Idiopathic 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

A case of thromboembolic events as first manifestation of membranous nephropathy

We present a case of idiopathic membranous glomerulonephritis that presented with venous thromboembolism and was successfully managed with corticosteroid, cyclosporin, appropriate anticoagulant therapy. A 59-year old male patient was referred to our nephrology department who had an outpatient history of swelling in the feet and flank pain was detected proteinuria and thrombosis in the inferior vena cava. Warfarin sodium treatment was started when thrombus was detected in the femoral vein, renal vein and inferior vena cava in the imaging. The patient had 12 g/day proteinuria, hypoalbuminemia, hyperlipidemia and antiphospholipase A2 receptor antibody positivity and treatment was started with the diagnosis of idiopathic membranous nephropathy. The patient who was discharged with oral steroid, cyclosporine and warfarin sodium, but warfarin sodium was changed to rivaroxaban in another clinic due to incompatibility problems, was presented again with dsypnea. Pulmonary embolism was detected. Rivaroxaban was discontinued and low molecular weight heparin treatment was started. There was a very high risk of morbidity and mortality and with appropriate treatment, clinical status and renal function were stabilized. In conclusion, although thromboembolism can be seen in nephrotic syndrome, it may rarely be encountered as the first presentation of nephrotic syndrome. This situation should not be overlooked, appropriate treatments should be provided without delay.

The Role of IgG4 in Autoimmunity and Rheumatic Diseases

The distinguishing of the IgG4-related disease (IgG4-RD) from among other rheumatic diseases has brought attention to the IgG4 subclass of immunoglobulins. It is the least numerous subclass among immunoglobulins G. In general, IgG4 is considered to be non-inflammatory and tolerance inducing, due to its unique structure. However, in IgG4-RD this antibody plays a pathogenic role in activation of the fibrinogenesis and of the inflammatory process; there are also suggestions that it may be a marker of an abnormal inflammatory response. The importance of IgG4 for the pathogenesis of allergic diseases, with a vital role of its ratio to immunoglobulin E (IgE/IgG4 ratio), has been known for years. The role of IgG4 in the course and pathogenesis of rheumatic diseases is still being researched and is not yet fully understood. Increased IgG4 levels have been revealed in rheumatoid arthritis, although no clear link between this phenomenon and disease activity has been demonstrated. There are articles on the potential importance of IgG4 concentration (of both elevated and decreased serum levels) in Sjogren’s syndrome. Additionally, anti-nuclear IgG4 antibody significant titers have been detected in SLE patients, and it has been suggested that the effect of these antibodies on complement consumption and the production of proinflammatory cytokines may play a role in inhibiting the progression of SLE. IgG4 plays a role in autoimmune diseases other than rheumatic diseases, such as pemphigus, bullous pemphigoid, idiopathic membranous glomerulonephritis, or myasthenia gravis, but also in helmints infections. Research shows the importance of IgG4 in malignancy of neoplasms. Melanoma cells are known to stimulate IgG4 production through a modified Th2-based inflammatory response. The role of this immunoglobulin in cholangiocarcinoma is also considered as possible. The aim of this review article is to discuss the current knowledge of IgG4 not only from the perspective of the IgG4-RD but also from a point of view of other autoimmune diseases with particular emphasis on rheumatic diseases.

Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis.

Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies. Kidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB. Glomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p-containing exosomes in a paracrine manner. Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.

FC 029PODOCYTE AND GLOMERULAR ENDOTHELIAL CELL DERIVED MICRORNAS REGULATE PODOCYTE NEPHRONECTIN IN MEMBRANOUS GLOMERULONEPHRITIS

Abstract Background and Aims Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier is normally size selective and impermeable for antibodies. Method Kidney biopsies from patients with MGN, cell culture, zebrafish and mice models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the glomerular filtration barrier. Results We found that endothelial cell-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in patients with anti-phospholipase A2 receptor antibody positive (PLA2R-ab+) iMGN and regulate glomerular NPNT expression (Fig. 1). Overexpression of miR-378a-3p and miR-192-5p as well as morpholino mediated npnt knockdown in zebrafish induced edema, proteinuria, loss of podocyte markers and podocyte effacement. The most prominent phenotype however were structural changes of the glomerular basement membrane (GBM) with increased lucidity, slicing and lamellation especially of the lamina rara interna (Fig. 2, Fig. 3). The phenotype was comparable to ultrastructural findings seen in iMGN. IgG sized nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte specific Npnt knockout mice (Fig. 4). Conclusion Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by podocyte and glomerular endothelial cell derived miRs. We hypothesize that loss of NPNT in the GBM is part of the pathophysiology of iMGN and enables subepithelial immune complex deposition in iMGN.

