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Podocytopathies represent a group of glomerular disorders associated with minimal changes (MC) or focal segmental glomerulosclerosis (FSGS) lesion patterns at biopsy and heterogeneous responses to steroids. Anti-nephrin antibodies were previously found in such patients, suggesting an autoimmune form of podocytopathy. High resolution confocal microscopy on kidney biopsies of a cohort of 128 pediatric patients revealed localization of IgG along the slit diaphragm in 30% of patients with MC and 25% of those with FSGS, but not in other lesion patterns. Anti-nephrin IgG ELISA assay in the serum and stimulated emission depletion microscopy of kidney biopsies showed IgG-nephrin co-localization only in 77.8% of cases. Similar observations were obtained in a cohort of 48 adult patients with MC or FSGS at kidney biopsy, where IgG-nephrin colocalization was only 44.4%, suggesting the existence of autoantibodies binding to other slit proteins. Patients with anti-slit antibodies showed nephrotic syndrome at onset in 94.4% of cases. Patients with primary steroid-resistance had anti-slit antibodies in 27%, while those with secondary steroid-resistance in 87.5% of cases, irrespective of the histopathological lesion pattern. Steroid-resistant patients with anti-slit antibodies responded to second-line immunosuppressants in 92.3% vs. only 20% of patients that were anti-slit negative. No patient with anti-slit antibodies developed kidney failure vs. 51.7% of those negative for antibodies (66.7% with a genetic cause and 41.2% with a non-genetic cause). Thus, the detection of anti-slit antibodies can identify patients with an autoimmune podocytopathy responsive to treatment with second-line immunosuppressants, irrespective of the histopathological lesion pattern at biopsy., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear., Methods: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin., Results: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice., Conclusions: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Minimal change disease represents a common cause of nephrotic syndrome in both pediatric and adult patients. Although much remains to be discovered, there have been significant recent advancements in our understanding of the pathophysiology of minimal change disease, including the discovery of antinephrin antibodies as a marker for diagnosis of disease. Here we will review what is known about the pathophysiology, treatment, and prognosis of minimal change disease and the differences between pediatric and adult patients. Recent advances in our understanding of the mechanisms of disease will be noted. We will discuss how this may change the treatment of minimal change disease going forward and what remains to be studied., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The therapeutic efficacy of B-cell depletion by anti-CD20 treatment in pediatric and, more recently, in adult idiopathic nephrotic syndrome patients suggests a key role of B cells in the pathogenesis of the disease. However, their exact role is still unclear. B cells are able to secrete a large variety of antibodies that can protect against infections. However, B-cell dysregulation is well-established in a variety of autoimmune diseases. In parallel with their ability to produce antibodies, pathogenic B cells display altered effector functions by expressing activating surface molecules, which can strongly modify the immune homeostasis, or by producing specific cytokines, which can directly affect either podocyte structure and functions or modulate T-cell homeostasis. Herein, we report the most relevant clinical and experimental evidences of a pathogenic role of B cells in idiopathic nephrotic syndrome. We further highlight similarities and differences between children and adults affected by non-genetic forms of the disease and discuss what needs to be investigated in order to define the exact mechanisms underlying the pathogenic role of B cells and to identify more tailored therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Colucci, Oniszczuk, Vivarelli and Audard.)

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD. NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P<0.001], PMA-stimulated IL-2 [0.03 (0, 1.85)% vs 4.78 (0.90, 9.18)%, P=0.014] and IFNγ [2.22 (0.18, 6.89)% vs 9.47 (2.72, 17.0)%, P=0.035] levels. Lower baseline Treg strongly predicted early relapse (ROC-AUC 0.99, 95% CI 0.97-1.00, P<0.001). There were no differences in baseline plasma cytokine levels. Following rituximab, there was significant downregulation of Th2 cytokines in sustained remission group (P=0.038). In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Renal biopsy is useful to better understand the histological pattern of a lesion (glomerular, tubulointerstitial, and vascular) and the pathogenesis that leads to kidney failure. The potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the kidneys is still undetermined, and a variety of lesions are seen in the kidney tissue of coronavirus disease patients. This review is based on the morphological findings of patients described in case reports and a series of published cases. A search was conducted on MEDLINE and PubMed of case reports and case series of lesions in the presence of non-critical infection by SARS-CoV-2 published until 15/09/2020. We highlight the potential of the virus directly influencing the damage or the innate and adaptive immune response activating cytokine and procoagulant cascades, in addition to the genetic component triggering glomerular diseases, mainly collapsing focal segmental glomerulosclerosis, tubulointerstitial, and even vascular diseases. Kidney lesions caused by SARS-CoV-2 are frequent and have an impact on morbidity and mortality; thus, studies are needed to assess the morphological kidney changes and their mechanisms and may help define their spectrum and immediate or long-term impact.

Minimal change disease (MCD) is a common cause of nephrotic syndrome. Treatment with steroids is usually effective, but frequent relapses are therapeutic challenges. The anti-CD20 antibody rituximab has shown promising results for treatment of steroid-sensitive nephrotic syndrome. Since predictive biomarkers for treatment efficacy and the accurate rituximab dosage for effective induction of remission are unknown, measurement of CD19 + B cells in blood is often used as marker of successful B cell depletion and treatment efficacy. A male patient with relapsing MCD was successfully treated with rituximab, but developed relapse of proteinuria 1 year later, although no B cells were detectable in his blood. B and T cell populations in the patient's blood were analyzed before and after treatment with rituximab using FACS analysis. Rituximab binding to B and T cells were measured using Alexa Fluor 647 conjugated rituximab. We identified a population of CD20 + CD19 - cells in the patient's blood, which consisted mostly of CD20 + CD3 + T cells. Despite the absence of B cells in the blood, the patient was again treated with rituximab. He developed complete remission of proteinuria and depletion of CD20 + T cells. In a control patient with relapsing MCD initial treatment with rituximab led to depletion of both CD20 + B and T cells. Rituximab induces remission of proteinuria in patients with MCD even if circulating B cells are absent. CD20 + T cells may play a role in the pathogenesis of MCD and might be a promising treatment target in patients with MCD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Webendörfer, Reinhard, Stahl, Wiech, Mittrücker, Harendza and Hoxha.)

