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

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.

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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: 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

ϮϯйͿ͘

1-8

/ŶƚĞƌĞƐƚŝŶŐůLJ͕ ĂůďƵŵŝŶƵƌŝĂ ŚĂƐ ďĞĞŶ ƌĞƉŽƌƚĞĚ ĂƐ Ă ƌŝƐŬ ŵĂƌŬĞƌ ĨŽƌ ƌĞŶĂů ĂŶĚ

ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͗ƚŚĞŚŝŐŚĞƌƚŚĞĂůďƵŵŝŶŝŶƵƌŝŶĞ͕ƚŚĞŚŝŐŚĞƌƚŚĞƌŝƐŬĨŽƌƌĞŶĂůĂŶĚͬ

ŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘

9-15

_{dŚŝƐŝŵŵĞĚŝĂƚĞůLJƌĂŝƐĞƐƚŚĞƋƵĞƐƟŽŶǁŚĞƚŚĞƌǁĞƐŚŽƵůĚ}

ůŽǁĞƌĂůďƵŵŝŶƵƌŝĂƚŽƉƌĞƐĞƌǀĞĨƵŶĐƟŽŶŽĨƚŚĞƐĞŽƌŐĂŶƐ͘,ŽǁĞǀĞƌ͕ƚŚĞŝŵƉŽƌƚĂŶĐĞŽĨ

ĂůďƵŵŝŶƵƌŝĂĂƐĂƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚŝŶƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞŝƐƵŶĚĞƌĚŝƐĐƵƐƐŝŽŶ͘

/ŶŽƌĚĞƌƚŽĂĐĐĞƉƚĂďŝŽŵĂƌŬĞƌ͕ŝŶƚŚŝƐĐĂƐĞĂůďƵŵŝŶƵƌŝĂ͕ĂƐĂŶĂƉƉƌŽƉƌŝĂƚĞƚŚĞƌĂƉĞƵƟĐ

ƚĂƌŐĞƚ͕ƚŚƌĞĞŝŵƉŽƌƚĂŶƚĐƌŝƚĞƌŝĂƐŚŽƵůĚďĞŵĞƚ͘

16,17

_{First, evidence of a consistent and}

ŝŶĚĞƉĞŶĚĞŶƚĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶůĞǀĞůƐŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚƌĞŶĂůͬĐĂƌĚŝŽǀĂƐĐƵůĂƌĞŶĚ

ƉŽŝŶƚƐĚƵƌŝŶŐĨŽůůŽǁͲƵƉŵƵƐƚďĞĂǀĂŝůĂďůĞ͘^ĞĐŽŶĚ͕ĐůŝŶŝĐĂůƚƌŝĂůĞǀŝĚĞŶĐĞŶĞĞĚƐƚŽƐŚŽǁ

ĂŶĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƚŚĞĞīĞĐƚƐŽĨĚŝīĞƌĞŶƚŝŶƚĞƌǀĞŶƟŽŶƐƚŚĂƚůŽǁĞƌĂůďƵŵŝŶƵƌŝĂ

ĂŶĚƚŚĞƐƵďƐĞƋƵĞŶƚƌĞĚƵĐƟŽŶŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬ͘ŶĚƚŚŝƌĚ͕ĂďŝŽůŽŐŝĐĂů

ŵĞĐŚĂŶŝƐŵƐŚŽƵůĚďĞĂǀĂŝůĂďůĞƚŽĞdžƉůĂŝŶŚŽǁĂůďƵŵŝŶƵƌŝĂĐĂƵƐĞƐƌĞŶĂůĚĂŵĂŐĞ͘

/ŶĚĞĞĚ͕ĐŽŚŽƌƚƐƚƵĚŝĞƐŚĂǀĞƐŚŽǁŶĂƐƚƌŽŶŐ͕ĐŽŶƐŝƐƚĞŶƚĂŶĚŝŶĚĞƉĞŶĚĞŶƚĂƐƐŽĐŝĂƟŽŶ

ďĞƚǁĞĞŶƚŚĞĂŵŽƵŶƚŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚƌŝƐŬŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͕ďŽƚŚŝŶ

ŚĞĂůƚŚLJƐƵďũĞĐƚƐĂŶĚŝŶƉĂƟĞŶƚƐǁŝƚŚĚŝĂďĞƚĞƐŽƌŚLJƉĞƌƚĞŶƐŝŽŶ͕ŵĞĞƟŶŐƚŚĞĮƌƐƚĐƌŝƚĞƌŝŽŶ

ĨŽƌƚŚĞĂĐĐĞƉƚĂŶĐĞŽĨĂůďƵŵŝŶƵƌŝĂĂƐĂƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚ͘

9-15

_{DŽƌĞŽǀĞƌ͕ůŽǁĞƌŝŶŐŽĨ}

ĂůďƵŵŝŶƵƌŝĂŚĂƐďĞĞŶƐŚŽǁŶƚŽƐůŽǁĚŽǁŶƌĞŶĂůĚŝƐĞĂƐĞƉƌŽŐƌĞƐƐŝŽŶ͘dŚŝƐŚĂƐďĞĞŶ

ŝŶǀĞƐƟŐĂƚĞĚŝŶŵƵůƟƉůĞƉŽƐƚͲŚŽĐĂŶĂůLJƐĞƐ͕ĂŶĚĨŽƌĂůůƚŚĞƐĞƐƚƵĚŝĞƐƚŚĞƐĂŵĞƉĂƌĂĚŝŐŵ

ŚŽůĚƐ͗ƚŚĞŐƌĞĂƚĞƌƚŚĞƌĞĚƵĐƟŽŶŝŶĂůďƵŵŝŶƵƌŝĂĚƵƌŝŶŐƚŚĞĮƌƐƚŵŽŶƚŚƐŽĨƚŚĞƌĂƉLJ͕

ƚŚĞůĂƌŐĞƌƚŚĞƌĞĚƵĐƟŽŶŽĨƌĞŶĂůŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬĚƵƌŝŶŐƐƵďƐĞƋƵĞŶƚĨŽůůŽǁͲƵƉ͘

18-22

_{dŚĞďŝŽůŽŐŝĐĂůŵĞĐŚĂŶŝƐŵƚŚĂƚĞdžƉůĂŝŶƐƚŚĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶĂůďƵŵŝŶƵƌŝĂĂŶĚ}

ƌĞŶĂůĚĂŵĂŐĞŚĂƐďĞĞŶŵƵĐŚĚĞďĂƚĞĚ͘/ŶŝƟĂůůLJ͕ŝƚǁĂƐŚLJƉŽƚŚĞƐŝnjĞĚƚŚĂƚĂůďƵŵŝŶƵƌŝĂ

ŝƐĂĐŽŶƐĞƋƵĞŶĐĞŽĨƌĞŶĂůĚĂŵĂŐĞ͘/ŶĚĞĞĚ͕ǁŚĞŶƚŚĞŐůŽŵĞƌƵůĂƌĮůƚĞƌŝŶƚŚĞŬŝĚŶĞLJ

ŝƐĚĂŵĂŐĞĚ͕ŝŶĐƌĞĂƐĞĚĂŵŽƵŶƚƐŽĨĂůďƵŵŝŶĐŽƵůĚƉĂƐƐƚŚĞŐůŽŵĞƌƵůŝĂŶĚůĞĂŬŝŶƚŽƚŚĞ

ƵƌŝŶĞ͘,ŽǁĞǀĞƌ͕ƌĞĐĞŶƚůLJĞǀŝĚĞŶĐĞŚĂƐďĞĞŶƉƌŽǀŝĚĞĚƚŚĂƚĂůďƵŵŝŶƵƌŝĂŵĂLJďĞŵŽƌĞƚŚĂŶ

ŽŶůLJĂŵĂƌŬĞƌŽĨŬŝĚŶĞLJĚĂŵĂŐĞ͕ĂŶĚĐŽƵůĚďĞĂĐĂƵƐĞŽĨŬŝĚŶĞLJĚĂŵĂŐĞ͘dŚĞƌĞůĂƟǀĞůLJ

ƌĞĐĞŶƚůLJĚŝƐĐŽǀĞƌĞĚŐůLJĐŽĐĂůLJdž;ĂůĂLJĞƌĐŽǀĞƌŝŶŐƚŚĞĞŶĚŽƚŚĞůŝƵŵͿĂƉƉĞĂƌƐƚŽďĞĂďĂƌƌŝĞƌ

ĨŽƌĂůďƵŵŝŶƚŽůĞĂŬŽƵƚŽĨƚŚĞǀĂƐĐƵůĂƚƵƌĞ͕ŝŶĐůƵĚŝŶŐƚŚĞŐůŽŵĞƌƵůƵƐ;&ŝŐƵƌĞϭͿ͘

23

_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;&ŝŐƵƌĞϮͿ͘

24-33

ŶĞdžƉůĂŶĂƟŽŶĨŽƌƚŚĞƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶĂůďƵŵŝŶƵƌŝĂĂŶĚƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌ

ĚŝƐĞĂƐĞŚĂƐďĞĞŶƉƌŽƉŽƐĞĚďLJƚŚĞ^ƚĞŶŽŚLJƉŽƚŚĞƐŝƐ͕ǁŚŝĐŚƐƚĂƚĞƐƚŚĂƚĞdžĐĞƐƐŝǀĞƵƌŝŶĂƌLJ

ĂůďƵŵŝŶůŽƐƐŝƐƚŚĞƌĞƐƵůƚŽĨǁŝĚĞƐƉƌĞĂĚƉĞƌŝƉŚĞƌĂůǀĂƐĐƵůĂƌĚĂŵĂŐĞŽƌĞŶĚŽƚŚĞůŝĂů

ĚLJƐĨƵŶĐƟŽŶ͘

34

_{ĐĐŽƌĚŝŶŐƚŽƚŚŝƐŚLJƉŽƚŚĞƐŝƐĂůďƵŵŝŶůĞĂŬĂŐĞŝƐŶŽƚĐŽŶĮŶĞĚƚŽƚŚĞŬŝĚŶĞLJ͕}

ďƵƚŝƐƉƌĞƐĞŶƚƚŚƌŽƵŐŚŽƵƚƚŚĞƉĞƌŝƉŚĞƌĂůǀĂƐĐƵůĂƚƵƌĞ͘^ĞǀĞƌĂůƐƚƵĚŝĞƐƵƐŝŶŐƌĂĚŝŽĂĐƟǀĞůLJ

ůĂďĞůĞĚ ĂůďƵŵŝŶ͕ ŝŶĚĞĞĚ ĚĞŵŽŶƐƚƌĂƚĞ ƚŚĂƚ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ĂŶ

ŝŶĐƌĞĂƐĞĚƉĞƌŵĞĂďŝůŝƚLJŽĨƚŚĞƉĞƌŝƉŚĞƌĂůǀĂƐĐƵůĂƌďĞĚƐƚŽŵĂĐƌŽŵŽůĞĐƵůĞƐ͘

35-37

_{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

ƉƌĞŐŶĂŶĐLJ͘

38

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

ŽƉƟŵĂůƐƚƌĂƚĞŐLJƚŚĂƚŝŶƚƌŽĚƵĐĞƐƚŚĞůĞĂƐƚďŝĂƐ͘

39-43

_{ƵƌƌĞŶƚůLJ͕ƚŚĞŐŽůĚƐƚĂŶĚĂƌĚŝŶĂĚƵůƚƐŝƐ}

ƐƟůůƚŚĞϮϰͲŚŽƵƌƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶƌĂƚĞ͕ĂůƚŚŽƵŐŚĂŐŽŽĚĂŶĚƉƌĂĐƟĐĂůĂůƚĞƌŶĂƟǀĞ

ŝƐƚŚĞŵĞĂƐƵƌĞŵĞŶƚŽĨƚŚĞĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽŝŶĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƐĂŵƉůĞƐ;ĂǀĞƌĂŐĞ

