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Clinical Science (2004) 107, 125136 (Printed in Great Britain)

Role of the immune system in the pathogenesis


of idiopathic nephrotic syndrome
Jose G.

VAN DEN

BERG and Jan J. WEENING

Department of Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam,
The Netherlands

Idiopathic NS (nephrotic syndrome) is characterized by massive proteinuria, due to a leak in


the glomerular barrier to proteins. Genetic defects that affect the function and the composition
of the glomerular capillary wall, in particular of the visceral epithelial cells, have recently been recognized as the cause of familial forms of NS. MCNS (minimal change NS) and FSGS (focal and
segmental glomerulosclerosis) are common non-familial forms of NS in which the causative defect
has not yet been identified. Several studies have shown that non-familial NS is associated with
the presence of circulating permeability factors and with complex disturbances in the immune
system. Thus far, there is no direct evidence that these factors directly alter glomerular permeability to proteins, and some of these factors may be a consequence, rather than a cause, of NS.
In this review, we will briefly highlight the mechanisms that underlie proteinuria in general and
focus on the immunological disturbances associated with idiopathic NS, with attention to potential
mechanisms whereby the immune system may directly act on the glomerular capillary filter.

INTRODUCTION
Urine is practically devoid of high-molecular mass proteins, which is achieved by the sieving characteristics of
the glomerular filtration barrier and by resorption of proteins in the proximal tubules of the kidney. Many glomerular diseases result in a pathological increase in glomerular permeability to proteins. If proteinuria exceeds
40 mg m2 h1 , hypoalbuminaemia accompanied by
oedema will ensue. The clinical picture of proteinuria,
hypoalbuminaemia and oedema is referred to as
nephrotic syndrome (NS).
The term idiopathic NS is often used to describe
a heterogeneous group of proteinuric glomerulopathies
that occur predominantly in children. Over the last few
years it has become recognized that some forms of
NS formerly assigned as idiopathic NS are caused by
mutations in genes that encode structural components

of the glomerular filter (as reviewed in [1]). Although


mainly familial, sporadic cases of these diseases have
been described [2,3]. Clinically, they are characterized by
therapy-resistance and eventual progression to end-stage
renal failure.
Non-familial forms of NS are more common. Based
on the renal biopsy findings, non-familial idiopathic NS
can be grossly subdivided into MCNS (minimal change
NS) and FSGS (focal segmental glomerulosclerosis).
As indicated by its name, renal tissue from MCNS
patients shows no changes under light microscopy. More
explicitly, there are no signs of inflammation, immune
complex deposition or sclerosis. FSGS is characterized
by collapse of the glomerular capillaries with sclerosis
and hyalinosis and the formation of adhesions of the
glomerular tuft.
Advances in the field of molecular biology have
enabled the elucidation of the causes of various familial

Key words: allergy, atopy, focal and segmental glomerulosclerosis (FSGS), minimal change nephrotic syndrome (MCNS), nephrotic
syndrome, podocyte.
Abbreviations: FSGS, focal and segmental glomerulosclerosis; GBM, glomerular basement membrane; IFN- , interferon- ;
IL, interleukin; NS, nephrotic syndrome; MCNS, minimal change nephrotic syndrome; PBMC, peripheral blood mononuclear
cells; TNF, tumour necrosis factor.
Correspondence: Dr Jose G. van den Berg (email j.g.vandenberg@amc.uva.nl).

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forms of NS in the late 1990s. Concomitantly, this has


provided a wealth of information on the molecular makeup of the glomerular filtration barrier. In contrast with
these rapid advances in the field of hereditary NS, our
insight in the pathogenesis of non-familial NS is still
limited. In this review, we discuss the aetiology of nonfamilial idiopathic NS, focusing mainly on the possible
role of immunological factors.

MCNS
In children, MCNS is the most common form of NS,
accounting for 3580 % of the cases of NS, depending
on ethnicity [49]. In adults, MCNS is the third most
common form of NS, next to membranous nephropathy
and FSGS, accounting for 1525 % of the cases of unexplained adult NS [10]. MCNS is more common in
Hispanics, Asians, Arabs and Caucasians than in African
Americans [9,1114]. Depending on race, the reported
incidence of MCNS varies from 216 per 100 000 children
under 16 years of age [11,1517]. Previous studies report
higher incidences of MCNS than more recent studies do,
probably because the incidence of FSGS has increased
over time while the incidence of MCNS may be
decreasing [9,10,18].
Clinically, MCNS is characterized by highly selective
proteinuria, i.e. mainly albuminuria, which generally
responds well to treatment with corticosteroids. Approx.
90 % of children with MCNS and up to 70 % of adult patients will respond with a complete remission to a course
of corticosteroids [7,19], yet are prone to relapse. Relapses
are most frequent in children. In a follow up study, 95 %
of children with biopsy-proven MCNS relapsed during
17 years follow-up [20]. Lower relapse rates have been
reported, depending on the therapy regimen [21,22]. If
responsive to steroids, the outcome of the disease is
excellent. Long-term studies with a follow-up of up to
20 years have shown that practically none of the children
with steroid-sensitive biopsy-proven MCNS develop
hypertension, loss of renal function or FSGS [20,23,24].
In adults, the outcome is similar [2527]. Therefore
MCNS is often referred to as steroid-sensitive NS.
In frequently relapsing patients and in steroid-dependent patients, prolonged or repeated steroid therapy can
lead to a variety of serious side effects. In these patients,
alternative therapeutic strategies can be used to induce
long-lasting remission. These include other drugs that
modulate the immune system, such as cyclosporine [28
31] and levamisole [3235], and alkylating agents, such as
cyclophosphamide [3638] and chlorambucil [39].

FSGS
FSGS is a non-specific pattern of glomerular injury
that is frequently encountered in human renal biopsies.
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In adults, only some cases represent idiopathic FSGS,


whereas, in children, almost all cases are idiopathic. Clinically, FSGS is characterized by increased urinary protein
excretion and decreasing kidney function. In idiopathic
FSGS, proteinuria is massive and associated with NS.
In non-idiopathic forms, FSGS develops secondary
to other processes that affect the glomerulus, such as
hyperfiltration and hypertension, or scarring following
inflammatory, proliferative or thrombotic glomerulopathies; usually, these cases present with less extensive
proteinuria [18]. The incidence of idiopathic FSGS
has progressively increased and FSGS now constitutes
the most frequent diagnosis in native adult kidneys,
accounting for 3550 % of cases of adult NS, depending
on race [10]. In children, FSGS is the second most
frequent cause of idiopathic NS, accounting for 2032 %
of NS [40]. The diagnosis of idiopathic FSGS is most
frequent in AfricanAmericans. It has become clear that
a significant proportion of children with steroid-resistant
FSGS, both familial and non-familial, have mutations in
the gene that encodes for the podocyte protein podocin
[2,3]. The large heterogeneity of the disease is illustrated
by the various responses to treatment with corticosteroids. Idiopathic FSGS, both in children and in adults,
may respond to corticosteroids [41,42], yet many patients
show steroid-dependence [43,44]. Steroid-dependent and
steroid-unresponsive patients may benefit from treatment with cyclosporine or cyclophosphamide [4348].
However, more prolonged therapy than in MCNS is
generally required to induce remission.
Progression of FSGS lesions leads to renal insufficiency
and finally to end-stage renal failure, requiring renal replacement therapy. Upon transplantation, the disease
relapses in 2050 % of patients [49,50].

MCNS AND FSGS: ONE DISEASE?