Background: Tertiary lymphoid organs (TLOs) occur after multiple chronic kidney injuries. interleukin-17A (IL-17A) has been reported to associate with the development of TLOs in inflammatory diseases. However, regulation of the renal TLOs and its clinical significance to the pathogenesis of chronic kidney injury are unknown. Methods: To evaluate the clinical significance and regulation of renal TLOs, we analyzed the progression of patients with kidney damage based on the existence and absence of TLOs in a larger multicenter cohort. We also blocked the recruitment of lymphocyte cells into the kidney by FTY720 (fingolimod) in vivo . Besides, we used aged IL-17A genetic knocked out mice and IL-17A-neutralizing antibody to explore the role of IL-17A in renal TLOs formation. Results : We demonstrated that renal TLOs of IgA nephropathy patients were associated with disease severity and were independent risk factors for renal progression after adjustment for age, sex, mean arterial pressure, proteinuria and, baseline eGFR and MEST-C score, especially in the early stage. Plasma levels of TLO-related chemokines CXCL13, CCL19, and CCL21 were higher in patients with renal TLOs. Inhibiting the formation of renal TLOs by FTY720 could reduce the intrarenal inflammation and fibrosis, and early intervention was found to be more effective. IL-17A was increased in renal TLOs models, and genetic depletion of IL-17A or treatment with anti-IL-17A antibody resulted in a marked reduction of the TLOs formation as well as alleviation of renal inflammation and fibrosis. Conclusion: These results indicate that TLOs are associated with the progression of kidney damage and regulated by IL-17A and may be effective targets for the treatment of kidney damage., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Rituximab (RTX) has been reported to effectively treat minimal change disease (MCD) in adults. However, the efficacy of RTX as maintenance therapy, especially in older patients, remains unclear. This study aimed to evaluate the efficacy of repeat-dose RTX maintenance therapy regardless of age., Methods: We retrospectively reviewed the clinical courses of 13 biopsy-proven adult MCD patients receiving RTX and evaluated the relapse rate, concomitant steroid and immunosuppressant use, relationship between B-cell depletion time and relapse, and adverse events., Results: Mean patient age at start of RTX therapy was 51.5 ± 20.1 years. Each RTX induction consisted of a single 375 mg/m 2 dose. One patient received two RTX doses with a 1-year interval. The remaining 12 patients received RTX at 6-month intervals up to four times after RTX introduction. The median observation period was 28 (16-60) months after RTX induction, median relapse frequency was significantly decreased from 0.83 (0.18-1.92) to 0 (0-0.71) times/year (P < 0.001), and median prednisolone dose was reduced from 25 (5-40) mg to 2.5 (0-10) mg (P < 0.001). CD19-positive B cells remained depleted during RTX administration in 6-month intervals. No serious adverse events were observed after RTX administration., Conclusions: Repeat-dose RTX as maintenance therapy efficiently prevented recurrence and was well tolerated in adult MCD patients including older. This regimen has the potential to maintain prolonged remission. Future studies in larger cohorts are needed to identify the optimal dose and frequency and evaluate the long-term effectiveness and safety of this regimen.

Background: Although many pediatric nephrologists consider focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) as separate clinical entities, whether the initial histology could affect clinical courses in children with steroid-resistant nephrotic syndrome (SRNS) suspected of having an immune-based etiology remains unknown, especially for long-term outcomes., Methods: We retrospectively reviewed long-term outcomes (> 3 years; median follow-up, 9.1 years) of 21 children with initial SRNS (FSGS, N = 9; MCD, N = 12) who achieved complete remission with immunosuppressive agents, including cyclosporine., Results: At NS onset, incidence of acute kidney injury (67% vs. 8%, P < 0.05) and proportion of patients with non-selective proteinuria (56% vs. 0%, P < 0.01) were significantly higher in the FSGS group than the MCD group. Furthermore, median days until complete remission after treatment was significantly longer in the FSGS group than the MCD group (116 days vs. 45 days, P < 0.001). Although subsequent biopsy histology of the 12 patients in the MCD group was still identical in all MCD, three of nine patients in the FSGS group were reclassified from FSGS to MCD at second biopsy. At last visit, all patients maintained complete remission, and none developed chronic kidney disease., Conclusions: Initial presentation in the FSGS group was characterized by more severe clinical manifestations than the MCD group. If complete remission is achieved, FSGS and MCD in children with immune-mediated SRNS may constitute a single disease spectrum because the long-term outcomes are favorable, irrespective of initial histology.

Background: Nivolumab has been associated with immune-related adverse events, including nephritis, with acute interstitial nephritis being the most commonly reported renal manifestation., Case: We describe the first case to our knowledge of minimal change disease with nephrotic syndrome associated with the PD-1 checkpoint inhibitor, Nivolumab. Minimal change disease has been reported with other immune checkpoint inhibitors; however, this is the first reported case with Nivolumab. We report development of nephrotic syndrome with acute kidney injury in a 57-year-old man, 1 month after commencement of Nivolumab for metastatic squamous cell carcinoma of the tongue. Minimal change disease was confirmed by renal biopsy. Management with corticosteroids and cessation of Nivolumab failed to improve kidney function or nephrosis., Conclusion: This case adds to current literature identifying minimal change as an additional complication of immune checkpoint inhibitor-associated acute kidney injury. Given the increasing use of immune checkpoint inhibitors for a range of malignancies, nephrologists, oncologist and generalists should be aware of the spectrum of kidney pathologies associated with their use., (© 2020 Wiley Periodicals LLC.)

