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Inherited Diseases of the
Glomerular Basement
Membrane
Scope
Introduction
 Inherited diseases of glomerular basement
membrane

 Description
treatment
Summary
 Key points

– clinical-pathological features,
Introduction

The glomerular basement membrane
(GBM)
 Unique
type of basement membrane
 Great
thickness (300–350 nm) and
 Position between two cell layers, podocytes and
endothelial cells
 Specific
role in maintenance of the glomerular
filtration barrier
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Introduction

(contd)
Major GBM components
 Type
IV collagen
 Laminin
 Nidogen (entactin) and
 Heparan sulfate proteoglycans (HSPGs)

Mutations in
 type
IV collagen or laminin genes have been
shown to be associated with hereditary
glomerular diseases
Eur J Biochem 1989;180: 487–502.
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Alport syndrome
 Characterized
by the familial occurrence of
progressive hematuric nephritis and hearing
loss
 Depending on the population studied, Alport
syndrome affects 0.3–2.3% of all patients
who develop end-stage renal disease (ESRD)
in Europe, India or the US
Br Med J 1927; 1: 504–6
Hereditary Diseases of Type IV Collagen

Alport syndrome
(contd)
 Hematuria—macroscopic/microscopic—
is the
principal and constant feature
 Early-onset symptom, usually detected in
childhood
 Episodes
of macroscopic hematuria precipitated by
exercise/upper respiratory tract infection are
observed in about 60% of patients < 15 years
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Alport syndrome



(contd)
Proteinuria increasing with age and progressive renal
failure are observed, depending on the sex of the
patient and the mode of transmission of the disorder
Hypertension does not usually develop before the
onset of chronic renal insufficiency
Bilateral sensorineural hearing loss affecting high and
middle frequencies is never congenital in Alport
syndrome, but it can be detected during the first
decade of life
Am J Med 1981 70: 493–505, Am J Kidney Dis 1993; 22: 627–40,
Acta Paediatr 1996; 85: 1300–6
Hereditary Diseases of Type IV Collagen

Alport syndrome


(contd)
Anterior lenticonus is a conical protrusion of the
anterior aspect of the lens that develops progressively
Retinal changes are characterized by the progressive
appearance of asymptomatic perimacular yellowish
flecks

Both types of ocular lesion are specific to Alport syndrome,
and are observed in about 1/3 of patients
Detecting such lesions can, therefore, be useful for diagnosis of
the disorder
 Nonspecific lesions of the cornea have also been reported

Clin Nephrol 1980;13: 163–7
Hereditary Diseases of Type IV Collagen
Electron microscopy images of renal tissue from patients with Alport
syndrome.
(A) Thickening and splitting of the GBM in an 11-year-old patient. The inner
and outer contours of the GBM are ‘festooned’. Magnification ×30,000.
(B) In tissue from a 12-year-old patient observed under low magnification, the
irregular thickness of the GBM is evident. Magnification ×5,400.
(C) Diffuse thinning of the GBM in a 3-year-old male patient. Magnification
×6,200. All sections stained with uranyl acetate and lead citrate.
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Immunohistological analysis of the renal distribution of type IV collagen chains. The
analysis was carried out in (A–D) control, X-linked (E,F) male and (G,H) female Alport
syndrome patients, and (I–L) patients with autosomal recessive Alport syndrome, using
antibodies to α1(IV) (A,E,I), α3(IV) (B,F,J), or α5(IV) (C,G,K,L) chains. Double labeling was made with anti-α2(IV) in red, and antiα5(IV) in green (D,H). In control kidney, the α1(IV) chain is present in the mesangial matrix, Bowman’s capsule, and the
extraglomerular basement membranes (A). The α3(IV) and α5(IV) chains are distributed within the GBM (B and C, respectively).
The Bowman’s capsule is strongly α5(IV)-positive (C). In X-linked Alport syndrome, no α3(IV) expression was detected in a male
patient (id for α4–α5) (F), whereas the distribution is segmental in a female patient (G). In autosomal recessive Alport syndrome,
no α3(IV)–α5(IV) labeling is detected in the GBM (J) whereas α5(IV) is expressed in Bowman’s capsule (K) and the basement
membranes of the collecting ducts (L). In both types of Alport syndrome, α1(IV) is diffusely expressed in the GBM (E,I).
Abbreviation: GBM, glomerular basement membrane
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

X-linked Dominant Alport Syndrome
 In
about 85% of affected families of European
origin, Alport syndrome is transmitted as an
X-linked dominant trait
 This mode of transmission is characterized by
 Greater
disease severity in males > females and
 Absence of father-to-son transmission
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

X-linked Dominant Alport Syndrome
(contd)
 Two
forms on the basis of the rate of
progression
 'juvenile'

type
Highly stereotypical course within each affected family
and by the occurrence of ESRD in men at about 20 years
of age;
 'nonprogressive'

or 'adult' type
ESRD develops at approximately 40 years of age and the
disease course is much more variable
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

