J Nephrol
DOI 10.1007/s40620-016-0315-4
REVIEW
Lessons from genetics: is it time to revise the therapeutic approach
to children with steroid-resistant nephrotic syndrome?
Francesca Becherucci1 Benedetta Mazzinghi1 Aldesia Provenzano2
Luisa Murer3 Sabrina Giglio2,4 Paola Romagnani1,4
Received: 2 February 2016 / Accepted: 29 April 2016
Italian Society of Nephrology 2016
Abstract Primitive nephrotic syndrome is one of the most
common glomerular diseases in childhood and represents
the clinical manifestation of various pathologic changes in
the kidney. In children, nephrotic syndrome is classified
based on the initial response to empiric corticosteroid
treatment, which is considered as the best predictor of
patients final outcome. The advent of next-generation
sequencing technology showed that genetic alterations in
structural genes of the podocyte can be recognized in a
significant proportion of not only familial or syndromic
patients with steroid-resistant nephrotic syndrome (SRNS),
but also of sporadic cases, raising the question of whether it
is time to update current protocols of patient care. In this
review, we discuss the implications derived from several
studies describing a high prevalence in children with SRNS
of pathogenic mutations in a group of genes and their
unresponsiveness to immunosuppressive therapy. We pro-
pose a diagnostic and therapeutic algorithm to reduce the
exposure to immunosuppressants in individuals with
unresponsive forms of the disease, sparing patients the
untoward side effects of prolonged ineffective treatments,
and at the same time guaranteeing the optimal immuno-
suppressive or other new therapy in potentially responsive
patients.
& Paola Romagnani
p.romagnani@dfc.unifi.it; romagnani@meyer.it
1
Nephrology and Dialysis Unit, Meyer Childrens Hospital,
Florence, Italy
2
Medical Genetics Unit, Meyer Childrens Hospital, Florence,
Italy
3
Department of Pediatrics, University of Padua, Padua, Italy
4 to respond to initial steroid treatment and are classified as
Department of Biomedical Experimental and Clinical
Sciences Mario Serio, University of Florence, Viale steroid-resistant [1]. Even though we still lack complete
Pieraccini 6, 50139 Florence, Italy
Keywords Steroid-resistant nephrotic syndrome

Mutation
Genetics
Children
Gene
Immunosuppressive
therapy
Introduction
Primitive nephrotic syndrome (NS) represents the most
common glomerular disease in childhood, with an annual
incidence in unselected cohorts of children of approxi-
mately 26:100,000 per year in the United States and
Europe [13]. The global prevalence is estimated to be
around 16:100,000 children [2]. Primary NS is defined by
the absence of recognizable causes of kidney damage that
conversely characterize secondary forms (e.g. viral infec-
tions, vasculitis, systemic lupus erythematosus). NS is the
clinical manifestation of various pathologic changes in the
kidney [4], the most common in children being minimal
change disease (MCD), focal segmental glomerulosclerosis
(FSGS) and diffuse mesangial sclerosis (DMS). Interest-
ingly enough, numerous studies have demonstrated that the
clinical picture does not necessarily correlate with patho-
logic findings, although FSGS tends to be a more common
finding in patients with steroid-resistant NS (SRNS) [3, 5].
In clinical practice, NS is classified based on patients
initial response to corticosteroid therapy, especially in the
pediatric population. The great majority of children (ap-
proximately 8090 %) who present with NS respond
promptly to steroid therapy, which is therefore empirically
performed at the onset of the clinical picture. This group of
patients is defined according to their clinical behavior as
steroid-sensitive. However, about 1020 % of patients fail
accordance on how to define resistance to steroids [6, 7], it
123

is commonly accepted that a patient presenting with NS
and failing to achieve remission after 68 weeks of treat-
ment with corticosteroids could be defined as steroid-re-
sistant [6, 8]. SRNS represents the second most frequent
cause of chronic kidney disease (CKD) in children after
congenital abnormalities of the kidney and the urinary tract
(CAKUT), and is responsible for a high fraction of cases of
end-stage renal disease (ESRD) in the pediatric population
[9], that usually occurs within 210 years of diagnosis [2,
9, 10]. In addition, children affected by SRNS have a
considerably high risk of infections, thromboembolic
events, growth retardation, acute kidney injury, and CKD
that significantly reduce life expectancy, as well as of
developing potentially threatening side effects from pro-
longed and often combined immunosuppressive treatments.
