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Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes 
Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes
  Kazunari Kaneko, Shoji Tsuji, Takahisa Kimata, Tetsuya Kitao, Sohsaku Yamanouchi, Shogo Kato
 [Abstract] [Full Text] [PDF]   Pageviews: 10439 Times
Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes
Kazunari Kaneko, Shoji Tsuji, Takahisa Kimata, Tetsuya Kitao, Sohsaku Yamanouchi, Shogo Kato
Osaka, Japan
Author Affiliations: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan (Kaneko K, Tsuji S, Kimata T, Kitao T, Yamanouchi S, Kato S)
Corresponding Author: Kazunari Kaneko, MD, Professor and Chair, Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka 573-1010, Japan (Tel: +81-72-804-0101 ext. 2560; Fax: +81-72-804-2758; Email: kanekok@hirakata.kmu.ac.jp)
doi: 10.1007/s12519-015-0003-9
Background: Nephrotic syndrome is the most common cause of kidney disease in children, but its pathogenesis remains unclear. This article reviews the novel aspects of the mechanisms underlying massive proteinuria in minimal-change disease, which is the most common form of childhood nephrotic syndrome.
Data sources: This article integrates the findings of a PubMed database search for English language articles published in the past 40 years (from September 1974 to February 2014) using the key words "pathogenesis", "minimal change nephrotic syndrome" or "idiopathic nephrotic syndrome".
Results: Unknown humoral factors associated with T-cell dysfunction have been thought to play an important role in the pathogenesis of minimal-change disease. However, recent findings are changing this paradigm, i.e., visceral glomerular epithelial cells (podocytes) may be involved via expression of molecules such as CD80 and angiopoietin-like 4.
Conclusions: Recent evidence suggests that minimal-change disease results from interactions between humoral factors and dysfunctional podocytes. In addition to immunosuppressant drugs that target lymphocytes, a biological agent such as an antibody against the abnormal molecule(s) expressed by podocytes may provide novel drug treatment for minimal-change disease.
                                                                                                          World J Pediatr 2015;11(1):21-28
Key words: angiopoietin-like 4;
                   minimal change nephrotic syndrome;
Nephrotic syndrome (NS) is characterized by heavy proteinuria (urine protein:creatinine ratio ≡2000 mg/g or ≡300 mg/dL, or 3+ protein on urine dipstick), hypoalbuminemia (≒2.5 g/dL), and edema.[1] Leakage of massive amounts of serum proteins into the urine leads to a hypercoagulable state, a higher rate of infectious disease, and the dysregulation of fluid balance. However, 80%-90% of children with NS achieve complete remission after glucocorticoid (GC) therapy. The annual incidence of NS is estimated to be 2-7 per 100 000 children, with a cumulative prevalence of 16 per 100 000 children.[2,3]
Childhood NS is classified into three groups: idiopathic (INS, 90% of cases), secondary (10%), and congenital (<1%). INS is further classified into the two major histological variants: minimal-change disease (MCD, 85%) and focal segmental glomerulosclerosis (FSGS, 10%). It is still debatable whether MCD and FSGS represent different ends of the same disease spectrum with the same underlying pathophysiological processes, or whether they are two distinct disease entities.[4,5] Secondary NS is defined as NS associated with a systemic disease, such as lupus nephritis, Henoch-Schönlein purpura nephritis, or Alport syndrome. Congenital NS is defined as heavy proteinuria starting before the age of 3 months, and may be associated with congenital infections (such as syphilis, toxoplasmosis, or cytomegalovirus) or with mutations of the genes coding for podocyte proteins (such as NPHS1, NPHS2, and WT1).[6]
MCD, which is almost equivalent to steroid-sensitive INS, accounts for the vast majority of cases of childhood NS, but its pathogenesis remains unknown. In this review, we discuss recent research findings and the paradigm shift regarding the likely pathogenesis of MCD (including steroid-sensitive INS).
