Chapter 47. Familial Hematurias: Alport Syndrome & Thin Basement Membrane Nephropathy

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

Sensorineural hearing loss (SNHL) is detectable in 50% of males with XLAS by the age of 25 years and 90% by the age 40 of years, while the prevalence of SNHL in females is 10% before the age of 40 years and 20% by the age of 60 years. SNHL in Alport syndrome is never congenital, always bilateral, and invariably accompanied by renal symptoms.

In affected males SNHL is frequently detectable by audiometry in late childhood or early adolescence, and initially affects high-frequency tones (2000–8000 Hz). Over time the hearing deficit extends into conversational speech. Recent histologic studies of the Alport's cochlea suggest that SNHL may be due to a defective function of the basement membrane of the organ of Corti, leading to abnormal mechanical relationships between outer hair cells and the basilar membrane.

Ocular

Ocular defects occur in 15–30% of individuals with Alport syndrome. The pathognomonic ocular lesion of Alport syndrome is anterior lenticonus, in which the central region of the lens protrudes into the anterior chamber. Anterior lenticonus is associated with marked attenuation of the lens capsule, the basement membrane that surrounds the lens, and becomes apparent during adolescence and young adulthood. Other ocular changes associated with Alport syndrome include perimacular retinal flecks, corneal endothelial vesicles, and recurrent corneal erosions. These lesions may also arise from defective basement membranes: Bruch's membrane (perimacular flecks), Descemet's membrane (corneal endothelial vesicles), and corneal epithelial basement membrane (corneal erosions).

Leiomyomatosis

Coinheritance of XLAS and leiomyomatosis of the esophagus, tracheobronchial tree, and female external genitalia has been described in approximately 20 kindreds. In addition to symptoms of Alport syndrome, affected individuals may display dysphagia, postprandial vomiting, retrosternal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor, typically beginning in late childhood.

Imaging Studies

Leiomyomatosis suspected by chest x-ray or barium swallow may be confirmed by computed tomography or magnetic resonance imaging.

Differential Diagnosis

The cardinal symptom of Alport syndrome is persistent microscopic hematuria. In children the differential diagnosis of persistent microscopic hematuria includes Alport syndrome, TBMN, IgA nephropathy and other chronic forms of glomerulonephritis, and hypercalciuria. The clinical features of these conditions are compared in Table 47–1. The differential diagnosis in adults would include these conditions as well as urologic lesions, particularly in individuals over 40 years of age.

Kidney biopsy, supplemented by clinical and pedigree data, is still the key procedure for the differentiation of Alport syndrome from other glomerular causes of persistent microscopic hematuria. The presence on electron microscopy of diffuse thickening of the GBM with multilamellar splitting of the lamina densa is diagnostic of Alport syndrome. However, GBM thinning due to lamina densa attenuation is typical of both early Alport syndrome and TBMN, so that in some instances these conditions cannot be distinguished by routine renal biopsy evaluation.

Immunostaining for the α3, α4, and α5 chains of type IV collagen is a very valuable tool for confirming a diagnosis of Alport syndrome and for distinguishing the X-linked and autosomal recessive forms of the disorder. These chains are entirely absent from renal basement membranes in about 80% of males with XLAS, while 60–70% of female heterozygotes with XLAS exhibit mosaic expression of these chains. In most patients with ARAS, the α3 (IV) and α4 (IV) chains are not expressed in renal basement membranes, while the α5 (IV) chain is absent from the GBM but present in Bowman's capsule and distal and collecting TBM. The heterozygous mutations in COL4A3 or COL4A4 responsible for many cases of TBMN cause no discernible changes in the expression of α3α4α5 trimers in basement membranes.

XLAS can also be diagnosed by skin biopsy, since the α5 (IV) chain is undetectable in EBMs of about 80% of XLAS males and is mosaically expressed in 60–70% of females with XLAS. In interpreting the results of type IV collagen immunostaining of skin and kidney it is important to remember that normal expression of the α3 (IV), α4 (IV), and α5 (IV) chains does not exclude a diagnosis of Alport syndrome. However, normal results of type IV collagen immunostaining can buttress a provisional diagnosis of TBMN in patients with attenuated GBM, normal hearing, and no family history of ESRD.

Complications

Common complications of Alport syndrome include hypertension, ESRD, and SNHL. Some patients with anterior lenticonus develop cataracts that require removal. Patients with XLAS and diffuse leiomyomatosis may need surgical treatment of esophageal and tracheobronchial smooth muscle tumors.

Treatment

To date there have been no controlled therapeutic trials in patients with Alport syndrome. In an uncontrolled study of a small number of males with XLAS, cyclosporine reduced proteinuria and appeared to stabilize renal function, but this observation has yet to be confirmed by other investigators. Studies of murine and canine models of Alport syndrome suggest that angiotensin blockade may retard progression to ESRD.

