌŶĞ <Z͕ ƌŝŐĂŶƚŝ D͕ ^ŚĂǁ :͕ ŝŵŵĞƚ W͕ ŚĂĚďĂŶ ^:͘ Prevalence of albuminuria in australia: The ƵƐŝĂď ŬŝĚŶĞLJ ƐƚƵĚLJ͘ Kidney Int Suppl͘ ϮϬϬϰ͖;ϵϮͿ͗^ϮϮͲϰ͘ĚŽŝ;ϵϮͿ͗^ϮϮͲϰ͘ ϵ͘ <ĞĞŶ,͕ŚůŽƵǀĞƌĂŬŝƐ͕&ƵůůĞƌ:͕:ĂƌƌĞƩZ:͘ dŚĞ ĐŽŶĐŽŵŝƚĂŶƚƐ ŽĨ ƌĂŝƐĞĚ ďůŽŽĚ ƐƵŐĂƌ͗ ^ƚƵĚŝĞƐŝŶŶĞǁůLJͲĚĞƚĞĐƚĞĚŚLJƉĞƌŐůLJĐĂĞŵŝĐƐ͗ //͘ƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶ͕ďůŽŽĚƉƌĞƐƐƵƌĞ ĂŶĚƚŚĞŝƌƌĞůĂƟŽŶƚŽďůŽŽĚƐƵŐĂƌůĞǀĞůƐ͘Int J Epidemiol͘ϮϬϭϰ͖ϰϯ;ϭͿ͗ϭϭͲϭϱ͘ ϭϬ͘ sŝďĞƌƟ'͕,ŝůůZ͕:ĂƌƌĞƩZ:͕ƌŐLJƌŽƉŽƵůŽƐ ͕DĂŚŵƵĚh͕<ĞĞŶ,͘DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂƐ Ă ƉƌĞĚŝĐƚŽƌ ŽĨ ĐůŝŶŝĐĂů ŶĞƉŚƌŽƉĂƚŚLJ ŝŶ ŝŶƐƵůŝŶͲĚĞƉĞŶĚĞŶƚĚŝĂďĞƚĞƐŵĞůůŝƚƵƐ͘Lancet͘ ϭϵϴϮ͖ϭ;ϴϮϴϳͿ͗ϭϰϯϬͲϭϰϯϮ͘ ϭϭ͘ DĂƩŽĐŬD͕DŽƌƌŝƐŚE:͕sŝďĞƌƟ'͕<ĞĞŶ ,͕ &ŝƚnjŐĞƌĂůĚ W͕ :ĂĐŬƐŽŶ '͘ WƌŽƐƉĞĐƟǀĞ ƐƚƵĚLJ ŽĨ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂƐ ƉƌĞĚŝĐƚŽƌ ŽĨ ŵŽƌƚĂůŝƚLJ ŝŶ E/D͘ Diabetes͘ ϭϵϵϮ͖ϰϭ;ϲͿ͗ϳϯϲͲϳϰϭ͘ ϭϮ͘ WĂƌǀŝŶŐ,,͕DŽŐĞŶƐĞŶ͕:ĞŶƐĞŶ,͕ǀƌŝŶ W͘ /ŶĐƌĞĂƐĞĚ ƵƌŝŶĂƌLJ ĂůďƵŵŝŶͲĞdžĐƌĞƟŽŶ ƌĂƚĞ ŝŶ ďĞŶŝŐŶ ĞƐƐĞŶƚŝĂů ŚLJƉĞƌƚĞŶƐŝŽŶ͘ Lancet͘ϭϵϳϰ͖ϭ;ϳϴϲϴͿ͗ϭϭϵϬͲϭϭϵϮ͘ ϭϯ͘ :ĞŶƐĞŶ :^͕ &ĞůĚƚͲZĂƐŵƵƐƐĞŶ ͕ ŽƌĐŚͲ :ŽŚŶƐĞŶ<͕ůĂƵƐĞŶW͕ƉƉůĞLJĂƌĚD͕:ĞŶƐĞŶ '͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂŶĚ ŝƚƐ ƌĞůĂƟŽŶ ƚŽ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞ ĂŶĚ ƌŝƐŬ ĨĂĐƚŽƌƐ͘  ƉŽƉƵůĂƚŝŽŶͲďĂƐĞĚ ƐƚƵĚLJ ŽĨ ϭϮϱϰ ŚLJƉĞƌƚĞŶƐŝǀĞŝŶĚŝǀŝĚƵĂůƐ͘J Hum Hypertens͘ ϭϵϵϳ͖ϭϭ;ϭϭͿ͗ϳϮϳͲϳϯϮ͘

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: 17PDF page: 17PDF page: 17PDF page: 17 17 ϭϰ͘ ,ŝůůĞŐĞ,>͕&ŝĚůĞƌs͕ŝĞƌĐŬƐ'&͕ĞƚĂů͘hƌŝŶĂƌLJ ĂůďƵŵŝŶĞdžĐƌĞƟŽŶƉƌĞĚŝĐƚƐĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĂŶĚŶŽŶĐĂƌĚŝŽǀĂƐĐƵůĂƌŵŽƌƚĂůŝƚLJŝŶŐĞŶĞƌĂů ƉŽƉƵůĂƟŽŶ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϮ͖ϭϬϲ;ϭϰͿ͗ϭϳϳϳͲ ϭϳϴϮ͘ ϭϱ͘ ZŽŵƵŶĚƐƚĂĚ^͕,ŽůŵĞŶ:͕<ǀĞŶŝůĚ<͕,ĂůůĂŶ ,͕ ůůĞŬũĂĞƌ ,͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂŶĚ ĂůůͲ ĐĂƵƐĞŵŽƌƚĂůŝƚLJŝŶϮ͕ϬϴϵĂƉƉĂƌĞŶƚůLJŚĞĂůƚŚLJ ŝŶĚŝǀŝĚƵĂůƐ͗  ϰ͘ϰͲLJĞĂƌ ĨŽůůŽǁͲƵƉ ƐƚƵĚLJ͘ ƚŚĞ ŶŽƌĚͲƚƌŽŶĚĞůĂŐ ŚĞĂůƚŚ ƐƚƵĚLJ ;,hEdͿ͕ ŶŽƌǁĂLJ͘Am J Kidney Dis͘ϮϬϬϯ͖ϰϮ;ϯͿ͗ϰϲϲͲ ϰϳϯ͘ ϭϲ͘ /, ŚĂƌŵŽŶŝƐĞĚ ƚƌŝƉĂƌƚŝƚĞ ŐƵŝĚĞůŝŶĞ͘ ƐƚĂƚŝƐƚŝĐĂů ƉƌŝŶĐŝƉůĞƐ ĨŽƌ ĐůŝŶŝĐĂů ƚƌŝĂůƐ͘ ŝŶƚĞƌŶĂƟŽŶĂůĐŽŶĨĞƌĞŶĐĞŽŶŚĂƌŵŽŶŝƐĂƟŽŶ ϵ ĞdžƉĞƌƚ ǁŽƌŬŝŶŐ ŐƌŽƵƉ͘ Stat Med͘ ϭϵϵϵ͖ϭϴ;ϭϱͿ͗ϭϵϬϱͲϭϵϰϮ͘ ϭϳ͘ >ĂŵďĞƌƐ ,ĞĞƌƐƉŝŶŬ ,:͕ 'ĂŶƐĞǀŽŽƌƚ Zd͘ ůďƵŵŝŶƵƌŝĂŝƐĂŶĂƉƉƌŽƉƌŝĂƚĞƚŚĞƌĂƉĞƵƟĐ ƚĂƌŐĞƚŝŶƉĂƟĞŶƚƐǁŝƚŚ<͗dŚĞƉƌŽǀŝĞǁ͘ Clin J Am Soc Nephrol͘ ϮϬϭϱ͖ϭϬ;ϲͿ͗ϭϬϳϵͲ ϭϬϴϴ͘