Old paradigm for the pathogenesis of MCD
In 1974, Shalhoub[7] proposed that MCD was a disorder of T-cell function resulting in increased plasma levels of lymphocyte-derived permeability factor. This hypothesis was based on the absence of immune complexes in glomeruli, the rapid response to steroid therapy, the association of MCD with Hodgkin's disease, and the observation that measles infection often induced remission of MCD. The massive proteinuria and hypoalbuminemia that characterize MCD were thought to result from increased permeability of the glomerular capillary wall due to T-cell activation triggered by stimuli such as viral infection or allergens.[3] The most compelling evidence came from experience with renal allografts: NS disappeared when MCD kidneys were transplanted into patients without NS.[8] The following clinical findings further support the concept that vascular permeability factors produced from activated T-cells play an important role in MCD: in patients with MCD, there is a risk of recurrence of the disease when transplanted;[9] placental transfer of proinflammatory cytokines from a mother to a newborn results in neonatal NS;[10] the potential of apheresis monotherapy to induce and maintain complete remission of MCD suggests that circulating factors play an important role in the pathogenesis of MCD.[11]
Role of cytokines in the pathogenesis of MCD
Since Koyama et al[12] found that injection of supernatants from T-cell hybridomas from patients with MCD relapse into rats caused immediate proteinuria and glomerular podocyte foot process fusion, researchers have tried to identify the circulating factors released from T-cells that increase the glomerular permeability to serum proteins. Cytokines were considered to be the most likely pathogenic factors. Cytokines are small proteins (molecular weight 8-80 kDa) that function as soluble mediators in an autocrine or paracrine manner, which are produced by both immune and non-immune cells. Patients with MCD relapse were found to have increased levels of various cytokines in the serum or urine including interleukin (IL)-2,[13] soluble IL-2 receptor,[13-16] interferon-gamma,[13,17] IL-4,[17,18] IL-12,[19] IL-18,[20] tumor necrosis factor (TNF)-汐,[21] and vascular endothelial growth factor (VEGF).[22] Isolation of peripheral blood mononuclear cells (PBMCs) from patients with MCD relapse and measurement of the in vitro mitogen-stimulated production of cytokines in the cultured cell supernatants demonstrated increased production of various cytokines including IL-1,[23] IL-2,[17,24] IL-4,[17,18] IL-10,[24] IL-12,[25] IL-18,[20] and TNF-汐.[26] Yap et al[27] also reported increased expression of IL-13 mRNA in patients with MCD relapse. However, few studies have investigated the direct effects of specific cytokines on the development of proteinuria. VEGF is known to increase capillary permeability by stimulating the release of nitric oxide and thereby inducing endothelial cell fenestration, but VEGF infusion does not induce proteinuria in rats.[28,29] Other cytokines that may be involved in the pathogenesis of MCD include IL-13 and TNF-汐. IL-13-transfected rats develop nephrotic proteinuria and display an MCD-like phenotype.[30] However, proteinuria does not occur in many pathological conditions that are associated with increased levels of IL-13 such as asthma, psoriasis, and allergic dermatitis. Infusion of TNF-汐 has been reported to result in increased urinary albumin excretion in rats.[29] Furthermore, Raveh et al[31] reported remission of MCD after treatment with infliximab, a chimeric TNF-汐 monoclonal antibody, in a 13-year-old boy with MCD that was refractory to the standard treatment protocols. However, there is controversy over the relationship between increased production of TNF-汐 and capillary permeability,[32] and infliximab therapy carries a risk of inducing proteinuria secondary to membranous nephropathy.[33]
Role of T-cells in the pathogenesis of MCD
The aberrant T-cells in MCD are thought to be T helper (Th) type 2 cells,[34-37] because MCD is often associated with atopy and allergy,[38-40] which are caused by Th2 immunologic responses. The increased serum immunoglobulin (Ig) E level and preservation of IgG4 observed in MCD are also characteristic of a Th2 response.[41-43] However, some observations do not support this hypothesis.[24,44] Our study of Th cell subsets in children with MCD using 3-color flow cytometry found no significant differences in the proportions of Th cell subsets [such as Th0 (naive T-cells), Th1, or Th2 CD4+ cells] or the Th1/Th2 ratio among patients with relapse of NS, patients with remission of NS, and normal controls.[45] It has therefore not been definitively established that MCD is a Th2-dependent disorder.
