Pediatr Nephrol

DOI 10.1007/s00467-017-3677-5

REVIEW

Immunology of idiopathic nephrotic syndrome

Received: 23 February 2017 / Revised: 5 April 2017 / Accepted: 7 April 2017

Abstract The pathogenesis of idiopathic nephrotic syndrome permeability barrier [1]. Electronic microscopy examination
(INS) is as yet unknown, but several lines of evidence indicate of renal biopsies, when performed, reveals diffuse foot pro-
that the immune system may play a crucial pathogenic role in cess effacement; in light microscopy studies these changes are
non-genetic INS. The most important of these are, first, the either absent, which is the most common finding [referred to
effectiveness of therapy based on immunosuppression and, as minimal change disease (MCD)], or focal and segmental
second, a vast body of data derived both from experimental glomerulosclerosis (FSGS) is detected. However, a renal bi-
models and from patient studies that implicate T cells and opsy is not performed in most children who are initially re-
more recently B cells as major players in INS pathogenesis. sponsive to treatment because response to prednisone is pre-
However, recent findings also suggest a direct role of dictive of a favorable course and drives clinical decisions [2].
podocytes as drivers of the disease process, and the interplay Whether MCD and FSGS (reviewed in [3] and [4]) are differ-
between the glomerulus and the immune system is still being ent entities or two extremes of the same disease remains open
elucidated. In this review we provide an overview of current to debate (reviewed in [5]), and both options may be valid.
knowledge on the role of different components of the immune Congenital NS is caused by genetic mutations in genes
system in determining disease. Advances in our understanding encoding proteins essential for the integrity of the glomerular
of the pathogenesis of INS may help drive new, more tailored filtration barrier, such as NPHS1, NPHS2, WT1, PLCE1,
therapeutic approaches. LAMB2 and TRPC6 [6], with progression to terminal renal
failure. However, in most non-genetic forms, the pathogenesis
of proteinuria lies outside the kidney and is secondary to cir-
Keywords Idiopathic nephrotic syndrome . Circulating
culating factors that directly or indirectly disrupt the normal
permeability factors . T cells . B cells . Podocytes .
architecture of podocyte cells (reviewed in [7, 8]). Compelling
Rituximab . Immunosuppressive therapy
evidence for this disease mechanism stems from numerous
clinical observations of disease recurrence immediately post-
renal transplant [9, 10], of trans-placental transmission of a
Introduction Bpermeability factor^ leading to neonatal transient proteinuria
[11] and of disease resolution when transplanted kidneys are
Idiopathic nephrotic syndrome (INS) is the most frequent glo- removed and implanted in a different recipient [12]. In addi-
merular disease in childhood. It is characterized by intense tion, experiments in animal models have suggested that serum
proteinuria caused by damage to podocytes and foot process from patients with post-transplant relapse of INS can induce
effacement that leads to alterations of the selective glomerular proteinuria in rats [13].
The efficacy of different immunosuppressive approaches
* Marina Vivarelli
and the pivotal role of prednisone in the treatment of non-
[email protected] genetic forms of INS strongly implicates the immune system
in the pathogenesis of this disease. However, despite extensive
1
Division of Nephrology and Dialysis, Ospedale Pediatrico Bambino investigation, the mechanism by which immune dysregulation
Gesù–IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy leads to disruption of the glomerular filtration barrier and
 Pediatr Nephrol

consequently to proteinuria is as yet ill-defined. Activation of episodes (after exposure to both allergens and insect stings). In
the immune system, antigen presentation, T-cell dysregulation particular, upper airway infections have been reported as the
and the production of a circulating permeability factor are all more frequent infections causing relapse, independently of the
potentially implicated. Recent studies have also suggested that viral load or antibody responses [16]. Increasing corticoste-
under inflammatory stimuli the podocyte itself plays a direct roid treatment during upper respiratory tract infections has
role in activating cell pathways that cause proteinuria [14]. been shown to decrease the likelihood of relapses [17, 18].
Changes in the electrochemical charges of the glomerular Vaccination and atopy have also been associated with relapse,
basement membrane and in the composition of the glycocalyx suggesting that immune activation is involved in INS exacer-
lining the glomerular endothelial layer may also play facilitat- bation [19–21].
ing roles in promoting albuminuria [15].
Overall, multiple mechanisms have been hypothesized to
produce circulating factors or to act on podocytes and disrupt
the integrity of the glomerular filtration barrier, leading to T cells
proteinuria. Most of these mechanisms involve immune cells
and are schematized in Fig. 1. Herein we review the strongest Peripheral T cells arise from immature lymphoid precursors
and/or most recent evidence of the immunopathogenesis of derived from the bone marrow which migrate to the thymus,
INS. where they are committed to respond to antigens processed
and presented by specialized antigen-presenting cells (APCs).
Intracellular antigens are presented via MHC class I molecules
to CD8+ cytotoxic T cells, which in turn produce specific
Trigger events cytotoxins and express surface molecules that induce apopto-
sis in target cells. Extracellular antigens are presented via
Whereas INS usually arises in healthy individuals, disease MHC class II molecules to CD4+ T helper (Th) cells, which
onset and subsequent relapses are frequently associated with differentiate into several subsets based on the cytokines re-
intercurrent infections (mostly viral), vaccinations or allergic leased by APCs in response to the trigger event. For example,

