Pediatric Alport Syndrome Workup

  • Author: Prasad Devarajan, MD; Chief Editor: Craig B Langman, MD   more...
 
Updated: Nov 29, 2011
 

Laboratory Studies

  • Urinalysis
    • In individuals with Alport syndrome, urinalysis reveals microscopic or gross hematuria. The urinary sediment is usually active, with dysmorphic RBCs indicating glomerular bleeding. RBC casts are occasionally observed.
    • Proteinuria is usually absent in the first few years of life but eventually develops in male patients with X-linked Alport syndrome and in people of both sexes with autosomal recessive disease. The degree of proteinuria usually increases with age and may reach the nephrotic range in 30-40% of young adults with Alport syndrome.
  • Blood analysis
    • Blood counts and serum electrolyte, BUN, and creatinine levels reflect the degree of renal insufficiency.
    • Individuals with nephrotic syndrome may have clinically significant hypoalbuminemia and hypercholesterolemia.
    • Some patients with the autosomal dominant form of Alport syndrome also have thrombocytopenia, giant platelets, and granulocytic inclusions.
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Imaging Studies

  • Renal ultrasonography is indicated for children with persistent microscopic hematuria, primarily to exclude stone disease, cystic dysplasia, and other structural anomalies.
  • Ultrasonographic findings are usually normal in individuals with early Alport syndrome. In late stages, the kidneys shrink symmetrically and progressively.
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Other Tests

  • Audiometry: All children with a history suggestive of Alport syndrome should undergo high-frequency audiometry to confirm the diagnosis (ie, high-frequency sensorineural hearing loss), as well as periodic monitoring.
  • Ophthalmologic evaluation: Ophthalmologic examination is important for the early detection and monitoring of anterior lenticonus, perimacular flecks, and other eye lesions.
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Procedures

  • Renal biopsy
    • Percutaneous renal biopsy is an important part of the diagnostic workup. The test should be performed at a medical center equipped for ultrastructural analysis with electron microscopy. A medical center that has facilities for evaluating collagen chains of the basement membrane by means of immunohistochemistry is also desirable but not required.
    • Biopsy may be deferred in a patient with a strong family history of biopsy-proven Alport disease who presents with characteristic clinical features.
  • Skin biopsy
    • Because the a5 chain of type IV collagen is also expressed in the epidermis, immunofluorescence examination of a skin biopsy specimen can be used to establish the diagnosis. Approximately 80% of male patients and 60% of female patients with X-linked Alport syndrome have no a5(IV) collagen in epidermal basement membrane. The interruption of a5(IV) expression is total in males and is segmental in females. Studies have shown that many individuals with X-linked Alport syndrome also display abnormalities of a2(IV) collagen expression in the skin.[10] In addition, most individuals with autosomal recessive Alport syndrome do not express a3(IV), a4(IV), or a5(IV) collagens in skin. Healthy individuals and patients with thin-membrane disease have normal expression of a5(IV) in the skin.
    • This approach is especially useful if a kidney biopsy poses an excessive risk, such as in patients with end-stage renal disease (ESRD).
  • Genetic analysis
    • Genetic analysis is the only means for diagnosing the carrier state in asymptomatic female individuals with a family history of X-linked Alport syndrome. Genetic analysis is also the only means for making a prenatal diagnosis.
    • Both linkage analysis and direct collagen-chain gene sequencing are performed in select research laboratories. However, screening for randomly distributed mutations within the large collagen-chain genes is tedious, expensive, and time consuming.[11, 12] In addition, the sensitivity is not high, and the current rate of identification of mutations in Alport kindreds is 50-80% at best.
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Histologic Findings

  • On light microscopy, renal histologic findings are nonspecific. Abnormalities might not be observed in early Alport syndrome. With progression, increased mesangial matrix, segmental proliferation, and segmental sclerosis may appear. Conventional immunofluorescence studies of renal tissue usually yield negative results.
  • Electron microscopy reveals the characteristic lesions of Alport syndrome (see image below).Electron micrograph from a patient with Alport synElectron 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.
  • Glomerular basement membrane is irregularly thickened. The central lamina densa is split and splintered into a heterogeneous network of strands, which enclose electron-lucent areas that may contain microgranulations. The epithelial aspect of the capillary wall is irregular, and epithelial foot processes are fused. Thickening of the glomerular basement membrane is usually diffuse in adults with Alport syndrome; however, in young children with the disorder, the thickening is segmental, and thinning of the basement membrane may be observed or even predominate. The degree of thickening increases with the patient's age and the degree of proteinuria. Therefore, a thick and split glomerular basement membrane is specific for Alport syndrome; however, its absence does not exclude the syndrome, especially in young children.
  • The basement membranes can be immunohistochemically evaluated by using monoclonal antibodies directed against the a3, a4, and a5 chains of type IV collagen. The absence of these chains in the glomerular basement membrane is characteristic of Alport syndrome. Because the a5 chain is also expressed in the epidermal basement membrane, skin biopsy is an additional tool for diagnosis. Male patients with X-linked Alport syndrome have a complete absence of a3, a4, and a5 chains in the glomerular and epithelial basement membranes, whereas female patients with X-linked disease have mosaicism and segmental loss of staining.
  • In patients with the autosomal recessive variety, glomerular basement membrane demonstrates no expression of the a3, a4, and a5 chains, but expression of the a5 chain is present in the epidermal basement membrane. These observations suggest that a mutation affecting one of the chains can affect the expression of all 3 chains, perhaps because of degradation of normal chains that have not assembled into functional trimers.
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Contributor Information and Disclosures
Author

Prasad Devarajan, MD  Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, CEO of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

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.

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.

Howard Trachtman, MD  Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine

Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

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, Children's Memorial Hospital

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

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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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