ŽĨƚŚƌĞĞĐŽŶƐĞĐƵƟǀĞĚĂLJƐͿ͘

44

_{dŚĞƌĞĂƌĞŶŽĐůĞĂƌŐƵŝĚĞůŝŶĞƐĂǀĂŝůĂďůĞŝŶĐŚŝůĚƌĞŶ͕ƐŝŶĐĞ}

ŶŽĞdžŚĂƵƐƟǀĞƐƚƵĚŝĞƐŽŶŽƉƟŵĂůƵƌŝŶĞĐŽůůĞĐƟŽŶƐĂŶĚŵĞĂƐƵƌĞŵĞŶƚƐŝŶĐŚŝůĚƌĞŶŚĂǀĞ

ďĞĞŶĐŽŶĚƵĐƚĞĚ͘

ƉƌŽďůĞŵŝŶĂƐƐĞƐƐŝŶŐƚŚĞůĞǀĞůŽĨĂůďƵŵŝŶƵƌŝĂŝŶLJŽƵŶŐĐŚŝůĚƌĞŶŝƐƚŚĞĐŚŽŝĐĞ

ŽĨƚŚĞƵƌŝŶĞĐŽůůĞĐƟŽŶŵĞƚŚŽĚŝƚƐĞůĨ͘ĂďŝĞƐĂŶĚƚŽĚĚůĞƌƐĂƌĞŝŶĐŽŶƟŶĞŶƚĨŽƌƵƌŝŶĞ͘

dŚŝƐŵĂŬĞƐƚŚĞĐŽůůĞĐƟŽŶŽĨƵƌŝŶĞĨŽƌĂůďƵŵŝŶŵĞĂƐƵƌĞŵĞŶƚƐĐƵŵďĞƌƐŽŵĞ͘DŽĚĞƌŶ

ĚŝĂƉĞƌƐĂƌĞĞdžƚƌĞŵĞůLJĞĸĐŝĞŶƚŝŶƌĞƚĂŝŶŝŶŐƵƌŝŶĞ͕ƚŚƵƐŽůĚĨĂƐŚŝŽŶĞĚĐŽƩŽŶǁŽŽůŽƌ

ŵŽĚĞƌŶƉĂŶƚLJůŝŶĞƌƐĐĂŶďĞƵƐĞĚƚŽŚĞůƉƌĞĐŽǀĞƌŝŶŐƵƌŝŶĞ͘dŚŝƐƚĞĐŚŶŝƋƵĞŝƐŶŽƚŽŶůLJ

ƵŶŚĂŶĚLJŝŶƵƐĞďƵƚĂůƐŽŝƌƌĞƉƌŽĚƵĐŝďůĞ͘

45,46

_{dĂƉĞĚƉůĂƐƟĐďĂŐƐĂƌĞĨƌĞƋƵĞŶƚůLJƵƐĞĚĂƐĂŶ}

ĂůƚĞƌŶĂƟǀĞŝŶĐůŝŶŝĐĂůƉƌĂĐƟĐĞ͕ďƵƚƚŚĞƐĞŚĂǀĞƚŚĞĚŝƐĂĚǀĂŶƚĂŐĞƚŚĂƚƚŚĞLJĚĞƚĂĐŚĞĂƐŝůLJ

ĨƌŽŵƚŚĞƐŬŝŶĂŶĚĂƉƉĞĂƌƚŽďĞƵŶĐŽŵĨŽƌƚĂďůĞ͘

45

_{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 ƐƚĂďŝůŝnjĞ͘

47,48

^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^ŝŽŶƚŚĞŐůLJĐŽĐĂůLJdžĐĂŶƉůĂLJĂƌŽůĞ͘

49,50

tŚĂƚĞǀĞƌƚŚĞƌĞůĂƟŽŶďĞƚǁĞĞŶZ^ŝĂŶĚĂůďƵŵŝŶƵƌŝĂůŽǁĞƌŝŶŐŝƐ͕ŝƚŝƐĐůĞĂƌƚŚĂƚZ^ŝ

ƉƌŽƚĞĐƚƐƚŚĞŬŝĚŶĞLJĂŶĚƚŚĂƚƚŚŝƐƉƌŽƚĞĐƟŽŶĂƉƉĞĂƌƐƚŽďĞĂƐƐŽĐŝĂƚĞĚǁŝƚŚƚŚĞůŽǁĞƌŝŶŐ

ŽĨƌŝƐŬĨĂĐƚŽƌƐĂŵŽŶŐǁŚŝĐŚĂůďƵŵŝŶƵƌŝĂ͘

ůƚŚŽƵŐŚƚŚĞƌĞŝƐŽǀĞƌǁŚĞůŵŝŶŐƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůůĞĚĐůŝŶŝĐĂůƚƌŝĂůĞǀŝĚĞŶĐĞĂǀĂŝůĂďůĞ