There has been a long debate as to whether or not MCNS
can evolve into FSGS. There have been reports on some
cases of NS in children who were initially corticosteroid
responsive with presumed MCNS histology, but later
progressed to renal failure [51]. Ahmad and Tejani
[52] reported that, in more than 50 % of 49 MCNS
patients, the renal disease evolved into FSGS over a 10year period of repeated renal biopsies. However, the
natural history of MCNS and FSGS is often hard to
define, since only a few children undergo initial renal
biopsy before corticosteroid treatment is started [20]. It
has been suggested that long-standing proteinuria may
contribute to the transformation of MCNS to FSGS [53].
Studies on familial NS would support the hypothesis
that MCNS and FSGS are part of the same disease spectrum [54], since patients with the same genetic defect
exhibit a range of pathologies from minimal changes to
FSGS [2]. Altogether, it is still unclear whether MCNS
and FSGS are aetiologically related. In this review, we

Immunological factors in nephrotic syndrome

Figure 1 The glomerular capillary wall

Cross-sections of the glomerular capillary wall in a non-proteinuric patient (A and B) and in a patient with MCNS (C and D) as revealed by electron microscopy. Cell
bodies of podocytes (P) extend into the urinary space, while their foot processes attach to the GBM. In normal individuals, foot processes are arranged in a regular
interdigitating pattern (B) with interconnecting slit diaphragms (small arrows). In nephrotic patients, foot processes are irregularly flattened and show distorted slit
diaphragms (D; arrowhead). US, urinary space; CL, capillary lumen. Magnification, 11 000 (A and C) and 108 000 (B and D).
will discuss the pathogenesis of both MCNS and FSGS
as separate entities.

THE GLOMERULAR CAPILLARY WALL


The glomerular filtration barrier consists of three layers:
(i) the endothelium lining the inner side of the glomerular
capillaries; (ii) the GBM (glomerular basement membrane), and (iii) the glomerular visceral epithelial cells or
podocytes that cover the outer side of the glomerular
capillary loops. Podocytes are polarized differentiated
cells, which owe their name to their complex shape that
appears to be designed to allow ultrafiltration. The cell
bodies have numerous primary, secondary and tertiary
extensions, the latter called foot processes or peduncles.
The foot processes cover the GBM in an interdigitating
pattern, so that adjacent foot processes are derived from
different epithelial cells (Figure 1A). On the basal side,
the foot processes adhere to the GBM. Laterally, the foot
processes are interconnected by slit diaphragms through
which the filtration route is arranged (Figure 1B). The
apical side of foot processes extends into the urinary
space.

PODOCYTE INJURY IN NS
NS is associated with dramatic changes in podocyte
architecture, as detected by electron microscopy. These
changes consist of loss or effacement of the podocyte foot
processes (Figures 1C and 1D) and suggest a process of
transdifferentiation. The precise mechanism underlying

podocyte foot process effacement and its relationship to


proteinuria are not fully understood.
As stated above, the genetic basis for several forms of
hereditary NS has been solved recently, and the causative
genes indeed all appear to affect a single cell type: the
podocyte. Briefly, these diseases include congenital NS
of the Finnish type, autosomal-recessive steroid-resistant
NS, familial forms of FSGS, diffuse mesangial sclerosis
associated with DenysDrash syndrome and with Frasier
syndrome, and NS associated with nail-patella syndrome.
Studies on genetically modified mice have confirmed that
proteinuria associated with podocyte dedifferentiation
can be induced by disruption of single genes encoding
proteins that appear indispensable for podocyte function.
These proteins include molecules that locate at the slit
diaphragm (nephrin, neph1, podocin, CD2AP and the
Src family kinase Fyn), transcription factors (WT-1,
Lmx1B, Pod1 and Krml1/MafB), cytoskeletal components (-actinin-4 and RhoGDI), adhesion molecules
(3 integrin) and components of the GBM (S-laminin/
laminin 2) (as reviewed in [5557]).
Proteinuria and a distorted podocyte phenotype can be
induced not only by intrinsic damage to podocytes, but
also by extrinsic damage to podocytes. Studies in animal
models have shown that injection of antibodies directed
against podocyte epitopes, such as slit diaphragm components nephrin and neph1, the apically located epitopes
podoplanin [58] and aminopeptidase A [59], and also
against the GBM component heparan sulphate [60], cause
immediate and massive proteinuria. In addition, podocyte
damage by administration of puromycin aminonucleoside and adriamycin, which are compounds that are
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directly toxic to podocytes, to experimental animals is