The classification of NS by the response to steroids in
steroid-sensitive NS (SSNS) and SRNS highlights the
possibility that different pathophysiologic mechanisms
confer the response to steroids [3]. Although the patho-
genesis of NS is still not completely understood, con-
verging evidence identifies the glomerular filtration barrier
(GFB) as the primary site of different kinds of insults that
finally lead to protein leakage and to the development of
nephrotic proteinuria. The GFB is composed of three lay-
ers, the specialized fenestrated endothelium, the glomerular
basement membrane (GBM) and the podocyte. Damage to
any of these components can result in nephrotic proteinuria
in various types of NS, but the podocyte is now recognized
as the key component in maintaining the anatomical and
functional integrity of the GFB. Hence, SRNS could be
defined as a structural podocytopathy, where genetic for NS received a great impulse. Mutations in NPHS2
alterations play a major role [2, 3, 11].
In this review, we summarize the impact of the knowl-
edge derived from the application of genetics to SRNS and
we propose a new approach to children affected by this
disease.
What did we know about SRNS? Historical notes
and traditional knowledge
Increasing evidence suggests that the podocyte is the cul-
prit in many glomerular diseases including NS and that a
loss of more than 30 % of podocytes induces the occur-
rence of glomerulosclerosis [11]. Different types of pri-
mary insult lead podocytes to react with an apparently
stereotypic pattern that includes foot processes effacement,
detachment from the GBM, and/or death, finally impairing
the GFB to function and determining the deposition of
extra-cellular matrix with the formation of glomerular scars
[1214]. Whatever the starting event inducing podocyte
injury and loss, the road toward glomerulosclerosis and
123
J Nephrol
CKD is tracked, even though evidence exists that remission
and even regression of glomerular damage can occur [13,
1518].
In recent years, a vast amount of studies have therefore
been focused on this issue, even for NS, with genetic
alterations of podocytes structure progressively emerging
as an important mechanism in the pathogenesis of SRNS,
particularly in children.
The role of genetics
Inherited diseases are caused by mutations in genes whose
expression is critical for the development, survival and
function of a specific tissue. They are predominantly
monogenic disorders, since mutations of a single gene are
sufficient to cause the disease. First reports on the possible
role of genetic abnormalities in determining podocyte
dysfunction date back to 1998, when, by means of posi-
tional cloning studies in neonates with congenital NS and
their families, mutations in the NPHS1 gene encoding for
the protein nephrin were recognized as the cause of con-
genital NS of the Finnish type, an autosomal recessive form
of NS that is not responsive to steroid treatment [19].
Nephrin is specifically expressed by podocytes and is
involved in slit diaphragm formation and in regulating
cellular functions; the loss of the proper function of this
protein determines an early onset (usually during preg-
nancy or in the first months after birth) of massive pro-
teinuria and NS, inevitably leading to ESRD. Following
this discovery, the hunt for other possible genes responsible
encoding for another slit diaphragm protein, podocin, were
recognized as a relatively common etiology of autosomal
recessive SRNS in childhood [20, 21]. Although mutations
in NPHS1 and NPHS2 represent the most common genetic
cause of SRNS in infancy and childhood, in the last two
decades the number of genes potentially causative for
SRNS has continuously increased [2, 22]. All of these
genes encode for proteins that are expressed by podocytes
and that are probably essential to maintain the anatomical
or functional integrity, since their loss of function deter-
mines protein leakage from the GFB and the sequence of
events that finally lead to glomerular scarring and FSGS.
As a direct consequence, patients with NS related to a
genetic alteration of the podocyte structure are insensitive
to corticosteroid treatment, since alterations in podocyte
integrity are intrinsic and not affected by the drug. These
discoveries led to a fundamental improvement in our
understanding of the pathophysiology of SRNS and of
podocyte biology, although this was considered as poten-
tially involving only a rare subset of patients until the
advent of extended genetic sequencing techniques.
J Nephrol
What do we now know about SRNS? Recent
advances and pathogenic classification of SRNS
Next-generation sequencing (NGS), also known as high-
throughput sequencing, is a method of sequencing that
allows to simultaneously obtain a large amount of genetic
data in a single run of sequencing. Independently of the
specific aim (e.g. whole-exome sequencing, target rese-
quencing) and the technology used, NGS is a time- and
cost-effective strategy to unravel the genetic sequence of
more than one gene at a time, usually in more than one
patient. For this reason, NGS is also referred to as mas-
sive-parallel sequencing. These techniques were intro-
duced in the 1990s and have progressively substituted the
traditional Sanger sequencing for genetic analysis. The
advent of NGS, together with the possibility to study large
cohorts of patients and to establish precise genotypephe-
notype correlations, has led to an impressive improvement
in our understanding of the pathogenesis of SRNS, allow-
ing us to identify specific groups of patients that could
therefore benefit from a specific clinical approach. This
knowledge has prepared the ground for a critical revision
of the causative mechanisms of the disease.
