Chapter 46: Familial Hematurias: Alport Syndrome and Hematuria with Thin Glomerular Basement Membranes

GENERAL APPROACH TO HEMATURIA

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 work-up 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 most people with familial hematuria have microscopic hematuria, it is likely that these conditions are under diagnosed, and that the true prevalence of familial hematuria is higher than we might think. Familial hematuria accounts for a substantial fraction of children with isolated hematuria referred to pediatric nephrology clinics. So-called “thin basement membrane nephropathy” was diagnosed in 40–70% of patients with asymptomatic microscopic hematuria and a negative urological evaluation.

ALPORT SYNDROME

General Considerations

Alport syndrome is a disorder of the kidneys, frequently associated with sensorineural hearing loss and ocular abnormalities, that is caused by mutations in specific subspecies of collagen IV, 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 collagen IV protein 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; COL4A5-COL4A6, X chromosome. Within each pair the genes are oriented in a 5′-5′ fashion, separated by regulatory domains of varying length.

Collagen IV α chains associate into trimers that in turn form supermolecular networks. Three trimers have been identified in mammalian basement membranes: α₁α₁α₂, α₃α₄α₅ and α₅α₅α₆. The α₁α₁α₂ trimer is found in all basement membranes, including glomerular mesangium, but it is a relatively minor component of mature glomerular basement membranes (GBM). The predominant collagen IV 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 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 ...