Alport Syndrome Workup

  • Author: Ramesh Saxena, MD, PhD; Chief Editor: Vecihi Batuman, MD, FACP, FASN   more...
 
Updated: Nov 21, 2011
 

Laboratory Studies

  • Urinalysis: Urinary dipstick test and a 24-hour urine specimen for protein and creatinine should be performed to detect hematuria and proteinuria. Also, urinary sediment should be analyzed by microscope to detect dysmorphic red blood cells and red blood cell casts.
  • Hematuria: Urinary sediment frequently reveals dysmorphic red blood cells and red blood cell casts. Whenever possible, screening of the first-degree relatives for microscopic hematuria of glomerular origin should be performed.
  • Proteinuria: Proteinuria is usually absent in early childhood, but it eventually develops. Proteinuria usually progresses with age and can be in the nephrotic range in as many as 30% of patients.
Next

Imaging Studies

  • Renal ultrasound: In early stages, a renal ultrasound shows healthy-sized kidneys; however, with advancing renal failure, the kidneys become smaller and echogenic.
Previous
Next

Other Tests

  • Genetic analysis: If diagnosis remains doubtful after skin or kidney biopsy, screening for genetic mutations may be considered; however, the screening for COL4A3, COL4A4, and COL4A5 mutations is expensive, time consuming, extremely difficult, and not widely available. Moreover, the current detection rate of COL4A5 mutations in relatives with Alport syndrome is only about 50%; thus, for now, genetic analysis should be restricted for prenatal diagnosis or when uncertainty about diagnosis or mode of transmission of Alport syndrome exists.[3]
Previous
Next

Procedures

  • Biopsy: Obtain tissue from the kidneys and skin to reveal ultrastructural abnormalities.
    • Skin biopsy is less invasive than renal biopsy and should be obtained first.
    • Kidney biopsy most often provides the diagnosis if it is not established by skin biopsy.
Previous
Next

Histologic Findings

The absence of alpha-5 (IV) chains of type IV collagen in the epidermal basement membrane on skin biopsy is diagnostic of XLAS. In such cases, kidney biopsy is not necessary for diagnosis; however, the absence of alpha-5 (IV) chains in the epidermal basement membrane is observed in only 80% of males with XLAS. Therefore, the presence of alpha-5 (IV) chains in the epidermal basement membrane does not rule out the diagnosis of XLAS; moreover, the alpha-5 (IV) chain is expressed in the epidermal basement membrane in autosomal recessive disease. Thus, the presence of alpha-5 (IV) chain in the epidermal basement membrane indicates a mutation in the alpha-5 (IV) chain that permits its expression in skin but not in the kidney in XLAS, ARAS, or another disorder.

Findings on light microscopy of kidney biopsy specimens contribute little toward the diagnosis. The findings are nonspecific and include segmental and focal glomerulosclerosis, tubular atrophy, interstitial fibrosis, and infiltration by lymphocytes and plasma cells with clusters of foam cells of uncertain origin. Findings on standard immunofluorescence studies are usually negative.

Monoclonal antibodies directed against alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen can be used to evaluate the GBM for the presence or absence of these chains. The absence of these chains from the GBM is diagnostic of Alport syndrome and has not been described in any other condition. In addition, renal expression of type IV collagen alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains can differentiate XLAS and ARAS. In most patients with XLAS, alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains are absent from the GBM and distal TBM. On the other hand, in ARAS, no expression of alpha-3 (IV) and alpha-4 (IV) chains exists, while the alpha-5 (IV) chain is expressed in the GBM and distal TBM; however, normal staining of the GBM for alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains does not rule out the diagnosis of Alport syndrome.

Electron microscopy reveals diffuse thickening and splitting of the basement membrane in 60-90% of patients. Diffuse thinning is observed in some patients with Alport syndrome. A normal ultrastructure of the GBM makes a diagnosis of Alport syndrome highly unlikely.