ϭϴ͘ >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 Arch Intern Med͘ ϮϬϬϱ͖ϭϲϱ;ϴͿ͗ϵϰϳͲϵϱϯ͘ ϭϵ͘ ŝũŬĞůŬĂŵƉt͕ŚĂŶŐ͕ZĞŵƵnjnjŝ'͕ĞƚĂů͘ ůďƵŵŝŶƵƌŝĂŝƐĂƚĂƌŐĞƚĨŽƌƌĞŶŽƉƌŽƚĞĐƟǀĞ ƚŚĞƌĂƉLJŝŶĚĞƉĞŶĚĞŶƚĨƌŽŵďůŽŽĚƉƌĞƐƐƵƌĞŝŶ ƉĂƟĞŶƚƐǁŝƚŚƚLJƉĞϮĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͗ WŽƐƚ ŚŽĐ ĂŶĂůLJƐŝƐ ĨƌŽŵ ƚŚĞ ƌĞĚƵĐƟŽŶ ŽĨ ĞŶĚƉŽŝŶƚƐŝŶE/DǁŝƚŚƚŚĞĂŶŐŝŽƚĞŶƐŝŶ //ĂŶƚĂŐŽŶŝƐƚůŽƐĂƌƚĂŶ;ZE>ͿƚƌŝĂů͘J Am Soc Nephrol͘ϮϬϬϳ͖ϭϴ;ϱͿ͗ϭϱϰϬͲϭϱϰϲ͘ ϮϬ͘ ,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 Diabetes Care͘ ϮϬϭϭ͖ϯϰ;ϵͿ͗ϮϬϳϴͲϮϬϴϯ͘ Ϯϭ͘ ĚĞĞĞƵǁ͕ZĞŵƵnjnjŝ'͕WĂƌǀŝŶŐ,,͕ĞƚĂů͘ WƌŽƚĞŝŶƵƌŝĂ͕ĂƚĂƌŐĞƚĨŽƌƌĞŶŽƉƌŽƚĞĐƟŽŶŝŶ ƉĂƟĞŶƚƐǁŝƚŚƚLJƉĞϮĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͗ >ĞƐƐŽŶƐ ĨƌŽŵ ZE>͘ Kidney Int͘ ϮϬϬϰ͖ϲϱ;ϲͿ͗ϮϯϬϵͲϮϯϮϬ͘

ϮϮ͘ /ďƐĞŶ ,͕ KůƐĞŶ D,͕ tĂĐŚƚĞůů <͕ Ğƚ Ăů͘ Reduction in albuminuria translates to reduction in cardiovascular events ŝŶ ŚLJƉĞƌƚĞŶƐŝǀĞ ƉĂƚŝĞŶƚƐ͗ >ŽƐĂƌƚĂŶ intervention for endpoint reduction ŝŶ ŚLJƉĞƌƚĞŶƐŝŽŶ ƐƚƵĚLJ͘ Hypertension͘ ϮϬϬϱ͖ϰϱ;ϮͿ͗ϭϵϴͲϮϬϮ͘

Ϯϯ͘ ZĂďĞůŝŶŬd:͕ĚĞĞĞƵǁ͘dŚĞŐůLJĐŽĐĂůLJdžͲ ͲůŝŶŬŝŶŐ ĂůďƵŵŝŶƵƌŝĂ ǁŝƚŚ ƌĞŶĂů ĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞ͘ Nat Rev Nephrol͘ ϮϬϭϱ͖ϭϭ;ϭϭͿ͗ϲϲϳͲϲϳϲ͘ Ϯϰ͘ WĞƌŝĐŽE͕ŽĚƌĞĂŶƵ/͕^ĐŚŝĞƉƉĂƟ͕ZĞŵƵnjnjŝ '͘WĂƚŚŽƉŚLJƐŝŽůŽŐLJŽĨĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ ŝŶ ƉƌŽƚĞŝŶƵƌŝĐ ŶĞƉŚƌŽƉĂƚŚŝĞƐ͘ Kidney Int Suppl͘ϮϬϬϱ͖;ϵϰͿ;ϵϰͿ͗^ϳϵͲϴϮ͘ Ϯϱ͘ ďďĂƚĞ D͕ ŽũĂ ͕ ZĞŵƵnjnjŝ '͘ ,Žǁ ĚŽĞƐ ƉƌŽƚĞŝŶƵƌŝĂĐĂƵƐĞƉƌŽŐƌĞƐƐŝǀĞƌĞŶĂůĚĂŵĂŐĞ͍ J Am Soc Nephrol͘ϮϬϬϲ͖ϭϳ;ϭϭͿ͗ϮϵϳϰͲϮϵϴϰ͘ Ϯϲ͘ ŽũĂ͕DŽƌŝŐŝD͕&ŝŐůŝƵnjnjŝD͕ĞƚĂů͘WƌŽdžŝŵĂů ƚƵďƵůĂƌ ĐĞůů ƐLJŶƚŚĞƐŝƐ ĂŶĚ ƐĞĐƌĞƚŝŽŶ ŽĨ ĞŶĚŽƚŚĞůŝŶͲϭ ŽŶ ĐŚĂůůĞŶŐĞ ǁŝƚŚ ĂůďƵŵŝŶ ĂŶĚ ŽƚŚĞƌ ƉƌŽƚĞŝŶƐ͘ Am J Kidney Dis͘ ϭϵϵϱ͖Ϯϲ;ϲͿ͗ϵϯϰͲϵϰϭ͘ Ϯϳ͘ ĚĚLJ͕'ŝĂĐŚĞůůŝD͘ZĞŶĂůĞdžƉƌĞƐƐŝŽŶŽĨ ŐĞŶĞƐƚŚĂƚƉƌŽŵŽƚĞŝŶƚĞƌƐƟƟĂůŝŶŇĂŵŵĂƟŽŶ ĂŶĚĮďƌŽƐŝƐŝŶƌĂƚƐǁŝƚŚƉƌŽƚĞŝŶͲŽǀĞƌůŽĂĚ ƉƌŽƚĞŝŶƵƌŝĂ͘ Kidney Int͘ ϭϵϵϱ͖ϰϳ;ϲͿ͗ϭϱϰϲͲ ϭϱϱϳ͘ Ϯϴ͘ ŽũĂ͕ŽŶĂĚĞůůŝZ͕ŽůůĞŽŶŝ^͕ĞƚĂů͘WƌŽƚĞŝŶ ŽǀĞƌůŽĂĚ ƐƟŵƵůĂƚĞƐ ZEd^ ƉƌŽĚƵĐƟŽŶ ďLJ ƉƌŽdžŝŵĂů ƚƵďƵůĂƌ ĐĞůůƐ ĚĞƉĞŶĚŝŶŐ ŽŶ E&ͲŬĂƉƉĂ  ĂĐƚŝǀĂƚŝŽŶ͘ Kidney Int͘ ϭϵϵϴ͖ϱϯ;ϲͿ͗ϭϲϬϴͲϭϲϭϱ͘ Ϯϵ͘ DŽƌŝŐŝD͕DĂĐĐŽŶŝ͕ŽũĂ͕ĞƚĂů͘WƌŽƚĞŝŶ ŽǀĞƌůŽĂĚͲŝŶĚƵĐĞĚ E&ͲŬĂƉƉĂ ĂĐƚŝǀĂƚŝŽŶ ŝŶƉƌŽdžŝŵĂůƚƵďƵůĂƌĐĞůůƐƌĞƋƵŝƌĞƐ,;ϮͿK;ϮͿ ƚŚƌŽƵŐŚĂW<ͲĚĞƉĞŶĚĞŶƚƉĂƚŚǁĂLJ͘J Am Soc Nephrol͘ϮϬϬϮ͖ϭϯ;ϱͿ͗ϭϭϳϵͲϭϭϴϵ͘

