Hematuria is a relatively common abnormality. About 0.25% of school-age children have persistent microscopic hematuria. In adults the prevalence of hematuria increases with age and is greater in women. The causes and consequently the workup of hematuria vary with age. Glomerular disorders are responsible for most cases of pediatric hematuria, while urinary tract malignancy is an important cause of hematuria in individuals over 40 years of age.

Because thin basement membrane nephropathy (TBMN) typically has a benign course, it is likely that this condition is underdiagnosed, and that the true prevalence of familial hematuria is higher than we might think. TBMN and Alport syndrome account for a substantial fraction of children with isolated hematuria referred to pediatric nephrology clinics. TBMN was diagnosed in 40–70% of patients with asymptomatic microscopic hematuria and a negative urologic evaluation.

Essentials of Diagnosis

• Microscopic hematuria.
  
• Abnormal tissue expression of type IV collagen α3, α4, and α5 chains, or the presence of COL4A3, COL4A4, or COL4A5 mutation(s).
  
• Characteristic thickening and lamellation of glomerular basement membranes (GBM).
  
• High-frequency sensorineural deafness.
  
• Anterior lenticonus or perimacular retinal flecks.

General Considerations

Alport syndrome is a progressive nephropathy caused by mutations in type IV collagen, the predominant collagenous constituent of basement membranes. These mutations result in critical defects in the structure and function of glomerular, cochlear, and ocular basement membranes.

Pathogenesis

The type IV collagen family consists of six proteins, designated α1 (IV) − α6 (IV), encoded by six distinct genes, COL4A1–COL4A6. These genes are organized in pairs on three chromosomes: COL4A1–COL4A2, chromosome 13; COL4A3–COL4A4, chromosome 2; and COL4A5–COL4A6, X chromosome. Within each pair the genes are oriented in a 5′–5′ fashion, separated by regulatory domains of varying length.

Type IV collagen α chains associate into trimers that in turn form supermolecular networks. Three trimers have been identified in mammalian basement membranes: α1 α1α2, α3α4α5, and α5α5α6. The α1α1α2 trimer is found in all basement membranes, including glomerular mesangium, but it is a relatively minor component of mature GBM. The predominant type IV collagen species in GBM, and in the basement membrane of the organ of Corti and certain ocular basement membranes, is the α3α4α5 trimer. The α3α4α5 trimer is also present in Bowman’s capsules (BC) and the basement membranes of distal (dTBM) and collecting (cTBM) tubules. The α5α5α6 trimer is expressed in BC, dTBM, and cTBM, but not in GBM. The α5α5α6 trimer is also highly expressed in epidermal basement membranes (EBM).

Alport syndrome arises from mutations in the COL4A3, COL4A4, and COL4A5 genes. About 80% of individuals with Alport syndrome have the X-linked form of the disease (XLAS), due to mutations in COL4A5. Autosomal recessive Alport syndrome (ARAS) is caused by mutations in both alleles of COL4A3 or COL4A4, and accounts for about 15% of people with the disease. Finally, about 5% of individuals with Alport syndrome have autosomal dominant disease (ADAS), resulting from a mutation in one allele of COL4A3 or COL4A4. Heterozygous COL4A3 or COL4A4 mutations are an important cause of thin basement membrane nephropathy.

The usual result of COL4A5 mutations in males with XLAS is the complete disappearance of α3α4α5 and α5α5α6 trimers, and the supermolecular networks formed by these trimers, from all basement membranes. Heterozygous females with XLAS typically exhibit mosaic expression of these trimers in their basement membranes. In most patients with ARAS, α3α4α5 are absent from all basement membranes, but α5 α5 α6 trimers persist in BC, dTBM, cTBM, and EBM. These observations in human subjects have been confirmed in various animal models of XLAS and ARAS and have several implications that have received support from in vitro studies. First, the interactions among the six members of the type IV collagen family are specific and can produce only three trimers: α1α1α2, α3α4α5, and α5 α5 α6. Second, a mutation in a type IV collagen α chain disrupts the formation and deposition of all trimers in which that chain participates. Lastly, since disappearance of α3 (IV), α4 (IV), and α5 (IV) chains from basement membranes is specific for Alport syndrome, immunostaining for these chains in tissues is diagnostically useful.

Clinical Findings

Symptoms and Signs

Renal

Hematuria is a constant feature of Alport syndrome, occurring in 100% of affected males and about 95% of affected females. It is often detectable in infancy, and episodic gross hematuria is common during childhood.

Overt proteinuria develops in all affected males, typically in late childhood or adolescence, and in many affected females. In affected females, proteinuria is a risk factor for the development of end-stage renal disease (ESRD).

Cochlear