Recurrence of Anti-semaphorin-3B Mediated Membranous Nephropathy after Kidney Transplantation

2022 ◽  
pp. ASN.2021101323
Author(s):  
Marc Fila ◽  
Hanna Debiec ◽  
Hélène Perrochia ◽  
Nabila Djouadi ◽  
Verpont Marie-Christine ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Autoimmune Disease ◽  
Western Blot ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Pediatric Patients ◽  
Early Recurrence ◽  
Minimal Change ◽  
First Case ◽  
Nephrotic Range Proteinuria

Background: 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 membranous nephropathy associated with Semaphorin 3B in 9 children and 2 adults. Methods: 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. Results: 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 antiSemaphorin 3B antibodies. Recurrence of MN occurred 25 days after transplantation and manifested as nephrotic range proteinuria despite conventional immunosuppressive therapy. Kidney biopsies confirmed histological MN recurrence with colocalization of Semaphorin 3B antigen and IgG (1). The patient was treated with rituximab. Anti-Semaphorin 3B antibodies, which were detected at transplantation, were not detected 40 days after rituximab. Conclusion: This case provides evidence that anti-Semaphorin 3B antibodies are pathogenic and should be monitored in patients with membranous nephropathy.

scholarly journals Development and Validation of a Discrimination Model Between Primary PLA2R-Negative Membranous Nephropathy and Minimal Change Disease Confirmed by Renal Biopsy

2020 ◽  
Author(s):  
Feng Wu ◽  
Yiding Zhang ◽  
Wen Cui ◽  
Yijun Dong ◽  
Yingyang Geng ◽  
...  
Keyword(s):  
Renal Biopsy ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Multivariate Logistic Regression Analysis ◽  
Test Group ◽  
Minimal Change ◽  
Clinical Feature ◽  
Specific Marker ◽  
Discrimination Model ◽  
Phospholipase A2 Receptor

Abstract BackgroundMembranous nephropathy (MN) and minimal change disease (MCD) are two common causes leading to nephrotic syndrome (NS). They have similar clinical feature but different treatment strategy and prognosis. M-type phospholipase A2 receptor (PLA2R) is considered as a specific marker of membranous nephropathy. However, its sensitivity is only about 70%. Therefore, there is a lack of effective and noninvasive tools to distinguish PLA2R-negative MN and MCD patients without renal biopsy. We aim to develop a discrimination model using noninvasive parameters for distinguishing the two diseases and support immediate treatment before result of renal biopsy.MethodsA total 949 patients who were pathologically diagnosed as idiopathic MN or primary MCD in the First Affiliated Hospital of Zhengzhou University from January 2017 to August 2019 were enrolled in this study, including 805 idiopathic MN (605 PLAR2-positive MN and 200 PLA2R-negative MN) and 144 primary MCD. Based on the basic information and laboratory examination of 200 PLA2R-negative MN and 144 MCD, we used univariate and multivariate logistic regression analysis to select the relevant variables and develop the discrimination model. ROC curves and calibration curves were used to evaluate the diagnostic ability and calibration ability of the model. The decision curve was used to show the net benefit. We also tested the effectiveness of our model in all 949 patients.ResultsA novel model that included age, albumin, urea, high density lipoprotein, urea and red blood cell count was established for PLA2R-negative MN and MCD. The discrimination model has good differential capability (an AUC of 0.889 in training group and an AUC of 0.920 in test group) and calibration capability. When testing in all 949 patients, our model also showed good discrimination ability for all idiopathic MN and MCD.ConclusionWe constructed a discrimination model with high diagnostic effectiveness for PLA2R-negative MN and MCD. The model could also be used for all idiopathic MN and MCD patients.

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

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Ichiro Hada
Keyword(s):  
Electron Microscopy ◽  
Nephrotic Syndrome ◽  
Cell Line ◽  
Focal Segmental Glomerulosclerosis ◽  
Minimal Change Disease ◽  
Immunofluorescence Microscopy ◽  
Minimal Change ◽  
Podocyte Injury ◽  
Heavy Proteinuria ◽  
Foot Process

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.