The role of genetics
About 10 years ago, by means of traditional Sanger
sequencing technology, it was demonstrated that 85 % of
SRNS cases with onset by 3 months of age (congenital NS)
and 66 % of cases with onset in the first year of life (in-
fantile NS) could be explained by mutations in one of four
genes (NPHS1, NPHS2, LAMB2 and WT1) [23]. Nowa-
days, the list of genes responsible for SRNS is considerably
longer and continuously growing: besides classically rec-
ognized SRNS-associated genes, such as NPHS1, NPHS2,
WT1 or LAMB2, a number of other genes have been
identified as causative of SRNS in children and even in
adults. They can be classified based on their pattern of
inheritance (autosomal recessive, autosomal dominant or
X-linked), that frequently reflects in a different age of onset
of the clinical phenotype and in different familial history.
While autosomal recessive forms of SRNS (the most
common being caused by mutations in NPHS1, NPHS2,
LAMB2 and PLCE1 genes) usually occur in infancy or
childhood and do not present familial grouping, genes
transmitted with an autosomal dominant pattern of inheri-
tance (e.g. WT1, ACTN4, CD2AP, TRPC6) tend to present
later in life, sometimes even in adulthood, and usually have
familial aggregation, even though de novo mutations are
not infrequent, particularly for some genes (such as
ACTN4). Moreover, they are characterized by a more
varied penetrance with different degrees of disease
severity, suggesting that different mechanisms of podocyte
injury may be involved. These phenotypic differences are
probably related to the time of nephron development and
maturation when these genes are expressed and start to
carry out their specific function. Therefore, genes that are
critical for early glomerular development would probably
lead to early onset of clinical manifestations, while genes
encoding for proteins that regulate functions of mature
podocytes determine a delayed onset of the clinical phe-
notype and frequently present a more variable penetrance.
From a functional point of view, gene products can now be
grouped in complexes that are often characterized by
specific sub-cellular location. These include glomerular slit
membrane components and signaling transducing proteins
(e.g. proteins expressed by genes NPHS1, NPHS2, CD2AP,
CRB2, PLCE1, TRPC6, DGKE, CUBN, ANLN, TTC21B),
transcription factors (e.g. WT1, PAX2, LMX1B, SMAR-
CAL1, WDR73, NUP107), actin-binding proteins (ACTN4,
MYO1E, MYH9, INF2), integrins (e.g. ITGA3, ITGB4),
GMB signaling components (e.g. LAMB2), actin-regulating
small GTPases (e.g. ARHGAP24, ARHGDIA, KANK1, -2,
-4), lysosomal proteins (e.g. SCARB2), proteins involved in
coenzyme Q10 biosynthesis (e.g. COQ2, COQ6, ADCK4,
PDSS2), and others (e.g. PTPRO) [2, 4].
Until the validation of NGS as a reliable diagnostic tool
for SRNS, the reported frequency of a genetic cause of the
disease was extremely variable, depending on the cohorts
and on the genes analyzed. This generated a tunnel view of
the problem, inducing the inappropriate belief that genetic
forms of NS represented a rare subset that did not signifi-
cantly influence the therapeutic choices, which were usu-
ally required well before the results of a genetic test could
be available.
Indeed, traditional sequencing technology permits to
study only single genes one at a time: it is therefore nec-
essary to have a high suspicion about which specific gene
might be responsible for the clinical phenotype of the
patient before studying it. Nevertheless, a negative result
does not exclude the genetic origin of the disease, since
other genes that were not sequenced could anyway be
altered. Moreover, genetic testing was traditionally per-
formed in selected groups of patients with congenital or
very early onset of clinical manifestations, or in familial
clusters of the disease that represent genetically informa-
tive populations and are characterized by a significant
likelihood of a genetic-determined pathogenesis. These
patients would benefit from a conservative therapy and
from avoidance of immunosuppressive treatments. How-
ever, in every-day clinical practice the challenge is repre-
sented by sporadic cases of SRNS, since they are not
distinguishable a priori from those who will respond to
steroid treatment solely on the basis of the clinical picture
123

or even pathologic data coming from kidney biopsy [2, 24].