X-linked Dominant Alport Syndrome
 Diffuse
(contd)
leiomyomatosis
 Associated
with Alport syndrome in 2–5% of
families with the juvenile form of the disease
 Affects the esophagus, the tracheobronchial tree
and the female genital tract
 Completely penetrant and fully expressed, even in
female patients with mild renal disease
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

X-linked Dominant Alport Syndrome

(contd)
Immunohistological analysis of the distribution of the
different chains of type IV collagen in the basement
membranes where COL4A5 is normally expressed is
of the utmost importance in the diagnosis of Alport
syndrome and the recognition of X-linked
transmission

In most patients, the α5(IV) chain defect (absence or
abnormal structure as a result of mutation) impairs protomer
assembly and the formation of normal collagen IV networks
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

X-linked Dominant Alport Syndrome
(contd)
 Within
the kidney, abnormal distribution of the
α5(IV) chain is observed in approximately
two-thirds of patients with X-linked Alport
syndrome:
 The
α5(IV) antigen is absent from the glomerular,
capsular and distal tubular basement membranes
in male patients, and has a discontinuous
distribution in related female patients
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Immunohistological analysis of the distribution of the α5(IV) collagen chain. The
analysis was carried out in the skin of (A) controls, (B) male and (C) female patients
with X-linked Alport syndrome, and (D) patients with autosomal recessive Alport
syndrome.
The α5(IV) chain is (A) present in the epidermal basement membrane (arrow) of the
skin of controls, but is (B) absent from the skin basement membrane (arrow)
of the male patient with X-linked Alport syndrome. (C) Segmental labeling (single
arrow) is seen in the X-linked female patient. Nonspecific labeling of the keratin layer
is indicated by a double arrow. (D) Normal staining patterns of the epidermal
basement membrane (single arrow) are observed in autosomal recessive Alport
syndrome. Nonspecific labeling of the keratin layer is indicated by a double arrow.
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Autosomal Recessive Alport Syndrome
About 10–15% of families affected by the disease
 Clinical and morphological features are identical in the
autosomal recessive and X-linked forms
 Usually severe




Nephritis progresses to early-onset ESRD
Hearing impairment affects the majority of patients, and
ocular lesions may or may not be present
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Autosomal Recessive Alport Syndrome (contd)
 Indicated
by one/more of the following:
 Severe
disease in young females
 Consanguinity in the family
 Absence of severe renal disease in the parents of a
patient
 Microscopic hematuria in the father of an affected
male; and
 Immunohistochemical findings
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Autosomal Dominant Alport Syndrome (contd)
 Male-to-male
transmission and similar disease
severity in men and women, has been
observed in a few families
 The clinical phenotype is variable and milder
than that of the X-linked dominant form
 Progression to ESRD and hearing defect are
not always seen and usually occur after 50
years of age
 No ocular involvement has been reported
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Benign Familial Hematuria (BFH) With
Thinning of the GBM
 The
exact prevalence of is not known
(estimates range from 1% to 10% of the
population), but it is the most common cause
of persistent hematuria
 Inherited in an autosomal dominant manner
 Characterized
by familial occurrence of persistent
or recurrent hematuria that is often detected in
childhood
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

BFH
(contd)
 No
significant proteinuria
 No progression to renal failure and
 No extrarenal symptoms are observed, and
 The prognosis is excellent
 GBM
is uniformly thin
 'thin
basement membrane nephropathy' (TBMN) is
currently used as an alternative term for BFH
Arch Intern Med 1973;131: 257–62
Hereditary Diseases of Type IV Collagen

BFH
(contd)
 GBM
is uniformly thin
 'thin
basement membrane nephropathy' (TBMN) is
currently used as an alternative term for BFH

Use of a descriptive term (TBMN) for this disorder can
cause confusion,
 Because of the nonspecificity of thinning of the GBM,
which can also be evident in patients with Alport
syndrome, including adults
Arch Intern Med 1973;131: 257–62
Hereditary Diseases of Type IV Collagen

BFH
(contd)
 Comprehensive
familial investigations and
regular follow-up assessments are of the
utmost importance if BFH/TBMN is to be
correctly distinguished from progressive
nephritis
 The
onset of proteinuria or extrarenal symptoms
should lead to reconsideration of the benign
prognosis
J Am Soc Nephrol 1998; 9: 1736–1750
Hereditary Diseases of Type IV Collagen

Treatment
 Progression
to ESRD is ineluctable in males
with X-linked Alport syndrome and in all
patients with the autosomal recessive form of
the disease
 Renal transplantation is generally a
satisfactory treatment, but about 2.5% of
patients develop anti-GBM glomerulonephritis
leading to rapid graft loss
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Diseases of Type IV Collagen