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.

Recurrent glomerulonephritis after kidney transplantation: a practical approach.

This review will provide a practical approach in the assessment of kidney failure patients with primary glomerulonephritides (GN) being considered for kidney transplantation, focusing on high-risk subtypes of immunoglobulin A nephropathy, focal segmental glomerulosclerosis, idiopathic membranous glomerulonephritis and membranoproliferative glomerulonephritis. Recurrent glomerulonephritis remains one of the most common causes of allograft loss in kidney transplant recipients. Although the epidemiology and clinical outcomes of glomerulonephritis recurrence occurring after kidney transplantation are relatively well-described, the natural course and optimal treatment strategies of recurrent disease in kidney allografts remain poorly defined. With a greater understanding of the pathophysiology and treatment responses of patients with glomerulonephritis affecting the native kidneys, these discoveries have laid the framework for the potential to improve the management of patients with high-risk glomerulonephritis subtypes being considered for kidney transplantation. Advances in the understanding of the underlying immunopathogenesis of primary GN has the potential to offer novel therapeutic options for kidney patients who develop recurrent disease after kidney transplantation. To test the efficacy of novel treatment options in adequately powered clinical trials requires a more detailed understanding of the clinical and histological characteristics of kidney transplant recipients with recurrent glomerulonephritis.

Spinal cord infarction associated to retinal vein occlusion in a patient with chronic kidney disease.

A 70-year-old man presented to the emergency department with blood hypotension associated to a sudden paraplegia and thermalgesic analgesia. He had an history of colic and prostatic adenocarcinoma, hypertension and non-dialyzed Chronic Kidney Disease (CKD) related to an idiopathic membranous glomerulonephritis type 1 discovered 9 years ago. Magnetic resonance imaging confirmed a diagnosis of Spinal Cord Infarction (SCI). Few months later, he presented a blurred vision due to central Retinal Vein Occlusion (RVO), which was improved by Anti-VEGF therapy. This is the first reported case of a concomitance of retinal vascular event and SCI highlights the links between the central nervous system and retinal vascularization despite separate involvement of the two events in the arterial and venous systems. Additionally, CKD worsened the risk of cardiovascular incidents by induced oxidative stress, thrombophilia, chronic inflammation, and endothelial dysfunction. SCI occurrence indicates severe vascular dysfunction and elevates the risk of additional vascular disorders.

Contactin-1 Antibodies Link Autoimmune Neuropathies to Nephrotic Syndrome

Background: There is an established association between acquired inflammatory demyelinating neuropathies and nephrotic syndrome, but a common immunopathological mechanism has yet to be determined. Antibodies to known glomerular podocyte antigens occur in up to 90% of patients with nephrotic syndrome due to idiopathic membranous glomerulonephritis (MGN), the majority targeting the phospholipase A2 receptor (PLA2R). In patients with immune-mediated neuropathies, antibodies targeting molecules of the node of Ranvier, such as contactin-1 (CNTN1), are increasingly recognised. Methods: In this study, sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, were tested for CNTN1 antibodies. Topographical binding patterns were determined using teased nerve fibres and live myelinated nerve co-cultures. CNTN1 expression in human kidney was characterised by immunohistochemistry, western blotting and PCR. Findings: A total of 16 patients with an immune-mediated neuropathy and MGN were seropositive for IgG4 anti-CNTN1 antibodies. The onset and resolution of both disorders had a close temporal relationship. The majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Four further patients with isolated MGN were also positive for the same antibodies at lower titres. CNTN1 protein was detected within glomerular deposits in biopsies from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. Interpretation: 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. Funding Statement: Medical Research Council (MRC), GBS/CIDP Foundation International, MRC and Kidney Research UK. Declaration of Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. He has received a speaker’s honorarium and/or travel expenses from Fresenius Medical Care, Excemed, Alnylam and argenx. AR has received honoraria from Sarepta, Roche and Sanofi Aventis, is a member of MND Association Clinical Advisory Board, and was a member of NICE MND Guideline Development Group. ASC receives funding from NIHR University College London Hospitals Biomedical research centre. AM is a clinical fellow with grant reference number MR/P001777/1. SPi is was funded by a grant from the Karolinska Institutet during the course of the study. All other authors have nothing to declare. Ethics Approval Statement: Research Ethics Committee approval number 14/SC/0280