Fig. 1 Pathogenic mechanisms responsible for the disruption of the treatment and the presence of circulating anti-CD40 autoantibodies. In
glomerular permeability barrier in idiopathic nephrotic syndrome (INS). addition to the leukocyte-produced soluble factors, such as cytokines and
Trigger events, such as infections, vaccination or allergens, can stimulate autoantibodies, other circulating permeability proteins (i.e. hemopexin,
antigen-presenting cells (APCs) and B cells, which in turn can activate T the soluble form of the urokinase-type plasminogen activator receptor,
cells by antigen presentation and cytokine production. Several T-cell al- the cardiotrophin-like cytokine factor 1, and a hyposialylated form of the
terations have been described in INS: a reduction of CD4+ T helper (Th) angiopoietin-like-4 glycoprotein) can directly affect podocytes, leading to
cells associated with a prevalence of CD8+ cytotoxic T cells, an imbalance foot process effacement and disruption of the glomerular permeability
between Th2 and Th1 cells with an increase in the production of the Th2- barrier. Furthermore, podocytes can also sense microbial products by
specific interleukin-13 (IL-13) and a reduced frequency and function of specific toll-like receptors (TLRs) and can express costimulatory mole-
regulatory T cells (Tregs) opposed to an increased activity of Th17 cells. cules, such as CD40 and B7-1 which are able to induce activation of T
B-cell alterations have also been observed: an increased release of the cells. APCs Antigen-presenting cells, TLRs Toll-like receptors, GBM glo-
soluble form of CD23 (sCD23—the immunoglobulin E receptor), a cor- merular basement membrane
relation between memory B-cell recovery and relapse after rituximab
Pediatr Nephrol

bacterial infections induce the production of inflammatory (reviewed in [7, 23–25]). The results emerging from these
cytokines by APCs and induce the polarization of naïve T studies can be summarized as follows:
lymphocytes into interferon gamma (IFN-γ)-producing Th1
cells when exposed to interleukin (IL)-12 or into Th17 cells 1) Most patients were found to demonstrate an imbalanced
when exposed to IL-6, IL-23 and transforming growth factor expression of their T-cell subpopulations during the active
beta (TGF-β), both of which coordinate cell inflammatory phases of disease, with a reduction in CD4+ circulating T
responses (Fig. 2). Allergens or parasites stimulate APCs to cells and a prevalence of CD8+ cells [26, 27], whereas
produce IL-4, which induces the differentiation of Th2 cells other studies failed to find any difference in the CD4+
responsible of the activation of humoral and allergic responses and CD8+ T-cell subsets [28]. Interestingly, deple-
via the production of IL-4 and IL-13. On the contrary, antigen tion of CD4+ T cells aggravates renal damage in
presentation in the presence of IL-10 and TGF-β drives the mouse models of INS, suggesting a protective role
development of regulatory T cells (Tregs), which downregu- for these cells [29].
late immune responses via the production of immunosuppres- 2) Whereas an increased expression and production of the
sive cytokines such as IL-10 and TGF-β (Fig. 2). Th2-specific IL-13 in patients with INS was described
In 1974, Shalhoub hypothesized that INS represents the [30], no distinct Th1 or Th2 profile in INS can be defi-
renal manifestation of a systemic T-cell dysregulation, nitely identified and confirmed due to the heterogeneity
resulting in the production of a circulating mediator which of the experimental conditions in the different studies
modifies podocyte structure and leads to foot-process fusion (dosing of circulating cytokines, in vitro stimulation, im-
[22]. At the time this hypothesis was based on indirect evi- munosuppressive therapy) [31].
dence, such as sensitivity to steroids and cyclophosphamide, 3) An increase in Th17 cells, Th17-related circulating cyto-
which are known to modify cell-mediated responses, the as- kines and in IL-17 deposition in kidney biopsies in con-
sociation of INS with T-cell lymphomas and spontaneous re- junction with a reduction of CD4+CD25+FoxP3+ Tregs
mission after measles infection, which causes cell-mediated was observed in INS patients [32]. INS severity has also
immunosuppression. In this assumption, the absence of anti- been associated with decreased activity of Tregs [33].
body depositions in the kidney negates a role of humoral im- Moreover, IPEX syndrome, a disease driven by a genetic
munity. The publication of this hypothesis prompted numer- defect of Foxp3 leading to defective T-cell regulatory
ous subsequent studies, both in patients and in animal models functions, can develop INS [34]. Furthermore, Bertelli