Background: The seroprevalence of human Parvovirus B19 (PVB19) is 70-85% in adults worldwide. PVB19 is the etiologic agent of the fifth disease, is a cause of aplastic anemia, and can be associated with kidney injury. We aimed to describe the cases of 4 patients with kidney injury related to PVB19 primary infection, and to evaluate the seroprevalence of PVB19 and the incidence of PVB19 primary infection in patients undergoing a native kidney biopsy., Methods: Cases of PVB19 infection with kidney injury were reviewed from the archives of the department of Nephrology. A systematic screening of anti-PVB19 IgG and IgM antibodies and viral DNA was performed in sera from 100 consecutive patients with a kidney biopsy in 2017-2018., Results: The 4 patients with PVB19 infection-associated kidney disease displayed: one lupus-like glomerulonephritis (GN) without lupus auto-antibodies, one minimal change disease with tubular necrosis, one secondary hemolytic and uremic syndrome and one membrano-proliferative GN. In the 100 patients biopsied, 67 had elevated anti-PVB19 IgG, among whom 8 had elevated IgM, without circulating viral DNA, without any particular renal pathological pattern. One additional patient showed a seroconversion at the time of kidney biopsy, which revealed a class V lupus nephritis., Conclusion: PVB19 primary infection can be associated with different kidney diseases. The seroprevalence of PVB19 among patients with a kidney biopsy is similar to the overall population, and primary infection is rarely documented (1%) after systematic screening. Whether PV19 is nephrotoxic, or triggers renal endothelial injury and immune activation, remains to be elucidated.

Background: Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion., Aim: To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS., Design: A prospective, open-label, randomized clinical trial., Methods: Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10)., Results: After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group., Conclusion: EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Recent reports have described the efficacy of rituximab in treating steroid-dependent nephrotic syndrome (SDNS) in pediatric patients. However, few reports describe data regarding adult-onset SDNS. We investigated the efficacy of rituximab for the management of adult-onset SDNS., Methods: We performed a retrospective cohort study investigating eight patients with adult-onset SDNS who were treated with rituximab. Clinical data were obtained at the initiation of rituximab therapy. The primary outcomes evaluated were successful suppression of relapses and CD19+ cells after rituximab treatment. The corticosteroid- and immunosuppressant-sparing effect and adverse events were additionally evaluated., Results: All eight patients were diagnosed with minimal change nephrotic syndrome and received immunosuppressants in addition to corticosteroid. Total number of relapses was 10.5 times as a median value. Rituximab administration was repeated in two patients, whereas six received single-dose rituximab. Three of eight (37.5%) patients showed relapse after rituximab therapy. A rituximab-induced depletion in CD19+ cells noted initially was followed by their reappearance in all patients. There were cases with no relapse after the reappearance of CD19+ cells. The median relapse time pre- and post-rituximab therapy showed a decrease from 1 time/year (interquartile range [IQR] 1-3 times/year) to 0 time/year (IQR 0-1 time/year). Rituximab treatment induced a significant reduction in the required doses of corticosteroid and cyclosporine (P < 0.01). No serious adverse events were observed., Conclusion: Rituximab treatment was effective not only in childhood-onset but also in adult-onset SDNS. Further studies are needed to establish optimal treatment regimens.

Background/aim: The aim of this study was to investigate the prevalence and significance of antiphospholipid antibodies in patients with membranous nephropathy (MN)., Methods: Patients hospitalized with MN during June 2015 to June 2017 were selected and patients with minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) in the same period were selected as controls., Results: Overall, 267 patients with MN and 131 patients with MCD/FSGS (n = 101 MCD and n = 30 FSGS) were analyzed. There was a significant difference in the detection rate of anti-β2-glycoprotein I (anti-β2-GPI) antibodies (11.9% in MN vs. 4.5% in MCD/FSGS, p = 0.018) and IgG-anti-β2-GPI antibodies (3.7% in MN vs. 0% in MCD/FSGS, p = 0.034) between the 2 groups. Anti-β2-GPI antibody-positive MN patients (n = 32) had a lower serum C4 level than anti-β2-GPI antibody-negative MN patients (n = 235; 21.6 ± 7.6 vs. 24.6 ± 7.1 mg/dL, p = 0.030). Anti-β2-GPI antibody-positive MN patients had significant improvement of serum creatinine compared to anti-β2-GPI antibody-negative patients after 24 weeks of treatment (p = 0.006)., Conclusions: Anti-β2-GPI antibody may play a role in the progression of MN, and this process might involve classic complement activation., (© 2019 S. Karger AG, Basel.)