There are clinical reports of MCD remission after depletion of B-cells using monoclonal antibodies or the anti-CD20 drug rituximab (RTX).[46-48] These reports suggest that there are not any underlying T-cell disorders in MCD. Furthermore, the increased nitric oxide production by B-cells exclusively found in the relapse phase of MCD further supports the possibility of B-cell involvement.[49] These findings indicate that T-cells may not play a central role in the pathogenesis of MCD.
Limitations to the hypotheses focusing on lymphocyte-derived permeability factors
As described above, studies of alterations in cytokine production in MCD reported variable results. The differences may have resulted from the different immunogenetic characteristics of the patients, or the heterogeneity of the stimulated cells in non-physiological environments. Lack of documentation of biopsy findings, inclusion of steroid-treated patients, and differences in methodology among studies makes it difficult to determine the factors associated with glomerular permeability. Furthermore, the complex interactions among cytokines make it very difficult to determine which cytokine is increased first.
New paradigm for the pathogenesis of MCD
A new paradigm for the pathogenesis of MCD has emerged since the discovery by Kestila et al[50] in 1998 that mutations in the gene NPHS1, which encodes the podocyte-expressed immunoglobulin superfamily protein nephrin, cause congenital NS in humans. This landmark study led to a substantial increase in our understanding of glomerular biology and physiology. Additionally, the development of proteinuria in lipopolysaccharide (LPS)-injected severe combined immunodeficient mice, which are devoid of T- and B-cells, suggests that this mouse model of MCD may be independent of T- or B-cells.[51] Based on these findings, visceral glomerular epithelial cells (podocytes) have attracted particular attention as a key player in the pathogenesis of MCD.[52,53]
Podocyte ultrastructure is the final barrier to urinary protein loss
Podocytes are terminally differentiated cells that line the outer aspect of the glomerular basement membrane (GBM). Podocytes form the final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes (FPs) and the interposed slit diaphragms (SDs) (Fig. 1).[54] The SDs are the main selectively permeable barrier in the kidney.[55] Podocyte FPs contain a contractile and dynamic apparatus consisting of actin, myosin II, 汐-actinin-4, talin, vinculin, and synaptopodin.[56,57] The FPs are anchored to the GBM via 汐3/汕1-integrin[58] and dystroglycans.[59] Our knowledge of SD structure is based on genetic studies of familial NS, which led to identification of SD proteins such as podocin, nephrin, 汐-actinin-4, and TRPC6. The genes for these proteins may be mutated in inherited NS.[6] In contrast, no mutation has been found in MCD characterized by selective albuminuria associated with FP effacement, where the expression of these proteins is unchanged or downregulated.[60,61] It is easily understandable that various proteins can leak from the impaired SD between podocytes due to reduced nephrin expression in congenital NS of the Finnish type or podocyte detachment in FSGS.[62] However, it remains unclear how albumin can diffuse across the effaced podocyte FP in MCD. The effaced podocyte FPs extensively cover the glomerular capillary wall and podocyte SD density is decreased by 80% at most, with half of the slits displaying a tight-junction-like structure.[63] These structural observations raise questions regarding the route by which albumin passes through the glomerular wall. Tojo et al[62] proposed a receptor-mediated albumin transport mechanism that transports albumin through the podocyte cell body by endocytosis and exocytosis. This mechanism of receptor-mediated transport through podocytes may explain the selective albuminuria observed in MCD.
Hypotheses for the pathogenesis of MCD with a central focus on podocytes
In the last decade, several hypotheses have been proposed that focus on the role of the podocyte in the mechanism underlying the proteinuria in MCD.[53,64-69] Two representative hypotheses are discussed below.