1

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: 18PDF page: 18PDF page: 18PDF page: 18 18 ϯϬ͘ ďďĂƚĞ D͕ ŽũĂ ͕ ZŽƚƚŽůŝ ͕ ŽƌŶĂ ͕ dŽŵĂƐŽŶŝ^͕ZĞŵƵnjnjŝ'͘WƌŽdžŝŵĂůƚƵďƵůĂƌ ĐĞůůƐ ƉƌŽŵŽƚĞ ĨŝďƌŽŐĞŶĞƐŝƐ ďLJ d'&Ͳ ďĞƚĂϭͲŵĞĚŝĂƚĞĚ ŝŶĚƵĐƟŽŶ ŽĨ ƉĞƌŝƚƵďƵůĂƌ ŵLJŽĮďƌŽďůĂƐƚƐ͘Kidney Int͘ϮϬϬϮ͖ϲϭ;ϲͿ͗ϮϬϲϲͲ ϮϬϳϳ͘ ϯϭ͘ dĂŶŐ ^͕ >ĞƵŶŐ :͕ ďĞ <͕ Ğƚ Ăů͘ ůďƵŵŝŶ ƐƚŝŵƵůĂƚĞƐ ŝŶƚĞƌůĞƵŬŝŶͲϴ ĞdžƉƌĞƐƐŝŽŶ ŝŶ ƉƌŽdžŝŵĂůƚƵďƵůĂƌĞƉŝƚŚĞůŝĂůĐĞůůƐŝŶǀŝƚƌŽĂŶĚ ŝŶǀŝǀŽ͘J Clin Invest͘ϮϬϬϯ͖ϭϭϭ;ϰͿ͗ϱϭϱͲϱϮϳ͘ ϯϮ͘ ŽŶĂĚĞůůŝZ͕ĂŶĐŚŝ͕DŽƌŝŐŝD͕ĞƚĂů͘WƌŽƚĞŝŶ ŽǀĞƌůŽĂĚŝŶĚƵĐĞƐĨƌĂĐƚĂůŬŝŶĞƵƉƌĞŐƵůĂƟŽŶ ŝŶƉƌŽdžŝŵĂůƚƵďƵůĂƌĐĞůůƐƚŚƌŽƵŐŚŶƵĐůĞĂƌ ĨĂĐƚŽƌŬĂƉƉĂͲĂŶĚƉϯϴŵŝƚŽŐĞŶͲĂĐƟǀĂƚĞĚ ƉƌŽƚĞŝŶŬŝŶĂƐĞͲĚĞƉĞŶĚĞŶƚƉĂƚŚǁĂLJƐ͘J Am Soc Nephrol͘ϮϬϬϯ͖ϭϰ;ϭϬͿ͗ϮϰϯϲͲϮϰϰϲ͘ ϯϯ͘ WĞƌŝĐŽE͕ĞŶŝŐŶŝ͕ZĞŵƵnjnjŝ'͘WƌĞƐĞŶƚĂŶĚ ĨƵƚƵƌĞĚƌƵŐƚƌĞĂƚŵĞŶƚƐĨŽƌĐŚƌŽŶŝĐŬŝĚŶĞLJ ĚŝƐĞĂƐĞƐ͗ǀŽůǀŝŶŐƚĂƌŐĞƚƐŝŶƌĞŶŽƉƌŽƚĞĐƟŽŶ͘ Nat Rev Drug Discov͘ϮϬϬϴ͖ϳ;ϭϭͿ͗ϵϯϲͲϵϱϯ͘ ϯϰ͘ ĞĐŬĞƌƚ d͕ &ĞůĚƚͲZĂƐŵƵƐƐĞŶ ͕ ŽƌĐŚͲ :ŽŚŶƐĞŶ<͕:ĞŶƐĞŶd͕<ŽĨŽĞĚͲŶĞǀŽůĚƐĞŶ͘ ůďƵŵŝŶƵƌŝĂƌĞŇĞĐƚƐǁŝĚĞƐƉƌĞĂĚǀĂƐĐƵůĂƌ ĚĂŵĂŐĞ͘ƚŚĞƐƚĞŶŽŚLJƉŽƚŚĞƐŝƐ͘Diabetologia͘ ϭϵϴϵ͖ϯϮ;ϰͿ͗ϮϭϵͲϮϮϲ͘ ϯϱ͘ &ĞůĚƚͲZĂƐŵƵƐƐĞŶ͘/ŶĐƌĞĂƐĞĚƚƌĂŶƐĐĂƉŝůůĂƌLJ ĞƐĐĂƉĞ ƌĂƚĞ ŽĨ ĂůďƵŵŝŶ ŝŶ ƚLJƉĞ ϭ ;ŝŶƐƵůŝŶͲĚĞƉĞŶĚĞŶƚͿ ĚŝĂďĞƚŝĐ ƉĂƚŝĞŶƚƐ ǁŝƚŚ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘ Diabetologia͘ ϭϵϴϲ͖Ϯϵ;ϱͿ͗ϮϴϮͲϮϴϲ͘ ϯϲ͘ :ĞŶƐĞŶ:^͕ŽƌĐŚͲ:ŽŚŶƐĞŶ<͕:ĞŶƐĞŶ'͕&ĞůĚƚͲ ZĂƐŵƵƐƐĞŶ͘DŝĐƌŽĂůďƵŵŝŶƵƌŝĂƌĞŇĞĐƚƐĂ ŐĞŶĞƌĂůŝnjĞĚƚƌĂŶƐǀĂƐĐƵůĂƌĂůďƵŵŝŶůĞĂŬŝŶĞƐƐ ŝŶĐůŝŶŝĐĂůůLJŚĞĂůƚŚLJƐƵďũĞĐƚƐ͘Clin Sci (Lond)͘ ϭϵϵϱ͖ϴϴ;ϲͿ͗ϲϮϵͲϲϯϯ͘ ϯϳ͘ WĞĚƌŝŶĞůůŝ Z͕ WĞŶŶŽ '͕ Ğůů͛KŵŽ '͕ Ğƚ Ăů͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂŶĚ ƚƌĂŶƐĐĂƉŝůůĂƌLJ ĂůďƵŵŝŶůĞĂŬĂŐĞŝŶĞƐƐĞŶƟĂůŚLJƉĞƌƚĞŶƐŝŽŶ͘ Hypertension͘ϭϵϵϵ͖ϯϰ;ϯͿ͗ϰϵϭͲϰϵϱ͘ ϯϴ͘ ,ĂůĞƐE͕ĂƌŬĞƌ:͘dŚĞƚŚƌŝŌLJƉŚĞŶŽƚLJƉĞ ŚLJƉŽƚŚĞƐŝƐ͘Br Med Bull͘ϮϬϬϭ͖ϲϬ͗ϱͲϮϬ͘ ϯϵ͘ tŝƩĞ͕>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ,:͕ĚĞĞĞƵǁ ͕ĂŬŬĞƌ^:͕ĚĞ:ŽŶŐW͕'ĂŶƐĞǀŽŽƌƚZ͘&ŝƌƐƚ ŵŽƌŶŝŶŐǀŽŝĚƐĂƌĞŵŽƌĞƌĞůŝĂďůĞƚŚĂŶƐƉŽƚ ƵƌŝŶĞƐĂŵƉůĞƐƚŽĂƐƐĞƐƐŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘ J Am Soc Nephrol͘ϮϬϬϵ͖ϮϬ;ϮͿ͗ϰϯϲͲϰϰϯ͘ ϰϬ͘ ĞůŵĂŶŽǀŝƚnjd͕'ƌŽƐƐ:>͕KůŝǀĞŝƌĂ:Z͕WĂŐŐŝ ͕ dĂƚƐĐŚ D͕ njĞǀĞĚŽ D:͘ dŚĞ ƌĞĐĞŝǀĞƌ ŽƉĞƌĂƚŝŶŐ ĐŚĂƌĂĐƚĞƌŝƐƚŝĐƐ ĐƵƌǀĞ ŝŶ ƚŚĞ ĞǀĂůƵĂƟŽŶŽĨĂƌĂŶĚŽŵƵƌŝŶĞƐƉĞĐŝŵĞŶĂƐ ĂƐĐƌĞĞŶŝŶŐƚĞƐƚĨŽƌĚŝĂďĞƟĐŶĞƉŚƌŽƉĂƚŚLJ͘ Diabetes Care͘ϭϵϵϳ͖ϮϬ;ϰͿ͗ϱϭϲͲϱϭϵ͘ ϰϭ͘ /ŶĐĞƌƟ:͕ĞůŵĂŶŽǀŝƚnjd͕ĂŵĂƌŐŽ:>͕'ƌŽƐƐ :>͕ĚĞnjĞǀĞĚŽD:͘ǀĂůƵĂƟŽŶŽĨƚĞƐƚƐĨŽƌ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ƐĐƌĞĞŶŝŶŐ ŝŶ ƉĂƚŝĞŶƚƐ ǁŝƚŚ ĚŝĂďĞƚĞƐ͘ Nephrol Dial Transplant͘ ϮϬϬϱ͖ϮϬ;ϭϭͿ͗ϮϰϬϮͲϮϰϬϳ͘ ϰϮ͘ EĂƚŚĂŶ D͕ ZŽƐĞŶďĂƵŵ ͕ WƌŽƚĂƐŽǁŝĐŬŝ s͘^ŝŶŐůĞͲǀŽŝĚƵƌŝŶĞƐĂŵƉůĞƐĐĂŶďĞƵƐĞĚ ƚŽĞƐƟŵĂƚĞƋƵĂŶƟƚĂƟǀĞŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘ Diabetes Care͘ϭϵϴϳ͖ϭϬ;ϰͿ͗ϰϭϰͲϰϭϴ͘ ϰϯ͘ :ĞƌŵĞŶĚLJ'͕&ĂƌŬĂƐ<͕EĂĚĂƐ:͕ĂƌŽĐnjLJ͕ WĞƚĞƌĨĂŝ͘WƌĂĐƟĐĂůĂƐƉĞĐƚƐŽĨŵĞĂƐƵƌŝŶŐ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝŶ ĚŝĂďĞƚŝĐ ƉĂƚŝĞŶƚƐ͘ Diabetes Nutr Metab͘ϮϬϬϭ͖ϭϰ;ϰͿ͗ϭϵϱͲϮϬϬ͘ ϰϰ͘ 'ĂƌĂďĞĚ͕>ĂŵĞŝƌĞE͘</'KϮϬϭϮĐůŝŶŝĐĂů ƉƌĂĐƟĐĞŐƵŝĚĞůŝŶĞĨŽƌƚŚĞĞǀĂůƵĂƟŽŶĂŶĚ ŵĂŶĂŐĞŵĞŶƚŽĨĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͘͘ ϮϬϭϮ͘ ϰϱ͘ >ŝĂǁ>͕EĂLJĂƌD͕WĞĚůĞƌ^:͕ŽƵůƚŚĂƌĚD'͘ ,ŽŵĞĐŽůůĞĐƟŽŶŽĨƵƌŝŶĞĨŽƌĐƵůƚƵƌĞĨƌŽŵ ŝŶĨĂŶƚƐďLJƚŚƌĞĞŵĞƚŚŽĚƐ͗^ƵƌǀĞLJŽĨƉĂƌĞŶƚƐ͛ ƉƌĞĨĞƌĞŶĐĞƐ ĂŶĚ ďĂĐƚĞƌŝĂů ĐŽŶƚĂŵŝŶĂƟŽŶ ƌĂƚĞƐ͘BMJ͘ϮϬϬϬ͖ϯϮϬ;ϳϮϰϱͿ͗ϭϯϭϮͲϭϯϭϯ͘ ϰϲ͘ DĂĐĨĂƌůĂŶĞW/͕ůůŝƐZ͕,ƵŐŚĞƐ͕,ŽƵŐŚƚŽŶ ͕ >ŽƌĚ Z͘ hƌŝŶĞ ĐŽůůĞĐƚŝŽŶ ƉĂĚƐ͗ ƌĞ ƐĂŵƉůĞƐ ƌĞůŝĂďůĞ ĨŽƌ ƵƌŝŶĞ ďŝŽĐŚĞŵŝƐƚƌLJ ĂŶĚ ŵŝĐƌŽƐĐŽƉLJ͍ Pediatr Nephrol͘ ϮϬϬϱ͖ϮϬ;ϮͿ͗ϭϳϬͲϭϳϵ͘ ϰϳ͘ DĂŶŶ :&͕ ZĞŝƐĐŚ ͕ Zŝƚnj ͘ hƐĞ ŽĨ ĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐĞŶnjLJŵĞŝŶŚŝďŝƚŽƌƐ ĨŽƌ ƚŚĞ ƉƌĞƐĞƌǀĂƟŽŶ ŽĨ ŬŝĚŶĞLJ ĨƵŶĐƟŽŶ͘  ƌĞƚƌŽƐƉĞĐƟǀĞ ƐƚƵĚLJ͘ Nephron͘ ϭϵϵϬ͖ϱϱ ^ƵƉƉůϭ͗ϯϴͲϰϮ͘