Fig. 2 T-cell development. During their ontogeny, bone marrow mediates cellular immunity and inflammation; IL-4 induces Th2 cell de-
immature T-cell precursors migrate into the thymus and develop into velopment during allergic responses and drives the activation of humoral
CD4+ T helper (Th) cells or CD8+ cytotoxic lymphocytes (CTL), follow- immunity; in contrast, a tolerogenic milieu represented by high levels of
ing which they enter the circulation. Once in the circulation, naïve acti- TGF-β without IL-6 can elicit the formation of Tregs, which are able to
vated Th0 cells produce IL-2 to drive T-cell proliferation and differenti- downregulate the immune responses through their secretion of immuno-
ation and acquire several phenotypes and functions based on the cyto- modulatory cytokines, such as IL-10 and TGF-β. In parallel, CTL, which
kines released by the APCs exposed to different conditions. These include can be activated in the presence of IFN-γ and IL-2, are differentiated to
the development of interferon gamma (IFN-γ)-producing Th1 cells or IL- kill infected cells or tumor cells, by the production of granzymes and
17-secreting Th17 cell differentiation, promoted by IL-12 or IL-6, IL-23, perforine and the expression of the apoptosis-inducing molecule Fas li-
and transforming growth factor beta (TGF-β), respectively, which gand (FASL)
 Pediatr Nephrol