Data on the frequency of a genetic cause in sporadic cases
of SRNS have rarely been reported and were frequently
mixed up with those of familial forms. Moreover, since no
markers predicting a genetic defect were available, many
patients used to undergo immunosuppressive treatment
until a clear diagnosis was established.
However, evidence that genetic abnormalities account
for a significant proportion of patients affected by sporadic
SRNS has recently appeared. It was demonstrated in a
cohort of 69 children diagnosed with non-familial and non-
syndromic NS [25] that, using NGS to target a panel of 46
podocyte genes and a standardized protocol for variants
prioritization, more than 30 % of children with a steroid-
resistant phenotype showed heterogeneous genetic variants
that could be recognized as disease-causing. By contrast,
patients with SSNS did not present any pathogenic muta-
tion in the analyzed genes. The authors also demonstrated
that neither the age at onset of SRNS nor the pathologic
findings on renal biopsy are helpful in distinguishing
patients with pathogenic variants from those who are
negative. More importantly, there was a significant corre-
lation between the presence of genetic abnormalities and
the lack of response to immunosuppressive treatment,
demonstrating that resistance to immunosuppressive treat-
ments in children with NS is associated with heterogeneous
genetic mutations in podocyte genes [25]. These data were
subsequently confirmed in a large cohort of 1783 patients
with SRNS manifesting before 25 years of age [26]. This
study identified a single-gene cause of SRNS in 29.5 % of
patients, with a frequency of genetic diagnosis in sporadic
cases of nearly 25 % which, even if less in comparison to
that found in consanguineous families (approximately
50 %), was nevertheless significant. Although the propor-
tion of patients with a genetic disease decreased with
increasing age at onset, a significant fraction of a single-
gene cause was identified also in older children and in
young adults (more than 10 %), suggesting that a molec-
ular diagnosis is not negligible even after infancy and early
childhood, as traditionally thought. Finally, a further study
from the German registry of pediatric patients reported an
overall mutations detection rate as high as 41 % in patients
with SRNS; 79 % of all mutations were identified by the
analysis of three single genes only (NPHS1, NPHS2, and
WT1) [27]. Remission of the disease in non-genetic SRNS
was observed in 78 % of patients after a median treatment
period of 2.5 months with calcineurin inhibitors, and 98 %
of patients with non-genetic SRNS and cyclosporine A
(CsA)-induced complete remission (normalbuminemia and
no proteinuria) maintained a normal renal function over
time. On the contrary, genetic SRNS was associated with a
high rate of ESRD (66 % of patients). Only one patient
with genetic SRNS experienced a complete remission and
123
J Nephrol
only 16 % of patients with genetic SRNS experienced a
partial remission after CsA therapy. However, all genetic
SRNS patients who had partial remission after treatment
with CsA reached ESRD, suggesting that a reduction of
proteinuria in those patients may represent a hemodynamic
effect that does not mirror a true therapeutic effect [27].
Interestingly enough, the authors also reported that of those
patients with renin-angiotensin aldosterone system inhibi-
tors (RAAS-I) therapy without concomitant CsA (n = 24),
54 % developed ESRD (n = 13), while in patients with
RAAS-I and CsA therapy (n = 28), 71 % developed
ESRD (n = 20) [27]. Although the number of cases is
limited and the difference is not significant, these results
suggest that a prolonged treatment with CsA in patients
may even be harmful, considering the nephrotoxicity of the
drug. Taken together, these results, that other groups [22,
28] have also confirmed, show that a single-gene cause of
SRNS is anything but rare, even in sporadic cases. In fact,
if causative genes are considered and analyzed one at a
time, they account for a negligible fraction of patients; in
contrast, by means of massive-parallel NGS strategies,
when genetic screening includes a larger group of causative
genes, a molecular diagnosis can be obtained in up to one-
third of patients.
Should we change our clinical approach
to children with SRNS?