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: 19PDF page: 19PDF page: 19PDF page: 19 19 ϰϴ͘ ƌŝĐŚĂƌĚ^D͕^ĂŶƚŽŶŝ:W͕dŚŽŵĂƐ:Z͕ǀĂŶĚĞ sŽŽƌĚĞ<͕<ĞƚĞůƐůĞŐĞƌƐ:D͕>ĂŵďĞƌƚ͘>ŽŶŐ ƚĞƌŵƌĞĚƵĐƟŽŶŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂĂŌĞƌ ϭLJĞĂƌŽĨĂŶŐŝŽƚĞŶƐŝŶĐŽŶǀĞƌƟŶŐĞŶnjLJŵĞ ŝŶŚŝďŝƟŽŶ ďLJ ƉĞƌŝŶĚŽƉƌŝů ŝŶ ŚLJƉĞƌƚĞŶƐŝǀĞ ŝŶƐƵůŝŶͲƚƌĞĂƚĞĚĚŝĂďĞƟĐƉĂƟĞŶƚƐ͘ Diabete Metab͘ϭϵϵϬ͖ϭϲ;ϭͿ͗ϯϬͲϯϲ͘ ϰϵ͘ <ƵǁĂďĂƌĂ͕^ĂƚŽŚD͕dŽŵŝƚĂE͕^ĂƐĂŬŝd͕ <ĂƐŚŝŚĂƌĂE͘ĞƚĞƌŝŽƌĂƟŽŶŽĨŐůŽŵĞƌƵůĂƌ ĞŶĚŽƚŚĞůŝĂů ƐƵƌĨĂĐĞ ůĂLJĞƌ ŝŶĚƵĐĞĚ ďLJ ŽdžŝĚĂƟǀĞ ƐƚƌĞƐƐ ŝƐ ŝŵƉůŝĐĂƚĞĚ ŝŶ ĂůƚĞƌĞĚ ƉĞƌŵĞĂďŝůŝƚLJŽĨŵĂĐƌŽŵŽůĞĐƵůĞƐŝŶnjƵĐŬĞƌ ĨĂƩLJƌĂƚƐ͘Diabetologia͘ϮϬϭϬ͖ϱϯ;ϵͿ͗ϮϬϱϲͲ ϮϬϲϱ͘ ϱϬ͘ zŽŶĞĚĂ ,͕ hĞƚĂ <͕ EĂŐĂƐĂŬŝ D͕ ƌĂŬĂǁĂ <͘/ŶǀŽůǀĞŵĞŶƚŽĨŚĞƉĂƌĂŶƐƵůĨĂƚĞŝŶƚŚĞ renoprotective effects of imidapril, an ĂŶŐŝŽƚĞŶƐŝŶͲĐŽŶǀĞƌƟŶŐ ĞŶnjLJŵĞ ŝŶŚŝďŝƚŽƌ͕ ŝŶ ĚŝĂďĞƚŝĐ ĚďͬĚď ŵŝĐĞ͘ J Recept Signal Transduct Res͘ϮϬϭϰ͖ϯϰ;ϭͿ͗ϮϭͲϮϱ͘