Recurrent and de novo Glomerulonephritis After Kidney Transplantation.

The prevalence, pathogenesis, predictors, and natural course of patients with recurrent glomerulonephritis (GN) occurring after kidney transplantation remains incompletely understood, including whether there are differences in the outcomes and advances in the treatment options of specific GN subtypes, including those with de novo GN. Consequently, the treatment options and approaches to recurrent disease are largely extrapolated from the general population, with responses to these treatments in those with recurrent or de novo GN post-transplantation poorly described. Given a greater understanding of the pathogenesis of GN and the development of novel treatment options, it is conceivable that these advances will result in an improved structure in the future management of patients with recurrent or de novo GN. This review focuses on the incidence, genetics, characteristics, clinical course, and risk of allograft failure of patients with recurrent or de novo GN after kidney transplantation, ascertaining potential disparities between “high risk” disease subtypes of IgA nephropathy, idiopathic membranous glomerulonephritis, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. We will examine in detail the management of patients with high risk GN, including the pre-transplant assessment, post-transplant monitoring, and the available treatment options for disease recurrence. Given the relative paucity of data of patients with recurrent and de novo GN after kidney transplantation, a global effort in collecting comprehensive in-depth data of patients with recurrent and de novo GN as well as novel trial design to test the efficacy of specific treatment strategy in large scale multicenter randomized controlled trials are essential to address the knowledge deficiency in this disease.

Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases

The pathophysiology of many proteinuric kidney diseases is poorly understood, and microRNAs (miRs) regulation of these diseases has been largely unexplored. Here, we tested whether miR-378a-3p is a novel regulator of glomerular diseases. MiR-378a-3p has two predicted targets relevant to glomerular function, the glomerular basement membrane matrix component, nephronectin (NPNT), and vascular endothelial growth factor VEGF-A. In zebrafish (Danio rerio), miR-378a-3p mimic injection or npnt knockdown by a morpholino oligomer caused an identical phenotype consisting of edema, proteinuria, podocyte effacement, and widening of the glomerular basement membrane in the lamina rara interna. Zebrafish vegf-A protein could not rescue this phenotype. However, mouse Npnt constructs containing a mutated 3'UTR region prevented the phenotype caused by miR-378a-3p mimic injection. Overexpression of miR-378a-3p in mice confirmed glomerular dysfunction in a mammalian model. Biopsies from patients with focal segmental glomerulosclerosis and membranous nephropathy had increased miR-378a-3p expression and reduced glomerular levels of NPNT. Thus, miR-378a-3p-mediated suppression of the glomerular matrix protein NPNT is a novel mechanism for proteinuria development in active glomerular diseases.

Development of Phospholipase A2 Receptor Antigen Binding Monobodies for the Inhibition of the Idiopathic Membranous Glomerulonephritis Auto‐antibody Binding