CD80 expression on podocytes as a key player in the induction of proteinuria
CD80, also known as B7.1, is a T-cell costimulatory molecule that is involved in both activation and termination of the T-cell response. Activation of CD80 on antigen-presenting cells and binding to the CD28 receptor on T-cells has a key role in T-cell activation. In contrast, binding of CD80 to cytotoxic T-lymphocyte-associated (CTLA)-4 terminates the T-cell response.[70] CTLA-4 is expressed on the membrane of the Foxp3+ T-regulatory cell (Treg), and Treg may further inhibit the immune response by release of soluble CTLA-4, IL-10, and transforming growth factor-汕 (TGF-汕). CTLA-4 also suppresses CD80 expression on antigen-presenting cells. Experimental results suggest that direct activation of podocytes, independent of T-cell involvement, can induce CD80 expression and proteinuria. Injection of LPS into mice increased CD80 expression on podocytes by binding to toll-like receptor (TLR)-4 in association with the development of proteinuria and FP effacement, and LPS also induced CD80 expression in cultured podocytes, with actin reorganization and shape change.[51] CD80 expression can also be induced by T-cell cytokines such as IL-13,[27] and by polyinosinic-polycytidylic acid.[71] Polyinosinic-polycytidylic acid stimulates TLR3 and is structurally similar to the double-stranded RNA found in some viruses, which may be related to the observation that MCD relapse is frequently preceded by an upper respiratory tract infection.[72] Furthermore, MCD is associated with pronounced expression of CD80 on podocytes, and increased urinary excretion of CD80.[66,67] Shimada et al[53] proposed the "two-hit" podocyte immune disorder underlying MCD. Briefly, the "first hit" is induction of podocyte expression of CD80 in response to a circulating factor (such as a cytokine, allergen, or microbial product). The increased CD80 expression on podocytes results in shape change and proteinuria, although the underlying mechanism is unclear.
The proteinuria induced by LPS injection in mice is only transient,[51] and it is hypothesized that CD80 expression in humans is also usually transient because of autoregulatory mechanisms mediated by the T cells and/or podocytes. The "second hit" is dysfunction of this autoregulatory mechanism, resulting in persistent CD80 expression and proteinuria. CD80 expression is inhibited by both CTLA-4 and IL-10[70,73] resulting in resolution of proteinuria. If dysfunctional Tregs in MCD patients cannot turn off podocyte CD80 expression by secretion of soluble CTLA-4, IL-10, and TGF-汕, proteinuria may persist. However, this mechanism has not been confirmed in humans. Consistent with this hypothesis, the urinary soluble CD80/CTLA-4 ratio was reported to be >100-fold higher in patients with MCD relapse than in patients with remission,[66] and impaired function of Tregs was observed in MCD patients.[74,75] Evidence that abatacept (CTLA-4-immunoglobulin fusion protein) may inhibit the pathogenesis of rheumatoid arthritis at several levels via selective modulation of CD80/CD86 co-stimulatory molecules expressed by a variety of activated cell types also provides direct and indirect support for this hypothesis.[76]
It is currently unknown why children with MCD may have defective Treg or podocyte autoregulatory function, but this may be related to delayed or ineffective maturation of the T-cell response, possibly because of genetic or environmental factors. Further research is required to determine the mechanism by which CD80 signaling alters podocyte function and disrupts the glomerular barrier.
