Genetic testing for podocyte genes in sporadic focal segmental glomerulosclerosis
Nephrol Dial Transplant
In Focus Genetic testing for podocyte genes in sporadic focal segmental glomerulosclerosis
Tri Q. Nguyen 1 2
Roel Goldschmeding 1 2
Lambert P. van den Heuvel 0 1
0 Department of Paediatric Nephrology , Radboud
1 University Nijmegen Medical Center , Nijmegen , Netherlands
2 Department of Pathology, University Medical Center Utrecht , Utrecht , Netherlands
Correspondence and offprint requests to: Roel Goldschmeding; E-mail:
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Focal segmental glomerulosclerosis (FSGS) is a
clinicopathological entity that manifests with severe proteinuria and/or nephrotic
syndrome. FSGS is considered to represent a pattern of
glomerular scarring, rather than a specific disease entity. The histological
hallmark of FSGS is characterized by sclerosis that involves
some, but not all, glomeruli and the affected glomeruli typically
show involvement of only a portion of the capillary tuft.
The aetiology of FSGS is diverse and can be divided into
primary and secondary causes. Identifying the exact cause of
FSGS has important therapeutic and prognostic consequences.
Secondary FSGS is usually associated with a maladaptive
response of the glomerulus to hyperfiltration or nephron loss,
and can occur in conditions like hypertension, obesity, viral
infection or drug toxicity. Secondary FSGS can also result
from nonspecific scarring in the context of other
glomerulopathies, including diabetic nephropathy, IgA nephropathy and
lupus nephritis. Primary FSGS can be either ‘genetic’ or
‘idiopathic’. Genetic primary FSGS can be associated with
mutations in several podocyte-associated genes, while idiopathic
primary FSGS might be caused by either as yet unknown
mutations, or by a circulating permeability factor [
1
].
In the current issue of Nephrology Dialysis
Transplantation, Laurin et al. have examined the utility of genetic testing
in sporadic FSGS. For this, pathogenic mutations in five
podocyte-related genes (i.e. NPHS2, ACTN4, INF2 and PLCE1)
and APOL1 risk alleles were tested in 28 children and 37
adults with sporadic FSGS. The authors identified biallelic
pathogenic NPHS2 mutations in two Caucasian children. In
addition, one novel nonsynonymous variant in INF2 was
detected in an African American patient with adult-onset FSGS
that could be potentially pathogenic.
Some clinical features might be helpful in differentiating
primary and secondary FSGS. Patients with secondary FSGS
commonly present with slowly increasing proteinuria in the
non-nephrotic range, while patients with primary FSGS show
acute onset of nephrotic range proteinuria, often associated
with features of nephrotic syndrome.
The role of genetic factors in the development of primary
FSGS has become increasingly obvious. Podocyte disorders lead
to a spectrum of clinical presentations like congenital nephrotic
syndrome, minimal change disease and FSGS. The
heterogeneity of these disorders is reflected by the variability in disease
phenotypes. Age of presentation, severity of proteinuria,
response to steroids, time to dialysis and recurrence after
transplantation may vary depending on the mechanism of injury.
This complexity supports the impression that primary FSGS is
probably a common downstream manifestation of a number of
different mechanisms leading to glomerular damage.
As for histopathological characteristics of different forms of
FSGS, the Columbia classification distinguishes five subtypes,
i.e. tip lesion, cellular, perihilar, collapsing and not otherwise
specified. These variants are defined by light microscopy
features, some of which correlate with prognosis and response to
therapy. Although the perihilar variant has more often been
associated with secondary forms of FSGS [
2, 3
], the Columbia
classification does not clearly differentiate between primary or
secondary FSGS.
Podocyte foot process effacement is an ultrastructural
feature of all glomerular proteinuric diseases and does not
discriminate between different variants of primary and secondary
FSGS. However, morphometric determination of the foot
process width by electron microscopy can help to distinguish
primary from secondary FSGS. There is only little overlap
between foot process width in primary and secondary FSGS,
and a cut-off of 1500 nm accurately differentiated primary
from secondary FSGS [
4
]. However, there is no evidence that
the degree of foot process effacement might also help to
distinguish genetic from non-genetic primary FSGS.
The last decades have witnessed an increase of interest in
the role of the podocyte in primary FSGS. Podocytes are
highly differentiated postmitotic cells whose function is based
on their specific architecture. Numerous proteins important
for the normal function of podocytes and the development of
proteinuria have been identified. Mutated genes in familial
forms of FSGS encode podocyte proteins involved in the
maintenance of glomerular slit diaphragm, which, in turn, are
responsible for holding back macromolecular structures like
p (...truncated)