associated with aselective proteinuria [6165].
Taken together, proteinuria can be induced by several
types of podocyte injury, including intrinsic and extrinsic
damaging factors. The extensive effacement of podocyte
foot processes as the hallmark of non-familial idiopathic
NS suggests a pivotal role for the podocyte in the
pathogenesis of these forms of NS. An intrinsic defect at
any level in the glomerular filtration barrier may underlie
these diseases, but this defect has thus far not been
identified. Alternatively, podocyte injury in non-familial
idiopathic NS may result from extrinsic damage caused
by a circulating factor. The possible role of circulating
factors has been favoured by many studies and will be
addressed below.

the induction of remission by removal of the tumour


suggested that circulating factors might play a causal role
in the mechanism of proteinuria.
Several candidate permeability factors have been
identified to date; however, most have only been partially
characterized biochemically. Some of these factors are
not entirely specific for any particular glomerular lesion
causing NS. Also, it is still unknown what would be
the constituent of the glomerular capillary wall that represents the target of such permeability factors [88]. Yet,
the data presented above suggest that a putative circulating factor in MCNS would be produced by PBMC or,
more specifically, T-cells, pointing to a role of the immune
system.

CIRCULATING PERMEABILITY FACTORS

ROLE OF THE IMMUNE SYSTEM

For FSGS, the involvement of a circulating permeability


factor in its pathogenesis has been suggested by several
lines of evidence. Proteinuria frequently recurs in
the donor kidney of FSGS patients after receiving a
non-FSGS kidney transplant [6668]. However, it has
been reported that proteinuria in two FSGS kidneys
disappeared after transplantation in two recipients [69].
Likewise, in a rat model of FSGS, the spontaneously
proteinuric Buffalo/Mna rat model, disease recurs in the
donor kidney from healthy control rats transplanted into
Buffalo/Mna recipients and proteinuria and renal lesions
regress when the Buffalo/Mna kidneys are transplanted
into normal control rats [70]. These data suggest that the
FSGS kidney does not bear the causative defect.
Also, the efficacy of plasmapheresis in the treatment of
proteinuria in FSGS patients [7174] and the transmission
of proteinuria from an FSGS mother to her child during
gestation [75] point to the presence of a causative factor
in plasma. The latter is supported by experimental data
showing the induction of albuminuria in rats upon intravenous administration of plasma from FSGS patients
[76,77]. Also, serum from FSGS was shown to increase
the permeability of isolated glomeruli to albumin in an
in vitro system [78,79].
For MCNS, the involvement of a circulating permeability factor in the pathogenesis is less well established, due
to the fact that MCNS by definition does not require renal
transplantation and, therefore, clinical transfer studies are
not present. In MCNS, the hypothesis of a pathogenic
circulating factor is based merely on experimental data
showing the induction of albuminuria in rats upon
injection of culture supernatants of stimulated PBMC
(peripheral blood mononuclear cells) from patients with
MCNS [8082] or of a factor produced by human T-cell
hybridomas derived from an MCNS patient in relapse
[83]. Also, the association of MCNS with lymphoproliferative disease, in particular Hodgkins disease
[84,85], T-cell lymphoma [86] and thymoma [87], and

