Alport Syndrome Workup

Updated: Jun 28, 2021
  • Author: Ramesh Saxena, MD, PhD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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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 patients of both sexes with autosomal recessive disease. Hematologic studies demonstrate the extent of kidney insufficiency.


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

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.


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, ultrasonograms show healthy-sized kidneys; with advancing kidney failure, however, the kidneys shrink symmetrically and progressively and become echogenic.


Urine and Blood Analysis


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.



Kidney biopsy

Percutaneous kidney 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 the 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. [21] 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).


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, expression of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains in the kidney 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.

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. [22, 23] It is also the only means for diagnosing the carrier state in asymptomatic females with a family history of X-linked Alport syndrome.