In individuals with Alport syndrome, urinalysis reveals microscopic or gross hematuria with dysmorphic RBCs indicative of glomerular bleeding.
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 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.
Renal ultrasonography is indicated for children with persistent microscopic hematuria, primarily to exclude renal tumors, stone disease, cystic disease, and other structural anomalies.
Ultrasonographic findings are usually normal in individuals with early Alport syndrome. In late stages, the kidneys shrink symmetrically and progressively.
- Audiometry: All children with a history suggestive of Alport syndrome should undergo high-frequency audiometry to confirm the diagnosis (i.e., 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
Percutaneous renal biopsy is an important part of the diagnostic workup. Ultrastructural analysis using electron microscopy is a critical component of evaluation for Alport syndrome. Assessment of collagen chains in basement membranes by means of immunohistochemistry is also very helpful in making the diagnosis of Alport syndrome.
Biopsy may be deferred in a patient with a strong family history of biopsy-proven Alport disease who presents with characteristic clinical features.
Because the a5 chain of type IV collagen is normally expressed in the epidermis, immunofluorescence examination of a skin biopsy specimen can be used to establish a diagnosis of X-linked Alport syndrome. Approximately 80% of male patients and 60% of female patients with X-linked Alport syndrome exhibit abnormal staining for the a5 (IV) chain.
This approach is especially useful if a kidney biopsy poses an excessive risk, such as in patients with ESRD.
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. Genetic analysis may be useful when results of skin or kidney biopsy are ambiguous.
Both linkage analysis and direct gene sequencing are performed in select research laboratories. At present, several clinical laboratories in the U.S. offer COL4A5 gene analysis for diagnosis of X-linked Alport syndrome. Direct gene sequencing identifies up to 80% of COL4A5 mutations in males with X-linked Alport syndrome. Current information on genetic testing for Alport syndrome is available at genereviews.org.
On light microscopy, renal histologic findings are nonspecific. Abnormalities may be absent in early Alport syndrome. Features of disease prgression include expansion of mesangial matrix, mesangial proliferation, and focal segmental glomerulosclerosis. Conventional immunofluorescence studies of renal tissue usually yield negative results.
Electron microscopy reveals the characteristic lesions of Alport syndrome. Glomerular basement membranes (GBM) exhibit irregular thickening. 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, but in young children with the disorder the thickening is segmental, and thinning of the basement membrane frequently is the predominant abnormality. 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 Alport 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 usually show complete absence of a3, a4, and a5 chains in the glomerular and renal tubular basement membranes, as well as epidermal basement membranes. Female patients with X-linked disease typically exhibit segmental loss of staining (mosaicism). In patients with autosomal recessive Alport syndrome, glomerular basement membranes demonstrate loss of expression of the a3, a4, and a5 chains, but expression of the a5 chain is present in renal tubular basement membranes and Bowman’s capsules and in epidermal basement membranes.