Nephrotic syndrome

2018 ◽  
Author(s):  
William G. Herrington ◽  
Aron Chakera ◽  
Christopher A. O’Callaghan
Keyword(s):  
Nephrotic Syndrome ◽  
Diabetic Nephropathy ◽  
Membranous Nephropathy ◽  
Clinical Syndrome ◽  
Minimal Change ◽  
Renal Amyloidosis ◽  
Creatinine Ratio ◽  
Heavy Proteinuria ◽  
Nephrotic Range Proteinuria ◽  
Secondary Causes

Nephrotic syndrome is a clinical syndrome of heavy proteinuria (greater than 3.5 g per 24 hours), oedema, and hypoalbuminaemia, which is associated with hyperlipidaemia and a procoagulant state. Causes of nephrotic syndrome are traditionally classified by their histopathological descriptions. In most cases, the histological picture can have a primary (idiopathic) or secondary cause. Minimal change, membranous nephropathy, and focal segmental glomerulosclerosis account for over 60% of cases. Diabetic nephropathy and renal amyloidosis are common secondary causes of nephrotic syndrome. Nephrotic-range proteinuria will show up as at least 3+ protein on urinalysis. The diagnosis is confirmed by a urinary protein-to-creatinine ratio over 300 mg/mmol, and hypalbuminaemia. In adults, renal biopsy is the diagnostic test. This chapter addresses the causes, diagnosis, and management of nephrotic syndrome in adults.

scholarly journals Development and validation of a discrimination model between primary PLA2R-negative membranous nephropathy and minimal change disease confirmed by renal biopsy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Feng Wu ◽  
Yiding Zhang ◽  
Wen Cui ◽  
Yijun Dong ◽  
Yingyang Geng ◽  
...  
Keyword(s):  
Renal Biopsy ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Treatment Strategies ◽  
Test Group ◽  
Minimal Change ◽  
Specific Marker ◽  
Discrimination Ability ◽  
Discrimination Model ◽  
Phospholipase A2 Receptor

AbstractMembranous nephropathy (MN) and minimal change disease (MCD) are two common causes leading to nephrotic syndrome (NS). They have similar clinical features but different treatment strategies and prognoses. M-type phospholipase A2 receptor (PLA2R) is considered as a specific marker of membranous nephropathy. However, its sensitivity is only about 70%. Therefore, there is a lack of effective and noninvasive tools to distinguish PLA2R-negative MN and MCD patients without renal biopsy. A total 949 patients who were pathologically diagnosed as idiopathic MN or MCD were enrolled in this study, including 805 idiopathic MN and 144 MCD. Based on the basic information and laboratory examination of 200 PLA2R-negative MN and 144 MCD, we used a univariate and multivariate logistic regression to select the relevant variables and develop a discrimination model. A novel model including age, albumin, urea, high density lipoprotein, C3 levels and red blood cell count was established for PLA2R-negative MN and MCD. The discrimination model has great differential capability (with an AUC of 0.904 in training group and an AUC of 0.886 in test group) and calibration capability. When testing in all 949 patients, our model also showed good discrimination ability for all idiopathic MN and MCD.

Response Predictors to Calcineurin Inhibitors in Patients with Primary Membranous Nephropathy

2018 ◽  
Vol 47 (4) ◽  
pp. 266-274 ◽  
Author(s):  
Xiaofang Yu ◽  
Jieru Cai ◽  
Xiaoyan Jiao ◽  
Shu Zhang ◽  
Hong Liu ◽  
...  
Keyword(s):  
Roc Curve ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Operating Characteristic ◽  
Calcineurin Inhibitors ◽  
Minimal Change ◽  
Ms Analysis ◽  
Response Predictors ◽  
Phospholipase A2 Receptor ◽  
Serum Amyloid A1

Background: Currently, there is an urgent need to find ways of identifying primary membranous nephropathy (PMN) patients who are likely to benefit from calcineurin inhibitors (CNI) or who are resistant to them. In this study, we employed nano-HPLC-MS/MS analysis to identify serum biomarkers that predict the clinical response to CNI therapy in PMN patients. Methods: The endpoint was complete remission (CR) after CNI treatment. PMN patients were grouped into no-remission (NR) or CR groups to screen predictive candidates using the nano-HPLC-MS/MS analysis. Results: Compared with NR patients, 3 upregulated proteins and 5 downregulated proteins were found to present a twofold change in CR patients’ serum. Serum amyloid A1 protein (SAA1) was further validated by ELISA; it was decreased in patients in the NR group compared with patients in the CR group, but SAA1 in patients in these groups was lower than in healthy controls and minimal change disease patients. The area under the receiver operating characteristic (ROC) curve of SAA1 was used to distinguish PMN NR patients from those in remission and was 0.901, with a sensitivity of 78.3% and specificity of 86.8%, similar to that of the phospholipase A2 receptor (PLA2R) antibody. Combining SAA1 with the PLA2R antibody, the area under the ROC curve was 0.956, which was higher than that of SAA1 or the PLA2R antibody alone. Conclusions: Serum SAA1 may be a candidate PMN biomarker that can be used to discriminate CNI NR cases from remission patients. The combination of SAA1 and the PLA2R antibody increases the accuracy of diagnosis.

