Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former\'s function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, \"atypical\" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).

We present a case of nephrotic syndrome caused by semaphorin 3B-associated membranous nephropathy. The patient was an 8-month-old male infant who presented with severe proteinuria and hypertension. He was treated with prednisolone (PSL) for nephrotic syndrome; however, remission was not achieved within 4 weeks. He was diagnosed with steroid-resistant nephrotic syndrome and underwent kidney biopsy. Pathological examination revealed membranous nephropathy with IgG deposits on both the glomerular basement membrane (GBM) and the tubular basement membrane (TBM). He was treated with cyclosporine (CsA) in addition to PSL and achieved complete remission. However, frequent relapses occurred after the discontinuation or tapering of immunosuppressants. Two years after treatment initiation, a second biopsy was performed and showed worsening of the disease, which required treatment with several immunosuppressants to achieve complete remission. After that, we performed additional immunostaining for semaphorin 3B, which confirmed the diagnosis of semaphorin 3B-associated membranous nephropathy. Although extremely rare in infantile cases, semaphorin 3B-associated membranous nephropathy should be considered in the differential diagnosis, as strong treatment with immunosuppressants might be needed. In addition, mycophenolate mofetil showed an effective clinical response in this case, indicating that it can be considered for future treatment strategies.

When the physiopathology of membranous nephropathy was first described, almost 30% of cases were recognized to be secondary to well-known diseases such as autoimmune diseases, tumors or infections. The remaining 70% cases were called primary membranous nephropathy as the exact mechanism or pathogenic factor involved was unknown. The discovery of the M type phospholipase A2 receptor and thrombospondin type 1 domain containing 7A as causative antigens in these \"so called\" primary membranous nephropathies provided new insights into the effective causes of a large proportion of these cases. Novel techniques such as laser microdissection and tandem mass spectrometry as well as immunochemistry with antibodies directed against novel proteins allowed the confirmation of new involved antigens. Finally, using confocal microscopy to localize these new antigens and immunoglobulin G and Western blot analysis of serum samples, these new antigens were detected on the glomerular membrane, and the related antibodies were detected in serum samples. The same antigens have been recognized in some cases of secondary membranous disease due to autoimmune diseases, tumors and infections. This has allowed examination of the relationship between antigens in primary membranous nephropathy and their presence in some secondary nephropathies. The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases.

Depression is a global health problem, and there is a pressing need for a better understanding of its pathogenesis. Semaphorin 3B (Sema 3B) is an important axon guidance molecule that is primarily expressed in neurons and contributes to synaptic plasticity. Our previous studies using a high-throughput microarray assay suggested that Sema 3B expression was tremendously decreased during the development of depression, but the specific role and mechanisms of Sema 3B in depression are still unknown. Herein, we report that levels of Sema 3B protein are decreased in the hippocampus and serum of chronic mild stress (CMS)-treated mice. Increasing the levels of Sema 3B, either by injecting AAV-Sema 3B into the hippocampus or by injecting recombinant Sema 3B protein into the lateral ventricles, alleviated CMS-induced depression-like behaviours and enhanced the resistance to acute stress by increasing dendritic spine density in hippocampal neurons. In contrast, interfering with the function of Sema 3B by injecting anti-Sema 3B antibody into the lateral ventricles decreased the resistance to acute stress. In vitro, corticosterone (CORT) treatment decreased the survival rate and protein levels of Sema 3B and synapse-associated proteins in HT22 cells. Overexpression of Sema 3B improved the decreased survival rate caused by CORT by inhibiting apoptosis and increasing levels of synaptic-associated proteins, and knockdown of Sema 3B reduces the cellular resistance to CORT and the levels of synapse-associated proteins. These findings represent the first evidence for the neuroprotective mechanism of Sema 3B against stresses, suggesting that Sema 3B could be a promising novel target for the prevention and treatment of depression.

Membranous nephropathy (MN) is rare in pediatric patients, although its diagnosis may be underestimated in children who are responsive to corticosteroid therapy prescribed for a suspicion of minimal change disease. It is most often associated with an autoimmune disease, predominantly lupus. We previously reported the occurrence of early-onset MN associated with semaphorin 3B in nine children and two adults.
Biopsies were performed on native kidney and at 1 and 5 months after transplantation. Semaphorin 3B antigen was detected in immune deposits by immunohistochemistry and confocal microscopy on paraffin-embedded biopsies. Anti-semaphorin antibodies were detected by Western blot and analyzed sequentially.
We report the first case of early recurrence after transplantation in a 7-year-old boy who presented with severe nephrotic syndrome and advanced kidney failure. There was no evidence of hereditary or associated autoimmune disease. Abundant, almost coalescent deposits were seen by electron microscopy and bright granular, subepithelial staining was observed for semaphorin 3B antigen. Western blot analysis of serum revealed anti-semaphorin 3B antibodies. Recurrence of MN occurred 25 days after transplantation and manifested as nephrotic range proteinuria despite conventional immunosuppressive therapy. Kidney biopsies confirmed histologic MN recurrence with colocalization of semaphorin 3B antigen and IgG. The patient was treated with rituximab. Anti-semaphorin 3B antibodies, which were detected at transplantation, were not detected 40 days after rituximab.
This case provides evidence that anti-semaphorin 3B antibodies are pathogenic and should be monitored in patients with MN.

