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.
