Pathogenesis Of Minimal Change Disease Research Articles

Screening core genes for minimal change disease based on bioinformatics and machine learning approaches.

Based on bioinformatics and machine learning methods, we conducted a study to screen the core genes of minimal change disease (MCD) and further explore its pathogenesis. First, we obtained the chip data sets GSE108113 and GSE200828 from the Gene Expression Comprehensive Database (GEO), which contained MCD information. We then used R software to analyze the gene chip data and performed functional enrichment analysis. Subsequently, we employed Cytoscape to screen the core genes and utilized machine learning algorithms (random forest and LASSO regression) to accurately identify them. To validate and analyze the core genes, we conducted immunohistochemistry (IHC) and gene set enrichment analysis (GSEA). Our results revealed a total of 394 highly expressed differential genes. Enrichment analysis indicated that these genes are primarily involved in T cell differentiation and p13k-akt signaling pathway of immune response. We identified NOTCH1, TP53, GATA3, and TGF-β1 as the core genes. IHC staining demonstrated significant differences in the expression of these four core genes between the normal group and the MCD group. Furthermore, GSEA suggested that their up-regulation may be closely associated with the pathological changes in MCD kidneys, particularly in the glycosaminoglycans signaling pathway. In conclusion, our study highlights NOTCH1, TP53, GATA3, and TGF-β1 as the core genes in MCD and emphasizes the close relationship between glycosaminoglycans and pathogenesis of MCD.

Mechanisms and Clinical Research Progress of Rituximab in the Treatment of Adult Minimal Change Disease

Introduction: Minimal change disease (MCD) is a common subtype of primary nephrotic syndrome in adults. The pathogenesis of MCD is still not well understood, but some studies suggest that MCD is a T cell-mediated disease related to podocyte dysfunction. Previous research has also indicated the crucial role of B cells in the pathogenesis of MCD. Rituximab (RTX) is a recombinant chimeric mouse/human antibody targeting CD20 antigen. In recent years, RTX has been increasingly used in adult MCD patients. Methodology: We searched the PubMed database using the keywords “Minimal change disease”, “Nephrotic syndrome”, and “Rituximab” and obtained a total of 140 articles. We will now provide a literature review based on these 140 articles, according to our research topic. Discussion: This article provides an overview of the mechanisms and clinical research progress of RTX in the treatment of adult MCD. We have also discussed the current treatment methods for MCD, exploring the potential of using RTX as a first-line therapy for refractory adult MCD. Conclusion: MCD is a common pathological type of nephrotic syndrome, and the exact mechanisms are still not fully understood. Although RTX as a treatment of adult MCD has shown promising clinical results in patients with refractory adult MCD, the safety and efficacy of RTX still lack high-quality clinical evidence. Further research is needed to explore the pathogenesis of MCD and the RTX treatment for MCD.

β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease

IntroductionActivation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. MethodsWe used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. ResultsLPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. ConclusionsPodocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury.

β1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease

IntroductionActivation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte β1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. MethodsWe used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific β1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. ResultsLPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a β1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, β1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. ConclusionsPodocyte β1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury.

New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid.

Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system’s role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.

POS-363 TREATMENT WITH RECOMBINANT MUTATED HUMAN ANGIOPOIETIN-LIKE 4 AMELIORATES RELAPSE OF PRIMARY GLOMERULAR DISEASES INDUCED BY A COMMON COLD

In nearly 70% of patients with primary glomerular diseases like Minimal Change Disease (MCD) and Focal and Segmental Glomerulosclerosis (FSGS), relapse is preceded by a common cold. In addition, most patients with MCD have a chronic atopic state. Recent studies from our group (Mace et al Kidney International 2020) showed the importance of low podocyte ZHX2 expression in the pathogenesis of MCD and FSGS. At least half of all Common Colds are caused by Rhinovirus infections. Using different components innate and adaptive immunity, the circulating Rhinovirus A and B receptor, and a marker of chronic atopy, we developed and tested a Rhinovirus cytokine storm cocktail in Zhx2 deficient BALB/cJ mice.

Increased number and activation of peripheral basophils in adult-onset minimal change disease.

