@article{698d7b099b794b90af54af46fc2f7651,
title = "Alport Syndrome Classification and Management",
abstract = "Alport syndrome affects up to 60,000 people in the United States. The proposed reclassification of thin basement membrane nephropathy and some cases of focal segmental glomerulosclerosis as Alport syndrome could substantially increase the affected population. The reclassification scheme categorizes Alport syndrome as 3 distinct diseases of type IV collagen α3/4/5 based on a genetic evaluation: X-linked, autosomal, and digenic. This approach has the advantage of identifying patients at risk for progressive loss of kidney function. Furthermore, the shared molecular cause of Alport syndrome and thin basement membrane nephropathy arises from mutations in the COL4A3, COL4A4, and COL4A5 genes, which contribute to downstream pathophysiologic consequences, including chronic kidney inflammation. Recent evidence indicates that chronic inflammation and its regulation through anti-inflammatory nuclear factor erythroid 2–related factor 2 (Nrf2) and proinflammatory nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) transcription factors plays a central role in renal tubular and glomerular cell responses to injury. Crosstalk between the Nrf2 and NF-κB pathways is important in the regulation of inflammation in patients with chronic kidney disease; moreover, there is evidence that an insufficient Nrf2 response to inflammation contributes to disease progression. Given the association between type IV collagen abnormalities and chronic inflammation, there is renewed interest in targeted anti-inflammatory therapies in Alport syndrome and other forms of progressive chronic kidney disease.",
keywords = "Alport syndrome, COL4A3, COL4A4, COL4A5, NF-κB, Nrf2, chronic inflammation, chronic kidney disease",
author = "Warady, {Bradley A.} and Rajiv Agarwal and Sripal Bangalore and Arlene Chapman and Adeera Levin and Peter Stenvinkel and Toto, {Robert D.} and Chertow, {Glenn M.}",
note = "Funding Information: Bradley A. Warady, MD, Rajiv Agarwal, MD, Sripal Bangalore, MD, MHA, Arlene Chapman, MD, Adeera Levin, MD, Peter Stenvinkel, MD, PhD, Robert D. Toto, MD, and Glenn M. Chertow, MD, MPH. Reata Pharmaceuticals, Inc. The authors made the final decision on the main points and conclusions of the manuscript. Dr Warady: Advisory Committee for Reata Pharmaceuticals, Inc; Medical Advisory Committee of the Alport Syndrome Foundation; Consultant for Bayer AG, Akebia Therapeutics, Relypsa, Inc, Amgen, and UpToDate, Inc; Research support from the National Institutes of Health (NIH) and Baxter Healthcare. Dr Agarwal: Consultant/Advisory Committee for Relypsa, Inc, Abbvie Inc, Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Celgene Corp, a Bristol-Myers Squibb Company, Daiichi Sankyo Company, Ltd, Eli Lilly and Co, Gilead Sciences, Inc, GlaxoSmithKline plc, Johnson & Johnson Services, Inc, Merck & Co, Inc, Novartis International AG, Sandoz International GmbH, ZS Pharma Inc, Akebia Therapeutics Inc, Takeda Pharmaceutical Co Ltd, Sanofi SA, Reata Pharmaceuticals, Inc, Ironwood Pharmaceuticals, Inc, Otsuka America Pharmaceutical, Inc, Opko Health, Inc, and Bird Rock Bio, Inc. Grants from the NIH and Veterans Affairs. Dr Bangalore: Advisory Committee for Reata Pharmaceuticals, Inc. Dr Chapman: Advisory Committee for Reata Pharmaceuticals, Inc, Sanofi SA, and Otsuka America Pharmaceutical, Inc; Speakers Bureau for Otsuka America Pharmaceutical, Inc; Contributor to UpToDate, Inc. Dr Levin: Advisory Committee for Reata Pharmaceuticals, Inc; Grants from Otsuka America Pharmaceutical, Inc, AstraZeneca, and Boehringer Ingelheim International GmbH. Dr