Association of NS with atopy

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In 1974, Shalhoub [89] proposed that MCNS was a


disorder of lymphocyte function with increased levels
of a lymphocyte-derived permeability factor. This hypothesis was based on several clinical observations that
suggested the involvement of the immune system in the
pathogenesis of idiopathic NS. In 1959, Hardwicke et al.
[90] first reported on a patient with NS in association
with pollen hypersensitivity. Since then, many reports
have been published on patients who developed NS after
having experienced allergic reactions to inhaled allergens
[9196], vaccinations [97,98], food [95,99103] and insect
stings [104,105]. Furthermore, the incidence of atopy was
reportedly higher in patients with idiopathic NS than
in healthy subjects, ranging from 1740 % in MCNS
patients compared with 1023 % in age-matched control
subjects [106112].
It should be remembered that there is no standard
definition of the entity atopy, that its prevalence varies
between populations and countries and, therefore, that
there is no official number on the prevalence of atopy
in the general paediatric population. Also, the incidence
of allergic reactions in children is high and a causal
relationship between allergic events and NS is hard to
prove. Reservations should also be made for intervention
studies that aim at the value of dietary interventions
or anti-allergic regimens in the treatment of NS. Some
investigators have shown that oligoantigenic diets, in
addition to immunosuppressive therapy, contributed to
achieve remission in some patients [103,113]; however,
others found no effect of anti-allergic regimens on NS
[114,115]. Here, the conflicting results may be explained
by the large heterogeneity of the disease, its various responses to treatment with corticosteroids and uncertainty
as to its natural course.
Allergy is associated with an elevated production of
IgE by B-lymphocytes, and several investigators have
reported an elevation of IgE in the serum of NS patients

Immunological factors in nephrotic syndrome

[103,116,117]. Studies on the glomerular presence of IgE


in NS kidneys are controversial [118,119].

Role of T-cells and cytokines


Later experimental studies have focused specifically on
the role of T-lymphocytes in the search for the putative
circulating T-cell factor described above. Peripheral
blood, PBMC or subsets of T-cells were collected from
patients with idiopathic NS and compared with control patients. Frank et al. [120] showed that CD8-positive
T-cells of idiopathic NS patients are clonally expanded,
which was not observed in healthy controls. Sahali
et al. [121] showed high levels of NF-B (nuclear
factor B) DNA-binding activity in T-cells from untreated MCNS patients during relapse compared with the
MCNS patients in remission while treated with immunosuppressants. This all points to activation of the T-cells
in MCNS.
Other workers have focused on the production of
cytokines by PBMC or T-lymphocytes. Cytokines are
small proteins (molecular mass of approx. 880 kDa) that
function as soluble mediators in an autocrine or paracrine
manner. Cytokines are produced by both immune cells
and non-immune cells, and their targets also include
both immune and non-immune cells. Based on their
profile of cytokine production, T-helper lymphocytes
can be divided into Th1 and Th2 cells. Th1 cells typically
produce IFN- (interferon- ), TNF (tumour necrosis
factor)- and IL (interleukin)-2, which activate cytotoxic
and inflammatory reactions. By contrast, Th2 cells
produce IL-4, IL-5, IL-9, IL-10 and IL-13, which are
associated with the regulation of strong antibody and
allergic responses [122,123]. For instance, in asthma,
cytokines IL-10 and IL-13, produced by activated Th2
lymphocytes, act directly on pulmonary fibroblasts and
bronchial epithelium and thereby cause an important part
of the phenotype [124127].
Studies on in vitro mitogen-stimulated production of
cytokines by PBMC from patients with idiopathic NS
have demonstrated an increased production of various
cytokines, including IL-1 [128], IL-2 [128,129], IL-4
[129,130] and TNF- [131], compared with patients
in remission or with healthy controls. Matsumoto
[132,133] and Matsumoto and Kanmatsuse [134,135]
reported a decreased production of IL-1 and IL-10
by PBMC from MCNS patients and increased
production of IL-12 and IL-18 compared with normal
controls. To circumvent artefacts induced by stimulation
with mitogens, Kimata et al. [136] studied the unstimulated production of cytokines by T-lymphocytes
of MCNS patients and found an increased production of
IL-13, whereas production of IL-4 was normal. An
elevated expression of IL-13 mRNA was shown by
Yap et al. [137] using a semi-quantitative RT (reverse
transcriptase)-PCR technique; this was associated with
decreased expression of TNF- and CD14 in monocytes

