scholarly journals Modern view on treatment of membranous nephropathy

2020 ◽  
Vol 92 (6) ◽  
pp. 99-104
Author(s):  
Irina N. Bobkova ◽  
Elena S. Kamyshova
Keyword(s):  
Nephrotic Syndrome ◽  
Monoclonal Antibodies ◽  
Membranous Nephropathy ◽  
Antibody Therapy ◽  
Calcineurin Inhibitors ◽  
Individual Choice ◽  
Treatment Protocols ◽  
Phospholipase A2 Receptor ◽  
Anti Cd20 ◽  
Optimal Approach

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Since the moment of animal model creation and the recognition of podocytes damage as a key mechanism of MN development, the identification of antigens, first of all the phospholipase A2 receptor (PLA2R), and the development of methods of PLA2R autoantibodies detection and its monitoring opened a new era in the idiopathic MN (iMN) diagnosis, treatment and prognosis evaluation. MN continues to be actively studied in the new millennium, since a number of aspects of its pathogenesis still need to be clarified, and there is still no clear opinion on the iMN treatment optimal approach. Comprehensive clinical and serological assessment of patients with iMN can be the key to individual choice of treatment protocols. In patients with aPLA2R-positive iMN, the predictor of disease remission is the aPLA2R titer decrease or aPLA2R disappearance in the blood serum, and disease relapse is associated with the aPLA2R appearance ore increase of aPLA2R titer in the circulation. Studies which were conducted by today (GEMRITUX, MENTOR, STARMEN, NICE, etc.) confirmed the acceptable safety profile and effectiveness of iMN therapy by anti-CD20 monoclonal antibodies (rituximab): more than half of of iMN patients had remission of nephrotic syndrome or proteinuria decrease, remissions in anti-CD20 monoclonal antibodies treated patients were longer compared to traditional therapy. The obtained data allows us to consider rituximab and anti-CD20 antibody therapy of a new generation not only as an alternative to the more toxic treatment with cyclophosphane and calcineurin inhibitors, but as an independent promising direction of therapy for patients with IMN, which completely changes the paradigm of treatment of this glomerulopathy.

scholarly journals Lupus Membranous Nephropathy

2021 ◽  
Vol 1 (1) ◽  
pp. 10-20
Author(s):  
Claudio Ponticelli ◽  
Gabriella Moroni ◽  
Alessia Fornoni
Keyword(s):  
Nephrotic Syndrome ◽  
Lupus Nephritis ◽  
Membranous Nephropathy ◽  
Calcineurin Inhibitors ◽  
Vitamin D Supplementation ◽  
Ckd Progression ◽  
Frequent Use ◽  
Phospholipase A2 Receptor ◽  
Life Threatening ◽  
Inflammatory Milieu

Background: Lupus membranous nephropathy (LMN) is a rare disease, usually associated with nephrotic syndrome. Methods: We reviewed the literature by searching for the following terms on Pubmed.gov: lupus nephritis, membranous nephropathy (MN), lupus membranous nephropathy, nephrotic syndrome, and Class V lupus nephritis. Results: The histology of LMN at light microscopy is similar to that of primary MN. Cases of MN associated with focal or diffuse proliferation are not considered LMN by the International Society of Nephrology/Renal Pathology Society classification. Immunofluorescence study of LMN shows deposits of all immunoglobulins and complement. Tubulo-reticular structures, extraglomerular deposits, subepithelial, and scanty subendothelial deposits can be seen on electron microscopy. Phospholipase A2 receptor deposits are usually but not necessarily absent in LMN. The pathogenesis is still not completely understood. The inflammatory milieu of lupus may favor the development of autoantigens and intraglomerular assembly of immune complexes. These are more often associated with mesangial or endocapillary hypercellular lesions. Alternatively, autoantibodies may bind autoantigens in the glomerular subepithelium, triggering a signaling cascade leading to LMN. A central role in the development of podocyte injury and proteinuria is played by the components of complement C5b-C9. CKD progression in LMN is slow but may be accelerated by the frequency of renal flares. Persistent nephrotic syndrome and/or the frequent use of corticosteroids may lead to a series of life-threatening complications. Discussion: Treatment of arterial hypertension, dyslipidemia, and diabetes are of paramount importance. Besides specific therapies of these complications, hydroxychloroquine and vitamin D supplementation are recommended. Immunosuppression should be limited to patients with nephrotic proteinuria. The most frequently used drugs are corticosteroids, calcineurin inhibitors, cyclophosphamide, mycophenolate, and rituximab, alone or combined. Early detection and treatment of renal flares is of paramount importance to prevent CKD progression.