Podocyte expressed angiopoietin-like 4 (Angptl4) as a key player in the induction of proteinuria
Recent studies[52,65,77] found that qualitative and quantitative changes in the expression of Angptl4 in podocytes can induce most of the characteristic features of MCD, including dyslipidemia. Angptl4 is a glycoprotein that shares some structural and functional similarities with angiopoietins, and is expressed in many tissues. Angptl4 inhibits endothelium-bound lipoprotein lipase activity,[78] resulting in increased plasma triglyceride levels. Clement et al[65] reported that glomerular expression of Angptl4 is highly upregulated in the serum and podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range proteinuria (over 500-fold increase in albuminuria), loss of GBM charge, and FP effacement. Angptl4 secreted from podocytes in some forms of NS was also shown to lack normal sialylation. Based on these findings, it has been proposed that podocytes secrete a hyposialylated form of Angptl4 in MCD,[52,65,77] whereas a sialylated form of Angptl4 is secreted by extrarenal organs (mostly skeletal muscle, the heart, and adipose tissue) in response to an elevated plasma ratio of free fatty acids to albumin when proteinuria reaches the nephrotic range.
High serum levels of sialylated Angptl4 were found in MCD as well as other glomerular diseases, and these circulating pools of Angptl4 may reduce proteinuria by interacting with glomerular endothelial 汕5-integrin.[77] Although the precise mechanism underlying the proteinuria caused by podocyte-specific overexpression of Angptl4 is still unclear, the high isoelectric point,[79] positively charged form of Angptl4 may play a key role.[79] Analysis of glomerular protein extracts from the rat model of MCD induced by puromycin aminonucleoside shows that Angptl4 is overproduced in two distinct forms: a positively charged form that migrates at a high pI (8-8.5) and a neutral form that migrates at or just less than a pI of 7. Both high-pI and neutral Angptl4 secreted by podocytes bind to the GBM to alter protein-protein interactions. Progressive accumulation and clustering of Angptl4 in the GBM likely activates signals at the podocyte-GBM interface and induces foot-process effacement, resulting in proteinuria.[52] The relationship between Angptl4 and CD80 has not yet been determined.[52] In a mouse model of MCD, injection with LPS (an activator of TLR4) increased both the expression of Angptl4 in adipose tissue[80] and CD80 on podocytes.[51] It is therefore possible that some pathogenic stimuli such as LPS activate common pathways to induce expression of Angptl4 and CD80 on podocytes.
Podocytes as a novel therapeutic target
Because MCD was historically considered to be a disease of T-cell dysfunction, it was thought that the immunosuppressant drugs used for the treatment of MCD such as GCs, cyclophosphamide, azathioprine, chlorambucil, mycophenolate mofetil, levamisole, cyclosporine A (CsA), tacrolimus, and RTX acted by correcting lymphocyte dysfunction, especially of T-cells. However, it has become clear over the past decade that some of these drugs have direct effects on podocytes, and novel putative modes of action of GCs, CsA, and RTX have been proposed (Fig. 2).[81,82]
Even though 80%-90% of children with MCD achieve complete remission after treatment with GCs, the mechanism by which GCs induce remission is still unknown. As GC receptor expression is ubiquitous, any cell type can theoretically be affected by these drugs. Identification of the podocyte as the key player in MCD resulted in investigation of the effects of GCs on podocytes that may explain their efficacy in MCD. An initial study[83] found that dexamethasone had potent effects on human podocyte structure and function. GCs inhibit the intracellular signaling of nuclear factor 百B (NF-百B) transcription factor, which is known to be important in the podocyte.[84] We also confirmed that podocyte NF-百B has a role in the development of proteinuria in a mouse model of MCD induced by puromycin aminonucleoside. Pretreatment with dehydroxymethylepoxyquinomicin (DHMEQ), which potently inhibits the DNA-binding activity of NF-百B, reduced the proteinuria and reversed the serum abnormalities. Electron microscopic analyses indicated that DHMEQ can inhibit podocyte FP effacement by blocking the translocation of podocyte NF-百B from the cytoplasm to the nucleus.[85]
The calcineurin inhibitor CsA is widely used in the treatment of MCD, especially when there is an insufficient response to GCs. Although it was thought that the efficacy of CsA in MCD was due to the inhibition of intracellular signaling in the activated T cells, Faul et al[86] challenged this by demonstrating its action on podocytes. They reported that CsA acts on podocytes by the calcineurin-dependent dephosphorylation of synaptopodin, which in turn leads to destabilization of the podocyte actin cytoskeleton. The net effect is that CsA can stabilize the actin cytoskeleton in podocytes and thereby reduce proteinuria directly. Using sera collected from patients with FSGS recurrence, Fornoni et al[87] recently demonstrated that RTX, a monoclonal antibody directed against CD20 expressed on B-cells, also recognizes CD20 and binds to sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) on podocytes. They confirmed that RTX prevented proteinuria in nephrotic patients by preserving SMPDL-3b expressed on podocytes and by preventing disruption of the actin cytoskeleton of the podocytes.
