Guidelines Summary

The Alport Variant Collaborative have released the following guidelines for the molecular diagnosis of Alport syndrome^[29]:

Comprehensive parallel genetic testing of the entire coding sequence of each gene is recommended for detection of the causative pathogenic variant in the COL4A5, COL4A3 and COL4A4 genes.
Genetic testing for diagnosis should take precedence over kidney biopsy.
When a causative variant is demonstrated, a kidney biopsy may not be needed for diagnosis.
Multigene Massively Parallel Sequencing kidney disease panels for the extended Alport phenotypes should include COL4A3–COL4A5

In 2020, the Alport syndrome research collaborative updated its 2013 guidelines. The initiation of treatment with angiotensin-converting enzyme inhibition at the time of diagnosis in males with X-linked Alport syndrome and in males and females with autosomal recessive Alport syndrome is now recommended. For females with X-linked Alport syndrome and males and females with autosomal dominant Alport syndrome, treatment should be initiated at the onset of microalbuminuria.^[30]

Medication

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Kashtan CE. Renal transplantation in patients with Alport syndrome: patient selection, outcomes, and donor evaluation. Int J Nephrol Renovasc Dis. 2018. 11:267-270. [QxMD MEDLINE Link]. [Full Text].
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Borza DB. Autoepitopes and alloepitopes of type IV collagen: role in the molecular pathogenesis of anti-GBM antibody glomerulonephritis. Nephron Exp Nephrol. 2007. 106(2):e37-43. [QxMD MEDLINE Link]. [Full Text].
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Armstead S, Hellmark T, Wieslander J, Zhou X, Saxena R, Rajora N. A case of Alport syndrome with post-transplant anti-glomerular basement membrane disease despite negative anti-glomerular basement membrane antibodies by ELISA treated with plasmapheresis and intravenous immunoglobulin. Case Report Transpl. 2013. In press.
United States Renal Data System. 2017 Annual Data Report. USRDS. Available at https://www.usrds.org/2017/view/Default.aspx. 2017; Accessed: April 20, 2019.
Massella L, Gangemi C, Giannakakis K, Crisafi A, Faraggiana T, Fallerini C, et al. Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome. Clin J Am Soc Nephrol. 2013 May. 8(5):749-55. [QxMD MEDLINE Link]. [Full Text].
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Mallett A, Tang W, Clayton PA, Stevenson S, McDonald SP, Hawley CM, et al. End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases. Nephrol Dial Transplant. 2014 Dec. 29 (12):2277-86. [QxMD MEDLINE Link].
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[Guideline] Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults–an update for 2020.
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Media Gallery

Electron micrograph of a kidney biopsy from a patient with Alport syndrome. Note the splitting and lamellation of the glomerular basement membrane (see arrows).
Electron micrograph from a patient with Alport syndrome revealing the typical splitting and splintering of the glomerular basement membrane (original magnification X3000). Courtesy of Glen S. Markowitz, MD, Department of Pathology, Columbia University College of Physicians and Surgeons, New York.

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Table 1. Location and Mutations of the Genes Coding for Alpha (IV) Chains of Type IV Collagen in Alport Syndrome

Alpha (IV) Chain	Genes	Chromosomal Location	Mutation
Alpha-1 (IV)	COL4A1	13	Unknown
Alpha-2 (IV)	COL4A2	13	Unknown
Alpha-3 (IV)	COL4A3	2	ARAS^a
Alpha-4 (IV)	COL4A4	2	ARAS
Alpha-5 (IV)	COL4A5	X	XLAS^b
Alpha-6 (IV)	COL4A6	X	Leiomyomatosis^c
^a Autosomal recessive Alport syndrome (mutations spanning 5' regions of COL4A5 and COL4A6 genes). ^b X-linked Alport syndrome. ^c Autosomal recessive Alport syndrome.

Table 2. Tissue Distribution of Alpha (IV) Chains

Alpha (IV) Chain	Tissue Distribution
Alpha-1 (IV)	Ubiquitous
Alpha-2 (IV)	Ubiquitous
Alpha-3 (IV)	GBM, distal TBM^a, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea
Alpha-4 (IV)	GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea
Alpha-5 (IV)	GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea
Alpha-6 (IV)	Distal TBM, epidermal basement membrane
^a Tubular basement membrane.

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Author

Ramesh Saxena, MD, PhD Professor, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center

Ramesh Saxena, MD, PhD is a member of the following medical societies: International Society for Peritoneal Dialysis, National Kidney Foundation, Texas Medical Association, American Society of Nephrology, International Society of Nephrology

Disclosure: Received honoraria from e-medicine for authoring review articles.

Coauthor(s)

Prasad Devarajan, MD, FAAP Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of the Nephrology Fellowship Program, Medical Director of the Kidney Stone Center, Co-Director of the Institutional Office of Pediatric Clinical Fellowships, Director of Clinical Nephrology Laboratory, CEO of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine

Prasad Devarajan, MD, FAAP is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, Society for Pediatric Research

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Consultant for Reata, Dicerna, Alnylam<br/>Received none from Coinventor on patents submitted for the use of NGAL as a biomarker of kidney injury for none.

Chief Editor

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Acknowledgements

Uri S Alon, MD Director of Bone and Mineral Disorders Clinic and Renal Research Laboratory, Children's Mercy Hospital of Kansas City; Professor, Department of Pediatrics, Division of Pediatric Nephrology, University of Missouri-Kansas City School of Medicine

Uri S Alon, MD is a member of the following medical societies: American Federation for Medical Research

Disclosure: Nothing to disclose.

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology

Disclosure: NIH Grant/research funds None; Raptor Pharmaceuticals, Inc Grant/research funds None; Alexion Pharmaceuticals, Inc. Grant/research funds None

Eleanor Lederer, MD Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa

Disclosure: Dept of Veterans Affairs Grant/research funds Research; American Society of Nephrology Salary ASN Council Position

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Luther Travis, MD Professor Emeritus, Departments of Pediatrics, Nephrology and Diabetes, University of Texas Medical Branch School of Medicine

Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, and Texas Pediatric Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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