[138]. It has been shown that the increased expression


of IL-13 was not related to known polymorphisms in
the IL-13 gene [139] or in the genes encoding the transmembrane receptors for IL-4 and IL-13 [140,141].
The studies mentioned above all investigated only a
set of preselected cytokines. Using a subtractive cDNA
library screening technique, Sahali et al. [142] applied an
unbiased technique and reported differential expression
of transcripts involved in the T-cell receptor-mediated
complex signalling cascade and a decreased expression of
IL-12 receptor 2 mRNA by PBMC in untreated MCNS
patients during relapse compared with MCNS patients in
remission.
The studies described here not only reveal the
involvement of T-cells in the pathogenesis of idiopathic
NS and, more specifically, Th2-mediated immunity, they
also illustrate the difficulties that are encountered when
studying samples of patients with idiopathic NS. It is
difficult to obtain a homogeneous patient group. At the
time of presentation, the duration of proteinuria varies
and some patients may have already started treatment.
Treatment with immunosuppressive drugs will affect not
only the production of the presumed permeability factor,
but also of many other factors that are not involved in
the disease. Furthermore, it may be difficult to select a
correct control group, which would ideally consist of the
same NS patients when in remission and not taking any
medication; this may seem most feasible in the frequentlyrelapsing patients, yet these patients are often steroiddependent. Also, in the nephrotic state, the composition
of circulating blood changes, with hyperlipidaemia as a
common and hazardous complication. This altered state
itself may activate the immune system, as shown by
Lenarsky et al. [143], who reported that the presumed
immunosuppressive effect of serum of nephrotic patients,
which had been claimed before, could be reversed
simply by removal of the lipoprotein fraction. Thus
hyperlipidaemia itself modulates the immune system and
may also alter the production of circulating factors, which
may be easily misinterpreted as permeability factors.
The difficulties mentioned above are illustrated by
a recent study in our laboratory ( J. G. van den Berg,
unpublished work). By quantitative real-time PCR, we
studied the expression of IL-1, IL-1ra (IL-1 receptor
antagonist), IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, TNF, and IFN- by PBMC from patients with MCNS
during relapse and remission and from a control group
of patients with NS primarily caused by endogenous
alterations within the glomerular filter, for instance
mutations in the genes encoding nephrin and podocin.
Out of the cytokines studied, only the expression of
IL-10 and IL-13 mRNA was significantly up-regulated
in relapsing MCNS patients when compared with MCNS
patients in remission. The expression of IL-13 mRNA,
however, was also up-regulated in the nephrotic control
group. The results are shown in Figure 2, and clearly
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Figure 2 Expression of IL-10 in patients with MCNS

mRNA expression of IL-10 (A) and IL-13 (B) by PBMC from MCNS patients during relapse (n = 15) and in remission (n = 15), and from a control group of patients
with NS primarily caused by endogenous alterations within the glomerular filter (n = 7), as detected by quantitative real-time PCR. Values are expressed relative to
the mRNA levels of the house-keeping gene -actin, in arbitrary units. All patients were free of immunosuppressive drugs for at least 3 weeks. (C) Plasma IL-10 levels
in the same patients, as detected by ELISA. Horizontal lines denote median values. KruskalWallis tests and MannWhitney tests were applied to evaluate differences
between the patient groups.
illustrate the heterogeneity of the patient groups studied;
approximately half of the patients had up-regulation of
the particular cytokine.