First-line therapy of minimal change nephrotic syndrome (MCNS) in adults is extrapolated largely from pediatric studies and consists of high-dose oral corticosteroids. We assessed whether a low corticosteroid dose combined with mycophenolate sodium was superior to a standard oral corticosteroid regimen. We enrolled 116 adults with MCNS in an open-label randomized controlled trial involving 32 French centers. Participants randomly assigned to the test group (n=58) received low-dose prednisone (0.5 mg/kg/day, maximum 40 mg/day) plus enteric-coated mycophenolate sodium 720 mg twice daily for 24 weeks; those who did not achieve complete remission after week 8 were eligible for a second-line regimen (increase in the prednisone dose to 1 mg/kg/day with or without Cyclosporine). Participants randomly assigned to the control group (n=58) received conventional high-dose prednisone (1 mg/kg/day, maximum 80 mg/day) for 24 weeks. The primary endpoint of complete remission after four weeks of treatment was ascertained in 109 participants, with no significant difference between the test and control groups. Secondary outcomes, including remission after 8 and 24 weeks of treatment, did not differ between the two groups. During 52 weeks of follow-up, MCNS relapsed in 15 participants (23.1%) who had achieved the primary outcome. Median time to relapse was similar in the test and control groups (7.1 and 5.1 months, respectively), as was the incidence of serious adverse events. Five participants died from hemorrhage (n=2) or septic shock (n=3), including 2 participants in the test group and 3 in the control group. Thus, in adult patients, treatment with low-dose prednisone plus enteric-coated mycophenolate sodium was not superior to a standard high-dose prednisone regimen to induce complete remission of MCNS., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Purpose: The diagnosis of minimal change disease in adults relies mainly on renal biopsy, but this procedure is not without complications. Despite the advancements in technique of percutaneous renal biopsy, biopsy-related complications still occur. Bleeding is one of the major complications, which may lead to hemodynamic instability and, sometimes, even death. Thus, we developed a model to predict MCD for high-risk patients unsuitable for renal biopsy., Methods: We enrolled 142 patients with nephrotic syndrome who received renal biopsy between October 2007 and April 2011 at one tertiary medical center in this study. Demographic, clinical, and prebiopsy laboratory variables were retrospectively recorded and analyzed., Results: The overall prevalence of MCD was 26.8%. Age, hemoglobin levels, 24-hour urine protein, immunoglobulin (Ig) G, and IgE differed significantly between the MCD and non-MCD groups. Logistic regression analysis showed a significant increase in the risk of developing MCD as the number of Ig risk factors, namely, IgG < 450 mg/dl and IgE > 110 mg/dl, increased. Having both risk factors significantly increased the chances of receiving a diagnosis of MCD (by 31.84-fold, P =.007) compared with having neither. Combining the aforementioned clinical model and the 2 Ig risk factors was the best in predicting the diagnosis of MCD, with the area under a receiver-operating characteristic curve of 0.91., Conclusions: Combining clinical model and this 2 Ig risk factors provides physicians simple and valuable clinical markers to diagnose MCD.

Background: Oncologic immunotherapy is a form of therapy intended to reactivate the immune response to tumor cells using agents that modulate immune checkpoints, such as programmed cell death protein 1 and its ligand (PD-1/PD-L), and cytotoxic T-lymphocyte-associated antigen 4. Along with activation of the immune system to tumors, immune-mediated kidney side effects have been reported, most of which are cases of interstitial nephritis. Glomerular disease, however, appears rare., Case Presentation: Herein, we describe a patient with nephrotic syndrome related to treatment with an anti-PD1 antibody for Hodgkin lymphoma. Following the third dose of anti-PD1 antibody, the patient developed massive proteinuria and nephrotic syndrome. Kidney biopsy showed diffuse podocyte foot process effacement upon electron microscopy, which was consistent with minimal change disease. Corticosteroid treatment yielded full and rapid remission of nephrotic syndrome in 1 month., Conclusion: The present case suggests an association between anti-PD1 therapeutic immune activation and the development of nephrotic syndrome. Given the increasing prevalence of oncologic immunotherapy, patients should be routinely monitored for kidney side effects associated with these agents.

Background: Immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN) and minimal-change disease (MCD) are three common types of glomerulonephritis in China. Pathological diagnosis based on renal biopsy is the criterion and the golden standard for diagnosing the sub-types of primary or secondary glomerulonephritis. Immunoglobulin and complements might be used in the differential diagnosis of glomerulonephritis without renal biopsies. However, the relationship between IF intensities of immune proteins and the corresponding serum levels remained unclear, and seldom studies combine histopathological examination results and blood tests together for a predictive purpose. This study was considered as a pilot study for integrating histopathological indicators into serum parameters for exploring the relationship of IF intensity and serum values of immunoglobulin and complement, and for screening and investigating effective indicators inIgAN, MN and MCD., Methods: Renal tissue immunofluorescence (IF) intensity grades and serum levels of immunoglobulin and complements (IgG, IgA, IgM, C3 and C4) were retrospectively analyzed in 236 cases with IgAN, MN or MCD. IF grades were grouped as negative (-), positive (+) or strong positive (++) with both high and low magnification of microscope. Other serum indicators such as urea nitrogen (BUN), creatinine (Crea) and estimated glomerular filtration rate (eGFR) were also evaluated among the groups., Results: There were difference in IgA, IgG and C3 IF intensity grades among IgAN, MN and MCD groups (p = 9.82E-43, 4.60E-39, 7.45E-15, respectively). Serum values of BUN, Crea, eGFR, IgG, IgA, IgM and C4 showed difference in three groups (BUN: p = 0.045, Crea: p = 3.45E-5, eGFR: p = 0.005, IgG: p = 1.68E-14, IgA: p = 9.14E-9, IgM: p = 0.014, C4: p = 0.026). eGFR had the trend to decrease with enhanced IgA IF positive grades (p = 8.99E-4); Crea had trends to decrease with both enhanced IgA and IgG IF intensity grades (p = 2.06E-6, 2.94E-5, respectively). In all subjects, serum IgA levels was inversely correlated with eGFR(r = - 0.216, p = 0.001) and correlated with Crea levels(r = 0.189, p = 0.004); serum IgG and Crea showed no correlation which were discordance with inverse correlation of IgG IF grade and Crea(r = 0.058,p = 0.379). IgG serum level was inverse correlated with its IF grades (p = 3.54E-5, p = 7.08E-6, respectively); C3 serum levels had significantly difference between Neg and positive (+) group (p = 0.0003). IgA serum level was positive correlated with its IF grades (Neg-(+): p = 0.0001; (+)-(++): p = 0.022; Neg-(++): p = 2.01E-10). After matching comparison among C3 groups, C3 Neg. group and C3 ++ group had difference (*p = 0.017). C4 had all negative IF expression in all pathological groups. In IgAN subjects, there were statistical differences of serum C3 levels between its pathological Neg and positive (+) group(p = 0.026), and serum IgA levels showed difference between IgA pathological positive(+) and (++)(p = 0.007). In MN subjects, sIgG levels showed difference between IgG pathological IF grade positive (+) and (++)(p = 0.044); serum C3 levels showed difference between C3 pathological IF grade Neg and positive(+)(p = 0.005); and serum IgA levels showed difference between Neg and positive(+)(p = 0.040). In IgAN, eGFR showed serum IgA levels had significant differences among groups (p = 0.007) and had increasing trend with enhanced its IF grades(P trend  = 0.016). There were also difference between IgG group Neg and positive (+) (p = 0.005, P trend  = 0.007) in IgAN. In MN, serum IgG levels had significant differences among IF groups (p = 0.034) and had decreasing trend with its enhanced IF grades (P trend  = 0.014). Serum C3 concentrations also were found distinctive among IF groups (p = 0.016) and had in inverse correlation with its enhanced IF grades (P trend  = 0.004)., Discussion: Our research cross contrasts several immunoprotein IF intensities and relevant serum levels in three kinds of primary glomerular nephritis, and finally acquired helpful results for understanding the relationships between pathological presentation and serological presentation of immunoproteins in kidney diseases. Furthermore, this pilot study is offering a possible method for the analysis of combination of pathology and serology., Conclusion: Different pathological types of nephritis presented different expression patterns of immunoglobulin and complement, especially IgA and IgG, which suggested different pathogenesis involved in the development of IgAN and MN. Furthermore, either in tissue or in serum, increased IgA level was closely related with renal function in all of the patients.