Nowadays, the pathogenesis of minimal change disease (MCD) is still not well‐known, and the current understanding on MCD is mainly based on data derived from children, and very few adults. Here, we comprehensively analysed the correlation between the changes of peripheral basophils and the incidence rate and relapse of adult‐onset MCD. The results showed that in patients at the onset of MCD, the ratio and activation of basophils were all higher than those of healthy controls (all P < .05). In vitro test results showed that basophils from healthy controls can be activated by the serum taken from patients with MCD. Among 62 patients at the onset of MCD, with complete remission after treatment and 1 year of follow‐up, the relative and absolute basophil counts before treatment were higher in the long‐term remission group (n = 33) than that of the relapse group (n = 29). The basophil counts were significantly higher in the infrequent relapse group (n = 13) than that of the frequent relapse group (n = 16; P < .05). These findings suggested that basophil may play a pathogenic role in adult‐onset MCD, and the increased number and activation of peripheral basophils could predict recurrence in adult MCD.

P0338CRUMBS HOMOLOG2-EZRIN SIGNALING INDUCED PODOCYTE INJURY, LEADING TO MINIMAL-CHANGE DISEASE(MCD) AND FOCAL SEGMENTAL GLOMERULOSCLEROSIS(FSGS)

Abstract Background and Aims The etiology and cellular pathogenesis of podocyte injury leading to minimal-change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remain largely obscure. Genetic mutation of crumbs homolog 2 (CRB2) is a cause of congenital nephrotic syndrome. Type-1 transmembrane proteins including CRB2 transduce outside-in signals that are involved in various cellular events including changes in the cytoskeletal network. The aim of the present study is to determine whether alteration of CRB2-mediated signaling in podocytes causes MCD and FSGS. Method Mice were immunized with a partial recombinant protein including the extracellular part of mouse CRB2. Urinalysis was obtained, and the kidney was subjected to histopathology. Kidney samples were also subjected to immunofluorescence microscopy and glomerular isolation to determine whether activation of the ezrin/radixin/moesin (ERM) family of cross-linkers between plasma membrane proteins and the actin cytoskeleton is involved in the pathogenesis of this nephrotic model. A CRB2-expressing mouse podocyte cell line was generated and incubated with anti-CRB2 antibody, and cell lysates were subjected to immunoblot analysis of ERM phosphorylation. The presence of anti-CRB2 antibody in the serum was determined by Western blot analysis. Results Apparent anti-CRB2 antibody was detected in the serum from 4 weeks onward. Immunized mice developed proteinuria at 4 weeks, which continued at least until 29 weeks. Mice developing extremely heavy proteinuria also developed hematuria from 18 weeks onward. Light microscopy revealed MCD in mice with proteinuria alone and FSGS in mice with heavy proteinuria and hematuria. Immunofluorescence microscopy revealed positive granular IgG staining in podocyte foot processes, but not complement C3. Electron microscopy and immuno-electron microscopy revealed alteration of actin organization associated with prominent foot process effacement. Strong phosphorylation of ezrin was observed in the glomerulus from the proteinuric stage and in the cellular lysates from the CRB2-expressing podocyte cell line incubated with anti-CRB2 antibody. Conclusion The current data revealed that binding of anti-CRB2 antibody to the extracellular domain of CRB2 on the podocyte foot process activated the ezrin-cytoskeleton network, leading to podocyte injury. Our data also indicated that signaling by this one molecular can induce two different phenotypes of glomerular injury: MCD and FSGS. In our model, the signaling was activated by anti-CRB2 antibody, but in patients with nephrotic syndrome the CRB2 ligands remain unknown. Therefore, it will be important to identify the soluble factors interacting with CRB2, which may be novel factors contributing to the pathogenesis of MCD and FSGS.

IL-13-driven alterations in hepatic cholesterol handling contributes to hypercholesterolemia in a rat model of minimal change disease.

