Primary Membranous Glomerulonephritis Research Articles

Immunohistochemical Analysis of Glomerular Phospholipase A2 Receptor in Primary and Secondary Membranous Glomerulonephritis

Background: A common cause of adult nephrotic syndrome (NS) is membranous glomerulonephritis (MGN). The larger portion of MGN in adults is the idiopathic/ primary MGN (iMGN). So many conditions like autoimmunity, malignant tumor, drugs and infections can cause a secondary form of MGN. We can diagnose primary/ idiopathic MGN after the omission of all known secondary causes. As we know M-type phospholipase A2 receptor (PLA2R) on podocytes is the target antigen in the pathogenesis of primary MGN. Phospholipase A2 receptor (PLA2R) can be detected by immunohistochemically. Differences between primary MGN (iMGN) and secondary MGN are essential because of treatment implications. Objective: To evaluate the histopathological pattern of MGN and to correlate with PLA2R deposition in primary and secondary MGN in a group of Bangladeshi people. Methods: The research method is descriptive cross- sectional and observational. The study population was 60 patients in the department of Histopathology, AFIP, Dhaka Cantonment, Dhaka for duration of six months period from January 2019 to June 2019. At first, adequate clinical information was taken and categorized as primary and secondary MGN on a clinical basis, thereafter immuno- histochemistry of anti-PLA2R was done from formalin-fixed paraffin block of those cases. Results: A total of 60 diagnosed cases of MGN, 56 patients were found primary, and 04 were secondary based on clinical data. In my study, all primary MGN was found as PLA2R positive. Conclusion: The present study exhibits that immuno- histochemistry with anti-PLA2R antibodies can be the best diagnostic method for diagnosis of idiopathic MGN which offers an opportunity for personalized medicine. JAFMC Bangladesh, Vol 19, No 2 (December) 2023: 24-28

Soluble Tumor Necrosis Factor Receptor 2: A Promising Predictive Biomarker for Renal Dysfunction in Membranous Glomerulonephritis.

Background and objective Membranous glomerulonephritis (MGN) is a common cause of adult nephrotic syndrome. Tumor necrosis factor-α (TNF-α)is a proinflammatory cytokine that signals by attaching to TNF receptors. TNF-α plays a pivotal role in the development and progression of different forms of glomerulonephritis. Several research findings suggest that TNF-α receptors (TNFR1 and TNFR2) arepredictors of estimated glomerular filtration rate(eGFR) decline. In light of this, this study aimed to explore the relationship between TNFR2 and eGFR, as well as the predictive role of TNFR2 in eGFR decline in MGN. Methods A total of 50 consecutive patients with a diagnosis of primary MGN based on renal biopsies and clinical workups were included in the study. TNFR2 levels in serum, urine, and gene expression were evaluated at baseline and after three months of follow-up by using enzyme-linked immunosorbent assay (ELISA) kits for TNFR2 (KTE60215, Abbkine, Wuhan, China). Cox regression was employed to determine the predictive significance of TNFR2 in persistent eGFR decline. Additionally, an ROC curve analysis was conducted to assess the prognostic value of TNFR2 in predicting persistent eGFR decline among MGN patients. Results Weassessed the levels of inflammatory markers TNF-α and TNFR2, examined their correlation with eGFR and renal injury, and investigated their potential in predicting persistenteGFR. Patients with MGN exhibited elevated levels of TNFR2 in their serum, urine, and gene expression compared to healthy individuals. Additionally, there was a positive correlation between serum TNFR2 and TNF-α, urine protein-creatinine ratio (UPCR), uric acid, and total cholesterol. Conversely, there was a negative correlation with eGFR, serum albumin, and calcium. Serum TNFR2 showed statistical significance in a univariate Cox regression analysis (HR: 1.010, 95% CI: 1.00-1.01, p = 0.045) for predicting a persistent decline in eGFR. However, it did not show significance concerning relapse and remission. An ROC curve was created to assess TNFR2's prognostic potential as a biomarker, demonstrating an AUC of 0.683, with a sensitivity of 68% and specificity of 64%. Conclusions Based on our findings, TNFR2 is a predictive biomarker for eGFR decline in MGN, correlating with renal inflammation and predicting deterioration in renal function. TNFR2 emerges as a promising biomarker for early identification in patients at risk of renal function decline.