Electron micrograph of kidney biopsy from a patienElectron micrograph of kidney biopsy from a patient with Alport syndrome. Note the splitting and lamellation of the glomerular basement membrane (see arrows).
Previous
Proceed to Treatment & Management
 
 
Contributor Information and Disclosures
Author

Ramesh Saxena, MD, PhD  Associate 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: American Medical Association, American Society of Nephrology, International Society of Nephrology, and National Kidney Foundation

Disclosure: e-medicine Honoraria authoring review articles

Specialty Editor Board

Frank C Brosius III, MD  Nephrology Program Director, Professor of Internal Medicine and Physiology, Department of Internal Medicine, Division of Nephrology, University of Michigan School of Medicine

Frank C Brosius III, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, American Society of Nephrology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

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

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

Rebecca J Schmidt, DO, FACP, FASN  Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Vecihi Batuman, MD, FACP, FASN  Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology

Disclosure: Nothing to disclose.

References

  1. Jain C, Malik VK, Kamboj R, Kumar S, Kumar S, Jain K. Alport Syndrome: case report and review of ocular manifestations. Nepal J Ophthalmol. Jul 2011;3(6):118-90. [Medline].

  2. Citirik M, Batman C, Men G, et al. Electron microscopic examination of the anterior lens capsule in a case of Alport's syndrome. Clin Exp Optom. Sep 2007;90(5):367-70. [Medline].

  3. 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. Sep 7 2011;[Medline].

  4. Wang XP, Fogo AB, Colon S, 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. Dec 2005;16(12):3563-71. [Medline].

  5. 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. [Medline]. [Full Text].

  6. Kashtan CE. Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol. Sep 1998;9(9):1736-50. [Medline].

  7. Alport AC. Hereditary familial congenital haemorrhagic nephritis. Br Med J. 1927;1:504-6.

  8. Brainwood D, Kashtan C, Gubler MC, et al. Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation. Kidney Int. Mar 1998;53(3):762-6. [Medline].

  9. Callis L, Vila A, Carrera M, et al. Long-term effects of cyclosporine A in Alport's syndrome. Kidney Int. Mar 1999;55(3):1051-6. [Medline].

  10. Charytan D, MacDonald B, Sugimoto H, et al. An unusual case of pulmonary-renal syndrome associated with defects in type IV collagen composition and anti-glomerular basement membrane autoantibodies. Am J Kidney Dis. Apr 2005;45(4):743-8. [Medline].

  11. Colville D, Dagher H, Miach P, et al. Ocular clues to the nature of disease causing end-stage renal failure. Nephrol Dial Transplant. Mar 2000;15(3):429-32. [Medline].

  12. Colville DJ, Savige J. Alport syndrome. A review of the ocular manifestations. Ophthalmic Genet. Dec 1997;18(4):161-73. [Medline].

  13. Flinter F. Alport's syndrome. J Med Genet. Apr 1997;34(4):326-30. [Medline].

  14. Gunwar S, Ballester F, Noelken ME, et al. Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem. Apr 10 1998;273(15):8767-75. [Medline].

  15. Harvey SJ, Zheng K, Jefferson B, et al. Transfer of the alpha 5(IV) collagen chain gene to smooth muscle restores in vivo expression of the alpha 6(IV) collagen chain in a canine model of Alport syndrome. Am J Pathol. Mar 2003;162(3):873-85. [Medline].

  16. Harvey SJ, Zheng K, Sado Y, et al. Role of distinct type IV collagen networks in glomerular development and function. Kidney Int. Dec 1998;54(6):1857-66. [Medline].

  17. Heidet L, Cai Y, Guicharnaud L, et al. Glomerular expression of type IV collagen chains in normal and X-linked Alport syndrome kidneys. Am J Pathol. Jun 2000;156(6):1901-10. [Medline].

  18. Heikkilä P, Tryggvason K, Thorner P. Animal models of Alport syndrome: advancing the prospects for effective human gene therapy. Exp Nephrol. Jan-Feb 2000;8(1):1-7. [Medline].

  19. Hudson BG. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family. J Am Soc Nephrol. Oct 2004;15(10):2514-27. [Medline].

  20. Hudson BG, Wieslander J, Wisdom BJ Jr, et al. Goodpasture syndrome: molecular architecture and function of basement membrane antigen. Lab Invest. Sep 1989;61(3):256-69. [Medline].

  21. Jais JP, Knebelmann B, Giatras I, et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol. Apr 2000;11(4):649-57. [Medline].

  22. Jefferson JA, Lemmink HH, Hughes AE, et al. Autosomal dominant Alport syndrome linked to the type IV collage alpha 3 and alpha 4 genes (COL4A3 and COL4A4). Nephrol Dial Transplant. Aug 1997;12(8):1595-9. [Medline].