Modern pharmacological approaches to primary treatment nephrotic syndrome

2020 ◽  
Vol 24 (4) ◽  
pp. 9-20
Author(s):  
Ya. F. Zverev ◽  
A. Ya. Rykunova
Keyword(s):  
Nephrotic Syndrome ◽  
Monoclonal Antibodies ◽  
Mycophenolate Mofetil ◽  
Beneficial Effect ◽  
Pharmacological Activity ◽  
Glucocorticoid Receptors ◽  
Calcineurin Inhibitors ◽  
Mechanisms Of Action ◽  
Immune Mechanism ◽  
Immune Mechanisms

The review is devoted to the consideration of the most common drugs currently used in the treatment of primary nephrotic syndrome. Mechanisms of pharmacological activity of glucocorticosteroids, ACTH, calcineurin inhibitors cyclosporine A and tacrolimus, alkylating compounds cyclophosphamide and chlorambucil, mycophenolate mofetil, levamisole, abatacept, rituximab and a number of other recently created monoclonal antibodies. An attempt is made to separate the immune and non-immune mechanisms of action of the most common drugs, concerning both the impact on the immunogenetics of the noted diseases and the direct impact on the podocytes that provide permeability of the glomerular filtration barrier and the development of proteinuria. It is shown that the immune mechanisms of corticosteroids are caused by interaction with glucocorticoid receptors of lymphocytes, and nonimmune – with stimulation of the same receptors in podocytes. It was found that the activation of adrenocorticotropic hormone melanocortin receptors contributes to the beneficial effect of the drug in nephrotic syndrome. It is discussed that the immune mechanism of calcineurin inhibitors is provided by the suppression of tissue and humoral immunity, and the non-immune mechanism is largely due to the preservation of the activity of podocyte proteins such as synaptopodin and cofilin. Evidence is presented to show that the beneficial effect of rituximab in glomerulopathies is related to the interaction of the drug with the protein SMPDL-3b in lymphocytes and podocytes. The mechanisms of action of mycophenolate mofetil, inhibiting the activity of the enzyme inosine 5-monophosphate dehydrogenase, which causes the suppression of the synthesis of guanosine nucleotides in both lymphocytes and glomerular mesangium cells, are considered. It is emphasized that the effect of levamisole in nephrotic syndrome is probably associated with the normalization of the ratio of cytokines produced by various T-helpers, as well as with an increase in the expression and activity of glucocorticoid receptors. The mechanisms of pharmacological activity of a number of monoclonal antibodies, as well as galactose, the beneficial effect of which may be provided by binding to the supposed permeability factor produced by lymphocytes, are considered.

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 Successful foetal outcome in a patient with primary membranous nephropathy and circulating anti-phospholipid antibodies: A case report

2018 ◽  
Keyword(s):  
Nephrotic Syndrome ◽  
Phospholipase A2 ◽  
Membranous Nephropathy ◽  
Membranous Glomerulonephritis ◽  
Antiphospholipid Antibody ◽  
Antiphospholipid Antibody Syndrome ◽  
Phospholipase A2 Receptor ◽  
Foetal Outcome ◽  
Circulating Autoantibodies ◽  
Patient’S History

There is little information about pregnancy outcomes in patients with active membranous nephropathy (MN), especially those with circulating autoantibodies to M-type phospholipase A2 receptor (PLA2R), the major autoantigen in primary MN. Membranous glomerulonephritis (MGN) represents an immunologically mediated disease characterized by deposition of immune complexes in the glomerular subepithelial space, frequently associated with circulating M-type phospholipase A2 receptor. Nephrotic syndrome (massive proteinuria and hypoalbuminemia) at diagnosis predicts poor prognosis. Pregnancy with active MGN is high risk for foetal loss, intrauterine growth restriction, and pre-eclampsia, and may worsen maternal renal function, especially with the presence of antiphospholipid antibody syndrome (APLA). We report a 23-year-old gravida in her first pregnancy, suffering from MGN and severe nephrotic syndrome, complicated by APLA syndrome. The patient was treated with enoxaparin, aspirin azathioprine, and Prednisone for a short time, in addition to furosemide and albumin intravenously. She was delivered at 30 weeks due to deteriorating maternal and foetal conditions. A successful neonatal and maternal outcome was achieved in this case. The patient's history revealed thrombocytopenia and APLA syndrome and continues to be treated chronically with enoxaparin. Kidney biopsy performed after delivery showed membranous MGN stage II-III. Herein, we present a case of successful pregnancy and foetal outcome in a young woman with APLA syndrome and MN. Keywords: Membranous GN, Nephrotic Syndrome, Anti-Phospholipid Antibodies.