A clinical case of primary membranous glomerulonephritis with nephrotic syndrome and resistance to standard treatment

The incidence of primary membranous glomerulonephritis is 1 case per 100,000 each year (75–80 %), with a male-to-female ratio of 2 : 1. It is the cause of idiopathic nephrotic syndrome in more than 20 % of cases (over 40 % in people aged 60 and older). The problem of membranous glomerulonephritis consists in a difficult differential diagnostic search and frequent cases of resistance to treatment. Resistance to treatment may develop in 10–20 % of patients, resulting in the end-stage renal disease requiring renal replacement therapy (dialysis or kidney transplantation). Our work presents the results of clinical observation of a patient with primary membranous glomerulonephritis, nephrotic syndrome and resistance to standard treatment. This patient had a positive dynamics of clinical-laboratory-instrumental indicators and an improvement in the quality of life against the background of taking rituximab.

RETRACTED: Maifata et al. Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis. Biomolecules 2020, 10, 319.

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Autoimmune diagnostics in nephrology and rheumatology

Autoimmune diagnostics plays a central role in the detection of various acute and/or chronic diseases in both nephrology and rheumatology, which are associated with high morbidity and mortality if left untreated or not detected in time. Patients are threatened with significant limitations in everyday skills and quality of life due to loss of kidney function and dialysis, immobilizing and destructive joint processes or also significant damage of organ systems. In all of these autoimmune diseases, early diagnosis and treatment is of central importance for the further course and prognosis of disease.Antibodies play an essential role in the pathogenesis of autoimmune diseases. Antibodies are either directed against organ or tissue-specific antigens, such as in primary membranous glomerulonephritis or Goodpasture's syndrome, or they lead to a systemic disease such as systemic lupus erythematosus (SLE) or rheumatoid arthritis.Knowledge of the sensitivity and specificity of antibodies is crucial for the interpretation of antibody diagnostics results. Antibody detection can precede the clinical onset of the disease, and antibody titers often reflect disease activity. However, there are also false positive results. Detection of antibodies in the absence of disease symptoms often leads to uncertainty and unnecessary further diagnostics. Therefore, an unfounded "antibody screening" is not recommended.A rational antibody diagnostics is an integral part of the diagnostics and during treatment of nephrological and rheumatological diseases like glomerulonephrititis, pulmorenal syndrome, SLE and other collagenosis, thrombotic microangiopathy (HUS/TTP) and rheumatoid arthritis.

Prevalence and Pattern of Glomerulonephritis: An Experience of Two Tertiary Centers in Malaysia.

The prevalence of glomerulonephritis (GN), especially membranous GN (MGN), changes from time to time. This change may be due to genetic predisposition, environmental factors race, age, and indications for a renal biopsy. This study was conducted to evaluate the distribution and changing patterns of GN by further assessing the prevalence of MGN. A 1000, 123 biopsies were performed from January 2012 to October 2019 in Hospital Serdang and Hospital Kuala Lumpur. Electron microscopy, immunohistochemistry, and clinical presentations were used to differentiate primary and secondary MGN, from which 611 and 457 primary and secondary subjects were diagnosed with primary and secondary GN, respectively. Primary MGN accounts for 13% of all the primary GN, while lupus nephritis (LN) accounts for 44.2% of all secondary GN followed by diabetes mellitus (25.6%). The proportions of primary and secondary MGN were 64.8% and 35.2%, respectively, with a male-to-female ratio of 1:1.1 in favor of females. The renal biopsy obtained from the registry of two prominent hospitals in Malaysia provided valuable prevalence and demonstrated changes in the prevalence of GN in Malaysia. Notwithstanding, immunoglobulin A nephropathy and LN remain the most common causes of primary and secondary GN in Malaysia.

Primary Membranous Nephropathy with Crescents

ABSTRACT We present the case of a 46-year-old patient with a history of hypertension, renal biopsy-proven primary membranous nephropathy, and a unique progression. He initially presented with edema and hypertension. Even though he responded initially to immunosuppression, later the clinical picture worsened, prompting the need for a rebiopsy. A second renal biopsy revealed acute crescentic transformation superimposed on primary membranous glomerulonephritis. Immunohistochemistry confirmed Phospholipase A2 Receptor (PLA2R) staining positivity. Following pulse steroid therapy, the patient’s azotemia improved, and creatinine levels stabilized. This case highlights the rare occurrence of acute crescentic transformation in primary membranous nephropathy, emphasizing the challenges and complexities of management.

