Sections

Alport Syndrome

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of Alport syndrome include the following:

Immunoglobulin A nephropathy
Thin glomerular basement membrane (GBM) disease
Urinary calculi

Differential Diagnoses

Acute Poststreptococcal Glomerulonephritis
Medullary Cystic Disease
Multicystic Renal Dysplasia
Nail-Patella Syndrome
Nephritis
Polycystic Kidney Disease

Workup

Zhang Y, Ding J. Renal, auricular, and ocular outcomes of Alport syndrome and their current management. Pediatr Nephrol. 2017 Sep 1. [QxMD MEDLINE Link].
Watson S, Bush JS. Alport Syndrome. 2017 Jun. [QxMD MEDLINE Link]. [Full Text].
Gross O, Perin L, Deltas C. Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol Dial Transplant. 2014 Sep. 29 Suppl 4:iv124-30. [QxMD MEDLINE Link].
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].
Kashtan CE. Familial hematuria. Pediatr Nephrol. 2009 Oct. 24(10):1951-8. [QxMD MEDLINE Link]. [Full Text].
Gross O. Understanding renal disorders as systemic diseases: the fascinating world of basement membranes beyond the glomerulus. Nephrol Dial Transplant. 2008 Jun. 23(6):1823-5. [QxMD MEDLINE Link].
Olaru F, Luo W, Wang XP, Ge L, Hertz JM, Kashtan CE, et al. Quaternary Epitopes of a345(IV) Collagen Initiate Alport Post-Transplant Anti-GBM Nephritis. J Am Soc Nephrol. 2013 May. 24(6):889-95. [QxMD MEDLINE Link]. [Full Text].
Wang XP, Fogo AB, Colon S, Giannico G, Abul-Ezz SR, Miner JH, et al. Distinct epitopes for anti-glomerular basement membrane alport alloantibodies and goodpasture autoantibodies within the noncollagenous domain of alpha3(IV) collagen: a janus-faced antigen. J Am Soc Nephrol. 2005 Dec. 16(12):3563-71. [QxMD MEDLINE Link].
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].
Kashtan CE. Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol. 1998 Sep. 9(9):1736-50. [QxMD MEDLINE Link].
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].
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, 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 Oct. 14(10):2603-10. [QxMD MEDLINE Link].
Rheault MN. Women and Alport syndrome. Pediatr Nephrol. 2012 Jan. 27(1):41-6. [QxMD MEDLINE Link]. [Full Text].
Lee JM, Nozu K, Choi DE, Kang HG, Ha IS, Cheong HI. Features of Autosomal Recessive Alport Syndrome: A Systematic Review. J Clin Med. 2019 Feb 3. 8 (2):[QxMD MEDLINE Link]. [Full Text].
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].
Ahmed F, Kamae KK, Jones DJ, Deangelis MM, Hageman GS, Gregory MC, et al. Temporal macular thinning associated with x-linked alport syndrome. JAMA Ophthalmol. 2013 Jun 1. 131(6):777-82. [QxMD MEDLINE Link].
Citirik M, Batman C, Men G, Tuncel M, Zilelioglu O. Electron microscopic examination of the anterior lens capsule in a case of Alport's syndrome. Clin Exp Optom. 2007 Sep. 90(5):367-70. [QxMD MEDLINE Link].
Raimundo M, Fonseca C, Silva R, Figueira J. Bilateral giant macular holes: A rare manifestation of Alport syndrome. Eur J Ophthalmol. 2019 Jan. 29 (1):NP13-NP16. [QxMD MEDLINE Link].
Patey-Mariaud de Serre N, Garfa M, Bessiéres B, Noël LH, Knebelmann B. Collagen alpha5 and alpha2(IV) chain coexpression: analysis of skin biopsies of Alport patients. Kidney Int. 2007 Aug. 72(4):512-6. [QxMD MEDLINE Link].
Gubler MC. Diagnosis of Alport syndrome without biopsy?. Pediatr Nephrol. 2007 May. 22(5):621-5. [QxMD MEDLINE Link].
Artuso R, Fallerini C, Dosa L, Scionti F, Clementi M, Garosi G, et al. Advances in Alport syndrome diagnosis using next-generation sequencing. Eur J Hum Genet. 2012 Jan. 20(1):50-7. [QxMD MEDLINE Link]. [Full Text].
Daina E, Cravedi P, Alpa M, Roccatello D, Gamba S, Perna A, et al. A multidrug, antiproteinuric approach to alport syndrome: a ten-year cohort study. Nephron. 2015. 130 (1):13-20. [QxMD MEDLINE Link].
Gross O, Tönshoff B, Weber LT, et al. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int. 2020 Jun. 97 (6):1275-1286. [QxMD MEDLINE Link]. [Full Text].
Charbit M, Gubler MC, Dechaux M, Gagnadoux MF, Grünfeld JP, Niaudet P. Cyclosporin therapy in patients with Alport syndrome. Pediatr Nephrol. 2007 Jan. 22(1):57-63. [QxMD MEDLINE Link].
Kelly YP, Patil A, Wallis L, Murray S, Kant S, Kaballo MA, et al. Outcomes of kidney transplantation in Alport syndrome compared with other forms of renal disease. Ren Fail. 2017 Nov. 39 (1):290-293. [QxMD MEDLINE Link].
Mojahedi MJ, Hekmat R, Ahmadnia H. Kidney transplantation in patients with alport syndrome. Urol J. 2007 Fall. 4(4):234-7. [QxMD MEDLINE Link].
[Guideline] Savige J, Storey H, Watson E, et al. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet. 2021 Apr 15. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults–an update for 2020.
Webb NJ, Shahinfar S, Wells TG, Massaad R, Gleim GW, McCrary Sisk C, et al. Losartan and enalapril are comparable in reducing proteinuria in children with Alport syndrome. Pediatr Nephrol. 2013 May. 28(5):737-43. [QxMD MEDLINE Link].
Callís L, Vila A, Carrera M, Nieto J. Long-term effects of cyclosporine A in Alport's syndrome. Kidney Int. 1999 Mar. 55(3):1051-6. [QxMD MEDLINE Link].
[Guideline] Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013 Feb. 24(3):364-75. [QxMD MEDLINE Link].

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.

Alport Syndrome Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

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