Introduction: Early diagnosis of minimal change disease (MCD) is challenging in nephrotic children. CD80 is a protein expressed on the surface of podocytes associated with nephrotic syndrome and it is implicated in the induction of proteinuria. This study aimed to investigate the use of urinary CD80 for the diagnosis of MCD., Materials and Methods: Urinary CD80 levels were evaluated in 36 children with nephrotic syndrome and normal glomerular filtration rate. They were divided into three groups of MCD (n = 21), focal segmental glomerulosclerosis (n = 9), and other glomerulopathies (n = 6). The MCD group was subdivided into 2 of those with remission (n = 11) and those in the active stage (n = 10). Forty healthy children were included as controls., Results: The urinary CD80 level was significantly higher in the MCD group (3.5 ± 2.1 ng/mg creatinine) than in the focal segmental glomerulosclerosis group (1.2 ± 0.5 ng/mg creatinine, P < .001), the other glomerulopathies group (1.4 ± 0.7 ng/mg creatinine, P < .001), and the control group (0.7 ± 0.2 ng/mg creatinine, P < .001), while it showed no significant difference among the non-MCD groups. There was no significant difference between MCD in remission and MCD in relapse, either. A urinary CD80 cutoff value of 1.5 ng/gm creatinine showed a sensitivity of 100% and a specificity of 86% for diagnosis of MCD., Conclusions: Urinary CD80 levels were significantly higher in the children with MCD than in the controls and patients with other causes of nephrotic syndrome.

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results., Methods: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed., Results: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05)., Conclusion: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Amelioration of podocyte injury, which can lead to podocyte detachment, is the target of therapeutic intervention in glomerular diseases. Since podocytes are terminally differentiated cells with little or no proliferative ability, their loss results in permanent glomerular dysfunction. In immune-mediated glomerular diseases, a variety of immunomodulatory agents are used to maintain podocytes by systemic immunosuppression, which indirectly ameliorates podocyte injury by interrupting the input of immunological stress. However, in contrast to the indirect therapeutic strategy mediated by immunosuppression, recent data now suggest that immunomodulatory agents directly act on podocytes in an agent-dependent manner. Indeed, the therapeutic efficacy of immunomodulatory agents is, at least in part, derived by the direct action on podocytes. In this review, we discuss the molecular targets and mechanisms by which immunomodulatory agents alleviate podocyte injury and examine their clinical significance., (© 2018 S. Karger AG, Basel.)

Background: Patients with minimal change nephrotic syndrome (MCNS) often also have allergic diseases. Abnormalities of Th2-derived cytokines and T-cell functions contribute to development of these diseases. On the other hand, imbalances between reactive oxygen species (ROS) and antioxidants have been implicated in MCNS and progression of atopic dermatitis. ROS, produced mainly within mitochondria, subject cells to oxidative stress, while prohibitin 2 protects mitochondria by increasing tolerance to ROS. Additionally, podocin, a member of the slit diaphragm protein complex, contains PHB-like domain that serves as a signaling platform regulating podocyte function through associated transmembrane proteins., Patients and Method: Then, we performed exome sequencing analysis in five patients with frequently relapsing their MCNS associated with allergic disease and serum IgE concentrations of 2000 IU/L or higher., Results: We detected a heterozygous prohibitin 2 polymorphism, c.873-3&#95;873-2 delCA (rs111523336), in 1 patient. This mutation in exon 9 caused frameshifts in regions connected to splicing sites, where they could disrupt transcription of prohibitin 2. Frequency of this polymorphism in exon 9 is 7.3% among Japanese. Increase in peripheral blood ROS even MCNS remission state suggests the heterozygous prohibitin 2 variant may contribute to give more susceptibility towards the recurrence of MCNS as well as atopic skin disease. This increase may have progression of atopic dermatitis, which sometimes heralded., Conclusion: The prohibitin-2 polymorphism may reduce ROS tolerance in glomerular epithelium and led to high local exposure to ROS, increasing permeability of the glomerular basement membrane to result in proteinuria. Imbalance between ROS and antioxidants together with failure of signal transduction in the glomerular slit membrane caused by prohibitin 2 abnormality could have contributed to nephrotic syndrome in our patients. Prohibitin 2 analysis is needed in additional MCNS patients with concomitant allergic disease.