scholarly journals Cellular Mechanisms Regulating CD20 As a Target of Monoclonal Antibody Therapy in B-Lymphoid Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3968-3968
Author(s):  
Michal Smida ◽  
Veronika Kozlova ◽  
Viera Vakulova ◽  
Aneta Ledererova ◽  
Michael Doubek ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
Antibody Therapy ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Monoclonal Antibody Therapy ◽  
Cd20 Expression ◽  
B Cell Receptor Signaling ◽  
Anti Cd20 ◽  
Cell Receptor Signaling

Abstract Standard treatment of B-lymphoid malignancies nowadays still relies on the administration of monoclonal antibodies (mAbs), with CD20 antigen being the prime target. Although initially effective, repeated cycles of anti-CD20 monoclonal antibody therapy often result in the loss of CD20 on the surface of malignant B cells and consequently in therapy resistance. In spite of the widespread use of CD20 monoclonal antibodies, the exact mechanisms regulating CD20 expression stay largely unrevealed and it mainly remains unclear whether they can be exploited pharmacologically to modulate expression of CD20 in the clinic. Interestingly, application of CD20 mAbs on various B-cell lines in vitro triggers active CD20 signaling within the cells. This signal transmission results in rapid CD20 downregulation at the surface accompanied by dramatically reduced CD20 transcription. Contrary to the prompt initial downmodulation of CD20 transcription, it takes several days upon mAb removal until CD20 transcriptional gene activity and thereafter CD20 surface levels are restored back to normal. To further study cellular mechanisms responsible for regulating CD20 expression, we have mimicked the situation in patients in an in vitro setting by repeated chronic treatments of diverse B-cell lines with gradually increasing doses of clinically used anti-CD20 monoclonal antibodies Rituximab, Ofatumumab and Obinutuzumab. Thereby, we managed to generate permanently resistant lines that no more respond to additional administration of any of the anti-CD20 mAbs. Notably, these cells have permanently strongly downregulated CD20 expression, both on the cell surface as well as already on the level of mRNA gene transcription. In addition, we have utilized the state-of-the-art CRISPR/Cas9 system to fully knock out CD20 gene in B-cell lymphoma (Ramos) and CLL (MEC1) cell lines. As expected, these cells are totally resistant to CD20 monoclonal antibodies. CD20 was originally proposed to function as a calcium channel and to contribute to B-cell receptor signaling, however the exact function of CD20 remains largely elusive yet. Using both experimental systems, we demonstrate that B cells with the loss of CD20 have fairly normal B-cell receptor signaling with no signs of any large defect. Specifically, activation of major signaling proteins like SYK, AKT, ERK, PLCgamma or p38 upon BCR stimulation was equal in CD20 depleted cells when compared to normal cells. Also calcium flux in response to BCR triggering seems to be normal in CD20-deficient cells, thus suggesting that CD20 is dispensable for proper B-cell receptor signaling. Next, we have performed RNA sequencing on these cells in order to better understand intracellular changes on a more global level that are imposed by the deletion or chronic downmodulation of CD20. We have compared the expression of individual genes and gene sets in cells upon CD20 removal and have performed the differential gene set enrichment analysis that will be presented. In summary, analysis of mechanisms regulating CD20 expression and/or function is critically needed for identification of potential novel drug targets that might be applied in the clinic to control CD20 persistence and thereby improve the outcome of anti-CD20 monoclonal antibody therapy. This research has been financially supported by the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601) and by the research grant AZV-MZ-CR 15-33561AA-4/2015 and grant MUNI/A/1028/2015. Disclosures No relevant conflicts of interest to declare.

scholarly journals An Overview of Molecular Mechanism of Nephrotic Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Juliana Reis Machado ◽  
Laura Penna Rocha ◽  
Precil Diego Miranda de Menezes Neves ◽  
Eliângela de Castro Cobô ◽  
Marcos Vinícius Silva ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Membranous Nephropathy ◽  
Epithelial Mesenchymal Transition ◽  
Membrane Damage ◽  
Membranous Glomerulonephritis ◽  
Basal Membrane ◽  
Experimental Models ◽  
Mesenchymal Transition ◽  
Disease Occurrence ◽  
Phospholipase A2 Receptor