The recent findings discussed above suggest that the molecules expressed by podocytes in MCD are therapeutic targets for GCs, CsA, and RTX. Novel therapeutic agents directed against these molecules may support the stabilization and reconstruction of podocytes in MCD. For example, inhibition of CD80 expression on podocytes could be of therapeutic interest in MCD, FSGS, and glomerular diseases. Yu et al[88] recently reported treatment of five patients with biopsy-proven CD80 positive podocytes (four with FSGS recurrence and one with primary FSGS) with abatacept, which is a CTLA-4 agonist and CD80 inhibitor, resulting in sustained remission of NS in all cases. Considering both in vitro and in vivo findings, they suggested that CD80 interferes with the binding of talin to 汕-integrin, thereby preventing 汕-integrin activation.[88] However, other findings may not support this suggestion.[89,90]
Limitations to the hypotheses focusing on podocyte-related molecules
There are several limitations to the hypotheses focusing on podocytes. First, a variety of pathogenic mechanisms contribute to the development of MCD, and there is a growing body of evidence suggesting that pathogenic mechanisms in other cells are also involved, such as alterations in the NF-百B/inhibitory 百B regulatory feedback loop of PBMCs,[91] increased vascular permeability resulting from increased hemopexin production by the liver,[92,93] and increased production of oxygen radicals or nitric oxides by leukocytes.[49,94] It has been suggested that c-maf inducing protein (c-mip) increases in the podocytes in MCD, and that c-mip interferes with podocyte signaling by preventing the interaction of nephrin with the tyrosine kinase Fyn.[69] Second, there is still debate over whether MCD and FSGS represent different ends of the same disease spectrum with the same underlying pathophysiological processes, or whether they are two distinct disease entities.[4,5] There is no clear distinction between steroid-sensitive INS[61] and steroid-resistant INS (FSGS), and findings from studies of each of these conditions are extrapolated to the other condition. Third, importance of the role of CD80 in MCD has been proposed mainly by one group,[53,66-68,71,95,96] and has not been confirmed by other researchers. Finally, the finding that most patients with genetic FSGS did not benefit from CsA[97] suggests that CsA may not have a stabilizing effect. The proposed mechanism of action of RTX on podocytes may also need to be reconsidered in light of the recent suggestion that phagocytes and other inflammatory cells not only remove anti-CD20-opsonized B cells, but also remove autoreactive T-cells that interact with the autoantigen-presenting B-cells.[98]
Historically, MCD was commonly thought to be caused by T-cell dysfunction. However, recent evidence suggests that lymphocytes and podocytes are both involved in the pathogenesis of this condition, and that MCD results from interactions between humoral factors and dysfunctional podocytes. A biological agent such as an antibody against one or more of the molecules expressed by podocytes could provide a novel drug for the treatment of MCD, in addition to immunosuppressant drugs that target lymphocytes.
The study from our institution cited in the text was partly supported by the Mami Mizutani Foundation.
Funding: There was no financial support to prepare the manuscript.
Ethical approval: This article does not include any ethical matters to be approved.
Competing interest: None declared.
Contributors: All authors contributed to the conception and design of the article and the collection of articles to review. Kaneko K performed the literature review, wrote the manuscript, and contributed to revisions of the manuscript for intellectual content. Kaneko K and Kitao T drew the figures. All authors approved the final version of the article.
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                                                        Received March 31, 2014  Accepted after revision July 11, 2014

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