et al. demonstrated that the neutrophil-induced oxidative producing plasma cells that are resident in the bone marrow
burst triggered by an infection is amplified during INS is less well established. The ability of this drug to inhibit, at
relapse by the downregulation of an inhibitory enzyme least in part, the production of autoantibodies with marginal
expressed by Tregs [35]. In this hypothesis, Treg dysfunc- disturbance of total immunoglobulin levels suggests that some
tion increases the production of reactive oxygen species, autoantibodies can be produced by short-lived plasma cells
which participate in the pathogenesis of INS. Consistent that need replenishment from CD20+ B cells [42]. However,
with this view, patients with FSGS demonstrate substan- whereas in adults the effect of rituximab on total serum im-
tial oxidation of serum albumin [35]. munoglobulins appears to be less pronounced, in children B-
4) Significant proteinuria and foot process effacement has cell depletion by rituximab can cause a decrease in circulating
been observed after engraftment into murine recipients immunoglobulin levels within a few weeks after the first in-
of immature CD34+ stem cells (thymic progenitors) ob- fusion, lasting for months and sometimes years. This effect
tained from patients with recurrence of INS, but not with appears to be more frequent in the presence of concomitant
cells obtained from healthy donors [36]. immunosuppressive therapy [43].
The possible role of antibodies in INS is sustained by a
number of clinical observations and experimental studies.
Data from Dantal et al. for example, show that a permeability
B cells and anti-CD20 therapy in INS factor inducing albuminuria may be or may bind to an immu-
noglobulin [44]. Persistent reduced IgG levels have also been
Circulating B cells migrate as transitional B cells from the described during remission, suggesting a disturbed immuno-
bone marrow, where the immature lymphoid precursors are globulin metabolism in this disease [45]. More recently, the
stored, to the periphery, where they acquire a naïve/mature presence of anti-CD40 antibodies in sera of recurrent FSGS
phenotype. Their continuous recirculation into secondary patients has also been reported (see below) [46].
lymph nodes favors encounters with antigens in the presence Apart from their potential effect on antibody production, B
of Th cells and induces their development into antibody- cells have other functions which may be implicated in the
producing plasma cells or memory B cells which initially mechanisms of action of rituximab, as suggested by several
produce immunoglobulin (Ig)M but subsequently undergo lines of research. sCD23, for example, is a soluble low-affinity
an isotype switching to IgG-, IgA-, or IgE-secreting B cells IgE receptor that represents a classical parameter of B-cell
(Fig. 3). Plasma cells are divided into short- and long-lived stimulation and has been shown to be markedly increased
plasma cells. Circulating short-lived plasma cells generally die during relapses of INS [47]. Epstein–Barr virus is known to
after few days, while long-lived plasma cells return to the bone affect B-cell function and has been associated with a higher
marrow and maintain antibody production independently of risk of developing INS [48]. HLA-DQA1 is highly expressed
antigen exposure (Fig. 3) [37, 38]. on the surface of B cells, and polymorphisms in this locus
Whereas the role of B cells in several renal diseases is well have recently been associated with steroid-sensitive INS
established [38], their contribution to the pathogenesis of INS [49]. However, the most important indications of the patho-
is still being debated. The first evidence of a potential role of genic role of B cells in INS are represented by the response to
these cells in the pathogenesis of INS stems from a report on therapies which directly or indirectly affect B-cell function. In
the unexpected remission of proteinuria in a young patient particular, the duration of remission after rituximab treatment
with steroid-dependent INS treated with rituximab for idio- in steroid-sensitive INS patients is correlated in most patients
pathic thrombocytopenic purpura [39]. Several retrospective with the duration of B-cell depletion [50]. In this regard, we
studies and clinical trials subsequently demonstrated the ther- recently demonstrated that this effect is related to the
apeutic efficacy of anti-CD20 antibodies in inducing and/or prolonged depletion of memory B cells, rather than of total
maintaining a prolonged remission of INS despite the with- CD19+ B cells [51], which could explain why prolonged re-
drawal of the concomitant immunosuppressive treatment (re- mission can be maintained in some rituximab-treated INS pa-
cently reviewed in [40]). CD20 is a specific marker of B cells tients following total B-cell recovery [52].
that is present in most differentiation stages, except lymphoid Alternatively, the results from in vitro experiments suggest
stem cells and antibody-secreting plasma cells. However, that the effectiveness of rituximab in INS is mediated through
treatment with rituximab can indirectly deplete short-lived a direct protective effect on podocytes’ actin cytoskeleton
plasma cells that are constantly regenerated from CD20+ acti- [53]. According to this hypothesis, the drug cross-reacts with
vated B cells [41]. In addition, results from studies involving an epitope of SMPDL-3b, a sphingomyelin phosphodiesterase
autoimmune murine models suggest that some short-lived expressed by podocytes, preventing the latter’s downregula-
autoreactive plasma cells may retain expression of the CD20 tion and downstream deregulation of the actin cytoskeleton
antigen [42]; whether this also occurs in human subjects is still and other cell signals [53]. In another disease model of xeno-
unknown. The action of rituximab on long-lived antibody- transplantation, the same mechanism has been proposed to
Pediatr Nephrol

Fig. 3 B-cell development. B cells migrate from the bone marrow, where IgA- or IgE-producing cells based on the nature of the stimulus. A frac-
immature precursors are stored, to the periphery where they acquire tion of the plasma cells, called Blong-lived plasma cells^, then returns to
mature phenotype and functions and become competent naïve cells the bone marrow where they maintain a stable and durable antibody
expressing the antigen-sensing immunoglobulin (Ig) D and IgM on their production without further antigen exposure. All B-cell subsets, exclud-
surface. Following activation, B cells can develop into short-lived anti- ing precursors and plasma cells, express the CD20 molecule, which is the
body-producing plasma cells or long-lived memory B cells, which can target of anti-CD20 monoclonal antibodies such as rituximab and
produce IgM antibodies before undergoing an isotype switching to IgG-, ofatumumab