A Retrospective Investigation of the Factors Associated with Remission in Patients Diagnosed Primary Membranous Glomerulonephritis

A Retrospective Investigation of the Factors Associated with Remission in Patients Diagnosed Primary Membranous Glomerulonephritis

Membranous glomerulonephritis: a retrospective study on prognostic outcome

Background: Membranous glomerulonephritis (MGN) is one of the most common causes of nephrotic syndrome in non-diabetic adults, accounting for up to one-third of biopsy diagnostics in some regions. A watchful waiting strategy has been adopted to accurately assess the success of MGN. In this study, we predict prognostic risk factors for primary MGN patients for effective intervention. Materials and Methods: This is a retrospective study design involving 125 biopsy-proven MGN subjects on follow-up from January 2012 to October 2019 in Hospital Serdang and Hospital Kuala Lumpur, Malaysia. Result and Conclusion: After the median follow-up of 36 (15.0-57.0) in months, 26 (20.8%) consisting of 17 (13.6%) primary MGN and 9 (7.2%) secondary MGN subjects achieved complete remission while 17 (13.6%) and 10 (8.0%) of primary and secondary MGN subjects respectively achieved spontaneous remission. Subjects with nephrotic range proteinuria have 2.917 odds more at risk of primary MGN while subjects with hypertension have 2.417 odds risk of primary MGN compared to those with no hypertension at presentation. Multiple logistic regression models retained only factors directly associated with MGN with only nephrotic range proteinuria associated with primary MGN. Those with nephrotic range proteinuria were 3.04 times the odds of primary MGN when compared with those without nephrotic syndrome (95% C. I = 1.089, 8.472). The nephrotic syndrome could be used to determine the prognosis in patients with primary MGN especially those at risk of end-stage renal disease.

Expression profile of miR-15 and miR-16 in peripheral blood mononuclear cells of patients with steroid-resistant nephrotic syndrome

Introduction: Steroids are considered first-line therapeutic opportunities in cases with idiopathic nephrotic syndrome (INS). The trustworthy biomarkers for steroid-resistant NS (SRNS) would permit more precise decisions in the treatment of INS. Objectives: This study aimed to evaluate the miR-15 and miR-16 levels in NS cases. Patients and Methods: Adult cases with primary NS (n=60) including 30 FSGS (Focal segmental glomerulosclerosis) and 30 membranous glomerulonephritis (MGN) patients and 24 healthy individuals were included. The evaluation of miR-15 and miR-16 expression in blood cells was performed using real-time polymerase chain reaction (qPCR). Moreover, gene ontology analysis and prediction of the miRNA targets were completed to recognize the biological procedures and signaling pathways involved in the pathophysiology of NS. Results: A significant increase was observed in miR-15a-5p expression in cases with primary MGN and FSGS compared with healthy subjects. Conversely, the miR-16-5p expression was significantly decreased in both conditions compared with healthy controls. In the clinical subdivision of FSGS group to steroid-resistant-FSGS and steroid-responsive-FSGS, significant elevated levels of miR-15a-5p and diminished levels of miR-16-5p were observed in both groups compared to normal controls. Gene annotation demonstrated that these miRNAs contribute to cell cycle, ion transport, biological adhesion, cation transport, cellular response to endogenous stimulus, and regulation of small GTPase-related signal transduction. Conclusion: Dysregulated levels of miR-15 and miR-16 may be involved in the pathogenesis and response to steroid therapy in patients with INS.

Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia A successfully managed with rituximab \u2013 case report and review of the literature

BackgroundHepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate.Case presentationWe present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results.ConclusionsPursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

FC 030CONTACTIN-1 IS A NOVEL ANTIGEN IN IDIOPATHIC MEMBRANOUS GLOMERULONEPHRITIS AND IN CIDP- ASSOCIATED GLOMERULONEPHRITIS

Abstract Background and Aims Recently a number of antigens have been identified as pathogenic antibody targets in cases of primary membranous glomerulonephritis(MGN), including phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain containing 7A(THSD7A), and NELL-1, while exostosin is found in secondary (lupus associated) MGN. However, other as yet undiscovered antigens are thought to exist. Although rare, there is a recognised association between chronic inflammatory demyelinating polyneuriopathy (CIDP) and nephrotic syndrome. Method We investigated the link between CICP and MGN and the associations with Contactin-1(CNTN1), a node of Ranvier neuronal protein, as a potential common autoantigen, by immunohistochemistry, RT-PCR and proteomic analysis of isolated glomeruli. We tested sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, for CNTN1 antibodies. Results We describe a series of 16 patients, all presenting with CIDP, nephrotic syndrome due to MGN, and with circulating and deposited anti-contactin-1 (CNTN1) antibodies (IgG4 predominant in those tested) in the kidney. The onset and resolution of both disorders had a close temporal relationship, and the majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Importantly, four (1.4%) further patients with isolated MGN identified from a serum bank of 295 idiopathic MGN patients with no CIDP were also positive for anti-CNTN1 antibodies. CNTN1 protein was detected by mass spectroscopy within glomeruli from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. CNTN1 mRNA was found in renal cortical tissue. Conclusion These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Other factors may explain presentation with isolated neurological disease or MGN.