We describe a 66-year-old male with immunoglobulin G4-related disease (IgG4-RD) presenting with minimal change disease (MCD). Three years prior to this admission, the patient had been diagnosed with IgG4-RD. The development of sudden massive proteinuria (4+; 16.7 g/gCr) with a weight gain of 8 kg within a two-week period was noted, and nephrotic syndrome was suspected. The patient's serum IgG4 level did not increase and hypocomplementemia was not found. A renal biopsy showed no cellular infiltration in the renal interstitium, and no spiking or bubbling was found on periodic acid methenamine silver staining. On electron microscopy, foot process effacement was seen, but no subepithelial electron-dense deposits were found. The patient was diagnosed with MCD. Ten days after starting prednisolone (60 mg/day), proteinuria was negative. Since IgG4-RD and MCD share a T-helper 2-dominant immunoreaction, the development of MCD in IgG4-RD patients may reflect more than a mere coincidence.

Objective: To examine the expression of phospholipase A2 receptor (PLA2R) in renal tissues and the level of anti-PLA2R antibody in serum in patients with idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (SMN), and to evaluate their diagnostic value in IMN.
 Methods: A total of 73 patients, who were diagnosed between May, 2014 and February, 2015 in the Department of Nephrology of the Second Xiangya Hospital, Central South University, were divided into three groups: an IMN group (n=48), an SMN group (n=17) and a minimal change disease group (n=8) according to the renal biopsy. PLA2R expression in renal tissues and the level of anti-PLA2R antibody in serum were detected by indirect immunofluorescence technique.
 Results: The positive rate and fluorescence intensity for PLA2R in the renal tissues in the IMN group were higher than those in the SMN group (91.7% in the IMN group vs 29.4% in the SMN group, P<0.05), while the positive rate and serum level for anti-PLA2R antibody in the IMN group were higher than those in the SMN group (85.4% in the IMN group vs 29.4% in the SMN group, P<0.05); the expression of PLA2R in renal tissues and the serum level for anti-PLA2R antibody were not detected in the minimal change disease group. The serum level of anti-PLA2R antibody was positively correlated with 24 h urine protein (r=0.432, P<0.01) and negatively correlated with serum albumin (r=-0.307, P<0.05).
 Conclusion: The expression of PLA2R in renal tissues and the serum level of anti-PLA2R antibody might be potential markers for diagnosis of IMN.

Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte., (Copyright © 2016 by the American Society of Nephrology.)

Background: Minimal-change glomerulopathy is defined histologically by the presence of normal glomeruli on light microscopy and diffuse podocyte effacement on electron microscopy. Although effective in children, corticosteroid treatment in adults is more variable and time to response can be prolonged. Data to support rituximab use in adults with corticosteroid-dependent or resistant minimal-change glomerulopathy are limited. Here, we describe the clinical course of adults with corticosteroid-dependent or -resistant minimal-change glomerulopathy who received rituximab., Methods: Demographic and clinical data were collected and analyzed from all adult patients with native kidney, biopsy-proven, minimal-change glomerulopathy who were administered rituximab between 2009 and 2014 and cared for at the UNC Kidney Center., Results: Ten patients with corticosteroid-resistant (n = 5) or corticosteroid-dependent (n = 5) idiopathic minimal-change glomerulopathy were treated with rituximab between 2009 and 2014. Rituximab treatment induced remission in all 10 patients with a median time to remission of 2 months. The median time from rituximab to corticosteroid discontinuation was 3.5 months. The median remission time was 29 months and follow-up time was 39.5 months. No serious adverse events attributable to rituximab were observed., Conclusion: Rituximab induced remission in all patients with corticosteroid-dependent or -resistant minimal-change glomerulopathy, and may hold great therapeutic potential with good efficacy and minimal toxicity. Mounting evidence implies that a well-conducted randomized controlled clinical trial using rituximab in adults with minimal-change glomerulopathy in both corticosteroid-resistant and corticosteroid-dependent patients is warranted., (© 2017 S. Karger AG, Basel.)