explain the anti-proteinuric effect of rituximab, with the addi- express toll-like receptors 3 and 4 (TLR3 and TLR4), to in-
tional suggestion that this effect is B-cell independent [54]. crease binding of IgG through the neonatal form of the Fc
However, ofatumumab, a fully humanized anti-CD20 mono- receptor (FcR), to be able to activate T cells through presen-
clonal antibody, has been shown to be effective in INS [55]. tation of antigens via MHC class I and class II molecules and
Interestingly, this latter drug binds to a different CD20 epi- through the expression of costimulatory molecules, such as
tope, which probably disproves the Boff target^ hypothesis of CD80 (B7-1) and CD40, to express receptors for CC and
the direct effect of rituximab on podocytes and favors a path- CXC chemokines and to produce several cytokines, including
ogenic role of B cells [56]. TGF-β, IL-6 and IL-8 [14, 46, 58–64]. In particular, B7-1
expression, a T cell-activating co-stimulatory molecule that
is generally present on the surface of B lymphocytes and
Podocytes antigen-presenting cells, can be induced in murine podocytes
by stimulation with TLR3 and TLR4, which leads to the de-
The glomerular filtration barrier consists of three different velopment of proteinuria and foot process effacement [59, 61].
structures, namely the endothelial fenestrated layer, which is Increased urinary levels of soluble B7-1 have also been de-
covered by a dense glycocalyx, the glomerular basement scribed in patients with MCD during relapse, but not in those
membrane and podocytes (Fig. 1). Although all three layers in remission [65]. Furthermore, expression of glomerular B7-
play a role in the filtration barrier, podocytes are the main 1 was recently observed in renal biopsies of several glomeru-
players in INS, which is appropriately included among the lopathies, and treatment with the B7-1-blocking agent
larger family of Bpodocytopathies^ [57]. Genetic forms of abatacept can induce partial or complete remission in post-
INS are with only few exceptions resistant to medical treat- transplant recurrence of FSGS, suggesting that B7-1 expres-
ment and are caused by mutations in genes encoding for inte- sion could represent a valuable marker that predicts response
gral proteins of the slit diaphragm or for proteins that directly to abatacept [66]. However, these data have not been con-
or indirectly regulate podocyte actin cytoskeleton or metabo- firmed in other studies that have evaluated B7-1 expression
lism [6]. in renal biopsy specimens of patients with INS and of animal
Apart from these genetic disorders, functional alterations of models of FSGS (reviewed in [67]).
podocytes can be caused by events that are closely linked to The expression of CD40 is another potentially intriguing
the immune system. When exposed to specific stresses, characteristic of podocytes. CD40 is a transmembrane protein
podocytes have been shown to increase phagocytosis, to that is mainly expressed by antigen-presenting cells, in
 Pediatr Nephrol