Primary Membranous Glomerulonephritis in a Young Patient with Proteinuria

Membranous nephropathy is a common form of glomerulonephritis that typically presents with nephrotic syndrome between the 3rd and 5th decades and one-third of patients experience spontaneous remission. Here, a patient with primary membranous nephropathy is presented.

PLA2R Immunohistochemistry Staining in Membranous Glomerulopathy: A Challenging Stain to Interpret But a Potentially Useful Diagnostic Tool.

Circulating autoantibodies to phospholipase A2 receptor (PLA2R-Ab) are detected in >70% of patients with primary membranous glomerulonephritis (MGN). Detection of PLA2R antigen in renal tissue, with immunohistochemistry (PLA2R IHC), strongly correlates with serum PLA2R-Ab, although it is more sensitive. As PLA2R IHC in literature has no univocal interpretation, we suggest reliable criteria for a standard approach for the assessment of immunostaining for differential diagnosis between primary and secondary MGN. We analyzed PLA2R IHC expression in 40 biopsies of patients with MGN and serum PLA2R-Ab titer at the time of biopsy. We carefully evaluated, at high magnification, the immunostaining pattern and distribution, regardless of intensity, in capillary loops, mesangium, and podocytes of all glomeruli.We defined, adopting this approach, positive stain when a granular pattern, coarse and/or fine, diffuse or focal, and global or segmental were observed. Negative stain was defined by mesangial staining, when there was a dirty pattern, or a peripheral staining of capillary loops with a smoky linear pattern. Podocytes showed homogenous cytoplasmatic stain both in positive and negative cases and in external negative controls. We found PLA2R IHC and serum PLA2R-Ab positivity in early-middle stage MGN compared with advanced stage more frequently. Correct stratification of patients with MGN needs PLA2R-Ab detection in serum and renal tissue. PLA2R IHC test, although a challenging stain, can be an easy diagnostic tool but requires reliable interpretation keys for a standard approach to the assessment of immunostaining.

A Rare Case of Primary Membranous Glomerulonephritis in HIV Successfully Treated with Adrenocorticotropin Injection Gel (Acthar)

A Rare Case of Primary Membranous Glomerulonephritis in HIV Successfully Treated with Adrenocorticotropin Injection Gel (Acthar)

Detection of Phospholipase A2 Receptor Related Membranous Nephropathy in Membranous Nephropathy Patient

Background: Membranous glomerulonephritis (MGN) considered as the most common causes ofnephrotic syndrome (NS) in the world. Eighty percent of cases are classified as primary MGN. PrimaryMGN is an autoimmune disease in which autoantibodies against podocyte antigens forming subepithelialimmune deposits and result in NS. Autoantibodies against M-type phospholipase A2 receptor (PLA2R)were found in 70-80% of patients with primary MGN but not in those with secondary MGN or other renaldiseases. So, we aim to identify PLA2R associated primary MGN.Patient and methods: Out of 5000 native biopsies received from 2014-17, 600 were diagnosed as MGN,out of which 62 were stained for anti-PLA2R by immunoperoxidase. Nine cases of Lupus (SLE) Class V,12 of hepatitis C&B Virus MGN (10 HCV+ve and 2 HBV+ve) were used as controls. Positive wasdetermined as diffuse glomerular capillary wall staining.Results: Anti-PLA2R was positive in 61%(38/62) of cases (33 idiopathic cases and 5 cases of the control group3:HCV, 1 HBV, 1 SLE). None of theclinical parameters showed significance difference but nephrotic range proteinuria in the anti-PLA2R +vegroup was more (66% vs 46%). Histologically, onlymesangial matrix expansion was significantlydifferent in the aPLA2R –ve group (33% vs 10%, p=0.04).Conclusion: anti-PLA2R tissue staining is a reliable and specific method to identify primary MGN andshould be done routinely in all MGN cases even those identified as secondary on clinical basis.

