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How Does Metabolic Acidosis Cause Chronic Kidney Disease Progression? DA-20-00010 Disclaimer The content contained within this slide deck is for educational purposes only. Not for promotional purposes or re-distribution. DA-20-00010 2

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How Does Metabolic Acidosis Cause Chronic Kidney Disease Progression?

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Disclaimer

The content contained within this slide deck is for educational purposes only. Not for promotional purposes or re-distribution.

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Donald Wesson, MD, MBA

Professor of Medicine Texas A&M University College of Medicine President Baylor Scott and White Health and Wellness Center

Disclosure: Dr. Wesson is a consultant to Tricida, Inc.

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Metabolic Acidosis is Both a Complication of CKD and an Underlying Cause of CKD Progression

Kraut JA et al., Am J Kidney Dis 67: 307-17, 2016. DA-20-00010 4

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Studies Show Low Serum Bicarbonate Levels are Independent and Modifiable Risk Factor for CKD Progression

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Adaptive Response to an Accumulating Acid Load

Acutely Increases Acid Excretion Chronically Leads to Kidney Damage and Furthers CKD Progression

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Adaptive Response to an Accumulating Acid Load

Acutely Increases Acid Excretion Chronically Leads to Kidney Damage and Furthers CKD Progression

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Adaptive Response to an Accumulating Acid Load

Acutely Increases Acid Excretion Chronically Leads to Kidney Damage and Furthers CKD Progression

Early Diagnosis and Treatment May Mitigate Chronic Deleterious Effects of Metabolic Acidosis

Alpern RJ et al., Am J Kidney Dis 29: 291-302, 1997. Goraya N et al., Nutrients 10, 2018. Kraut JA et al., Adv Chronic Kidney Dis 24: 289-97, 2017. Goraya N et al., Adv Chronic Kidney Dis 24:298-304, 2017. Goraya N et al., Curr Opin Nephrol Hypertens 28:267-77, 2019. Kraut JA et al., Curr Opin Nephrol Hypertens 27:94-101, 2018. Chen W et al., Curr Opin Nephrol Hypertens 28:409-16, 2019. DA-20-00010

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Sensors Monitor the Tubule Lumen and Coordinate Responses to Maintain Acid-Base Homeostasis

ACID BASE Pyk2 GPR4 V-ATPase ETB Receptor ET-1 Receptor ATA1 Receptor ERK 1/2 Kinase Erb 1/2 Receptor sAC

Cellular and Membrane Sensors

Brown D et al., J Am Soc Nephrol. 23:774-80, 2012. DA-20-00010 9

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Endothelin 1 (ET-1), Aldosterone and Angiotensin II

Activation of

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

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Increased Acid Excretion

Augmented Ammoniagenesis and Enhanced Proton Secretion Endothelin 1 (ET-1), Aldosterone and Angiotensin II

Activation of

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

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Increased Acid Excretion

Augmented Ammoniagenesis and Enhanced Proton Secretion

Persistent Acid Retention

Sustained Expression of ET-1, Aldosterone and Angiotensin II Endothelin 1 (ET-1), Aldosterone and Angiotensin II

Activation of

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

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Increased Acid Excretion

Augmented Ammoniagenesis and Enhanced Proton Secretion

Persistent Acid Retention

Sustained Expression of ET-1, Aldosterone and Angiotensin II Endothelin 1 (ET-1), Aldosterone and Angiotensin II

Activation of

Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

Further Diminishing Kidney Function

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

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Increased Acid Excretion

Augmented Ammoniagenesis and Enhanced Proton Secretion

Persistent Acid Retention

Sustained Expression of ET-1, Aldosterone and Angiotensin II Endothelin 1 (ET-1), Aldosterone and Angiotensin II

Activation of

Vicious Cycle

Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

Further Diminishing Kidney Function

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria

Laghmani K et al., J Clin Invest 107:1563-9, 2001. Wesson DE, J Am Soc Nephrol 12:1826-35, 2001. Wesson DE et al., Kidney Int 78:1128-35, 2010. Wesson DE et al., Kidney Int 82:1184-94, 2012. Wesson DE et al., Nephrol Dial Transplant 30:762-70, 2015. Phisitkul S et al., Kidney Int 77:617-23, 2010. Ruiz-Ortega M et al., J Hypertens Suppl 12:S51-58, 1994. Seccia TM et al., J Hypertens 26:2022-9, 2008. Wolf G et al., Nephron Physiol 93:P3-13,

2003. Greene EL et al., J Clin Invest 98:1063-8, 1996. Remuzzi G et al., Kidney Blood Press Res 19:182-3, 1996. Halperin ML et al., Am J Kidney Dis 14:267-71, 1989. Nath KA et al., J Clin Invest 76:667-75, 1985. Nath KA et

al., Am J Kidney Dis 17:654-7, 1991. Chen W et al., BMC Nephrol 15:55, 2014.

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A Positive Adaptive Response to Metabolic Acidosis can become Maladaptive and Promote CKD Progression, Underscoring the Need to Treat Metabolic Acidosis

Goraya N et al., Adv Chronic Kidney Dis 24:298-304, 2017. Goraya N et al., Curr Opin Nephrol Hypertens 28:267-77, 2019. Kraut JA et al., Curr Opin Nephrol Hypertens 27:94-101, 2018. Chen W et al., Curr Opin Nephrol Hypertens 28:409-416, 2019. DA-20-00010 15

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The End

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