Membranous nephropathy (MN) is defined as disease entity characterized by thickening of the glomerular basement membranes due to subepithelial (SE) deposition of immune complexes. It is typically classified into primary MN (70%) when there is no disease association, and secondary MN (30%) when there is an underlying disease association such as lupus, malignancy, infections or drugs. Phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are target antigens in 70% and 1-5% of primary MN, respectively. The antigens in the remaining MN were not known. Recently, multiple novel proteins/target antigens have been identified in MN. These include exostosin 1/2, neural epidermal growth-like 1 protein, semaphorin 3B, protocadherin 7 and neural cell adhesion molecule 1. Some of these antigens are present in the setting of primary MN, some in secondary MN and some in both, thus blurring the lines between primary and secondary MN. Preliminary studies show that each of the new antigen-associated MN has distinct clinical, kidney biopsy findings and outcome data. We propose that each new protein/antigen-associated MN is a specific disease that results in the common MN pattern of injury characterized by thickened glomerular basement membrane (GBM) with or without spikes or pinholes on light microscopy, granular immunoglobulin G with or without complement 3 on immunofluorescence microscopy and SE electron-dense deposits on electron microscopy. In other words, MN is truly only a pattern of injury resulting from specific diseases that cause deposition of SE immune deposits along the GBM. It is of paramount importance to ascertain the specific disease entity causing the MN pattern not only for precise diagnosis and management, but also for future studies on these newly described diseases.

Semaphorin 3B (SEMA-3B), which belongs to the semaphorin family, has an important role in cell apoptosis and inhibition of angiogenesis. A previous study by our group revealed that SEMA-3B was downregulated in tumor tissues of patients with hepatocellular carcinoma (HCC) and exerts anti-motility and anti-invasion effects on tumor cells. However, the serum levels of SEMA-3B and their clinical significance have remained elusive; therefore, the aim of the present study was to monitor its expression in HCC and investigate its clinical significance. ELISA was used to determine the serum levels of SEMA-3B in 132 patients with HCC and 57 healthy individuals. The association between SEMA-3B and clinicopathological parameters was investigated. Serum SEMA-3B was indicated to be significantly decreased in patients with HCC as compared with that in the controls (P<0.05) and it was negatively associated with tumor size (P=0.039), encapsulation (P=0.002) and TNM stage (P=0.034). The prognosis of patients with low expression of SEMA-3B was poor. In conclusion, the results of the present study revealed that serum SEMA-3B is decreased in HCC and is negatively associated with prognosis; therefore, it may be used as a prognostic marker in HCC.

Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leap combining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four \"new antigens\" were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine.

One of the most frequent complications associated with diabetes mellitus is apoptosis within the brain which can lead to cognitive disorders. Exercise is considered the best non-pharmacological approach to reduce the severity and extent of cell death through poorly-understood mechanisms. The aim of this study was to investigate the effects of voluntary complex and regular wheel running on the levels of 8-oxoguanine DNA glycosylase (OGG1 ), semaphorin 3B (sema3B), hydrogen peroxide (H2 O2 ), and apoptosis in the hippocampus of diabetic rats.
48 Wistar male rats were randomly divided into 6 groups: healthy control (C), diabetes control (D), regular wheel running + diabetes (RWD), complex wheel running + diabetes (CWD), healthy regular wheel running (RW), and healthy complex wheel running (CW). The diabetic rat model was produced by intraperitoneal injection of streptozotocin (STZ). The protocol encompassed a 4-week voluntary running training regimen on regular and complex wheel running apparatus. The rats were sacrificed 48 hr after the last training session. To measure the protein concentrations within the hippocampus, ELISA has been utilized. One-way ANOVA was used to compare the groups.
There were no significant differences in OGG1 protein levels between the groups. H2 O2 level in the D group was significantly higher than the C group (p = .002), while this in RWD and CWD groups was considerably lower than the D group (p = .002 and p = .003, respectively). In the D group, the levels of apoptosis and Sema3B were significantly (p = .001 and p = .007, respectively) higher than C, RWD (p = .001, p = .0001, respectively), and CWD groups (p = .001, p = .006, respectively). Nevertheless, there were not any significant differences between RWD and CWD groups.
The increased levels of Sema3B, H2O2, and apoptosis within the hippocampus associated with diabetes could be noticeably restored by both types of voluntary wheel running protocols.

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.