ϱϭ͘ DĂŶŶ :&͕ ^ĐŚŵŝĞĚĞƌ Z͕ LJĂů >͕ Ğƚ Ăů͘ īĞĐƚ ŽĨ ƚĞůŵŝƐĂƌƚĂŶ ŽŶ ƌĞŶĂů ŽƵƚĐŽŵĞƐ͗  ƌĂŶĚŽŵŝnjĞĚ ƚƌŝĂů͘ Ann Intern Med͘ ϮϬϬϵ͖ϭϱϭ;ϭͿ͗ϭͲϭϬ͕tϭͲϮ͘

ϱϮ͘ DĂŬŝŶŽ ,͕ ,ĂŶĞĚĂ D͕ ĂďĂnjŽŶŽ d͕ Ğƚ Ăů͘ Prevention of transition from incipient ƚŽŽǀĞƌƚŶĞƉŚƌŽƉĂƚŚLJǁŝƚŚƚĞůŵŝƐĂƌƚĂŶŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ƚLJƉĞ Ϯ ĚŝĂďĞƚĞƐ͘ Diabetes Care͘ϮϬϬϳ͖ϯϬ;ϲͿ͗ϭϱϳϳͲϭϱϳϴ͘ ϱϯ͘ ,ŽƵ&&͕ŚĂŶŐy͕ŚĂŶŐ',͕ĞƚĂů͘ĸĐĂĐLJ ĂŶĚ ƐĂĨĞƚLJ ŽĨ ďĞŶĂnjĞƉƌŝů ĨŽƌ ĂĚǀĂŶĐĞĚ ĐŚƌŽŶŝĐƌĞŶĂůŝŶƐƵĸĐŝĞŶĐLJ͘N Engl J Med͘ ϮϬϬϲ͖ϯϱϰ;ϮͿ͗ϭϯϭͲϭϰϬ͘ ϱϰ͘ ƌĞŶŶĞƌ D͕ ŽŽƉĞƌ D͕ ĚĞ ĞĞƵǁ ͕ Ğƚ Ăů͘ ĨĨĞĐƚƐ ŽĨ ůŽƐĂƌƚĂŶ ŽŶ ƌĞŶĂů ĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞƐŝŶƉĂƟĞŶƚƐǁŝƚŚ ƚLJƉĞϮĚŝĂďĞƚĞƐĂŶĚŶĞƉŚƌŽƉĂƚŚLJ͘N Engl J Med͘ϮϬϬϭ͖ϯϰϱ;ϭϮͿ͗ϴϲϭͲϴϲϵ͘ ϱϱ͘ >ĞǁŝƐ:͕,ƵŶƐŝĐŬĞƌ>'͕ůĂƌŬĞtZ͕ĞƚĂů͘ ZĞŶŽƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨƚŚĞĂŶŐŝŽƚĞŶƐŝŶͲ ƌĞĐĞƉƚŽƌĂŶƚĂŐŽŶŝƐƚŝƌďĞƐĂƌƚĂŶŝŶƉĂƟĞŶƚƐ ǁŝƚŚŶĞƉŚƌŽƉĂƚŚLJĚƵĞƚŽƚLJƉĞϮĚŝĂďĞƚĞƐ͘ N Engl J Med͘ϮϬϬϭ͖ϯϰϱ;ϭϮͿ͗ϴϱϭͲϴϲϬ͘ ϱϲ͘ ŚŵĞĚ<͕<ĂŵĂƚŚE^͕ů<ŽƐƐŝD͕ůEĂŚĂƐ D͘dŚĞŝŵƉĂĐƚŽĨƐƚŽƉƉŝŶŐŝŶŚŝďŝƚŽƌƐŽĨƚŚĞ ƌĞŶŝŶͲĂŶŐŝŽƚĞŶƐŝŶƐLJƐƚĞŵŝŶƉĂƟĞŶƚƐǁŝƚŚ ĂĚǀĂŶĐĞĚĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͘Nephrol Dial Transplant͘ϮϬϭϬ͖Ϯϱ;ϭϮͿ͗ϯϵϳϳͲϯϵϴϮ͘ ϱϳ͘ KŶƵŝŐďŽD͕KŶƵŝŐďŽEd͘>ĂƚĞͲŽŶƐĞƚƌĞŶĂů ĨĂŝůƵƌĞ ĨƌŽŵ Z^ ďůŽĐŬĂĚĞ͘ Kidney Int͘ ϮϬϬϲ͖ϳϬ;ϳͿ͗ϭϯϳϴͲϭϯϳϵ͘ ϱϴ͘ ,ĂŶƐĞŶ ,W͕ ZŽƐƐŝŶŐ W͕ dĂƌŶŽǁ >͕ EŝĞůƐĞŶ &^͕ :ĞŶƐĞŶ Z͕ WĂƌǀŝŶŐ ,,͘ /ŶĐƌĞĂƐĞĚ ŐůŽŵĞƌƵůĂƌĮůƚƌĂƟŽŶƌĂƚĞĂŌĞƌǁŝƚŚĚƌĂǁĂů ŽĨ ůŽŶŐͲƚĞƌŵ ĂŶƟŚLJƉĞƌƚĞŶƐŝǀĞ ƚƌĞĂƚŵĞŶƚ ŝŶ ĚŝĂďĞƚŝĐ ŶĞƉŚƌŽƉĂƚŚLJ͘ Kidney Int͘ ϭϵϵϱ͖ϰϳ;ϲͿ͗ϭϳϮϲͲϭϳϯϭ͘ ϱϵ͘ ^W dƌŝĂů 'ƌŽƵƉ͕ tƵŚů ͕ dƌŝǀĞůůŝ ͕ Ğƚ Ăů͘ ^ƚƌŝĐƚ ďůŽŽĚͲƉƌĞƐƐƵƌĞ ĐŽŶƚƌŽů ĂŶĚ ƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨĂŝůƵƌĞŝŶĐŚŝůĚƌĞŶ͘E ŶŐů:DĞĚ͘ϮϬϬϵ͖ϯϲϭ;ϭϳͿ͗ϭϲϯϵͲϭϲϱϬ͘ ϲϬ͘ tŽŶŐ ^͕ WŝĞƌĐĞ ͕ ŽůĞ ^Z͕ Ğƚ Ăů͘ ƐƐŽĐŝĂƟŽŶŽĨƉƌŽƚĞŝŶƵƌŝĂǁŝƚŚƌĂĐĞ͕ĐĂƵƐĞ ŽĨĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͕ĂŶĚŐůŽŵĞƌƵůĂƌ ĮůƚƌĂƟŽŶƌĂƚĞŝŶƚŚĞĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ ŝŶĐŚŝůĚƌĞŶƐƚƵĚLJ͘ůŝŶ:ŵ^ŽĐEĞƉŚƌŽů͘ ϮϬϬϵ͖ϰ;ϰͿ͗ϴϭϮͲϴϭϵ͘ ϲϭ͘ 'ĂƌƚĞŶŵĂŶŶ ͕ &ŽƐƐĂůŝ ͕ ǀŽŶ sŝŐŝĞƌ ZK͕ĞƚĂů͘ĞƩĞƌƌĞŶŽƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨ ĂŶŐŝŽƚĞŶƐŝŶ // ĂŶƚĂŐŽŶŝƐƚ ĐŽŵƉĂƌĞĚ ƚŽ ĚŝŚLJĚƌŽƉLJƌŝĚŝŶĞ ĐĂůĐŝƵŵ ĐŚĂŶŶĞů ďůŽĐŬĞƌ ŝŶĐŚŝůĚŚŽŽĚ͘<ŝĚŶĞLJ/Ŷƚ͘ϮϬϬϯ͖ϲϰ;ϰͿ͗ϭϰϱϬͲ ϭϰϱϰ͘ ϲϮ͘ ůůŝƐ ͕ DŽƌŝƚnj D>͕ sĂƚƐ ͕ :ĂŶŽƐŬLJ :͘ ŶƚŝŚLJƉĞƌƚĞŶƐŝǀĞ ĂŶĚ ƌĞŶŽƉƌŽƚĞĐƚŝǀĞ ĞĸĐĂĐLJĂŶĚƐĂĨĞƚLJŽĨůŽƐĂƌƚĂŶ͘ůŽŶŐͲƚĞƌŵ ƐƚƵĚLJŝŶĐŚŝůĚƌĞŶǁŝƚŚƌĞŶĂůĚŝƐŽƌĚĞƌƐ͘ŵ: ,LJƉĞƌƚĞŶƐ͘ϮϬϬϰ͖ϭϳ;ϭϬͿ͗ϵϮϴͲϵϯϱ͘ ϲϯ͘ sĂŶLJĐŬD͕WƌŽĞƐŵĂŶƐt͘ZĞŶŽƉƌŽƚĞĐƟŽŶ ďLJ  ŝŶŚŝďŝƚŽƌƐ ĂŌĞƌ ƐĞǀĞƌĞ ŚĞŵŽůLJƟĐ ƵƌĞŵŝĐ ƐLJŶĚƌŽŵĞ͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ ϮϬϬϰ͖ϭϵ;ϲͿ͗ϲϴϴͲϲϵϬ͘ ϲϰ͘ ƌĚŝƐƐŝŶŽ'͕sŝŐĂŶŽ^͕dĞƐƚĂ^͕ĞƚĂů͘EŽĐůĞĂƌ ĞǀŝĚĞŶĐĞŽĨŝĞĸĐĂĐLJŽŶƚŚĞƉƌŽŐƌĞƐƐŝŽŶ ŽĨĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞŝŶĐŚŝůĚƌĞŶǁŝƚŚ ŚLJƉŽĚLJƐƉůĂƐƟĐŶĞƉŚƌŽƉĂƚŚLJͲͲƌĞƉŽƌƚĨƌŽŵ ƚŚĞ/ƚĂů<ŝĚƉƌŽũĞĐƚĚĂƚĂďĂƐĞ͘EĞƉŚƌŽůŝĂů dƌĂŶƐƉůĂŶƚ͘ϮϬϬϳ͖ϮϮ;ϵͿ͗ϮϱϮϱͲϮϱϯϬ͘

1

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: 21PDF page: 21PDF page: 21PDF page: 21

Part 1

The prevalence and measurement

of albuminuria in children

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: 23PDF page: 23PDF page: 23PDF page: 23

Prevalence and distribution of (micro)

albuminuria in toddlers

Authors sĂůĞŶƟŶĂ'ƌĂĐĐŚŝ1*_{͕^ŽƉŚŝĞD͘ǀĂŶĚĞŶĞůƚ}2_{Ύ͕>ĞĂŶŶĞ<͘<ƺƉĞƌƐ}3_͕ǀĂ ŽƌƉĞůĞŝũŶ3_{͕ŝĐŬĚĞĞĞƵǁ}2_{͕,ŝĚĚŽ:͘>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ}2 ĸůŝĂƟŽŶƐ 1_{ĞƉĂƌƚŵĞŶƚŽĨWĞĚŝĂƚƌŝĐEĞƉŚƌŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ} 'ƌŽŶŝŶŐĞŶ͕dŚĞEĞƚŚĞƌůĂŶĚƐ 2_{ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůWŚĂƌŵĂĐLJĂŶĚWŚĂƌŵĂĐŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂů} ĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕dŚĞEĞƚŚĞƌůĂŶĚƐ 3_{ĞƉĂƌƚŵĞŶƚŽĨƉŝĚĞŵŝŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕} dŚĞEĞƚŚĞƌůĂŶĚƐ ΎŽƚŚĂƵƚŚŽƌƐĐŽŶƚƌŝďƵƚĞĚĞƋƵĂůůLJƚŽƚŚĞŵĂŶƵƐĐƌŝƉƚ EĞƉŚƌŽůŽŐLJŝĂůLJƐŝƐdƌĂŶƐƉůĂŶƚĂƟŽŶ͕ϮϬϭϲ͖ϯϭ;ϭϬͿ͗ϭϲϴϲͲϭϲϵϮ

