How Does Metabolic Acidosis Cause Chronic Kidney Disease - PowerPoint PPT Presentation

How Does Metabolic Acidosis Cause Chronic Kidney Disease Progression? DA-20-00010

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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. DA-20-00010 3

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

Studies Show Low Serum Bicarbonate Levels are Independent and Modifiable Risk Factor for CKD Progression DA-20-00010 5

Adaptive Response to an Accumulating Acid Load Chronically Leads Acutely Increases to Kidney Damage Acid Excretion and Furthers CKD Progression DA-20-00010 6

Adaptive Response to an Accumulating Acid Load Chronically Leads Acutely Increases to Kidney Damage Acid Excretion and Furthers CKD Progression DA-20-00010 7

Adaptive Response to an Accumulating Acid Load Early Diagnosis and Treatment May Chronically Leads Acutely Increases to Kidney Damage Mitigate Chronic Acid Excretion and Furthers CKD Deleterious Effects of Progression 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 DA-20-00010 8 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.

Sensors Monitor the Tubule Lumen and Coordinate Responses to Maintain Acid-Base Homeostasis Cellular and Membrane Sensors sAC Pyk2 GPR4 V-ATPase ET B Receptor ET-1 Receptor ATA1 Receptor ERK 1/2 Kinase ACID BASE Erb 1/2 Receptor Brown D et al., J Am Soc Nephrol. 23:774-80, 2012. DA-20-00010 9

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Activation of Endothelin 1 (ET-1), Aldosterone and Angiotensin II DA-20-00010 10

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Increased Acid Excretion Augmented Ammoniagenesis and Enhanced Proton Secretion Activation of Endothelin 1 (ET-1), Aldosterone and Angiotensin II DA-20-00010 11

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Increased Acid Excretion Augmented Ammoniagenesis and Enhanced Proton Secretion Persistent Acid Activation of Retention Endothelin 1 (ET-1), Sustained Expression of Aldosterone and ET-1, Angiotensin II Aldosterone and Angiotensin II DA-20-00010 12

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Increased Acid Excretion Augmented Ammoniagenesis and Enhanced Proton Secretion Persistent Acid Activation of Retention Endothelin 1 (ET-1), Sustained Expression of Aldosterone and ET-1, Angiotensin II Aldosterone and Angiotensin II Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Further Diminishing Kidney Function DA-20-00010 13

Chronic Response to Acidosis Promotes Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Increased Acid Excretion Augmented Ammoniagenesis and Enhanced Proton Secretion Persistent Acid Activation of Retention Endothelin 1 (ET-1), Sustained Expression of Vicious Cycle Aldosterone and ET-1, Angiotensin II Aldosterone and Angiotensin II Inflammation, Fibrosis, Tubular Atrophy and Proteinuria Further Diminishing Kidney Function 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, DA-20-00010 14 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.

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 DA-20-00010 15 27:94-101, 2018. Chen W et al., Curr Opin Nephrol Hypertens 28:409-416, 2019.

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