particular by B cells. In B lymphocytes, CD40 stimulation of FSGS [75]. CLCF-1 is a member of the IL-6 family, is
induces cell activation, acquisition of a memory phenotype expressed by several tissues and is known to activate B cells.
and differentiation into antibody-producing plasma cells Similar to unfractionated FSGS serum, CLCF-1 induces albu-
[68]. However, a non-inducible constitutive expression of minuria in mice and increases albumin permeability in isolat-
CD40 has been observed in human cultured podocytes and ed rat glomeruli through the activation of the JAK/STAT path-
in glomerular biopsies of FSGS patients [46]. Circulating anti- way; this effect can be reversed by incubation with anti-
CD40 IgG has also been identified in the serum of patients CLCF-1 antibodies or with JAK/STAT inhibitors [75].
with FSGS, but not in that of patients with other glomerular Finally, glomerular overexpression of angiopoietin-like-4
diseases [46]. In this study, purified anti-CD40 IgG from the (Angptl4) has a proteinuric effect, as demonstrated in human
sera of patients with recurrent FSGS was able to induce dis- subjects with MCD and in experimental models of the disease
ruption of the podocyte actin cytoskeleton in vitro, and this [76]. Interestingly, only hyposialylated Angplt4 secreted by
effect was partially inhibited by other CD40-blocking anti- podocytes induces proteinuria in animal models, while
bodies [46]. Furthermore, co-injection of purified FSGS normosialylated Angplt4 or hyposialylated Angplt4 treated
anti-CD40 IgG with the soluble form of the urokinase-type with sialic acid precursors have a protective effect [76].
plasminogen activator receptor (suPAR) (see below) caused
proteinuria in wild-type but not in CD40−/− mice [46]. While
the authors suggest a possible role of intrarenal CD40 expres- Immunosuppressive therapy
sion in the pathogenesis of INS, a direct effect of anti-CD40
IgG on B cells in patients with FSGS cannot be excluded [69]. Current therapy of INS is based on oral corticosteroids (pred-
Of note, the presence in FSGS sera of autoantibodies such as nisone), which induce complete remission in up to 80–90% of
anti-CD40 IgG suggests per se a pathogenic role of B cells in children. However, frequent relapsing-remitting episodes and
INS. steroid dependency occur in 40–50% of patients, thereby re-
quiring the use of steroid-sparing agents, including cyclophos-
phamide, calcineurin inhibitors (CNIs), azathioprine (AZA) or
Circulating permeability factors mycophenolate mofetil (MMF) [77]. More recently, anti-
CD20 monoclonal antibodies, namely rituximab or
As mentioned above, several forms of INS, and in particular ofatumumab, have been shown to be effective in inducing
those resulting in non-genetic forms of FSGS, are character- prolonged remission and in allowing the tapering of other
ized by the presence of circulating factors causing proteinuria. immunosuppressive treatments in patients with frequently re-
In addition to the soluble factors, such as cytokines, that are lapsing or steroid-dependent INS [78–81]. All of these drugs
produced by lymphocytes, or immunoglobulins, such as anti- decrease activation, proliferation and/or differentiation of im-
CD40 auto-antibodies, other circulating factors have been de- mune cells (Table 1). Corticosteroids act through binding to
scribed in past years (reviewed in [7, 8]). the glucocorticoid receptor, a transcription factor expressed by
Hemopexin is a protease secreted by the liver and has been all immune cells (and the majority of the other cells), exerting
shown to reduce the expression of glomerular several effects based on the differentiation and activation state
sialoglycoproteins and to alter the integrity of the actin cyto- of the individual cells [82]. Corticosteroids induce apoptosis
skeleton; its activated circulating isoform is increased during of T cells and downregulate cytokine production as well as the
relapses of MCD [70, 71]. expression of adhesion molecules, thus reducing T-cell acti-
The suPAR, a receptor expressed by several immune cells vation and migration to the site of inflammation [82–84]. This
but also by endothelial cells and by podocytes, can induce foot immunosuppressive activity is mediated, at least in part, by
process effacement and has been shown in some studies to be the inhibition of nuclear factor-kappaB (NF-kB) [85], a key
increased in the plasma of FSGS patients [72]. The pathological transcription factor responsible for T-cell activation. However,
levels of this protein are derived mainly from immature mye- different Th cell subsets exhibit different glucocorticoid sen-
loid cells [73]. However, suPAR injection does not induce pro- sitivity [86] and may also indirectly affect B-cell response.
teinuria in wild-type mice, unless injected with other podocyte- Cyclophosphamide is converted into its active metabolite,
damaging agents, such as anti-CD40 antibodies [46]. phosphoramide mustard, and induces DNA crosslinking and
Furthermore, plasma suPAR levels are influenced by renal s u b s e q u e n t a p o p t o s i s o f t h e t a rg e t c e l l s [ 11 9 ] .
function and are elevated in other kidney and liver diseases. Cyclophosphamide reduces total B-cell counts, but does not
Therefore, its role in INS has recently been challenged [8, 74]. modify levels of circulating memory B cells, plasma cells or
Another potential, interesting permeability factor is the total T cells [95]. However, it can reduce levels of splenic
cardiotrophin-like cytokine factor 1 (CLCF-1), which was short-lived (but not long-lived) plasma cells, which are
identified by affinity chromatography and mass spectrometry an important source of autoantibodies in autoimmune
in plasma samples of patients with post-transplant recurrence disorders [97].
Pediatr Nephrol

Table 1 Effects of the current immunosuppressive therapy of idiopathic nephrotic syndrome on different cells