The impressive burst in genetic knowledge about SRNS
raises the question of whether we can take advantage of the
information that comes from sequencing in order to modify
our current protocols to ameliorate patient care [3]. Since
patients with genetic forms of SRNS are known to be
unresponsive to immunosuppressive therapy, modifying
the intensity and duration of immunosuppression in indi-
viduals with monogenic SRNS, sparing patients the unto-
ward side effects of prolonged ineffective treatments, is
mandatory. We propose the following approach to children
with idiopathic NS (Fig. 1): first, renal biopsy should be
considered as soon as steroid-resistance becomes evident,
in order to unravel possible rare different diagnoses (e.g.
membranous nephropathy or C3 glomerulopathy). If such
cases are excluded, genetic testing should be immediately
performed. In addition to patients with familial history,
syndromic features and congenital onset of the disease, all
patients with sporadic forms of NS failing to respond to an
appropriate course of corticosteroid treatment (e.g. pred-
nisone 60 mg/m2/day for 6 weeks, eventually followed by
intravenous methylprednisolone, depending on the proto-
cols) should start a course of immunosuppressive treatment
and simultaneously undergo extensive genetic testing with
NGS strategies (target resequencing or whole-exome
J Nephrol
Fig. 1 Flow chart illustrating the approach to children with nephrotic
syndrome. In addition to patients with familial history, syndromic
features and congenital onset of the disease, all patients with sporadic
forms of NS failing to respond to an appropriate course of
corticosteroid treatment should undergo an extended genetic screen-
ing with NGS. All the known SRNS causative genes should be
analyzed: NPHS1, NPHS2, CD2AP, CRB2, PLCE1, TRPC6, DGKE,
CUBN, ANLN, TTC21B, WT1, PAX2, LMX1B, SMARCAL1, WDR73,
NUP107, ACTN4, MYO1E, MYH9, INF2, ITGA3, ITGB4, LAMB2,
ARHGAP24, ARHGDIA, KANK1, KANK2, KANK4, SCARB2, COQ2,
COQ6, ADCK4, PDSS2, PTPRO, FAT1, NUP93, NUP205, XPO5,
SGPL1, AVIL, TUBAL3. NS nephrotic syndrome, CCS corticos-
teroids, SRNS steroid-resistant nephrotic syndrome, SSNS steroid-
sensitive nephrotic syndrome, MCD minimal change disease, DMS
diffuse mesangial sclerosis, FSGS focal segmental glomerulosclero-
sis, CNIs calcineurin inhibitors, RAAIs renin-angiotensin-aldosterone
system inhibitors
sequencing, depending on the availability). This implies
that patients should be referred to nephrology centers
where extended genetic screening can be performed with a
proven experience in data interpretation and application to
clinical practice. While waiting for results of genetic test-
ing (that can be potentially available within a few weeks,
depending on the technology used), a therapeutic course
with an immunosuppressive drug (usually calcineurin
inhibitors) can be performed, together with anti-proteinuric
treatment (RAAS-I) and the response to such a therapy
evaluated over a few months. However, since current data
do not support the efficacy of immunosuppressive agents in
patients with proven genetic disease involving the podo-
cyte genes described to date [29], if the presence of
pathogenic mutations in one of these genes is observed in
the genetic testing, immunosuppressive therapy should be
interrupted and only anti-proteinuric treatment maintained
in order to preserve renal function and to avoid undesired
and potentially threatening side effects. On the other hand,
if genetic screening for mutations in such genes fails to
identify a cause of the disease, immunosuppressive treat-
ment should be continued, because the chance of a
response to immunosuppressive therapy is high [27]. This
may include anti-CD20 drugs (e.g. rituximab), even though
the long-term effects of this therapy are still far from being
completely assessed. In addition, while effective in patients
with forms of NS responsive to and even dependent on
steroids, rituximab and other anti-CD20 drugs have not
been compellingly demonstrated to have efficacy in
patients with SRNS, especially those who were multi-drug
resistant [30, 31]. Besides these consequences, genetic
testing can also provide other significant advantages.
Establishing a genetic diagnosis in SRNS can be of great
help in streamlining kidney transplant management, and
identifying the best donation option. In general, the precise
identification of a molecular diagnosis is of critical
importance for genetic counseling to the proband and to the
family. In addition, the assessment of a genetic cause of
SRNS could help in reconsidering the presence of extra-
renal clinical findings of syndromic pictures that were not
immediately evident on clinical examination (e.g. pale
bone abnormalities in LMX1B mutations) or in the evalu-
ation of specific risks related to the molecular diagnosis
(e.g. risk of developing Wilms tumor in patients with
genetic variants of WT1). Genetic screening may also guide
in establishing effective specific therapies (e.g. coenzyme
Q10 supplementation in mutations of COQ10 genes or
vitamin B12 supplementation in mutations of the CUBN
gene) to delay or prevent renal function deterioration and
ameliorate extra-renal manifestations [3]. Finally, by col-
lecting clinical and pathologic data, more precise geno-
typephenotype correlations can be established.