Response to immunosuppressive drugs


The favourable response of NS to immunosuppressive
drugs in most patients has been regarded as additional
proof of the involvement of the immune system in the
pathogenesis of NS. Interestingly, levamisole is a potent
down-regulator, specifically of Th2 immune responses,
whereas it augments Th1 responses [144]. The beneficial
effect of levamisole would again advocate the role for
Th2-mediated immune responses in the pathogenesis of
NS. However, the efficacy of immunomodulatory drugs
may be explained by another mechanism, i.e. by direct
effects on the glomerular capillary filter. For example,
both podocytes and endothelial cells express glucocorticoid receptors through which corticosteroids may exert
direct actions on the glomerular capillary wall [145,146].

Direct damage to the glomerular capillary


wall by cytokines
As stated above, there is no significant influx of inflammatory cells into glomeruli of patients with idiopathic NS
and there are no signs of immune complex deposition.
The activation state of T-cells in nephrotic patients, as
described above, thus does not result in inflammatory
events at the glomerular capillary wall. However, cytokines and other circulating factors may be able to act
directly on the glomerular capillary wall. These interactions may take place via cell-surface receptors.
The podocyte is equipped with cell-surface receptors
at the basal cell membrane. These receptors include 31
integrin with CD151 and integrin-linked kinase [147
149], and the dystroglycan complex [150,151]. These
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adhesion receptor complexes are linked to the submembranous actin cytoskeleton and mediate not only cell
adhesion, but also in inside-out and outside-in signalling.
We and others have shown that, in addition to adhesion
receptors, podocytes constitutively express functional
transmembrane receptor complexes for IL-4, IL-10,
IL-13 [152,153] and TNF- [154]. The IL-4/IL-13
receptor complex is also expressed by endothelial cells,
including glomerular epithelium in vivo [152,155]. The
presence of cytokine receptors at the glomerular capillary
wall is puzzling and raises teleological questions: what is
their significance in normal states and what is their role
in disease?
In immune cells, cytokines function as soluble messengers and binding of cytokines to their cognate
receptors induces a variety of intracellular changes, which
have been studied extensively. These changes include
cytoskeletal rearrangements, as has been shown for IL-4
and IL-13 in B-cells, granulocytes and macrophages
[156160]. Also, in cultured HUVECs (human umbilical
vein endothelial cells), IL-4 and IL-13 regulate cell
morphology, cytoskeleton and proliferation [161]. In
cultured podocytes, we have shown that IL-4 and IL-13
directly alter protein sorting, ion transport and activity of
lysosomal enzymes, such as cathepsin L and heparanase
[152,162]. Others have shown the effects of pro-inflammatory cytokines IL-1 and TNF- on the expression
of nephrin by podocytes [163] and on cytoskeleton
reorganization in podocytes [164].
Thus cytokine receptors render the glomerular capillary wall responsive to immunological signals from the
environment. One may hypothesize that, under physiological circumstances, the levels of circulating cytokines
are low and their effects at the glomerular capillary wall
may be less pronounced, whereas, in disease, elevated

Immunological factors in nephrotic syndrome

cytokine levels may induce several changes and eventually


lead to an increased glomerular permeability to protein.
Alternatively, binding of cytokines to their receptors
at the glomerular capillary wall may stimulate the
production of other factors by endothelial cells and/or
podocytes, which, in turn, may function as permeability
factors in a paracrine or autocrine manner.
It is particularly difficult to translate work in vitro to
the situation in vivo, since the glomerular capillary filter is
a complex structure with multiple interactions that cannot
be studied in vitro. The effect of IL-4 on the glomerular
capillary wall in vivo was elegantly shown in two successive studies on IL-4 transgenic mice. Transgenic
mice that overexpressed IL-4 under the control of an
MHC class I promoter developed glomerular FSGS-like
lesions associated with proteinuria [165]. This phenotype
was associated with increased production of autoantibodies and the presence of immunoglobulin deposits in
the glomerular filter, and renal disease could be prevented by treatment with IL-4-neutralizing antibodies.
In a cross-breeding experiment with these mice and with
-chain-deficient mice (MT/ ), IL-4 transgenic mice
were generated that were unable to produce immunoglobulins. In the absence of glomerular depositions, these
mice still displayed FSGS-like lesions and proteinuria
[166]. It is possible that, in these mice, direct effects of
IL-4 on the glomerular capillary wall via the IL-4 receptor
were involved in the development of disease. In contrast
with IL-4, overexpression of IL-13 in transgenic mice
under the control of the CD2 promoter [167] did not
induce glomerular abnormalities or proteinuria ( J. G. van
den Berg, unpublished work).