Immunosuppressive treatment Effects References

Corticosteroids
T cells Apoptosis (in vitro and in vivo) [82, 83]
Inhibition of activation and cytokine production (in vitro and in vivo), also by [82, 84, 85]
inhibiting NF-kB activation (in vivo and in vitro)
Inhibition of migration into inflamed tissues (in vitro and in vivo) [82]
Distinct steroid sensitivity in different Th cell subsets [86]
Indirect induction of regulatory T cells by generation of tolerogenic dendritic cells and [87, 88]
myeloid-derived suppressor cells (in vitro and in vivo)
B cells Apoptosis (in vitro and in vivo) [89, 90]
Suppression of early activation and proliferation (in vitro) [91]
Partial effect of high-dose treatment on T-cell-dependent antibody production from [83, 90]
plasma cells (in vivo)
Podocytes Induction of actin filament stability (in vitro) [92, 93]
Reduction of apoptosis (in vitro) [92, 94]
Inhibition of VEGF and IL-6 cytokine production (in vitro) [64, 92]
Cyclophosphamide
T cells No effect on total T cells (in vivo) [95]
Impairment of regulatory T cell expansion and function (in vivo) [96]
B cells Reduction of total B cells (in vivo) [95]
No effect on circulating memory B cells or plasma cells (in vivo) [95]
Inhibition of splenic short-lived plasma cell differentiation (in vivo) [97]
Podocytes Preservation of podocyte structure (in vivo) [98]
Calcineurin inhibitors
T cells Inhibition of activation and cytokine production by inhibiting NFAT and NF-kB [99–101]
activity (in vitro and in vivo)
Impairment of regulatory T cell expansion (in vitro and in vivo) [102]
B cells Inhibition of naïve but not total B cell proliferation and plasma cell differentiation [103]
(in vitro)
Inhibition of T cell-dependent immunoglobulin production (in vitro and in vivo) [90, 104, 105]
Podocytes Induction of actin filament stability (in vitro and in vivo) [92, 106, 107]
Inhibition of calcium influx TRPC-6-mediated (in vitro) [108]
Protection against mitochondria-dependent apoptosis by inhibiting MAPK signaling [107]
pathway (in vitro)
Antiproliferative agents
T cells Inhibition of proliferation and migration into inflamed tissues (in vitro and in vivo) [109]
No effect on the frequency of total and regulatory T cells (in vitro and in vivo) [95, 102]
B cells Inhibition of naïve and memory B cell proliferation (in vitro) [90, 109, 110]
Inhibition of plasma cell differentiation (in vitro and in vivo) [90, 95, 105, 109, 110]
No effect on antibody production from plasma cells (in vitro) [110]
Podocytes Reduction of podocyte hypertrophy and apoptosis (in vitro and in vivo) [111]
Rituximab
T cells Indirect modulation of T-cell homeostasis by impairment of B–T cell crosstalk [112, 113]
(hypothesis and in vivo)
Potential direct depletion of CD20+ T cells (in vivo) [114]
Inhibition of Th17 response (in vivo) [115]
Restoration of regulatory T cell number and function (in vivo) [116]
B cells Induction of apoptosis, antibody-dependent cellular cytotoxicity and [117]
complement-mediated cytotoxicity (in vitro and in vivo)
Depletion of all differentiation stages of B cells, excluding lymphoid precursors and [118]
plasma cells (in vivo)
Delay of recovery of memory B cells (in vivo) [51]
Controversial results about the effect on antibody production from plasma cells [118]
 Pediatr Nephrol

Table 1 (continued)

Immunosuppressive treatment Effects References

Podocytes Induction of actin filament stability and reduction of apoptosis by binding and [53]
preventing SMPDL-3b downregulation (in vitro)
inhibition of proteinuria in an animal model of xenotransplantation by binding [54]
SMPDL-3b (in vivo)

NF-kB, Nuclear factor-kappaB; Th cells, T helper cells; VEGF, vascular endothelial growth factor; IL, interleukin; NFAT, nuclear factor of activated T-
cells; TRPC-6, transient receptor potential cation channel, subfamily C, member 6; MAPK, mitogen-activated protein kinase; SMPDL-3b,
sphingomyelin phosphodiesterase acid-like 3B