Conclusions and perspectives
Since the beginning of the 21st century, the availability of
NGS technologies has revolutionized the field of human
genetics enabling high-throughput gene identification
studies and introducing novel strategies to unravel the
genetic etiology of Mendelian inherited disorders [32].
This revolution has challenged the traditional view of
kidney disorders, including SRNS. Indeed, experimental
and clinical studies have largely demonstrated that
123

Fig. 2 Etiology of steroid-
resistant nephrotic syndrome
(SRNS) across age groups.
Schematic representation of the
impact of different etiologic
factors of SRNS across age
groups, with a clear
predominance of genetic cause
in infancy, childhood and
adolescence. On the other hand,
environmental factors
(including infectious diseases,
drugs and immunologic
mechanisms) represent the main
cause of SRNS in increasing
age, although even in young
adults genetic causes are not
negligible
genetically-determined podocyte abnormalities are a pre-
viously underestimated cause of loss of permselectivity
properties of the GFB (Fig. 2). NGS techniques (targeted
resequencing of selected genes, whole-exome and genome
sequencing) have become progressively faster and cheaper,
allowing their application to clinical practice and to large-
scale genetic studies. This has gradually led us to under-
stand the genetic background and cellular pathways
involved in SRNS, influencing the accuracy of prognosis,
and guiding in treatment decisions and in genetic coun-
seling. Moreover, as the response to treatment is the best
predictor of a patients prognosis in NS, finding parameters
that are predictive of response to therapy is essential in
order to avoid non-effective and potentially dangerous drug
exposure. In SRNS patients, the genetic test can represent a
suitable tool to distinguish those who will benefit from
immunosuppressive treatments from those who will even-
tually only risk the side effects related to such therapies.
However, the possibility to identify patients with the
genetic form of SRNS is strictly dependent on a correct
selection of patients to steer towards genetic testing. In
fact, while the selection of patients based on the clinical
phenotype has been demonstrated to be highly informative
[25, 26], very different results have been obtained when
other criteria of selection have been applied [33]: this is
particularly true for biopsy findings, since the pathologic
pattern associated with the disease does not really distin-
guish between different etiologies [33].
However, NGS and the advent of the genomic era of eventually leading to a better understanding of disease
kidney diseases have tracked routes that are still far from
being definitively covered. As an example, very recent
results suggest that variations in six different genes
(MAGI2, TENC1, DLC1, CDK20, TLN1 and ITSN1) that
encode proteins of the Rho/Rac/Cdc42 network and induce
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J Nephrol
hyper- or hypo-activation of the RhoA pathway in podo-
cytes may lead to a type of nephrotic syndrome that is
instead partially sensitive to steroids [34], suggesting that
the type of genes involved can specifically predict the type
of response to treatment. These observations depict a (near)
future where an extended genetic analysis of the patient
with NS will be essential to predict outcome and person-
alize treatments.
On the other hand, it must be considered that extensive
genetic sequencing leads to the identification of an
impressive amount of variants that cannot be classified as
pathogenic but that may still play a role, even if sec-
ondary, in the determination of the clinical phenotype of
patients, that may even arise from primary immune injury
or the presence of a circulating permeability factor. Thus,
so-called modifier genes as well as di-genic and multi-
genic inheritance may deal with epigenetic events and
environmental effects [32]. This is the case of APOL1
variants that represent risk alleles for FSGS in African
Americans: their identification by means of genome-wide
association studies has opened new lines of investigation,
which may yield critical insights into the pathogenesis of
the disease [4].
In conclusion, SRNS is not a single disease entity but
rather part of a spectrum of diseases with clearly defined
etiology, whose precise nature is progressively being elu-
cidated [2]. Genetic information will expand our knowl-
edge about disease mechanisms involved in SRNS,
pathways and paving the way for the exploration of alter-
native pathogenic mechanisms, which may help in estab-
lishing a better clinical management of patients as well as
in identifying new possible therapeutic targets for this, still
as yet orphan, disease.
J Nephrol
Acknowledgments This article is supported by funding from the
Meyer Childrens Hospital Foundation and from the Fondazione
AMARTI to Paola Romagnani.
Compliance with ethical standards
Conflict of interest The results presented in this review have not
been published previously in whole or part, except in the abstract
format. All authors declare no conflict of interest.
Ethical approval This article does not contain any studies with
human participants performed by any of the authors.
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