Circulating factors have been implicated in the pathogenesis of minimal change disease (MCD), and may have direct effects on cholesterol metabolism. This study investigated the pathogenesis of hypercholesterolemia in an IL-13 overexpression rat model of MCD prior to the onset of proteinuria, so as to establish the direct contribution of IL-13, especially with regard to hepatic cholesterol handling. In this model of MCD, the temporal relationship between hypercholesterolemia and proteinuria was first identified. Plasma proprotein convertase subtilisin/kexin type 9 (Pcsk9) and liver ATP-binding cassette sub-family G member 5 (Abcg5) were measured using ELISA. Liver Ldlr and liver X receptor alpha (Lxra) were quantified with Western blot. Abcg5-mediated cholesterol efflux in IL-13-stimulated rat primary hepatocytes was measured using taurocholate as cholesterol acceptor. The role of Lxra was validated using a luciferase assay in Lxre-luciferase-transfected IL-13-stimulated hepatocytes. IL-13-transfected rats developed hypercholesterolemia prior to proteinuria, with 35% of rats hypercholesterolemic but only 11% proteinuric by Day 20 (P = 0.04). These pre-proteinuric hypercholesterolemic rats showed elevations in total and LDL-cholesterol, but not hypertriglyceridemia or hepatic steatosis. The hypercholesterolemia was associated with increased hepatic Pcsk9 synthesis and enhanced circulating Pcsk9 levels, which correlated strongly with plasma total cholesterol (r = 0.73, P<0.001). The hypercholesterolemia was also contributed by decreased Abcg5 expression and activity, due to reduced Lxra expression. Lxra expression correlated with plasma total cholesterol levels (r = -0.52, P = 0.01), and overexpression of pLxra in rat hepatocytes abrogated the IL-13-mediated down-regulation of Lxre-driven gene expression. In conclusion, we have shown that IL-13 induced changes in hepatic cholesterol handling in a cytokine-induced rat model of MCD, resulting in hypercholesterolemia which can precede the onset of proteinuria.

C1q modulates acute glial progenitor response after spinal cord injury

T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD-1)+ Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD-1+ Tfh cells and their functional effects in adult patients with minimal change disease (MCD). The frequencies of circulating PD-1+, PD-1+CD154+, and PD-1+interleukin (IL)-21+ Tfh cells, and CD38+CD19+ and CD38+CD19+CD40+ B cells, as well as serum IL-2, IL-4, IL-17A, IL-6, IL-21, and interferon (IFN)-γ were significantly increased in the MCD patients compared with the healthy controls (HCs) (P < 0.05). However, no significant difference was found in PD-1+BCL-6+ or PD-1+ICOS+ Tfh cells. Furthermore, the percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were negatively correlated with the estimated glomerular filtration rate (eGFR), but positively correlated with the 24-h urinary protein concentration and serum IL-21 level. The percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were positively correlated with the percentages of CD38+ plasma cells and active CD38+CD40+ plasma cells, respectively. After an 8–12-week treatment with prednisolone, the percentages of PD-1+, PD-1+CD154+, and PD-1+IL-21+ Tfh cells as well as the serum level of IL-21 were significantly reduced; in contrast, the serum levels of IL-4 and IL-10 were increased (P < 0.05). We conclude that increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ Tfh cells and may contribute towards the pathogenesis of MCD.

Increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ T follicular helper cells in adult patients with minimal change disease

T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD-1)+ Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD-1+ Tfh cells and their functional effects in adult patients with minimal change disease (MCD). The frequencies of circulating PD-1+, PD-1+CD154+, and PD-1+interleukin (IL)-21+ Tfh cells, and CD38+CD19+ and CD38+CD19+CD40+ B cells, as well as serum IL-2, IL-4, IL-17A, IL-6, IL-21, and interferon (IFN)-γ were significantly increased in the MCD patients compared with the healthy controls (HCs) (P < 0.05). However, no significant difference was found in PD-1+BCL-6+ or PD-1+ICOS+ Tfh cells. Furthermore, the percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were negatively correlated with the estimated glomerular filtration rate (eGFR), but positively correlated with the 24-h urinary protein concentration and serum IL-21 level. The percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were positively correlated with the percentages of CD38+ plasma cells and active CD38+CD40+ plasma cells, respectively. After an 8–12-week treatment with prednisolone, the percentages of PD-1+, PD-1+CD154+, and PD-1+IL-21+ Tfh cells as well as the serum level of IL-21 were significantly reduced; in contrast, the serum levels of IL-4 and IL-10 were increased (P < 0.05). We conclude that increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ Tfh cells and may contribute towards the pathogenesis of MCD.

Chronic Lyme borreliosis associated with minimal change glomerular disease: a case report

BackgroundThere are only few cases of renal pathology induced by Lyme borreliosis in the literature, as this damage is rare and uncommon in humans. This patient is the first case of minimal change glomerular disease associated with chronic Lyme borreliosis.Case presentationA 65-year-old Caucasian woman was admitted for an acute edematous syndrome related to a nephrotic syndrome. Clinical examination revealed violaceous skin lesions of the right calf and the gluteal region that occurred 2 years ago. Serological tests were positive for Lyme borreliosis and skin biopsy revealed lesions of chronic atrophic acrodermatitis. Renal biopsy showed minimal change glomerular disease. The skin lesions and the nephrotic syndrome resolved with a sequential treatment with first ceftriaxone and then corticosteroids.ConclusionWe report here the first case of minimal change disease associated with Lyme borreliosis. The pathogenesis of minimal change disease in the setting of Lyme disease is discussed but the association of Lyme and minimal change disease may imply a synergistic effect of phenotypic and bacterial factors. Regression of proteinuria after a sequential treatment with ceftriaxone and corticosteroids seems to strengthen this conceivable association.