Validation of phospholipase A2 receptor direct immunofluorescence staining in the diagnosis of primary membranous glomerulonephritis

Distinguishing between primary and secondary subtypes of membranous glomerulonephritis (MGN) is critical for its clinical management. We prospectively compared direct immunofluorescence (DIF) staining for phospholipase A2 receptor (PLA2R) on frozen renal biopsy with the presence of detectable serum PLA2R antibody assessed by enzyme linked immunosorbent assay (ELISA) in the diagnosis of primary MGN. Forty-six patients with biopsy-proven MGN were enrolled from April 2017 to June 2019 with 31/46 (67.4%) being primary and 15/46 (32.6%) being secondary as determined by comprehensive clinical assessment. This is currently deemed to be the gold standard for distinguishing primary from secondary MGN. Amongst the 31 primary MGN patients, 24/31 were positive on PLA2R DIF staining compared to 18/31 being positive on the PLA2R ELISA (p=0.03). Amongst the 15 secondary MGN patients, 1/15 was positive on PLA2R DIF compared to 0/15 on PLA2R ELISA (p=1.0). In conclusion, the presence of PLA2R staining on DIF demonstrated superior sensitivity and similar specificity compared to the detection of circulating PLA2R antibodies by ELISA in the diagnosis of primary MGN in a cohort of 46 patients with biopsy-proven MGN. We suggest that DIF should be considered as part of routine work-up in all newly diagnosed cases of MGN.

Role of Serum and Urine Biomarkers (PLA2R and THSD7A) in Diagnosis, Monitoring and Prognostication of Primary Membranous Glomerulonephritis.

Differentiating primary and secondary membranous glomerulonephritis (MGN) using biomarkers for MGN is essential in patients’ diagnosis, treatment and follow-up. Although biopsy has been the primary tool in making the diagnosis, not all patients can withstand it due to its invasive nature, and it cannot be used to monitor treatment. Hence, there is the need for less invasive or even non-invasive biomarkers for effective diagnosis, treatment monitoring and prognostication. This study aimed at providing an alternative way of differentiating primary and secondary MGN using enzyme-linked immunosorbent assay (ELISA) technique for serum and urine biomarkers (M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A)) for prompt diagnosis, treatment and prognosis. A total of 125 subjects, including 81 primary and 44 secondary MGN subjects, were diagnosed from January 2012 to October 2019 at Hospital Serdang and Hospital Kuala Lumpur from which 69 subjects consisting of 47 primary and 22 secondary MGN subjects participated in the study. Of these, 13 primary MGN subjects were positive for both serum and urine anti-PLA2R antibodies (Ab) whereas only one secondary MGN subject associated with hepatitis B virus was positive for both serum and urine anti-PLA2R Ab. At the same time, anti-THSD7A Ab was found positive in four primary MGN subjects and two secondary MGN subjects with malignancy.

The serum level of anti-phospholipase A2 receptor antibody does not predict severity of proteinuria in primary membranous glomerulonephritis

Introduction: Anti-phospholipase A2 receptor (anti-PLA2r) antibody is a marker in blood and has been recently reported that it is increased in patients with primary membranous glomerulonephritis (MGN). Objectives: To investigate the role of this receptor in severity of proteinuria in pMGN, we evaluated the relationship between serum levels of this receptor and proteinuria in patients with primary MGN. Patients and Methods: This study was conducted on patients with primary MGN referring to the nephrology clinic in Qazvin province during 2016-2017. Serum level of anti-PLA2r and level of proteinuria before and after medical treatments were measured. anti-PLA2r was measured using the enzyme-linked immunosorbent assay (ELISA) kits. Results: Anti-PLA2r was positive and negative in 42.3% and 57.7% of the patients with primary MGN, respectively. There was no significant relationship between serum level of anti-PLA2r and level of proteinuria before and after the medical treatments. Conclusion: Our data show that anti-PLA2r could not predict the severity of proteinuria in patients with primary MGN.

Primary Membranous Glomerulonephritis: The Role of Serum and Urine Biomarkers in Patient Management.

The detection of phospholipase A2 receptor (PLA2R) and thrombospondin domain containing 7A THSD7A among primary membranous glomerulonephritis (MGN) patients transformed the diagnosis, treatment monitoring, and prognosis. Anti-PLA2R can be detected in 70–90% of primary MGN patients while anti-THSD7A in 2–3% of anti-PLA2R negative primary MGN patients depending on the technique used. Serum and urine samples are less invasive and non-invasive, respectively, and thus can detect the presence of anti-PLA2R and anti-THSD7A with higher sensitivity and specificity, which is significant in patient monitoring and prognosis. It is better than exposing patients to a frequent biopsy, which is an invasive procedure. Different techniques of detection of PLA2R and THSD7A in patients’ urine and sera were reviewed to provide newer and alternative techniques. We proposed the use of biomarkers (PLA2R and THSD7A) in the diagnosis, treatment decision, and follow-up of patients with primary MGN. In addition, other prognostic renal biomarkers like retinol binding protein (RBP) and beta-2 microglobulin were reviewed to detect the progression of renal damage for early intervention.