Treatment
(contd)
 Temporary
or prolonged alleviation of
proteinuria has been achieved by blockade of
the renin–angiotensin system, but no data are
available on the long-term evolution of renal
function in response to this treatment
 Controversy over the effects of ciclosporin in
these patients
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Laminin β2 Disease

Pierson Syndrome
 In
1963, Pierson et al. reported
 The
curious association in siblings of eye
abnormalities with microcoria and congenital
nephrotic syndrome progressing rapidly to ESRD
 This association was also observed in a few
neonates
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Laminin β2 Disease

Pierson Syndrome (contd)
 Glomerular
lesions were classified as
mesangial sclerosis, with diffuse alteration of
the GBM
 Hypotonia and psychomotor retardation
developed in the few patients who survived
for several months after birth
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Laminin β2 Disease
Laminin α5β2γ1.
(A) Laminins are heterotrimeric molecules consisting of one α, one β, and one γ
chain, with a cruciform organization. The major laminin of the glomerular
basement membrane is α5β2γ1
(B) In the kidney, the laminin β2 chain is expressed at high levels in the
glomerular basement membrane and in the basement membranes of arterial
smooth muscle cells
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Laminin β2 Disease

Pierson Syndrome (contd)
defect involves the LAMB2 gene encoding
the β2 chain of laminin, which is expressed at
high levels in the GBM, synaptic basal laminae
and basement membranes of the eye
 Recessive missense mutations have also been
detected in two patients in a consanguineous
family with isolated congenital nephrotic
syndrome, a finding that expands the clinical
spectrum of LAMB2-associated disorders
 This
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Laminin β2 Disease

Pierson Syndrome (contd)
 Mice
lacking laminin β2 develop massive
proteinuria, and their retinal and
neuromuscular differentiation is abnormal
 Interestingly, the onset of proteinuria
precedes podocyte abnormalities, showing
 GBM
acts as a protein barrier and that the
glomerular slit diaphragm alone is not sufficient to
prevent the passage of albumin
Nat Genet 1995; 10: 400–6; J Clin Invest 2006;16: 2272–9.
Hereditary Renal Diseases With Type
III Collagen Deposits

Nail–patella Syndrome
Also k/as hereditary osteoonychodysplasia
 Rare autosomal dominant disorder (affecting 1 in
50,000 individuals)
 Characterized by an association between nail
hypoplasia or dysplasia and bone abnormalities that
primarily affect the knees, elbows and pelvis


Normal-tension glaucoma and sensorineural hearing
impairment have been recognized as additional features
J Med Genet 2005;40: 153–62
Hereditary Renal Diseases With Type
III Collagen Deposits

Nail–patella Syndrome
(contd)
 Prognosis
depends on the presence and
severity of renal involvement, which is
observed in 30–40% of patients
 Renal involvement usually manifests as
proteinuria, sometimes with hematuria
 Progression to kidney failure occurs in about
30% of patients with renal symptoms, usually
many years after the discovery of proteinuria,
but in some cases during childhood
Am J Pathol 2003;163: 145–155
Hereditary Renal Diseases With Type
III Collagen Deposits

Nail–patella Syndrome
(contd)
 Light
microscopy of renal tissue from people
with NPS reveals no specific changes
 The hallmark of the disease, observed by
electron microscopy, is the presence of
clusters of fibrillar type III collagen irregularly
distributed within thick GBM segments and
the mesangial matrix
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Nail–patella Syndrome
(contd)
 Staining
with phosphotungstic acid is often
needed to reveal the collagen bundles; when
standard staining techniques are used, the
GBM has a mottled appearance
 The extent and distribution of GBM lesions
vary widely from case to case
 There is no correlation between these
microscopical features and patient age or the
presence or severity of renal symptoms
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy
 Accumulation
of type III collagen in the
glomerular extracellular matrix has been
detected in some proteinuric patients—mostly
Japanese— in the absence of any other
symptoms of NPS
 In
contrast to NPS glomerulopathy, diffuse
glomerular changes (i.e. marked expansion of the
mesangial matrix and thickening of the capillary
walls) can be observed under the light microscope
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy
(contd)
 At
the ultrastructural level, the mesangial
matrix and the subendothelial aspect of the
GBM are enlarged and have a mottled
appearance due to the presence of fibrillar
collagen (which can be visualized after
staining with phosphotungstic acid)
 Unlike
the lesions observed in NPS, the lamina
densa is usually preserved
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy
(contd)
 The
clinical features of collagen type III
glomerulopathy are highly variable
 Two forms of the disease can be distinguished
on the basis of age at onset of symptoms
 In
Japanese and a few Caucasian patients, the
disease is usually sporadic and first symptoms—
persistent
proteinuria,
with
or
without
hypertension—are detected in adulthood
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy



(contd)
The severity of proteinuria and serum creatinine
concentration increase slowly, and renal dysfunction is
a late event
Glomeruli are strikingly enlarged as a result of
massive deposits of type III collagen
An elevated serum level of the type III procollagen
peptide seems to be a good marker for the disease,
indicating increased synthesis of type III collagen, but
the fundamental underlying defect remains unknown
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy
(contd)
 Onset
of first symptoms of collagen type III
glomerulopathy in early childhood indicates
autosomal recessive transmission of the
disease
 Under
light
microscopy,
subendothelial
enlargement of the capillary walls is moderate and
might mimic diffuse thrombotic microangiopathy
 This variant of the disease is severe
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy


(contd)
Collagen type III glomerulopathy is characterized by
progressive worsening of proteinuria; nephrotic
syndrome eventually develops, and early occurrence
of hypertension and progression to renal failure are
observed in most children
Anemia of the hemolytic type and unexplained
respiratory symptoms have been reported, as has
abrupt progression to ESRD resulting from
superimposed hemolytic– uremic syndrome
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy
(contd)
 Interestingly,
collagen type III glomerulopathy
has been reported in one patient who
presented with an inherited factor H
deficiency
 Collagen type III glomerulopathy associated
with factor H deficiency was also observed in
our laboratory (unpublished data), in a young
patient with consanguineous parents
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Hereditary Renal Diseases With Type
III Collagen Deposits

Collagen Type III Glomerulopathy
(contd)
 Such
findings indicate that factors that
contribute to familial hemolytic– uremic
syndromes might be involved in collagen type
III glomerulopathy
 These
factors should be systematically
evaluated in patients with the latter disorder
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Fibronectin Glomerulopathy

Fibronectin Glomerulopathy
 Several
familial cases of atypical lobular
glomerulopathies, transmitted as autosomal
dominant traits and
 Characterized by the presence of massive
parietal and mesangial fibrillar deposits of
fibronectin, have been reported
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Fibronectin Glomerulopathy

Fibronectin Glomerulopathy
(contd)
 Patients
have proteinuria, hematuria and
hypertension, and progress slowly to ESRD
 The fibronectin deposited in glomeruli is
derived primarily from plasma, and recurrence
in grafted kidneys has been observed
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Fibronectin Glomerulopathy

Fibronectin Glomerulopathy
(contd)
 Diagnosis
can easily be established by
immunohistochemical analysis of renal biopsy
material, but
 The pathophysiological role of fibronectin and
the genetic cause of the disease are unknown
Nat Clin Pract Nephrol CME. 2008;4(1):24-37.
Summary

Alport syndrome was the first characterized, and
is the most frequent hereditary hematuric
disorder of the GBM that progresses to ESRD

Analysis of the distribution of the collagen
α5(IV) chain in skin is an important step in the
diagnostic approach to the X-linked form of the
disease
Summary
(contd)

As technologies are improving rapidly, diagnosis
based on DNA sequencing will become a more
practical option in the near future

Therapeutic progress is expected to result from
extension of the promising results obtained in
animal models to human trials
Summary
(contd)

Distinguishing between Alport syndrome and
BFH/TBMN is sometimes difficult in young
patients, in sporadic cases and in small families
from which little useful information can be
derived

Thinning of the GBM is not a marker of a specific
disease entity, and does not guarantee a benign
disease course
Summary
(contd)

Long-term follow-up and repeat investigations
might be needed before a definitive diagnosis
can be made

The wide spectrum of phenotypes observed in
patients that carry a heterozygous COL4A3 or
COL4A4 mutation heralds a need for caution
during risk assessment and genetic counseling
Summary
(contd)

The recent identification of LAMB2 mutations in
congenital and infantile nephrotic syndromes
indicates that hereditary disorders resulting from
defects in genes encoding noncollagen
components of the GBM might not yet have
been identified

Clinical investigation and documentation of
atypical symptoms are the basis for the
recognition of new syndromes
Key Points

No specific treatments are available for inherited
diseases in which mutation of genes that encode
components of the glomerular basement
membrane (GBM) perturb its structure

Hematuria is a major clinical feature of Alport
syndrome, a progressive disease in which the
structure of type IV collagen in the GBM is
abnormal
Key Points
(contd)

Alport syndrome can be inherited in an X-linked
dominant, autosomal recessive or autosomal
dominant manner

Laminin glycoproteins are essential to the
assembly of the GBM and mutations of LAMB2,
which encodes the β2 chain of laminin, lead to
Pierson syndrome
Key Points
(contd)

Deposition of type III collagen within the GBM is
the hallmark of nail–patella syndrome and
accumulation of this protein in the glomerular
extracellular matrix is also observed in rare
nonsyndromic glomerulopathies

Parietal and mesangial deposition of fibronectin
also cause glomerulopathy