Minimal change disease and idiopathic FSGS: manifestations of the same disease.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the key histological findings in patients with idiopathic nephrotic syndrome (INS). Although MCD and idiopathic FSGS are often considered to represent separate entities based on differences in their presenting characteristics, histology and outcomes, little evidence exists for this separation. We propose that MCD and idiopathic FSGS are different manifestations of the same progressive disease. The gradual development of FSGS in patients with non-remitting or relapsing INS has been well documented. Moreover, FSGS is the uniform result of substantial podocyte loss in animal models, and a common feature of virtually all progressive human glomerulopathies. As evidence suggests a common aetiology, the pathogenesis of MCD and idiopathic FSGS should be studied together. In clinical trials, idiopathic FSGS should be considered to represent an advanced stage of disease progression that is less likely to respond to treatment than the earlier stage of disease, which is usually defined as MCD.

Cell biology and genetics of minimal change disease

Minimal change disease (MCD) is an important cause of nephrotic syndrome and is characterized by massive proteinuria and hypoalbuminemia, resulting in edema and hypercholesterolemia. The podocyte plays a key role in filtration and its disruption results in a dramatic loss of function leading to proteinuria. Immunologic disturbance has been suggested in the pathogenesis of MCD. Because of its clinical features, such as recurrent relapse/remission course, steroid response in most patients, and rare familial cases, a genetic defect has been thought to be less likely in MCD. Recent progress in whole-exome sequencing reveals pathogenic mutations in familial cases in steroid-sensitive nephrotic syndrome (SSNS) and sheds light on possible mechanisms and key molecules in podocytes in MCD. On the other hand, in the majority of cases, the existence of circulating permeability factors has been implicated along with T lymphocyte dysfunction. Observations of benefit with rituximab added B cell involvement to the disease. Animal models are unsatisfactory, and the humanized mouse may be a good model that well reflects MCD pathophysiology to investigate suggested “T cell dysfunction” directly related to podocytes in vivo. Several candidate circulating factors and their effects on podocytes have been proposed but are still not sufficient to explain whole mechanisms and clinical features in MCD. Another circulating factor disease is focal segmental glomerulosclerosis (FSGS), and it is not clear if this is a distinct entity, or on the same spectrum, implicating the same circulating factor(s). These patients are mostly steroid resistant and often have a rapid relapse after transplantation. In clinical practice, predicting relapse or disease activity and response to steroids is important and is an area where novel biomarkers can be developed based on our growing knowledge of podocyte signaling pathways. In this review, we discuss recent findings in genetics and podocyte biology in MCD.

New insight in pathogenesis of podocyte disfunction in minimal change disease

Minimal change disease (MCD) is a common pathological type of nephrotic syndrome. Its main histology is the fusion of podocyte foot process. The pathogenesis of MCD is not clear, but previously it was thought to be related to immune mechanism. In recent years more studies show that podocyte injury is the key link in the pathogenesis of MCD. In MCD mouse model and human kidney tissues, the expressions of podocyte slit membrane protein-nephrin and podocin, skeleton protein-synaptopodin are decreased, and the expression of synaptopodin is correlated with the response to hormone therapy. In addition, newest studies focused on another two potocyte associated proteins, CD80 and Angiopoietin-like-4. CD80, a T cell stimulating molecule, is expressed in potocyte. Kappa B gene sequences can be activated by external microbes, antigens through acting potocytes, which can induce the upregulation of CD80 expression, cytoskeletal protein damage and the glomerular filtration rate changes, resulting in proteinuria. Angiopoietin-like-4 can be expressed in normal potocytes, but over-expression of angiopoietin-like-4 may injure the GBM charge barrier and induce the foot process fusion, leading to MCD. However, further studies on the factors inducing CD80 and Angiopoietin-like-4 expression, and the interaction between glomerular basement membrane and the two proteins are needed. Based on the mechanism of MCD, NF-kappa B inhibitors and sialylation therapy would be a novel non-immune therapy for MCD.

Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes.

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. 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". 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. 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.

The roles of urine interleukin-13, CD80, CD28, matrix metalloproteinase-2 and granzyme B in the pathogenesis of childhood minimal change nephrotic syndrome

Objective: Minimal change disease (MCD) is the most common cause of nephrotic syndrome in childhood but its pathogenesis remains poorly understood. A T-cell-derived factor or factors were initially alleged as contributing to the disease pathogenesis. However, podocyte CD80 expression is now a commonly discussed theory. The aim of this study was to investigate the pathogenesis of MCD by determining urine interleukin-13, CD80, CD28, matrix metalloproteinase-2 (MMP-2), and granzyme B levels. Methods: Thirty patients and thirty healthy children were evaluated in this study. Six patients had biopsy proven MCD. The remaining patients were considered to have MCD because of their age at time of diagnosis; response to steroid treatment, absence of gross hematuria, hypocomplementemia or renal failure; and normal blood pressures in the active stage. The nephrotic-phase urine interleukin-13, CD80, CD28, MMP-2, and granzyme B levels of all patients were compared with the remission-stage urine levels of the same patients and control subjects. The urine samples were collected immediately before the application of immunosuppressive drugs or other treatment modalities. Results: Significantly higher interleukin-13, CD80, CD28, and MMP-2 levels were observed in the relapse period compared with both the remission period and control subjects. There was a significant positive correlation between the active-stage urine interleukin-13 and CD80 levels (r=0.619, p

Do Foxp3+Regulatory T Cells (Treg Cells) Play a Role in the Immunopathogenesis of Primary/Idiopathic Minimal Change Disease?

Minimal change disease constitutes a major cause of nephrotic syndrome. It is regarded as a non-immune-complex mediated primary glomerulopathy and pathogenetically is characterised by podocyte injury and effacement of foot processes; therefore, it is also classified as a type of podocytopathy. T cell dysfunction with increased levels of a soluble glomerular permeability factor has been proposed to play a major role in the pathogenesis of minimal change disease. It has been therefore suggested that a dysfunction of regulatory T cells, the orchestrators of immune homeostasis, could be implicated in perpetuating T cell activation in this condition. However, the actual contribution of regulatory T cell dysfunction in the immunopathogenesis of primary minimal change disease is still largely unclear. We here propose a theoretical model based on the available evidence.

Early Posttransplant Nephrotic Range Proteinuria as a Presenting Feature of Minimal Change Disease and Acute T Cell–mediated Rejection

Early-onset nephrotic range proteinuria is an extremely rare presentation of an acute rejection episode. Herein, we have reported a patient who developed nephrotic range proteinuria 7 days after receiving a renal allograft from his sister despite minor changes in serum creatinine levels. A kidney biopsy spcimen revealed a T cell–mediated acute rejection process concomitant with minimal change disease (MCD). Proteinuria and renal dysfunction improved dramatically in response to corticosteroids. The possibility of acute cellular rejection and coexisting MCD should be considered in patients with early posttransplantation nephrosis and normal serum creatinine levels. The coexistence of these entities provides support for the role of T cells in the pathogenesis of MCD.

New Insights Into Human Minimal Change Disease: Lessons From Animal Models

The pathogenesis of minimal change disease (MCD), considered to be the simplest form of nephrotic syndrome, has been one of the major unsolved mysteries in kidney disease. In this review, recent landmark studies that have led to the unraveling of MCD are discussed. A recent study now explains the molecular basis of major clinical and morphologic changes in MCD. Overproduction of angiopoietin-like 4 (ANGPTL4) in podocytes in MCD causes binding of ANGPTL4 to the glomerular basement membrane, development of nephrotic-range selective proteinuria, diffuse effacement of foot processes, and loss of glomerular basement membrane charge, but is not associated with changes shown by light microscopy in the glomerular and tubulointerstitial compartments. At least some of this ability of ANGPTL4 to induce proteinuria is linked to a deficiency of sialic acid residues because oral supplementation with sialic acid precursor N-acetyl-d-mannosamine improves sialylation of podocyte-secreted ANGPTL4 and significantly decreases proteinuria. Animal models of MCD, recent advances in potential biomarkers, and studies of upstream factors that may initiate glomerular changes also are discussed. In summary, recent progress in understanding MCD is likely to influence the diagnosis and treatment of MCD in the near future.