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

Processed on: 17-4-2018 PDF page: 24PDF page: 24PDF page: 24PDF page: 24 24

Abstract

Background DŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĐŽŵŵŽŶŝŶƚŚĞŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶǁŝƚŚĂƉƌĞǀĂůĞŶĐĞŽĨΕϳй ĂŶĚŝƐĂŶŝŶĚĞƉĞŶĚĞŶƚŝŶĚŝĐĂƚŽƌŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬƐ͘tŚĞƚŚĞƌĂůďƵŵŝŶƵƌŝĂ ŝƐĂĐƋƵŝƌĞĚĚƵƌŝŶŐůŝĨĞ;ĂƐĂƌĞƐƵůƚŽĨŚLJƉĞƌƚĞŶƐŝŽŶͬĚŝĂďĞƚĞƐͿŽƌŝƐĐŽŶŐĞŶŝƚĂůĂŶĚĂůƌĞĂĚLJ ƉƌĞƐĞŶƚĂƚďŝƌƚŚŝƐƵŶŬŶŽǁŶ͘tĞƐƚƵĚŝĞĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐ ĂŶĚĐŽŵƉĂƌĞĚƚŚĞĚŝƐƚƌŝďƵƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂǁŝƚŚƚŚĂƚŽĨƚŚĞŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶ͘ /ŶĂĚĚŝƟŽŶ͕ǁĞůŽŽŬĞĚĨŽƌƉŽƐƐŝďůĞĂƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂĂŶĚĂŶƚĞŶĂƚĂů͕ ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐ͘ Methods dŚĞƵƌŝŶĂƌLJĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶ;h_ͿǁĂƐŵĞĂƐƵƌĞĚŝŶϭϯϱϮĐŚŝůĚƌĞŶĂŶĚƚŚĞƵƌŝŶĂƌLJ ĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ;h_ZͿŝŶϭϮϴϴĐŚŝůĚƌĞŶĨƌŽŵƚŚĞ'ƌŽŶŝŶŐĞŶdžƉĞƌƚĞŶƚĞƌĨŽƌ<ŝĚƐ ǁŝƚŚKďĞƐŝƚLJ;'<KͿƌĞŶƚŚĞĐŽŚŽƌƚ;ĂŐĞƌĂŶŐĞϮϬͲϰϬŵŽŶƚŚƐͿ͘ůďƵŵŝŶƵƌŝĂĚŝƐƚƌŝďƵƟŽŶ ǁĂƐĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞĂůďƵŵŝŶƵƌŝĂĚŝƐƚƌŝďƵƟŽŶŝŶϰϬϴϱϰƉĂƌƟĐŝƉĂŶƚƐŽĨƚŚĞŐĞŶĞƌĂů ĂĚƵůƚĐŽŚŽƌƚŽĨƚŚĞWƌĞǀĞŶƟŽŶŽĨZĞŶĂůĂŶĚsĂƐĐƵůĂƌŶĚ^ƚĂŐĞŝƐĞĂƐĞ;WZsEͿƐƚƵĚLJ͘ ƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶĂůďƵŵŝŶƵƌŝĂ;ĞdžƉƌĞƐƐĞĚĂƐh_ĂŶĚh_ZͿĂŶĚĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂů ĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐǁĞƌĞƚĞƐƚĞĚǁŝƚŚůŝŶĞĂƌƌĞŐƌĞƐƐŝŽŶĂŶĂůLJƐŝƐ͘ Results dŚĞŵĞĚŝĂŶh_ŝŶƚŚĞ'<KƐƚƵĚLJǁĂƐϮ͘ϯŵŐͬ>;ϱth_-95th_{ƉĞƌĐĞŶƟůĞƐ͗Ϯ͘ϭͲϮϱ͘ϱͿĂŶĚŝŶ} ƚŚĞWZsEƐƚƵĚLJϲ͘ϬŵŐͬ>;Ϯ͘ϯͲϮϴ͘ϲͿ;WĚŝƐƚƌŝďƵƟŽŶĐŽŵƉĂƌŝƐŽŶϬ͘ϬϱϯͿ͘WƌĞǀĂůĞŶĐĞŽĨ h_шϮϬŵŐͬ>ǁĂƐϲ͘ϵйŝŶ'<KĂŶĚϳ͘ϴйŝŶWZsE;WсϬ͘ϭϵϱͿ͘dŚĞƉƌĞǀĂůĞŶĐĞŽĨh_Z шϯϬŵŐͬŐŝŶƚŚĞ'<KƐƚƵĚLJǁĂƐϮϯ͘ϰй͘h_ĂŶĚh_ZǁĞƌĞůŽǁĞƌŝŶďŽLJƐ͘h_ǁĂƐŶŽƚ ĂƐƐŽĐŝĂƚĞĚǁŝƚŚŽƚŚĞƌĚĞƚĞƌŵŝŶĂŶƚƐ͕ďƵƚh_ZǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŐĞĂŶĚŐĞƐƚĂƟŽŶĂů ĚŝĂďĞƚĞƐ͘ Conclusions dŚĞĚŝƐƚƌŝďƵƟŽŶŽĨh_ĂŶĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨh_хϮϬŵŐͬ>ŝŶƚŽĚĚůĞƌƐĂŶĚŝŶƚŚĞLJŽƵŶŐ ŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶĂƌĞĐŽŵƉĂƌĂďůĞ͘dŚĞƐĞĮŶĚŝŶŐƐƐƵŐŐĞƐƚƚŚĂƚŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝƐĂĐŽŶŐĞŶŝƚĂůĐŽŶĚŝƟŽŶƚŚĂƚŵĂLJƉƌĞĚŝƐƉŽƐĞƚŽĂŚŝŐŚĞƌĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬůĂƚĞƌŝŶůŝĨĞ͘

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: 25PDF page: 25PDF page: 25PDF page: 25 25