The use of non‐specific treatment options in autoimmune therapy today unfortunately causes patients to be prone to other infections. This non‐specific therapy suppresses the entire patient's immunes system also making it harder to fight of basic infections. Thus therapies need to be developed which can accurately target only the aberrant portion of the immune system that contributes to the autoimmune disorder (AD) specific to the individual. The work here focuses on design of antigen specific binding monobodies as a targeted means to treat AD, and specifically idiopathic membranous glomerulonephritis. Sixty monobodies were designed and optimized using in silico mutagenesis. Protein‐protein docking simulations were performed using Rosetta to evaluate for maximum binding efficiency against the ricin and the CTLD2 epitopes present on the PLA2R antigen. Our results show improved binding scores and selectivity of monobodies against the phospholipase A2 receptor (PLA2R) antigens. Initial binding energy, measured in rosetta energy units (REU), were −2.863 and −2.633 for the SH13 template and ySMB‐1 templates respectively. The M005 mutation designed in the SH13 improved binding scores to −5.32 REU. The M006 ySMB‐1 mutant showed the most in silico selectivity between the two epitope regions on the PLA2R antigen having a score of −2.966 REU against the CTLD2 epitope and a better score of −3.736 against the ricin epitope. The SH13 M005 mutant showed the greatest binding efficiency having a score of −5.319 REU. However, this mutant also binds the CTLD2 epitope (binding energy score produced was −5.32 REU), suggesting that it will not have selectivity. Several molecular interactions were identified that facilitated increased binding of the monobodies to the epitope regions compared to the original template monobodies. Molecular interactions leading to selectivity are also being evaluated. Seven monobody candidates were selected for expression which was performed in E. coli followed by subsequent purification using affinity chromatography for experimental verification of computational results is using ELISA. This work has implications for new antigen specific approach to AD therapy.Support or Funding InformationWilliam Randolph Hearst Foundation and Rhodes College Department of Chemistry

Out of Africa: Complete and partial remissions as a combined outcome in patients with idiopathic membranous glomerulonephritis in Cape Town.

Remission outcomes among patients with idiopathic membranous glomerulonephritis is unknown in Africa. We sought to determine remission outcomes in a cohort of South African adult patients with IMGN. This was a retrospective review of patients with biopsy-proven IMGN over a 10 year period. Secondary causes of MN were excluded. Demographic, clinical, biochemical and histological records were retrieved for analysis. The trends in biochemical parameters from baseline were determined. The primary outcome was the attainment of a complete or partial remission (CR / PR) at the last follow-up. Fifty-six patients met the criteria for inclusion and 43 had subsequent follow-up care with a median duration of follow-up of 23.0 (13.0-48.0) months. Sixteen patients (37.2%) were treated with immunosuppression (corticosteroids and cyclophosphamide) and 81.4% received anti-proteinuric agents. There were no significant differences in demographic and clinical features of patients categorized by immunosuppression (ISP) use. Changes in level of proteinuria and estimated glomerular filtration rate (eGFR) were also not significantly different between the two groups. Eighteen patients (41.9%) reached CR or PR at the last visit. The median times-to-remission of patients according to ISP status were similar at 48.6 and 48.7 months respectively (P = 0.104) while the proportions of patients not reaching CR/PR at 12 and 24 months were 94.6% and 80.8% respectively. Gender and race did not predict remission status (P > 0.05). Predictors of CR/PR at last visit were eGFR [OR 1.01 (95%CI: 1.00 - 1.02); P = 0.041], and systolic BP (OR 0.97 [95%CI: 0.95 - 0.99); P = 0.036]. Remission outcomes in this African IMGN cohort are delayed and poor.

Allotransplantation using a diseased kidney: when a swallow makes a summer.

