Overview

  • AS is the second most common inherited cause of renal failure after ADPKD and affects approximately 30,000 to 60,000 people in the US1
  • AS is caused by a genetic defect in type IV collagen, a component of the glomerular basement membrane (GBM) in the kidney, which results in alterations to the GBM structure and impairs its function2
  • Early and accurate diagnosis of AS is critical because in some inheritance patterns of AS, renal failure can occur in young adults3-5
  • As in other forms of CKD, chronic inflammation and mitochondrial dysfunction play important roles in the pathophysiology and progression of AS6,7
  • With no approved therapies to stop progressive loss of kidney function, AS represents a rare disorder with significant unmet need8,9
  • Reata is conducting a pivotal registration study of bardoxolone methyl for the treatment of AS

AS is caused by mutations in the genes that code for type IV collagen, an essential component of the GBM. Compromised GBM, along with other disease triggers, contribute to chronic inflammation, which results in glomerulosclerosis (scarring or hardening of the tiny blood vessels within the kidney), interstitial fibrosis, and progressive loss of kidney function that can ultimately lead to ESRD.2

There are three genetic types of AS. The different forms include: X-linked (XLAS), autosomal recessive (ARAS), and autosomal dominant (ADAS).1 XLAS is the most common form. All males with XLAS will develop kidney failure at some point in their lives, and 90% will develop kidney failure by age 40.2 Comparatively, X-linked females have up to a 25% risk of ESRD, and 12% have ESRD by age 40.10,11

Current approaches to AS include annual monitoring, supportive care, diet, lifestyle management, and use of blood pressure-lowering therapies. There is a significant unmet need for additional therapies in AS.12-15

Diagnosis and Prognosis

Early and accurate diagnosis is critical since timely management has the potential to improve life expectancy.3-5 Patients with AS generally present with blood in their urine (hematuria) and eventually develop progressive deterioration of kidney function, often in early adulthood. The progressive decline of kidney function in patients with AS leads to kidney failure and ESRD.6,16 Fifty percent of males with the most prevalent genetic subtype of AS, XLAS, require dialysis or kidney transplant by age 25.2

What Causes AS?

Defects in the genes that code for type IV collagen cause abnormalities in the structure of the GBM, which then impairs the kidney’s ability to filter waste and extra fluid from the blood.2

The abnormal expression of type IV collagen chains in the kidneys of patients with AS results in decreased mechanical stability and splitting of the GBM. Loss of GBM integrity results in aberrant leakage of proteins, which are then excessively reabsorbed in the tubules and induce chronic inflammation. As in other forms of CKD, activation of proinflammatory signaling pathways and resulting mitochondrial dysfunction contribute to the development of glomerulosclerosis, interstitial fibrosis, and progressive loss of kidney function that can lead to ESRD.6,7

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Acute Renal Inflammation

The normal acute phase of the inflammatory response to harmful stimuli involves a shift in mitochondrial function from being energy producers to immune responders. Nrf2, a transcription factor, orchestrates the resolution of inflammation by regulating antioxidative and detoxifying processes. Once the noxious insults are eliminated and cell damage is repaired, Nrf2 helps restore mitochondrial function back to energy production.17

acute-renal-inflammation

During the normal immune response, proinflammatory pathways are activated and the harmful stimuli are eradicated. Naturally occurring molecules promote the resolution of inflammation, in part, by activating the Keap1/Nrf2 pathway. Binding to Keap1 activates Nrf2, a transcription factor that increases the levels of antioxidants and transporters, thereby reducing the levels of oxidative stress caused by excess ROS. Nrf2 also restores normal mitochondrial function by increasing the availability of substrates and reducing equivalents that are required to support ATP production. Nrf2 activation inhibits inflammation by reducing ROS levels, restoring normal mitochondrial function, and directly inhibiting proinflammatory signaling.20-22
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Chronic Renal Inflammation

chronic-renal-inflammation

In CKD, mitochondrial dysfunction results when the presence of continuous disease prevents the mitochondria’s shift back from being immune responders to energy producers. This causes an inadequate Nrf2 response that leads to severe and sustained kidney injury and continuous inflammation that propagates further damage. In AS, chronic inflammation injures the tiny blood vessels in the kidney and is a key contributor of glomerular scarring.23,25,26

The body’s inability to resolve cellular inflammation leads to several pathologic processes. These include abnormal mitochondrial metabolism, decreased ATP levels, increased ROS production, and chronic inflammatory signaling. In turn, abnormal cellular proliferation, tissue fibrosis and remodeling, and organ damage—the hallmarks of many diseases, including CKD—can occur.27

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Fibrosis arising from chronic inflammation and resulting loss of kidney function eventually leads to ESRD requiring dialysis or transplantation. Strategies are needed to target AS pathogenesis earlier before conversion to ESRD.6,16

renal-fibrosis

Nrf2 activators have the potential to prevent long-term consequences of mitochondrial dysfunction, inflammation, and oxidative stress and improve the symptoms of many diseases by correcting the underlying pathologic processes.

aThese images are used under a Creative Commons Attribution 3.0 Unported License specific to the article published by The Company of Biologists Ltd: Mullins LJ, Conway BR, Menzies RI, et al. Renal disease pathophysiology and treatment: contributions from the rat. Dis Model Mech. 2016;9(12):1419-1433. doi: 10.1242/dmm.027276