Introduction

DŝůĚ ƚŽ ŵŽĚĞƌĂƚĞ ŝŶĐƌĞĂƐĞ ŽĨ ƵƌŝŶĂƌLJ ĂůďƵŵŝŶ ŚĂƐ Ă ŚŝŐŚ ƉƌĞǀĂůĞŶĐĞ ŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ĚŝĂďĞƚĞƐ ŵĞůůŝƚƵƐ͕ ŚLJƉĞƌƚĞŶƐŝŽŶ ĂŶĚ ĐŚƌŽŶŝĐ ŬŝĚŶĞLJ ĚŝƐĞĂƐĞ͘1,2 _{This so-called} ͚ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͛ĂƉƉĞĂƌƐƚŽďĞĂƌŝƐŬŵĂƌŬĞƌĨŽƌƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐ ůĂƚĞƌŝŶůŝĨĞ͘3,4 /ƚŚĂƐďĞĞŶĚŝƐĐƵƐƐĞĚǁŚĞƚŚĞƌƚŚĞƐĞŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂůĞǀĞůƐĂƌĞĂĐŽŶƐĞƋƵĞŶĐĞ ŽĨƌĞŶĂůĚŝƐĞĂƐĞŽƌŝĨĂůďƵŵŝŶƵƌŝĂŝƚƐĞůĨŝƐĂŶŝŶĚĞƉĞŶĚĞŶƚƌŝƐŬĨĂĐƚŽƌĨŽƌƌĞŶĂůĂŶĚͬŽƌ ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘/ŶƚĞƌĞƐƟŶŐŝŶƚŚŝƐĐŽŶƚĞdžƚŝƐƚŚĞĮŶĚŝŶŐƚŚĂƚĂƉƉĂƌĞŶƚůLJ͚ŚĞĂůƚŚLJ͛ ŝŶĚŝǀŝĚƵĂůƐǁŝƚŚŽƵƚƌĞŶĂůĚŝƐĞĂƐĞ͕ĚŝĂďĞƚĞƐ͕ŽƌŚLJƉĞƌƚĞŶƐŝŽŶĂůƐŽƐŚŽǁĂŚŝŐŚƉƌĞǀĂůĞŶĐĞ ŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͕ǀĂƌLJŝŶŐĨƌŽŵϱ͘ϱƚŽϲ͘ϲй͘DŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĂůƐŽĂƉƌĞĚŝĐƚŽƌĨŽƌ ĨƵƚƵƌĞĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘5-8_{dŚĞƐĞĮŶĚŝŶŐƐĂƉƉĞĂƌƚŽƐƵƉƉŽƌƚƚŚĞƐƵŐŐĞƐƟŽŶƚŚĂƚ} ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĂŶŝŶĚĞƉĞŶĚĞŶƚƌŝƐŬĨĂĐƚŽƌͲĂŶĚĐŽƵůĚŵĂLJďĞĞǀĞŶďĞĂĐĂƵƐĞͲĨŽƌ ƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐ͘ dŚĞƉƵƚĂƟǀĞŵĞĐŚĂŶŝƐŵŽĨƐƵĐŚĂĐĂƵƐĂůƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶĞdžĐĞƐƐŝǀĞĂůďƵŵŝŶ ůĞĂŬĂŶĚƌĞŶĂůͬĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞĐŽƵůĚďĞĂŶĞŶĚŽƚŚĞůŝĂůĚLJƐĨƵŶĐƟŽŶ͕ƐƵĐŚĂƐ ŐůLJĐŽĐĂůLJdžůŽƐƐ͘9_{dŚŝƐĚLJƐĨƵŶĐƟŽŶ͚ĂůůŽǁƐ͛ĂůďƵŵŝŶƚŽĞƐĐĂƉĞƚŚĞǀĂƐĐƵůĂƌƐƉĂĐĞĂŶĚ} ŝŶĚƵĐĞƐƐƵďĞŶĚŽƚŚĞůŝĂůǀĂƐĐƵůĂƌůŽǁͲŐƌĂĚĞŝŶŇĂŵŵĂƟŽŶ͕ǁŝƚŚƚŚĞƵůƟŵĂƚĞĐŽŶƐĞƋƵĞŶĐĞ ŽĨǁŝĚĞƐƉƌĞĂĚŽƌŐĂŶĚĂŵĂŐĞ͘10_{dŚĞĐĂƵƐĞŽĨƚŚŝƐĞŶĚŽƚŚĞůŝĂůĚLJƐĨƵŶĐƟŽŶͲĂŶĚƚŚƵƐŽĨ} ƚŚĞŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂͲŝƐƵŶŬŶŽǁŶďƵƚŝƚŵŝŐŚƚďĞĐŽŶŐĞŶŝƚĂů͕ŵĞĂŶŝŶŐƚŚĂƚĚŝīĞƌĞŶƚ ŝŶĚŝǀŝĚƵĂůƐĂƌĞďŽƌŶǁŝƚŚĂůĂƌŐĞǀĂƌŝĂďŝůŝƚLJŝŶǀĂƐĐƵůĂƌĨƵŶĐƟŽŶĂŶĚƚŚĞƌĞĨŽƌĞǀĂƌLJŝŶŐ ĐŽŶƐƟƚƵƟŽŶĂůƵƌŝŶĞĂůďƵŵŝŶĞdžĐƌĞƟŽŶƐ͘/ŶĚĞĞĚ͕ŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶĞdžĐƌĞƟŽŶŝƐŽďƐĞƌǀĞĚ ŝŶŶĞǁďŽƌŶƐĂŶĚƚŽĚĚůĞƌƐŝŶƐŵĂůůƐƚƵĚŝĞƐŵĞĂƐƵƌŝŶŐůĂďŽƌĂƚŽƌLJƌĞĨĞƌĞŶĐĞǀĂůƵĞƐ͘11 _This ŽďƐĞƌǀĂƟŽŶŝƐƐƵƉƉŽƌƚĞĚďLJĞdžƉĞƌŝŵĞŶƚĂůƐƚƵĚŝĞƐĚĞŵŽŶƐƚƌĂƟŶŐĂůĂƌŐĞǀĂƌŝĂďŝůŝƚLJŝŶ ĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶŝŶƌĂƚƐĂƚďŝƌƚŚ͘dŚĞƐĞĚĂƚĂĂůƐŽƐŚŽǁƚŚĂƚƚŚĞƌĂƚƐǁŝƚŚƚŚĞƉŽŽƌĞƐƚ ĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶǁĞƌĞƚŚĞŵŽƐƚƐƵƐĐĞƉƟďůĞƚŽƌĞŶĂůĚĂŵĂŐĞ͘12_{dŚŝƐĐŽƵůĚŝŵƉůLJ} ƚŚĂƚƐŽŵĞŝŶĚŝǀŝĚƵĂůƐŚĂǀĞĂůƌĞĂĚLJĂƚďŝƌƚŚŚŝŐŚůĞǀĞůƐŽĨĂůďƵŵŝŶƵƌŝĂ͕ĂƐĂƌĞƐƵůƚŽĨ ŝŶďŽƌŶŝŵƉĂŝƌĞĚĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶ͕ǁŚŝĐŚŽŶƚŚĞůŽŶŐƚĞƌŵůĞĂĚƐƚŽĂŚŝŐŚĞƌƌĞŶĂů ĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬ͘13 dŚĞĂŝŵŽĨƚŚĞĐƵƌƌĞŶƚƐƚƵĚLJǁĂƐƚŽĚĞƐĐƌŝďĞƚŚĞĚŝƐƚƌŝďƵƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚƚŚĞ ƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶǀĞƌLJLJŽƵŶŐĐŚŝůĚƌĞŶ͘&ƵƌƚŚĞƌŵŽƌĞ͕ǁĞŝŶƚĞŶĚĞĚƚŽ ŝĚĞŶƟĨLJĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐƚŚĂƚĐŽƵůĚĞdžƉůĂŝŶĚŝīĞƌĞŶĐĞƐďĞƚǁĞĞŶ ĐŚŝůĚƌĞŶ͘&ŽƌƚŚŝƐƉƵƌƉŽƐĞ͕ǁĞŝŶǀĞƐƟŐĂƚĞĚĂůĂƌŐĞĐŽŚŽƌƚŽĨƚŽĚĚůĞƌƐŽĨƚŚĞŐĞŶĞƌĂůƵƚĐŚ ƉŽƉƵůĂƟŽŶ;'ƌŽŶŝŶŐĞŶdžƉĞƌƚĞŶƚĞƌĨŽƌ<ŝĚƐǁŝƚŚKďĞƐŝƚLJ͖'<KͿ͘dŚĞƐĞĚĂƚĂǁĞƌĞ ĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞĚĂƚĂĨƌŽŵƚŚĞŐĞŶĞƌĂůĂĚƵůƚƵƚĐŚƉŽƉƵůĂƟŽŶŽĨƚŚĞWƌĞǀĞŶƟŽŶŽĨ ZĞŶĂůĂŶĚsĂƐĐƵůĂƌŶĚƐƚĂŐĞŝƐĞĂƐĞ;WZsEͿĐŽŚŽƌƚ͘

Methods

dŚŝƐƐƚƵĚLJǁĂƐĞŵďĞĚĚĞĚŝŶƚŚĞ'<KͲƌĞŶƚŚĞƐƚƵĚLJ͕ĂƉŽƉƵůĂƟŽŶͲďĂƐĞĚƉƌŽƐƉĞĐƟǀĞ ďŝƌƚŚĐŽŚŽƌƚƐƚƵĚLJŽĨĐŚŝůĚƌĞŶďŽƌŶďĞƚǁĞĞŶƉƌŝůϮϬϬϲĂŶĚƉƌŝůϮϬϬϳŝŶƌĞŶƚŚĞ͕Ă

2