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HEREDITARY NEPHRITIS ALPORT SYNDROME THIN BASEMENT MEMBRANE NEPHROPATHY


HEREDITARY NEPHRITIS (ALPORT SYNDROME)/THIN BASEMENT MEMBRANE NEPHROPATHY
Hereditary nephritis (HN, also known as Alport syndrome) and thin basement membrane nephropathy (TBMN) are both inherited disorders that feature structural defects in type IV collagen, an integral component of the glomerular basement membrane. Both conditions present in childhood with persistent microscopic hematuria.

HN is rare, affecting 1 in 50,000 individuals, and often progresses to end stage renal disease (ESRD). TBMN, in contrast, affects 1 in 20 to 100 individuals and typically does not have a progressive course.

PATHOPHYSIOLOGY
Hereditary Nephritis. In the glomerular basement membrane (GBM), the α-3, α-4, and α-5 chains of type IV collagen join to form a triple helix. Normal structure and function of the GBM requires that each chain in the collagen molecule possess a normal structure. HN can be caused by mutations in the genes encoding any of these chains, which prevents them from being effectively incorporated into a helical structure.
The genes encoding the α-3 and α-4 chains (COL4A3 and COL4A4) are located at chromosome 2q35-37, whereas the gene encoding the α-5 chain (COL4A5) is located on the X-chromosome; thus mutations can be transmitted in autosomal dominant, autosomal recessive, or X-linked patterns.
About 80% of cases result from X-linked mutations in COL4A5. Female carriers may have variable disease manifestations, depending on the severity of the mutation and the pattern of X-chromosome inactivation.
About 15% of cases reflect autosomal recessive mutations of COL4A3 or COL4A4. In the remaining 5% of cases, a single mutant copy of COL4A3 or COL4A4 is sufficient to cause HN.
The poor integrity of the abnormal collagen IV network leads to focal ruptures and holes in the GBM, which allow red blood cells and a subnephrotic quantity of protein to enter the urine. In patients with mutations so severe that essentially no α-3/α-4/α-5 type IV collagen is produced, the GBM is composed mainly of α-1/α-1/α-2 type IV collagen, a more fragile version that usually forms the GBM during embryogenesis. GBMs composed of α-1/α-1/α-2 type IV collagen appear to be more susceptible to oxidative and physical stress.
Because type IV collagen networks are also found in the cochlea, eye, skin, lungs, testis, and smooth muscle, patients with HN may also exhibit extrarenal disease. Generally, both renal and extrarenal manifestations are more severe in patients with large deletions or frame-shift mutations that severely distort the affected collagen chain.
Thin Basement Membrane Nephropathy. A substantial portion of TBMN cases reflect mutations in COL4A3 and COL4A4. The inheritance is considered autosomal dominant, but in fact those with TBMN could be considered carriers of the autosomal recessive mutations responsible for HN. The fact that these patients are heterozygous for these mutations, rather than homozygous, explains their milder phenotype. While patients with HN entirely lack the ability to make a normal version of one of the α chains, patients with TBMN are able to produce some normal α-3/ α-4/α-5 type IV collagen, resulting in thinner but otherwise intact GBMs. As in HN, however, these abnormal GBMs allow passage of red cells and protein into the urine.
Not all cases of TBMN can be linked to mutations in COL4A3 and COL4A4. Research to better understand the spectrum of mutations that cause TBMN is ongoing. Extrarenal manifestations in TBMN are uncommon because the mutations are milder than those seen in HN and cause less severe disruptions in type IV collagen networks.

PRESENTATION
Hereditary Nephritis. Early renal manifestations of HN include persistent microscopic hematuria, usually beginning in childhood and often accompanied by intermittent episodes of gross hematuria. On microscopic evaluation, the RBCs often appear dysmorphic or in cast form, reflecting their glomerular origin. In the second through fourth decades of life, proteinuria, hypertension, and progressive renal insufficiency emerge. Extrarenal manifestations include sensorineural hearing loss and ocular abnormalities. Among males with X-linked disease, sensorineural hearing loss affects up to 80%, depending on how carefully screening is performed, whereas ocular abnormalities (such as anterior lenticonus, which is nearly pathognomonic of HN) affect approximately 25%.
Thin Basement Membrane Nephropathy. Patients generally have persistent microscopic hematuria. Proteinuria is infrequent in childhood but develops in a substantial portion of adults. Extrarenal manifestations are not seen. The age of diagnosis varies considerably, ranging from early childhood to late adulthood.

DIAGNOSIS
Aside from HN and TBMN, the other major cause of microscopic hematuria in children is IgA nephropathy (see Plate 4-16), which should thus be part of the differential diagnosis. A positive family history of hematuria suggests either HN or TBMN over IgA nephropathy; additional history of end-stage renal disease, deafness, or visual abnormalities suggests HN over TBMN.
If HN is suspected, the diagnosis can sometimes be established with a skin biopsy. The α-5 chain of type IV collagen is normally expressed in the epidermal basement membrane, and a lack of staining with α-5- targeted antibodies indicates a mutation is present. Since the α-5 chain is mutated in the X-linked form of the disease, this procedure will detect many affected patients. Mutations in the α-3 or α-4 chains, however, cannot be detected with a skin biopsy because these chains are not normally expressed in the epidermal basement membrane. Thus, in the setting of a negative skin biopsy, a renal biopsy is typically required.
TBMN, in contrast, is usually presumptively diagnosed based on persistent hematuria, family history, and a nonprogressive course. If a skin biopsy is performed, immunofluorescence is unremarkable because the α-5 chain is not mutated in this disease. Thus renal biopsy, though not commonly performed, is required for definitive diagnosis.
Using light microscopy, no distinctive features are seen in either HN or TBMN. Electron microscopy, in contrast, reveals diagnostic findings in both conditions. In HN, the GBM shows irregular thickening and thin-ning, with multiple lamellations that produce a woven texture. Diffuse foot process effacement is seen. TBMN, in contrast, shows thinning of the GBM without complex lamellations. Because the earliest alteration seen in HN is patchy GBM thinning, differentiation between these two diseases is sometimes difficult. In these settings, immunofluorescence staining for α-3, α-4, and α-5 chains may help reveal the difference. In HN, there is usually loss or severely reduced expression of all three α chains, reflecting failure to assemble normal α-3/α-4/α-5 type IV collagen chains, with α-1/α-1/α-2 chains often produced instead. TBMN, in contrast, features positive staining for α-3, α-4, and α-5 chains. Direct genetic testing may be used for prenatal diagnosis or in cases where biopsy findings are equivocal.

TREATMENT AND PROGNOSIS
HN cannot be targeted with any specific medical treatment. Control of hypertension and proteinuria through renin-angiotensin blockade may slow the progression of glomerulosclerosis and renal insufficiency. The rate of progression to ESRD varies widely and depends on the severity of the genetic mutation.
TBMN is generally a nonprogressive disease and does not result in significant scarring of the kidney. No directed therapy is needed. If a patient presumptively diagnosed with TBMN shows evidence of progressive renal disease, a renal biopsy or the other diagnostic tests mentioned previously shou d be considered to exclude HN and IgA nephropathy.