Stenvinkel: Scientific Advisory Boards for Reata Pharmaceuticals, Inc, AstraZeneca, and Baxter Healthcare. Dr Toto: Executive Committee for AstraZeneca, Amgen; Consultant for Bayer AG, Boehringer Ingelheim International GmbH; Data Monitoring Committee for IQVIA Inc, Reata Pharmaceuticals, Inc, Akebia Therapeutics, Inc; Advisory Board for Relypsa Inc, Medscape (WebMD LLC), and Reata Pharmaceuticals, Inc. Dr Chertow: Board of Directors, Satellite Healthcare, Inc; Consultant/Advisor: Akebia Therapeutics, Amgen, Ardelyx, Inc, AstraZeneca, Baxter Healthcare, CloudCath, Cricket Health, DiaMedica Therapeutics, Inc, Durect Corp, DxNow, Inc, Gilead Sciences, Inc, Miromatrix Medical, Inc, Outset Medical, Reata Pharmaceuticals, Inc, Sanifit, and Vertex Pharmaceuticals Inc. The authors are part of the CKD Advisory Committee for Reata Pharmaceuticals, Inc. Reata is evaluating bardoxolone methyl, an Nrf2 activator, for the treatment of Alport syndrome in the phase 3 CARDINAL study (ClinicalTrials.gov Identifier: NCT03019185). Editing, referencing, and graphic support were provided by Fallon Medica LLC with special thanks to Christine Park. Received March 13, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from the Editor-in-Chief. Accepted in revised form May 30, 2020. Funding Information: Dr Warady: Advisory Committee for Reata Pharmaceuticals, Inc; Medical Advisory Committee of the Alport Syndrome Foundation; Consultant for Bayer AG, Akebia Therapeutics, Relypsa, Inc, Amgen, and UpToDate, Inc; Research support from the National Institutes of Health (NIH) and Baxter Healthcare. Dr Agarwal: Consultant/Advisory Committee for Relypsa, Inc, Abbvie Inc, Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Celgene Corp, a Bristol-Myers Squibb Company, Daiichi Sankyo Company, Ltd, Eli Lilly and Co, Gilead Sciences, Inc, GlaxoSmithKline plc, Johnson & Johnson Services, Inc, Merck & Co, Inc, Novartis International AG, Sandoz International GmbH, ZS Pharma Inc, Akebia Therapeutics Inc, Takeda Pharmaceutical Co Ltd, Sanofi SA, Reata Pharmaceuticals, Inc, Ironwood Pharmaceuticals, Inc, Otsuka America Pharmaceutical, Inc, Opko Health, Inc, and Bird Rock Bio, Inc. Grants from the NIH and Veterans Affairs. Dr Bangalore: Advisory Committee for Reata Pharmaceuticals, Inc. Dr Chapman: Advisory Committee for Reata Pharmaceuticals, Inc, Sanofi SA, and Otsuka America Pharmaceutical, Inc; Speakers Bureau for Otsuka America Pharmaceutical, Inc; Contributor to UpToDate, Inc. Dr Levin: Advisory Committee for Reata Pharmaceuticals, Inc; Grants from Otsuka America Pharmaceutical, Inc, AstraZeneca, and Boehringer Ingelheim International GmbH. Dr Stenvinkel: Scientific Advisory Boards for Reata Pharmaceuticals, Inc, AstraZeneca, and Baxter Healthcare. Dr Toto: Executive Committee for AstraZeneca, Amgen; Consultant for Bayer AG, Boehringer Ingelheim International GmbH; Data Monitoring Committee for IQVIA Inc, Reata Pharmaceuticals, Inc, Akebia Therapeutics, Inc; Advisory Board for Relypsa Inc, Medscape (WebMD LLC), and Reata Pharmaceuticals, Inc. Dr Chertow: Board of Directors, Satellite Healthcare, Inc; Consultant/Advisor: Akebia Therapeutics, Amgen, Ardelyx, Inc, AstraZeneca, Baxter Healthcare, CloudCath, Cricket Health, DiaMedica Therapeutics, Inc, Durect Corp, DxNow, Inc, Gilead Sciences, Inc, Miromatrix Medical, Inc, Outset Medical, Reata Pharmaceuticals, Inc, Sanifit, and Vertex Pharmaceuticals Inc. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = sep,
day = "1",
doi = "10.1016/j.xkme.2020.05.014",
language = "English (US)",
volume = "2",
pages = "639--649",
journal = "Kidney Medicine",
issn = "2590-0595",
publisher = "Elsevier Inc.",
number = "5",
}