CONCLUDING REMARKS AND PERSPECTIVES


In summary, idiopathic NS is associated with complex
disturbances in the immune system, such as atopy and
allergy, and a cytokine bias towards Th2 cytokines.
Although these cytokines can act directly on podocytes
and the glomerular filtration barrier, the action of a single
cytokine may not be sufficient to induce disease. The
finding that only few allergic patients develop NS, while
they all show high levels of circulating Th2 cytokines,
would suggest that one or more additional factors may
be required. Rather than being caused by one circulating
cytokine, we hypothesize that idiopathic non-familial
NS may be a multifactorial disease including intrinsic
and environmental factors. The search for complex interrelated mechanisms poses a great challenge, and lessons
should be drawn from the recent discoveries in the field
of familial NS.
As discussed above briefly, mutations in the gene
NPHS2 encoding the podocyte-specific protein podocin
are causative of autosomal recessive steroid-resistant
NS. Recent studies suggest that even in some NPSH2
patients, circulating factors play a role in addition to

the pathogenic mutation [168]. In a subgroup of NPSH2


patients, proteinuria has been reported to recur shortly
after renal transplantation in a manner that would exclude
the involvement of antibodies [169171]. In some
patients, the disease is partly responsive to treatment
with immunosuppressive drugs, which may point to the
involvement of the immune system even in this form of
NS [172].
Thus, in some patients, both circulating permeability
factors and podocyte factors are involved in the development of NS. Antignac [168] proposed that allelic
variants or heterozygous mutations in NPHS2 or other
podocyte genes may modulate the phenotype of a
nephropathy that would arise from the presence of a circulating permeability factor; these podocyte gene variants
would act not as causative genes, but as phenotype
modifiers. The prevalence of podocin mutations in
idiopathic non-familial NS patients is currently under
investigation. The first reports show that approx. one
quarter of sporadic FSGS is associated with mutations in
the podocin gene, whereas no mutations are found
in MCNS patients [171]. Other cases of non-familial
FSGS have recently been associated with mutations in the
gene encoding CD2AP [173]. The search for additional
(podocyte) factors involved in the pathogenesis in
idiopathic non-familial NS continues. A gene that may
encode a yet unknown factor involved in MCNS may be
located at chromosome 2p12-p13.2, as has been recently
suggested by linkage studies on three siblings with a
familial form of MCNS [174].
The involvement of multiple factors, including some
intrinsic to podocytes, in the pathogenesis of idiopathic
NS does not rule out the possibility of a simple specific
therapy. A multifactorial aetiology with involvement of
multiple cytokines and chemokines has been established
for Th2-associated diseases such as asthma and atopic
dermatitis; yet therapeutic strategies aimed at one of
the cytokines involved have shown promising results
[175177]. Large prospective multicentre studies that will
include genetic linkage analysis are warranted to unravel
further which factors are involved in the pathogenesis of
idiopathic NS and to develop rational targeted therapies.

ACKNOWLEDGMENTS
We wish to thank Nike Claessen, Sandrine Florquin and
Jan Aten for invaluable help and support. This work was
supported by grants from the Dutch Kidney Foundation
(No. C98.1720), and from The Netherlands Organization
for Scientific Research (NWO; Grant 920-903-062).

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Received 26 March 2004/11 May 2004; accepted 25 May 2004


Published as Immediate Publication 25 May 2004, DOI 10.1042/CS20040095

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2004 The Biochemical Society