scholarly journals P0468RENAL OUTCOME AND MORTALITY OF GLOMERULONEPHRITIS IN A THAI TERTIARY CARE CENTER

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Chitimaporn Janphram ◽  
Chagriya Kitiyakara
Keyword(s):  
Multiple Myeloma ◽  
Diabetic Nephropathy ◽  
Lupus Nephritis ◽  
Iga Nephropathy ◽  
Immune Complex ◽  
Membranous Nephropathy ◽  
Minimal Change Disease ◽  
Kidney Biopsy ◽  
Minimal Change ◽  
Different Types

Abstract Background and Aims Glomerulonephritis (GN) is a common cause of End-stage renal disease (ESRD) in Asia and around the world. Most studies from renal registries have focused on the prevalence or clinical characteristics of patients with GN. Only a few registry-based data have focused on mortality and ESRD risks of different types of GN. There is limited data from low to middle income countries or from Southeast Asia. The objectives of this study were to evaluate the mortality and ESRD rates among patients with different types of GN referred for a kidney biopsy at a Thai tertiary care hospital. Method In this retrospective study, the data of patients (n=1,025) referred for a kidney biopsy at Ramathibodi Hospital from 1 January 2011 to 31 December 2017 were reviewed. Patients were classified in to 11 different types of GN. Patient death and cause of death data was obtained from National Census office. ESRD data was obtained from the Thailand Nephrology Society ESRD registry which includes all patients on renal replacement therapies for greater than 3 months. Results Patients with inadequate specimen (n=66) or non-glomerular diseases (n=95) were excluded. Data from 864 patients with GN was analyzed. The age at kidney biopsy was 43.9 ± 16.8 years, median eGFR (CKD-EPI) was 42 (IQR 13-83) mL/min/1.73m2. The male:female ratio was 0.6. The prevalence of GN were: Lupus nephritis (26.8%), IgA nephropathy (18.2%), focal segmental glomerulosclerosis (FSGS 12.6 %), membranous nephropathy (11.9 %), diabetic nephropathy (10.8%), minimal change disease (9.7%), hypertensive nephrosclerosis (4.3%), pauci-immune complex glomerulonephritis (2.3%), membranoproliferative glomerulonephritis (MPGN 1.6%) and multiple myeloma (1.4%) Median time follow up was 42 (IQR 23-62) months. Overall mortality was 13 %. Lupus nephritis accounted for highest proportion of all deaths (25%), followed by diabetic nephropathy (19.1%), FSGS (9%). Listed causes of deaths were: sepsis 22% and chronic kidney disease 8%. Mortality rates by disease were: multiple myeloma (50%), diabetic nephropathy (28.7%), MPGN (21.4%), pauci-immune complex GN (20%), hypertensive nephrosclerosis (15.8%), lupus nephritis (14.6%), membranous nephropathy (8.7%), FSGS (8.2%), minimal change disease (5.8%), IgA nephropathy (4.4%) The incidence of ESRD was 14 %. LN accounted for the highest proportion (29%) of all ESRD, followed by IgA nephropathy (14%), and membranous nephropathy (13%). The rates of ESRD by disease were: multiple myeloma (33.3%), lupus nephritis (15%), membranous nephropathy (14.5%), minimal change disease (14.3%), MPGN (14.2%), IgA nephropathy (10.1%), FSGS (10.1%), diabetic nephropathy (7.4%), pauci-immune complex glomerulonephritis (5%), hypertensive nephroclerosis (2.6%). Conclusion Lupus nephritis is the most common GN and accounted for the highest proportion of all deaths and ESRD in this Thai cohort. IgA nephropathy is the most common primary GN and an important cause of ESRD, but the mortality rate is low compared to other GN. Membranous nephropathy has comparable prevalence to FSGS, but is a more important contributor to ESRD. Diabetic nephropathy has higher rate of mortality than ESRD. Multiple myleloma has the highest rate of both death and ESRD.

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