Background: Membranoproliferative glomerulonephritis (MPGN type I, II and III) was reclassified in 2013 as MPGN and C3 glomerulopathy (C3G) based on the complement system activation mechanism., Objectives: To evaluate whether C4d, a component of the classical pathway, could be a diagnostic tool in differentiating between MPGN and C3G., Methods: We conducted a retrospective study of 15 MPGN type I, II and III and 13 minimal change disease (MCD) patients diagnosed between 2000 and 2012. C4d staining using the peroxidase method was employed., Results: Using the 2013 C3G consensus classification, the 15 MPGN types I, II and III biopsies were re-classified as MPGN (8) and C3G (7). Following C4d staining, of the 8 biopsies diagnosed as MPGN, 4 had classical pathway involvement [C1q (+), C3 (+), C4d (+)]; two had lectin pathway involvement [C1q (-), C3 (+), C4d (+)]; and, two were reclassified as C3G because the absence of C4d and C1q suggested the presence of the alternative pathway [C1q (-), C3 (+), C4d (-)]. Three of the seven C3G biopsies presented classical pathway involvement and were reclassified as MPGN. The alternative pathway was present in one of the other 4 biopsies considered to be C3G. Two C3G biopsies involved the lectin pathway and the one case of dense deposit disease had lectin pathway involvement., Conclusions: C4d staining may help to differentiate between MPGN and C3G. In addition, the lectin pathway could play a role in the pathogenesis of these glomerulopathies., (Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Myasthenia gravis superimposed with proteinuria is a very rare disorder with only 39 cases reported so far. Of these cases, the most commonly associated disorder is minimal change disease. Myasthenia gravis and minimal change disease are both related to the dysfunction of T lymphocytes and hence the 2 disorders may be connected., Methods: Here we report the first case on a patient diagnosed with myasthenia gravis concurrently with the minimal change disease, and it was presented in the absence of thymoma or thymic hyperplasia., Results: Treatment for myasthenia gravis also lowered proteinuria of minimal change disease. He ever experienced good control for myasthenia gravis and minimal change disease. However, pneumonia related septic shock occurred to him and finally he was dead. Minimal change disease is generally considered to occur subsequent to the onset of myasthenia gravis with causal association. After extensive literature review, we noted only 47.8% minimal change disease had occurred after the onset of myasthenia gravis., Conclusion: Minimal change disease mostly occurs in children and if diagnosed in adults, clinicians should search for a potential cause such as myasthenia gravis and other associated thymic disorders., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: Nephrotic syndrome (NS) is a debilitating renal problem in children resulting from an interaction between environmental and genetic factors including human leukocyte antigen genes (HLA). The aim of this work was to study the probable link between HLA alleles/haplotypes and NS in south India., Methods: HLA DRB1*/DQB1* alleles were genotyped in 183 NS (76 steroid sensitive-SSNS; 107 steroid resistant-SRNS) and paediatric healthy controls (PHCs; n = 91) using polymerase chain reaction-sequence specific primers (PCR-SSP). HLA-A/-B genotyping was performed for patients (n = 70) positive for DRB1*07-DQB1*02 haplotype to identify four locus extended haplotype., Results: The following alleles and haplotypes were strongly associated with NS (P < 0.05 as significant): DRB1*07 (SSNS, P < 7.98 × 10(-6) ; SRNS, P < 0.008), DQB1*02 (SSNS, P < 3.99 × 10(-6) ; SRNS, P < 0.002), DRB1*07-DQB1*02 (SSNS, P < 1.32 × 10(-4) ; SRNS, P < 0.010), DRB1*07-DQB1*0301,0304 (DQ7) (SSNS, P < 0.001) and DRB1*03-DQB1*02 (SRNS, P < 0.048). Protective associations were observed for alleles DRB1*10 (SRNS, P < 0.013), DQB1*05 (SSNS, P < 4.34 × 10(-6) ; SRNS, P < 0.01), DQB1*06 (SSNS, P < 0.003), and haplotypes DRB1*10-DQB1*06 (SSNS, P < 0.046; SRNS, P < 0.032) and DRB1*15-DQB1*05 (SSNS, P < 0.018). HLA-A/-B typing of 70 NS cases with two locus haplotype DRB1*07-DQB1*02 (70/183; 38.25%) revealed the presence of an extended haplotype 'A*03-B*07-DRB1*07-DQB1*02' (n = 35; 50%)., Conclusion: Our study revealed strong susceptible association of DRB1*07 with SRNS and DQB1*02 with SSNS. A gender predominant protective association was observed for DRB1*10 with SRNS females; DQB1*05 with SSNS and SRNS males. Further, the study documented the presence of an extended haplotype and pleiotropic action of DRB1*/DQB1* alleles in immune-mediated aetiology of NS in south India., (© 2015 Asian Pacific Society of Nephrology.)

Minimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (Tregs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct Treg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating Tregs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of Tregs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigen-presenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years., (© 2015 British Society for Immunology.)

Background and Objectives: There has been little published information on risk factors for poor long-term outcome in adult biopsy-proven minimal change disease (MCD)., Methods: Data from sixty-three adult, biopsy-proven primary MCD patients treated at a tertiary university hospital between 2003 and 2013 were analyzed. Baseline clinical and pathologic factors were assessed for the associations with composite outcome of creatinine doubling, end stage renal disease, or all-cause mortality., Results: During a median (interquartile) 5.0 (2.8-5.0) years, the composite outcome occurred in 11.1% (7/63) of patients. The rate of glomerular immune deposits was 23.8% (15/63). Patients with glomerular immune deposits showed a significantly lower urine protein creatinine ratio than those without deposits (P = 0.033). The rate of non-responders was significantly higher in patients with glomerular immune deposits than in those without deposits (P = 0.033). In patients with deposits, 26.7% (4/15) developed the composite outcome, while only 6.3% (3/48) developed the composite outcome among those without deposits (P = 0.049). In multivariate Cox proportional hazards regression analysis, the presence of glomerular immune deposits was the only factor associated with development of the composite outcome (hazard ratio: 2.310, 95% confidence interval: 1.031-98.579, P = 0.047)., Conclusion: Glomerular immune deposits were associated with increased risk of a composite outcome in adult MCD patients. The higher rate of non-responders in patients with deposits might be related to the poor outcome. Future study is needed.

Results of 61 cases of various glomerulopathies with thin glomerular basement membranes are presented. The largest group of 31 cases consisted of mesangial glomerulonephritis. The second largest group consisted of 19 patients with small glomerular lesions described as non-specific. This group stood out in both clinical presentations and in the higher diversity of lesions within the lamina densa of the basement membrane. The results of measurements of the lamina densa in various glomerulopathies were compared to those obtained in control groups consisting of thin basement membrane syndrome and submicroscopic glomerulonephritis.

Background: The treatment of immune suppression dependent minimal change nephropathy (MCN) can be challenging and frequently leads to serious complications. In paediatric patients, successful treatment with rituximab is described in steroid-dependent MCN. There is limited information about the potential efficacy of rituximab for the treatment of MCN in adults and adolescence. We describe our experience with rituximab in adolescent and adult patients with immune suppression dependent MCN., Results: Ten adolescents and adults with immune suppression dependent MCN and therapy related complications were treated with rituximab. At a mean age of 26 years, about 10.5 years after first presentation, they received two doses of rituximab (375 mg/m(2)). Maintenance immunosuppressive medication was stopped. After a mean follow-up of 43 months, three patients had four relapses. Three relapses were successfully retreated with rituximab again, after induction therapy with 60 mg prednisone per day. Rituximab was well tolerated and no infectious complications were recorded., Conclusion: Treatment with rituximab induces a long-term remission of immune suppression dependent MCN in adolescents and adults. A timely treatment with rituximab could be considered to limit side effects of immunosuppressive medication.