Podocytopathies (minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS)) together with membranous nephropathy are the main causes of nephrotic syndrome. Some changes on the expression of nephrin, podocin, TGF-β, and slit diaphragm components as well as transcription factors and transmembrane proteins have been demonstrated in podocytopathies. Considering the pathogenesis of proteinuria, some elucidations have been directed towards the involvement of epithelial-mesenchymal transition. Moreover, the usefulness of some markers such as TGF-β1, nephrin, synaptopodin, dystroglycans, and malondialdehyde have been determined in the differentiation between MCD and FSGS. Experimental models and human samples indicated an essential role of autoantibodies in membranous glomerulonephritis, kidney damage, and proteinuria events. Megalin and phospholipase-A2-receptor have been described as antigens responsible for the formation of the subepithelial immune complexes and renal disease occurrence. In addition, the complement system seems to play a key role in basal membrane damage and in the development of proteinuria in membranous nephropathy. This paper focuses on the common molecular changes involved in the development of nephrotic proteinuria.

The Prevalence of Mesangial Electron-Dense Deposits in PLA2R-Positive Membranous Nephropathy

Nephron ◽  
2021 ◽  
pp. 1-5
Author(s):  
Gabriel Giannini ◽  
Lois J. Arend
Keyword(s):  
Electron Microscopy ◽  
Nephrotic Syndrome ◽  
Membranous Nephropathy ◽  
Immunofluorescence Microscopy ◽  
Common Cause ◽  
Electron Dense Deposit ◽  
Dense Deposit ◽  
Phospholipase A2 Receptor ◽  
Dense Deposits ◽  
Negative Biopsies

<b><i>Introduction:</i></b> Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults and can be primary or secondary. The antigenic target of antibodies in 70% of primary cases is phospholipase A2 receptor (PLA2R). The presence or absence of mesangial electron-dense deposits has been used to distinguish between primary and secondary MN. Mesangial deposits suggest MN due to lupus, infection, or other causes, though they are reported to occur in approximately 10% of primary MN. Staining for PLA2R is now frequently used for confirming a diagnosis of primary MN. If mesangial deposits predict a secondary cause, they should be more frequent in PLA2R-negative biopsies. <b><i>Methods:</i></b> A review of institutional kidney biopsies between March 2017 and June 2020 identified all cases of MN. Cases with a diagnosis of lupus or near “full-house” staining by immunofluorescence microscopy (IF) were excluded. Light microscopy, IF, and electron microscopy (EM) were performed. PLA2R staining was performed by IF. EM for all cases was reviewed and electron-dense deposit location, distribution, and size were determined. <b><i>Results:</i></b> Ninety-three cases of MN were identified, of which 86 had both PLA2R staining and EM performed. Of these, 51 cases (59%) were positive for PLA2R and 35 (41%) were negative. Mesangial electron-dense deposits were present in 22 (25.6%) of the 86 cases, including 27.5% (14/51) of PLA2R-positive cases and 22.8% (8/35) of PLA2R-negative cases. No difference was seen in size or distribution of deposits, or other features considered suggestive of secondary MN. <b><i>Conclusion:</i></b> PLA2R-negative cases were not more likely to have mesangial deposits than PLA2R-positive cases. Mesangial deposits should not be used as an indicator of secondary MN.

Membranous Nephropathy with Lambda Light Chain Restriction: A Rare Form with Serum Negative and Tissue Positive PLA2R Ab

Nephron ◽  
2021 ◽  
pp. 1-4
Author(s):  
Emel Isiktas Sayilar ◽  
Saba Kiremitci ◽  
Ihsan Ergun ◽  
Arzu Ensari
Keyword(s):  
Nephrotic Syndrome ◽  
Light Chain ◽  
Membranous Nephropathy ◽  
Capillary Wall ◽  
Glomerular Capillary Wall ◽  
Glomerular Capillary ◽  
Phospholipase A2 Receptor ◽  
Antibody Positivity ◽  
Immunoglobulin Deposits ◽  
Light Chain Deposition

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Subepithelial polyclonal immunoglobulin deposits and &#x3e;70% M-type phospholipase A2 receptor antibody positivity are typical findings in idiopathic MN. A 58-year-old female patient was admitted with clinical presentation of nephrotic syndrome. Autoimmune diseases, infections, and malignancies were ruled out after clinical and laboratory evaluations. Diagnostic work-up revealed serum PLA2R antibody negativity and diffuse thickening of glomerular capillary wall on biopsy, while glomerular capillary wall IgG, C3, and Lambda monotypic light chain deposition and PLA2R1 positivity were detected by immunofluorescence and immunohistochemical examination, respectively. Following prednisolone treatment, creatinine and proteinuria were markedly regressed. The MN cases with a light chain deposits are rare and experience regarding their treatment are insufficient.

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