In this issue of Nephrology, Dialysis, Transplantation, Mirza et al. [1] present a very interesting but also puzzling case of membranous nephropathy (MN) transplanted in a patient with a history of long-term diabetes mellitus and severe atherosclerosis. Simultaneous heart and kidney transplantation were carried out at a time when the recipient’s estimated glomerular filtration rate was 28 mL/min and proteinuria 1+. His native kidney histology was unknown and although the aetiology of his nephropathy was multifactorial, it can be safely ascertained that the grafted kidney benefitted, in a broad sense, from a ‘non-immunologic’ environment. This case thus provides a unique opportunity to observe the outcome of immune deposits after cessation of the immunological aggression. The donor was a young woman who had died from a hypertensive subarachnoid haemorrhage. Prior to her death, she was not proteinuric. A pre-transplant biopsy of the donor’s kidney led to the discovery of lesions of Stages II, III and IV MN, a puzzling finding in the absence of proteinuria. The authors hypothesize that the preservation of the glomerular filtration barrier to proteins might be explained by the mild podocyte injury that was observed on the four serial biopsies that were performed up to Day 812. Each yielded a substantial number of glomeruli and showed by light microscopy, electron microscopy and immunofluorescence, a striking improvement of the initially severe membranous lesions. As in the donor, and despite persistence of Stages II and III glomerular basement membrane (GBM) lesions and immunoglobulin and complement staining, proteinuria was never significant and the kidney recipient maintained good function. This case is exceptional, although not the first one describing progressive wash-out of membranous immune deposits in kidneys transplanted into a non-immunologic environment. Parker et al. [2] reported the case of a patient with end-stage renal disease (ESRD) secondary to Type II diabetes mellitus who received a cadaveric renal transplant from a 37-year-old woman who died of cerebral infarction. A biopsy of the donor’s kidney performed at the time of transplantation showed MN by electron microscopy. There was immediate graft function and the recipient continued to have good kidney function 3 years post-transplantation. Nakazawa et al. [3] presented the case of a 41-year-old man grafted with a cadaver kidney. An allograft biopsy obtained during the operation showed spike formation on periodic acid-silver methenamine staining and deposition of IgG along the glomerular capillary loop on immunoperoxidase staining. Immunofluorescence staining for IgG persisted in the specimens obtained on Day 11 and after 4 weeks, but markedly decreased in the specimen obtained 7 weeks after transplantation. Electron-dense deposits also decreased in amount, but irregular thickening of the glomerular basement membrane with spikes, electron-lucent lesions and small amounts of electron-dense deposits remained 20 months after the transplantation. Akioka et al. [4] transplanted a kidney from a father, diagnosed with MN and mild proteinuria, to his son. At 39 months after transplantation, allograft biopsy showed a wash-out of electron-dense deposits and electron-lucent lesions. These reports are interesting but were not analyzed as meticulously as Mirza et al. did in their case. Their recipient’s kidney was studied by a pre-transplant histology followed by four biopsies up to 27 months post-transplantation. Along with light and electron microscopy, they used a wide panel of antibodies for immunofluorescence including staining for type-M phospholipase A2 receptor (PLA2R) that was negative. This is suggestive of a secondary aetiology of membranous glomerulonephritis (GN) but does not exclude a PLA2R-unrelated primary form [5]. PLA2R is a major target antigen in autoimmune idiopathic membranous GN. PLA2R is revealed in normal human glomeruli, and in idiopathic MN, PLA2R and IgG4 are shown to co-localize within subepithelial deposits. Early recurrence of MN in kidneys transplanted to recipients with circulating anti-PLA2R antibodies lends credit to a pathogenic role of these antibodies [6–8]. Their decrease IN F O C U S

Varenicline induced acute interstitial nephritis in the setting of idiopathic membranous glomerulonephritis

BackgroundVarenicline is a nicotinic receptor partial agonist indicated for the cessation of smoking. It is regarded as having no or minimal renal toxicity. A single case report has linked it to acute interstitial nephritis.Case presentationA 56 year-old female with a long-standing history of idiopathic membranous glomerulonephritis presented on routine follow-up with an unexpected rise in her serum creatinine from a stable baseline of 225 umol/L to 319 umol/L Biopsy revealed acute interstitial nephritis. There were no preceding clinical events other than the initiation of varenicline therapy three months prior. This was discontinued with no improvement in renal function. A ten week course of prednisone was initiated and creatinine levels returned to baseline. Shortly after prednisone therapy was completed, renal function worsened but the patient declined further immunosuppressive therapy. Exposure to varenicline therapy two years prior had also resulted in a reversible decline in kidney function.ConclusionThis is only the second case report to document varenicline-induced acute interstitial nephritis. A careful medication history and renal biopsy were essential in identifying the etiology of the acute kidney injury in this patient with a complex renal history.

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression

Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3+) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P=0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P=0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.