ŝŶĂĚƵůƚƐĚĞŵŽŶƐƚƌĂƟŶŐƚŚĂƚZ^ŝŶŚŝďŝƟŽŶĚĞůĂLJƐƚŚĞƉƌŽŐƌĞƐƐŝŽŶŽĨƌĞŶĂůĨƵŶĐƟŽŶ

ĚĞĐůŝŶĞ͕ĂĚĞďĂƚĞĐŽŶƟŶƵĞƐĂƌŐƵŝŶŐƚŚĂƚŝŶĐĞƌƚĂŝŶƐĞƫŶŐƐZ^ŝŝƐŶŽƚĞĸĐĂĐŝŽƵƐĂŶĚ

ĞǀĞŶƵŶƐĂĨĞ͘

51-57

_{ŶĞdžĂŵƉůĞŝƐĂƌĞĐĞŶƚƉƵďůŝĐĂƟŽŶƚŚĂƚĂĚǀŽĐĂƚĞƐƚŽƐƚŽƉZ^ŝŝŶ}

ƉĂƟĞŶƚƐǁŝƚŚĂĚǀĂŶĐĞĚƌĞŶĂůĚŝƐĞĂƐĞ͘dŚĞŚĂĞŵŽĚLJŶĂŵŝĐĨĂůůŝŶĞ'&ZĂŌĞƌŝŶŝƟĂƟŽŶŽĨ

Z^ŝŚĂƐďĞĞŶƐŚŽǁŶƚŽďĞƌĞǀĞƌƐŝďůĞĂŌĞƌĚŝƐĐŽŶƟŶƵĂƟŽŶ͘

58

_{With this in mind, it has}

ďĞĞŶĂĚǀŽĐĂƚĞĚƚŽĚŝƐĐŽŶƟŶƵĞZ^ŝŝŶƉĂƟĞŶƚƐǁŝƚŚůĂƚĞƐƚĂŐĞĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ

ŝŶŽƌĚĞƌƚŽƌĞŐĂŝŶƌĞŶĂůĨƵŶĐƟŽŶĂŶĚĚĞůĂLJĚŝĂůLJƐŝƐ͘

56

_{,ŽǁĞǀĞƌ͕ƚŚĞĐŽŶƐĞƋƵĞŶĐĞŽĨƚŚŝƐ}

ĚŝƐĐŽŶƟŶƵĂƟŽŶŚĂƐŶŽƚďĞĞŶƉƌŽƉĞƌůLJƐƚƵĚŝĞĚ͘

/ŶĐŽŶƚƌĂƐƚƚŽƚŚĞůĂƌŐĞĂŵŽƵŶƚŽĨĚĂƚĂŽŶƚŚĞƌĞŶĂůƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨZ^

ŝŶŚŝďŝƟŽŶŝŶĂĚƵůƚƐ͕ƌĂŶĚŽŵŝnjĞĚƐƚƵĚŝĞƐŝŶĐŚŝůĚƌĞŶĂƌĞůĂĐŬŝŶŐ͘dŚĞ^WƐƚƵĚLJ͕

ŝŶǁŚŝĐŚĂůůĐŚŝůĚƌĞŶǁĞƌĞƚƌĞĂƚĞĚǁŝƚŚƐƚĂŶĚĂƌĚŝnjĞĚŝŶŚŝďŝƟŽŶƐŚŽǁĞĚƚŚĂƚ

ŝŶŚŝďŝƟŽŶǁĂƐĞīĞĐƟǀĞŝŶůŽǁĞƌŝŶŐŽĨƉƌŽƚĞŝŶƵƌŝĂǁŝƚŚĂŶĂǀĞƌĂŐĞŝŶŝƟĂůƌĞĚƵĐƟŽŶŝŶ

ƉƌŽƚĞŝŶƵƌŝĂŽĨϱϬй͘

59

_{/ŶƚŚĞŽďƐĞƌǀĂƟŽŶĂů<ŝƐƚƵĚLJ͕ŝŶŚŝďŝƚŽƌƵƐĞǁĂƐĂƐƐŽĐŝĂƚĞĚ}

ǁŝƚŚůŽǁĞƌƉƌŽƚĞŝŶƵƌŝĂůĞǀĞůƐ͘

60

_{hƐĞŽĨĂŶZǁĂƐƐŚŽǁŶƚŽďĞŵŽƌĞĞīĞĐƟǀĞŝŶůŽǁĞƌŝŶŐ}

ŽĨƉƌŽƚĞŝŶƵƌŝĂƚŚĂŶĂĐĂůĐŝƵŵĐŚĂŶŶĞůďůŽĐŬĞƌŝŶĂƐŵĂůůƌĂŶĚŽŵŝnjĞĚŽƉĞŶͲůĂďĞůƐƚƵĚLJ͘

61

dǁŽƐŵĂůůƵŶĐŽŶƚƌŽůůĞĚƐƚƵĚŝĞƐĚĞŵŽŶƐƚƌĂƚĞĚƐƚĂďŝůŝƐĂƟŽŶŽĨŬŝĚŶĞLJĨƵŶĐƟŽŶŝŶĐŚŝůĚƌĞŶ

ǁŝƚŚ<ƚŚĂƚǁĞƌĞƚƌĞĂƚĞĚǁŝƚŚĂŶŝŶŚŝďŝƚŽƌƐŽƌZ͘

62,63

_{&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

ĐŚŝůĚƌĞŶǁŝƚŚŽƵƚŬŝĚŶĞLJĚŝƐĞĂƐĞ͘

Chapter 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

/Ŷ

Chapter 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/Ŷ

Chapter 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

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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

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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

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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: 18PDF page: 18PDF page: 18PDF page: 18

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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

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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