Prognosis

Not surprisingly for an X-linked disorder, gender has a marked impact on the prognosis of XLAS. Fifty percent of males with XLAS reach ESRD by the age of 25 years, and close to 100% of XLAS males have reached ESRD by the age of 40 years. The nature of the underlying mutation in the COL4A5 is an important determinant of the rate of progression to ESRD in XLAS males. While only about 12% of females with XLAS develop ESRD before the age of 40 years, the probability of ESRD increases to about 30% by the age of 60 years and 40% by the age of 80 years. Risk factors for ESRD in XLAS females include a history of gross hematuria, sensorineural deafness, proteinuria, and extensive GBM thickening and lamellation.

Patients with ARAS typically reach ESRD before the age of 40 years, regardless of gender. ADAS tends to advance less aggressively than XLAS or ARAS, with 50% of affected men reaching ESRD by the age of 50 years, compared to 25 years of age for males with XLAS.

Web Sites

A detailed review of the molecular pathogenesis and clinical features of Alport syndrome can be found on the GeneReviews website at http://www.genereviews.org/.

Essentials of Diagnosis

• Microscopic hematuria.
• Diffuse attenuation of GBM.
• Normal tissue expression of type IV collagen α3, α4, and α5 chains.
• Absence of family history of renal failure.

General Considerations

TBMN is, like Alport syndrome, a heritable form of glomerular hematuria associated with genetic defects in type IV collagen. It is estimated that 40% of cases of TBMN arise from heterozygous mutations in COL4A3 and COL4A4, the genes that code for the α3 and α4 chains of type IV collagen, respectively. The absence of genetic linkage to COL4A3 or COL4A4 in some TBMN families suggests the existence of additional TBMN loci.

Although TBMN and Alport syndrome may have similar clinical presentations and pathologic manifestations, especially in childhood, the two disorders differ in several key respects. Unlike those with Alport syndrome, individuals with TBMN rarely exhibit deafness, ocular abnormalities, proteinuria, hypertension, or renal insufficiency, and the family history is typically negative for relatives with kidney failure.

Pathogenesis

Heterozygous mutations in the COL4A3 and COL4A4 genes are associated with at least three possible phenotypes: no symptoms, isolated microscopic hematuria with thin GBM, and hematuria progressing to renal failure and typical histologic features of Alport syndrome (autosomal dominant Alport syndrome). To date it has not been possible to correlate a particular phenotype with the type and/or location of the heterozygous defect in the COL4A3 or COL4A4 gene. Most of the mutations identified thus far are single nucleotide substitutions, although frame-shifting and splicing mutations have also been described.

It is tempting to speculate that heterozygous mutations in COL4A3 or COL4A4 result in haploinsufficiency of the relevant type IV collagen chain [α3(IV) or α4(IV)] and diminished expression of the α3α4α5 type IV collagen network in GBM, leading to an attenuated, mechanically fragile GBM. Hematuria in these patients would arise from focal, transient ruptures in the weakened GBM. The presence of some quantity of the α3α4α5 network in the renal basement membranes of TBMN patients may prevent the secondary processes that lead to renal fibrosis in Alport's patients, whose renal basement membranes typically lack expression of the α3α4α5 network.

Clinical Findings

The typical patient with TBMN has isolated microscopic hematuria, which may be persistent or intermittent. Acute infections may be associated with transient gross hematuria.

Family history is frequently positive for hematuria but negative for renal failure, and pedigree analysis often indicates that the hematuria is transmitted as an autosomal dominant trait. When a patient with isolated microscopic hematuria has such a family history, the clinician can make a presumptive diagnosis of TBMN without requiring confirmation of GBM attenuation by renal biopsy.

Proteinuria and hypertension are rarely observed in patients with TBMN, but have been described in association with glomerulosclerosis. Some patients with presumed TBMN who develop proteinuria and/or hypertension have been misdiagnosed and actually have Alport syndrome or a chronic glomerulonephritis. Patients with microscopic hematuria who have proteinuria, hypertension, or a family history of renal failure are candidates for histologic diagnosis.

Differential Diagnosis

The differential diagnosis of microscopic hematuria includes Alport syndrome, TBMN, immunoglobulin A (IgA) nephropathy and other chronic forms of glomerulonephritis, hypercalciuria, and, in adults, urologic abnormalities. A diagnostic approach is described in the section on Alport syndrome.

Complications

TBMN is typically a benign condition. Individuals with hematuria due to TBMN have on occasion encountered problems obtaining health or life insurance.

Treatment

Most people with TBMN do not require any form of therapeutic intervention. Treatment, preferably with an agent that targets the renin–angiotensin axis, is indicated in the TBMN patient with proteinuria and/or hypertension.

Prognosis

Individuals with TBMN have an excellent prognosis. Because some people who carry a diagnosis of TBMN eventually develop proteinuria and/or hypertension, intermittent monitoring of urinalysis and blood pressure is recommended.