Anti-TNF- therapy in membranous glomerulonephritis

A 43-year-old woman with a history of psoriasis vulgaris was admitted for nephrotic syndrome that had started 6 months before. Renal biopsy revealed membranous glomerulonephritis (MGN). She did not receive any therapy for MGN. Two months later she started therapy for psoriasis with adalimumab, which resulted in disappearance of psoriatic skin lesions with progressive reduction of 24-h proteinuria. This is the first report of therapeutic efficacy of adalimumab in MGN. Idiopathic membranous glomerulonephritis (MGN) is the most common cause of nephrotic syndrome in adults. It is considered an autoimmune disorder in which antibodies against some antigens result in generation of immune complex with subsequent activation of the complement cascade [1]. Recently, the M-type phospholipase A2 receptor (PLA2R), expressed in podocytes, has been identified as the autoantigen [2]. Psoriasis is an immune-mediated chronic inflammatory skin disease with a strong genetic background. Chronic glomerulonephritis associated with psoriasis vulgaris has been reported in the literature [3]. However, because of the limited number of cases and the lack of specific histological findings, the pathogenetic mechanisms of these associations remain unclear [4].

Hemoptysis in TB Endemic Area. Think Again!

This case report illustrates an acute presentation of hemoptysis in a 21-year-old man from a TB endemic region. Further clinical evaluation resulted in extensive hypercoagulability complications of nephritic syndrome due to idiopathic membranous glomerulonephritis (MGN.) This emphasizes that proteinuria seen at a subnephrotic level, or on urine dipstick in a setting where glomerular disease might not be initially apparent, may warrant a keener look.

Patterns of IgG Subclass Deposits in Membranous Glomerulonephritis in Renal Allografts

Background Membranous glomerulonephritis (MGN) may develop in the renal allograft either de novo or as a recurrence. These 2 forms of MGN may have different pathogenic mechanisms, with different IgG subclass profiles in the immune deposits. This study examined IgG subclass distributions in recurrent and de novo MGN in allograft kidneys. Methods We identified allograft kidneys with MGN, including 7 with recurrent MGN, 2 with de novo MGN, and 2 atypical/indeterminate, and determined the relative intensity of IgG1, IgG2, IgG3, and IgG4 staining in capillary wall deposits by immunofluorescence microscopy. Results IgG4 was the dominant or codominant IgG subclass in capillary loop deposits in all 7 cases of recurrent MGN. IgG1 staining was dominant in 3 of 4 de novo or atypical MGN cases and codominant with IgG4 in the fourth. Conclusions Although pretransplantation kidney biopsies were not available for comparisons, these findings suggest that all allograft recurrences represent idiopathic MGN and that de novo MGN cases had a different pathogenic mechanism.

An abundance of IgG4+ plasma cells is not specific for IgG4-related tubulointerstitial nephritis

IgG4-related tubulointerstitial nephritis (IgG4-TIN), the renal parenchymal lesion of IgG4-related sclerosing disease, is characterized, among other things, by the presence of numerous IgG4-positive plasma cells (IgG4+PC) in the kidney infiltrate. The specificity of this finding for IgG4-TIN has not been addressed. To address this we examined 100 consecutive renal biopsy samples with active interstitial inflammation for the presence of IgG4+PC, and correlated the findings with principal diagnosis, the available clinical histories, and the findings in four biopsy samples of IgG4-TIN. Eleven of the survey biopsy samples contained an average of more than 10 IgG4+PC per × 200 field, including two with IgG4+PC in numbers comparable to those in two of the IgG4-related tubulointerstitial disease biopsy samples. The principal pathological diagnoses in the IgG4+PC-rich cases included anti-neutrophil cytoplasmic antibody-positive necrotizing glomerulonephritis (five cases), diabetic nephropathy (two cases), idiopathic interstitial nephritis (two cases), membranous glomerulonephritis (one case), and lupus nephritis (one case). There was no reason, based on histology or clinical history, to believe that any of these cases represented previously unsuspected IgG4-related tubulointerstitial disease. We conclude that the presence of numerous IgG4+PC is essential to, but not sufficient for, the diagnosis of IgG4-TIN.