The two commercially available CNIs cyclosporine A and responses depends, at least in part, on their indirect suppres-
tacrolimus bind a cytoplasmic receptor and inhibit the cell sive effect on Th cells [90, 104, 105]. Conversely, MPA in-
phosphatase calcineurin. This prevents the dephosphorylation hibits both naïve and memory B cell proliferation and reduces
of nuclear factor of activated T-cells (NFAT) family members immunoglobulin production by inhibiting plasma cell differ-
and their nuclear translocation, resulting in the downregula- entiation, but this drug is ineffective in suppressing antibody
tion of genes encoding for cytokines and cytokine receptors production by differentiated plasma cells [90, 95, 105, 110,
[95]. Similar to the effect observed for glucocorticoids, it has 120]. As previously discussed, rituximab treatment impacts
recently been demonstrated that tacrolimus is also able to in- primarily on all differentiation stages of B lymphocytes, ex-
hibit the phosphorylation and subsequent nuclear transloca- cluding precursors and plasma cells which do not express
tion of NF-kB [99, 100]. Therefore, CNIs suppress T- CD20 [118], by inducing apoptosis, antibody-mediated cellu-
lymphocyte activation and proliferation by inhibiting cytokine lar cytotoxicity and complement-mediated cytotoxicity [117].
production [99, 101]. In addition to the above described effects on immune
Nonselective inhibitors of enzymes involved in purine syn- cells, immunosuppressive treatment can also directly act
thesis, such as AZA and mycophenolic acid (MPA), a specific on podocytes (reviewed in [92]). Dexamethasone increases
inhibitor of inosine-50-monophosphate dehydrogenase of actin filament stability by increasing the activity of the
which MMF is a pro-drug, reduce de novo guanosine nucle- actin-regulating RhoA GTPase, inhibits podocyte apoptosis
otide synthesis. This action has a cytostatic effect on prolifer- by restoring the PI3K/Akt pathway and downregulates vas-
ating T cells and results in decreased recruitment of T cells into cular endothelial growth factor and IL-6 cytokine produc-
sites of inflammation by reduced expression of adhesion mol- tion by podocyte cell lines [64, 93, 94]. Similar to cortico-
ecules [109, 120]. steroids, cyclophosphamide preserves the architecture of
Tregs are also affected by immunosuppressive treatments: podocytes in a murine model of lupus nephritis [98]. CNIs
steroid therapy can induce tolerogenic dendritic cells and are able to stabilize the actin cytoskeleton and to protect
myeloid-derived suppressor cells, both of which promote against mitochondria-dependent apoptosis by blocking the
Treg differentiation [87, 88]. MMF does not modify the levels calcineurin-mediated dephosphorylation of synaptopodin,
of circulating Tregs [109], while low-dose cyclophosphamide which is a regulator of RhoA GTPase, and in part by
or CNIs impair Treg levels and function [96, 102]. inhibiting the mitogen-activated protein kinase (MAPK)
Most likely, rituximab can also modulate T-cell homeosta- signaling pathway [106, 107]. In addition, tacrolimus may
sis by impairing the crosstalk between B and T cells or by also exert a protective effect by reducing calcium influx
directly depleting CD20+ T cells [112–114], but the latter hy- mediated by the podocyte cell membrane-associated tran-
pothesis is still being debated [121]. Interestingly, rituximab sient potential cation channel 6 (TRPC-6), whose mutations
can reduce Th17 responses and restores the frequency and have been reported in genetic forms of FSGS [6, 108]. MMF
function of Tregs in other autoimmune disorders [115, 116]. has also recently been described to influence in vitro and
In contrast to T cells, B cells are less sensible to immuno- in vivo podocyte homeostasis; it reduces podocyte hyper-
suppression. Corticosteroids induce apoptosis and inhibit ear- trophy and apoptosis in experimental models of diabetic
ly activation and the proliferation of B cells, but after activa- nephropathy in rats [111]. Surprisingly, rituximab can also
tion and differentiation into antibody-secreting plasma cells, B exert a direct protective effect on the podocyte actin cyto-
cells become resistant to low-dose steroids, whereas high skeleton by binding to and preventing sphingomyelin phos-
doses impair antibody production by modifying cytokine pro- phodiesterase acid like 3B (SMPDL-3b) downregulation
duction by T cells [83, 89–91]. Likewise, CNIs inhibit naïve B [53, 54]. However, as stated above, the efficacy of
cells, but not plasma cell differentiation and surface immuno- ofatumumab, which binds a different epitope of the CD20
globulin expression [103]; their inhibitory effect on antibody molecule, goes against this hypothesis.
Pediatr Nephrol

More recently, mesenchymal stem cell-based therapies 11. Kemper MJ, Wolf G, Muller-Wiefel DE (2001) Transmission of
glomerular permeability factor from a mother to her child. N Engl
have been proposed for the prevention of rejection following
J Med 344(5):386–387
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also for difficult INS, through their immunomodulatory and Resolution of recurrent focal segmental glomerulosclerosis after
paracrine effects (reviewed in [122]). retransplantation. N Engl J Med 366(17):1648–1649
13. Zimmerman SW (1984) Increased urinary protein excretion in the
rat produced by serum from a patient with recurrent focal glomer-
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nonhematopoietic professional antigen-presenting cells. J Am
Despite the wide number of clinical and experimental studies
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Non-genetic forms seem to derive from a complex interplay minuria with renal and cardiovascular disease. Nat Rev Nephrol
between circulating proteins, immune cells and podocytes. 11(11):667–676
Most likely, INS is not a single disease with a unique patho- 16. McDonald JC, Moore DL, Quennec P (1989) Clinical and epide-
miologic features of mumps meningoencephalitis and possible
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