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Alport Syndrome Workup

  • Author: Ramesh Saxena, MD, PhD; Chief Editor: Vecihi Batuman, MD, FACP, FASN  more...
 
Updated: Jul 21, 2015
 

Approach Considerations

Laboratory studies

In individuals with Alport syndrome, urinalysis reveals microscopic or gross hematuria. Proteinuria is found in male patients with X-linked Alport syndrome (XLAS) and in people of both sexes with autosomal recessive disease. Hematologic studies demonstrate the extent of renal insufficiency.

Biopsy

Tissue from the kidneys and skin should be examined for ultrastructural abnormalities. Skin biopsy is less invasive than renal biopsy and should be performed first. Kidney biopsy most often provides the diagnosis if it is not established by skin biopsy.

Genetic testing

If the diagnosis of Alport syndrome remains doubtful after skin or kidney biopsy, genetic analysis can be used to make a firm diagnosis and determine the condition’s mode of inheritance.

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.

Ophthalmic evaluation

Ophthalmic examination is important for the early detection and monitoring of anterior lenticonus, as well as perimacular flecks and other eye lesions.

Renal ultrasonography

In the early stages of Alport syndrome, renal ultrasonograms show healthy-sized kidneys; with advancing renal failure, however, the kidneys shrink symmetrically and progressively and become echogenic.

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Urine and Blood Analysis

Urinalysis

A 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.

Whenever possible, the first-degree relatives of a patient with Alport syndrome should also be screened for microscopic hematuria of glomerular origin.

Proteinuria is usually absent in the first few years of life but eventually develops in male patients with X-linked Alport syndrome (XLAS) 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, blood urea nitrogen (BUN), and creatinine levels reflect the degree of renal insufficiency in Alport syndrome.

In addition, 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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Biopsy

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 alpha-5 (IV) chain of type IV collagen is also expressed in the epidermis, immunofluorescent examination of a skin biopsy specimen can be used to establish the diagnosis. Approximately 80% of male patients and 60% of female patients with XLAS have no alpha-5 (IV) collagen in epidermal basement membrane, with the interruption of alpha-5 (IV) expression being total in males and segmental in females.

Studies have shown that many individuals with X-linked Alport syndrome also display abnormalities of alpha-2 (IV) collagen expression in the skin.[17] In addition, most individuals with autosomal recessive Alport syndrome do not express alpha-3 (IV), alpha-4 (IV), or alpha-5 (IV) collagens in skin. Healthy individuals and patients with thin-membrane disease have normal expression of alpha-5(IV) in the skin.

Skin biopsy is especially useful if a kidney biopsy poses an excessive risk, such as in patients with end-stage renal disease (ESRD).

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Histologic Findings

The absence of alpha-5 (IV) collagen chains 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. This indicates that a mutation in the alpha-5 (IV) chain permits its expression in skin but not in the kidney in XLAS and autosomal recessive Alport syndrome (ARAS).

Light microscopy

In early Alport syndrome, light microscopy findings for kidney biopsy specimens may be normal. The findings that occur with disease progression are nonspecific, contributing little toward the diagnosis. They 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

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 glomerular basement membrane (GBM) for the presence or absence of these chains. Their absence is diagnostic of Alport syndrome and has not been described in any other condition.

In addition, renal expression of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains can differentiate XLAS and ARAS. In most patients with XLAS, these 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 tubular basement membrane (TBM). However, normal staining of the GBM for these 3 chains does not rule out the diagnosis of Alport syndrome.

Electron microscopy

Electron microscopy reveals the characteristic lesions of Alport syndrome. The GBM is irregularly thickened, and 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 GBM is usually diffuse in adults with Alport syndrome, but 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 GBM is specific for Alport syndrome; however, its absence does not exclude the syndrome, especially in young children. (See the images below.)

Electron micrograph of a kidney biopsy from a pati 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 syn 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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Genetic Analysis

If the diagnosis of Alport syndrome 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%. At present, therefore, genetic analysis should be restricted to prenatal diagnosis or when uncertainty about diagnosis or mode of transmission of Alport syndrome exists.[18, 19] It is also the only means for diagnosing the carrier state in asymptomatic females with a family history of X-linked Alport syndrome.

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Contributor Information and Disclosures
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: 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, FACP, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, 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, International Society of Nephrology

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.

References
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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.
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 ARASa
Alpha-4 (IV) COL4A4 2 ARAS
Alpha-5 (IV) COL4A5 X XLASb
Alpha-6 (IV) COL4A6 X Leiomyomatosisc
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 TBMa, 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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