  23. Kalluri R, Shield CF, Todd P, et al. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest. May 15 1997;99(10):2470-8. [Medline].

  24. Kalluri R, Torre A, Shield CF 3rd, et al. Identification of alpha3, alpha4, and alpha5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies. Transplantation. Feb 27 2000;69(4):679-83. [Medline].

  25. Kashtan CE. Alport syndrome: is diagnosis only skin-deep?. Kidney Int. Apr 1999;55(4):1575-6. [Medline].

  26. Kashtan CE. Renal transplantation in patients with Alport syndrome. Pediatr Transplant. Sep 2006;10(6):651-7. [Medline].

  27. Kleppel MM, Fan WW, Cheong HI, et al. Immunochemical studies of the Alport antigen. Kidney Int. Jun 1992;41(6):1629-37. [Medline].

  28. Lemmink HH, Schroder CH, Monnens LA, et al. The clinical spectrum of type IV collagen mutations. Hum Mutat. 1997;9(6):477-99. [Medline].

  29. Mazzarella V, Splendiani G, Tozzo C, et al. Renal transplantation in patients with hereditary kidney disease: our experience. Contrib Nephrol. 1997;122:203-6. [Medline].

  30. Meleg-Smith S, Magliato S, Cheles M, et al. X-linked Alport syndrome in females. Hum Pathol. Apr 1998;29(4):404-8. [Medline].

  31. Miner JH. Alport syndrome with diffuse leiomyomatosis. When and when not?. Am J Pathol. Jun 1999;154(6):1633-5. [Medline].

  32. Nomura S, Naito I, Fukushima T, et al. Molecular genetic and immunohistochemical study of autosomal recessive Alport's syndrome. Am J Kidney Dis. Jun 1998;31(6):E4. [Medline].

  33. Pirson Y. Making the diagnosis of Alport's syndrome. Kidney Int. Aug 1999;56(2):760-75. [Medline].

  34. Plant KE, Green PM, Vetrie D, et al. Detection of mutations in COL4A5 in patients with Alport syndrome. Hum Mutat. 1999;13(2):124-32. [Medline].

  35. Sado Y, Kagawa M, Naito I, et al. Organization and expression of basement membrane collagen IV genes and their roles in human disorders. J Biochem. May 1998;123(5):767-76. [Medline].

  36. Swann PG, Patel S. Lenticular changes in Alport's syndrome. Clin Exp Optom. Jan 2005;88(1):53-4. [Medline].

  37. Timpl R, Wiedemann H, van Delden V, et al. A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem. Nov 1981;120(2):203-11. [Medline].

  38. van der Loop FT, Heidet L, Timmer ED, et al. Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int. Nov 2000;58(5):1870-5. [Medline].

  39. van der Loop FT, Monnens LA, Schroder CH, et al. Identification of COL4A5 defects in Alport's syndrome by immunohistochemistry of skin. Kidney Int. Apr 1999;55(4):1217-24. [Medline].

 
Previous
Next
 
Electron micrograph of kidney biopsy from a patient with Alport syndrome. Note the splitting and lamellation of the glomerular basement membrane (see arrows).
Table 1. Location and Mutations of the Genes Coding for Alpha (IV) Chains of Type IV Collagen in Alport Syndrome
Alpha (IV) ChainGenesChromosomal LocationMutation
Alpha-1 (IV)COL4A113Unknown
Alpha-2 (IV)COL4A213Unknown
Alpha-3 (IV)COL4A32ARAS*
Alpha-4 (IV)COL4A42ARAS
Alpha-5 (IV)COL4A5xXLAS †
Alpha-6 (IV)COL4A6xLeiomyomatosis ‡
* Autosomal recessive Alport syndrome (mutations spanning 5' regions of COL4A5 and COL4A6 genes)



† X-linked Alport syndrome



‡ Autosomal recessive Alport syndrome



Table 2. Tissue Distribution of Alpha (IV) Chains
Alpha (IV) ChainTissue Distribution
Alpha-1 (IV)Ubiquitous
Alpha-2 (IV)Ubiquitous
Alpha-3 (IV)GBM, distal TBM*, 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
* Tubular basement membrane
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.