References
  1. Alport Syndrome Foundation. What is Alport syndrome? http://alportsyndrome.org/what-is-alport-syndrome. Accessed November 8, 2018.
  2. Kashtan CE, Ding J, Gregory M, et al. Clinical practice recommendations for the treatment of Alport syndrome: A statement of the Alport Syndrome Research Collaborative. Pediatr Nephrol. 2013;28(1):5-11.
  3. Savige J, Colville D, Rheault M, et al. Alport syndrome in women and girls. Clin J Am Soc Nephrol. 2016;11(9):1713-1720.
  4. Alport Syndrome Foundation. Alport syndrome fast facts. http://alportsyndrome.org/wp-content/uploads/2015/09/Fast-Facts-About-AS-Rev-9-14-15.pdf. Accessed November 8, 2018.
  5. Romagnani P, Remuzzi G, Glassock R, et al. Chronic kidney disease. Nat Rev Dis Primers. 2017;3:17088.
  6. Noone D, Licht C. An update on the pathomechanisms and future therapies of Alport syndrome. Pediatr Nephrol. 2013;28(7):1025-1036.
  7. Savige J. Alport syndrome: Its effects on the glomerular filtration barrier and implications for future treatment. J Physiol. 2014;592(18):4013-4023.
  8. Gross O, Kashtan CE. Treatment of Alport syndrome: Beyond animal models. Kidney Int. 2009;76(6):599-603.
  9. Gross O, Kashtan CE, Rheault MN, et al. Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: Report from the 2015 International Workshop on Alport Syndrome. Nephrol Dial Transplant. 2017;32(6):916-924.
  10. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: Natural history and genotype-phenotype correlations in girls and women belonging to 195 families: A “European Community Alport Syndrome Concerted Action” study. J Am Soc Nephrol. 2003;14(10):2603-2610.
  11. Kashtan CE, Ding J, Garosi G, et al. Alport syndrome: A unified classification of genetic disorders of collagen IV α345: A position paper of the Alport Syndrome Classification Working Group. Kidney Int. 2018;93(5):1045-1051.
  12. Kovács G, Kalmár T, Endreffy E, et al. Efficient targeted next generation sequencing-based workflow for differential diagnosis of Alport-related disorders. PLoS One. 2016;11(3):e0149241.
  13. Alport Syndrome Foundation. 4 ways patients living with Alport syndrome can stay healthy. http://alportsyndrome.org/alport-syndrome-males/4-ways-patients-living-with-alport-syndrome-can-stay-healthy/. Accessed November 8, 2018.
  14. Alport Syndrome Foundation. The renal diet: Potassium. http://alportsyndrome.org/blog/the-renal-diet-potassium/. Accessed November 8, 2018.
  15. Savige J, Gregory M, Gross O, et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013;24(3):364-375.
  16. Chew C, Lennon R. Basement membrane defects in genetic kidney diseases. Front Pediatr. 2018;6:11.
  17. Tecklenborg J, Clayton D, Siebert S, Coley SM. The role of the immune system in kidney disease. Clin Exp Immunol. 2018;192(2):142-150.
  18. Hishikawa A, Hayashi K, Itoh H. Transcription factors as therapeutic targets in chronic kidney disease. Molecules. 2018;23(5):pii:E1123.
  19. Torres IB, Moreso F, Sarró E, Meseguer A, Serón D. The interplay between inflammation and fibrosis in kidney transplantation. Biomed Res Int. 2014;2014:750602.
  20. Ma Q. Role of Nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401-426.
  21. Uruno A, Furusawa Y, Yagishita Y, et al. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013;33(15):2996-3010.
  22. Kobayashi EH, Suzuki T, Funayama R, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624.
  23. Lv W, Booz GW, Wang Y, et al. Inflammation and renal fibrosis: Recent developments on key signaling molecules as potential therapeutic targets. Eur J Pharmacol. 2018;820:65-76.
  24. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif. 2015;39(1-3):84-92.
  25. Hennig P, Garstkiewicz M, Grossi S, et al. The crosstalk between Nrf2 and inflammasomes. Int J Mol Sci. 2018;19(2):pii:E562.
  26. Nezu M, Suzuki N, Yamamoto M. Targeting the KEAP1-NRF2 system to prevent kidney disease progression. Am J Nephrol. 2017;45(6):473-483.
  27. Gilroy D, De Maeyer R. New insights into the resolution of inflammation. Semin Immunol. 2015;27(3):161-168.
  28. Mullins LJ, Conway BR, Menzies RI, Denby L, Mullins JJ. Renal disease pathophysiology and treatment: Contributions from the rat. Dis Model Mech. 2016;9(12):1419-1433.
  29. Schlondorff DO. Overview of factors contributing to the pathophysiology of progressive renal disease. Kidney Int. 2008;74(7):860-866.
  30. Meng X, Nikolic-Paterson, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol. 2014;10(9):493-503.
  31. Falke LL, Gholizadeh S, Goldschmeding R, Kok RJ, Nguyen TQ. Diverse origins of the myofibroblast—implications for kidney fibrosis. Nat Rev Nephrol. 2015;11(4):233-244.
View References