Background: The etiology of minimal-change disease is not fully known, it is believed to be mediated by the immune system. Minimal-change disease also reported as having association with atopy. In this study, atopy history, the levels of serum IgE, and skin prick test in children with steroid-sensitive nephrotic syndrome were investigated., Methods: A group of 30 children (mean age 7.7 ± 2.2 years, 56.6% male) diagnosed with steroid-sensitive nephrotic syndrome were included in the study. Serum immunoglobulin E levels and eosinophil counts were evaluated in children with steroid-sensitive nephrotic syndrome both in relapse and remission. Skin prick test was performed in remission., Results: Of the 30 children investigated, 11 (36.7%) had a history of atopy. The median serum total IgE levels in nephrotic children in relapse, with (445 IU/mL) and without atopy (310 IU/mL) were significantly higher than those in remission (respectively, 200 IU/mL, p = 0.021, and 42 IU/mL, p = 0.001). The skin prick tests for all the allergens were evaluated as negative in all the patients., Conclusion: It was thought that increased IgE may reflect the activation of immune mechanism following various stimuli rather than a direct association with atopy in children with steroid-sensitive nephrotic syndrome.

Objective: To study the significance of trace immunoglobulin M (IgM) deposits in glomerular mesangium in children with minimal change primary nephrotic syndrome (PNS)., Methods: One hundred and six children who were clinically diagnosed with PNS and pathologically diagnosed with minimal change disease (MCD) and trace deposition of IgM in renal tissues were enrolled as subjects. Eighty-one PNS children with MCD but no deposition of immune complexes were used as the control group. The clinical characteristics and efficacies of glucocorticoids and immunosuppressants were retrospectively analyzed in the two groups. All patients were given full-dose prednisone by oral administration, and patients with glucocorticoid resistance or frequent relapses were additionally given immunosuppressants., Results: The incidence of glucocorticoid resistance in the IgM deposit group was significantly higher than that in the control group (27.2% vs 12.3%; P<0.05). The incidence of frequent relapses in the IgM deposit group was also significantly higher than that in the control group (48.1% vs 10.4%; P<0.05). The complete remission rate for glucocorticoid-resistant patients treated with prednisone combined with mycophenolate mofetil (MMF) was 68% and 62% respectively in the IgM deposit and control groups (P>0.05). The relapse frequency in patients with frequent relapses was significantly reduced in both groups after treatment with prednisone and MMF in combination (P<0.05)., Conclusions: Trace deposition of IgM in renal tissues may be an important factor for glucocorticoid resistance and frequent relapses in PNS children with MCD. Prednisone combined with MMF may be a better choice in the treatment of patients with glucocorticoid resistance or frequent relapses.

Background: Minimal-change nephrotic syndrome (MCNS) is a common cause of steroid sensitive nephrotic syndrome (NS) with frequent relapse. Although steroids and calcineurin inhibitors (CNIs) are the cornerstone treatments, the use of rituximab (RTX), a monoclonal antibody targeting B cells, is an efficient and safe alternative in childhood., Methods: Because data from adults remain sparse, we conducted a large retrospective and multicentric study that included 41 adults with MCNS and receiving RTX., Results: Complete (NS remission and withdrawal of all immunosuppressants) and partial (NS remission and withdrawal of at least one immunosuppressants) clinical responses were obtained for 25 and 7 patients, respectively (overall response 78%), including 3 patients that only received RTX and had a complete clinical response. After a follow-up time of 39 months (6-71), relapses occurred in 18 responder patients [56%, median time 18 months (3-36)]. Seventeen of these received a second course of RTX and then had a complete (n = 13) or partial (n = 4) clinical response. From multivariate analysis, on-going mycophenolate mofetil (MMF) therapy at the time of RTX was the only predictive factor for RTX failure [HR = 0.07 95% CI (0.01-0.04), P = 0.003]. Interestingly, nine patients were still in remission at 14 months (3-36) after B-cell recovery. No significant early or late adverse event occurred after RTX therapy., Conclusions: RTX is safe and effective in adult patients with MCNS and could be an alternative to steroids or CNIs in patients with a long history of relapsing MCNS., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: C1q nephropathy has been suggested as a separate disease entity. C1q positivity has also been described in association with nephrotic syndrome (NS) as a potential marker for worse outcome. The aims of this study were to describe the clinical characteristics, laboratory parameters and outcomes of 35 children whose renal histology revealed predominant mesangial C1q deposition and to investigate if the experience at our institution supports the above hypothesis., Method: Clinical and pathological characteristics of all children whose kidney biopsies showed positive C1q staining were retrospectively recorded. The outcome of children with minimal change nephrotic syndrome (MCNS) and predominant mesangial C1q deposition based on C1q staining was compared with that of a concurrent group of children with MCNS with no such immune staining., Results: The median age of the patient cohort was 4.5 years (range 6 months to 16 years), 69 % were boys and 88 % presented with nephrotic syndrome (NS). Children with C1q staining and MCNS had more relapses (p = 0.001) and shorter relapse-free periods (p = 0.033) than those with negative immunostaining, but the long-term outcomes were similar in both groups., Conclusion: Our data do not support C1q nephropathy as a separate diagnostic category. Children with MCNS and mesangial C1q deposition (staining) showed more relapses but no difference in long term renal outcome.