Structure of PLA2R reveals presentation of the dominant membranous nephropathy epitope and an immunogenic patch.

Membranous nephropathy is an autoimmune kidney disease caused by autoantibodies targeting antigens present on glomerular podocytes, instigating a cascade leading to glomerular injury. The most prevalent circulating autoantibodies in membranous nephropathy are against phospholipase A2 receptor (PLA2R), a cell surface receptor. The dominant epitope in PLA2R is located within the cysteine-rich domain, yet high-resolution structure-based mapping is lacking.

Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy.

Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus.

PLAR binds to the annexin A2-S100A10 complex in human podocytes.

Phospholipase A receptor (PLAR) is a member of the mannose receptor family found in podocytes in human kidney. PLAR is the target of the autoimmune disease, membranous nephropathy, characterised by production of anti-PLAR autoantibodies which bind to the podocyte. However the function of PLAR in health and in disease remains unclear.

Membranous nephropathy: integrating basic science into improved clinical management.

Idiopathic membranous nephropathy (INM) remains a common cause of the nephrotic syndrome in adults. The autoimmune nature of IMN was clearly delineated in 2009 with the identification of the glomerular-deposited IgG to be a podocyte receptor, phospholipase A2 receptor (PLA2R) in 70% to 75% of cases. This anti-PLA2R autoantibody, predominantly the IgG4 subclass, has been quantitated in serum using an enzyme-linked immunosorbent assay and has been used to aid diagnosis and monitor response to immunosuppressive therapy.

Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in New-incident and relapsing primary membranous nephropathy.

Aim: Primary membranous nephropathy is associated with progression to end stage renal diseasein some patients. Standard therapy with cyclical cyclophosphamide and corticosteroids can be associated with significant adverse effects. We aimed to assess immunological and clinical response with intravenous pulse cyclophosphamide and oral steroids in patients with severe nephrotic syndrome - in a prospective observational cohort study.

Long-term outcomes of persistent disease and relapse in primary membranous nephropathy.

Background: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood.

rhErythropoietin-b as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial.

Background: Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant.

Anti-heparanase aptamers as potential diagnostic and therapeutic agents for oral cancer.

Heparanase is an endoglycosidase enzyme present in activated leucocytes, mast cells, placental tissue, neutrophils and macrophages, and is involved in tumour metastasis and tissue invasion. It presents a potential target for cancer therapies and various molecules have been developed in an attempt to inhibit the enzymatic action of heparanase. In an attempt to develop a novel therapeutic with an associated diagnostic assay, we have previously described high affinity aptamers selected against heparanase.

Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.

Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location of a major epitope in the N-terminal cysteine-rich ricin domain of PLA2R that is recognized by 90% of human anti-PLA2R autoantibodies. The epitope was sensitive to reduction and SDS denaturation in the isolated ricin domain and the larger fragment containing the ricin, fibronectin type II, first and second C-type lectin domains (CTLD).

Association of anti-PLA₂R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy.

Background: The optimal timing and duration of immunosuppressive therapy for idiopathic membranous nephropathy (iMN) have been debated. This study aimed to evaluate whether measuring the antibody against the phospholipase A2 receptor (PLA2R-ab) at start and end of therapy predicts long-term outcome and therefore may inform this debate.

Design, Setting, Participants, & Measurements: This observational study included all consecutive high-risk patients with progressive iMN observed from 1997 to 2005 and treated with oral cyclophosphamide (CP) or mycophenolate mofetil (MMF) in combination with corticosteroids for 12 months.

The genetic contribution to recurrent autoimmune nephritis.

Glomerulonephritis is a significant cause of chronic kidney disease requiring renal replacement therapy. For patients receiving a transplant, it is known that specific primary pathologies such as membranous nephropathy, IgA nephropathy and FSGS have a high risk of recurrence in the transplant but the reasons for this are unknown and the ability to predict recurrence is poor. The recent discovery that primary MN is an autoimmune disease characterised by an autoantibody to phospholipase A2 receptor 1 and the identification of two genes, PLA2R1 and DQA1 which account for the genetic susceptibility to the disease, open up the potential to understand the mechanism of recurrent MN and therefore to design and manage therapy to prevent recurrence.

Outcomes of peritoneal dialysis patients and switching to hemodialysis: a competing risks analysis.

Background: We performed a review of a large incident peritoneal dialysis cohort to establish the impact of current practice and that of switching to hemodialysis.

Methods: Patients starting peritoneal dialysis between 2004 and 2010 were included and clinical data at start of dialysis recorded. Competing risk analysis and Cox proportional hazards model with time-varying covariate (technique failure) were used.

Global analysis reveals the complexity of the human glomerular extracellular matrix.

The glomerulus contains unique cellular and extracellular matrix (ECM) components, which are required for intact barrier function. Studies of the cellular components have helped to build understanding of glomerular disease; however, the full composition and regulation of glomerular ECM remains poorly understood. We used mass spectrometry-based proteomics of enriched ECM extracts for a global analysis of human glomerular ECM in vivo and identified a tissue-specific proteome of 144 structural and regulatory ECM proteins.

The role of mouse strain differences in the susceptibility to fibrosis: a systematic review.

In humans, a number of genetic factors have been linked to the development of fibrosis in a variety of different organs. Seeking a wider understanding of this observation in man is ethically important. There is mounting evidence suggesting that inbred mouse strains with different genetic backgrounds demonstrate variable susceptibility to a fibrotic injury.

Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy.

The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing.

Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.

Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months.

Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.

The phospholipase A(2) receptor (PLA(2)R) is the major target antigen in idiopathic membranous nephropathy. The technique for measuring antibodies against PLA(2)R and the relationship between antibody titer and clinical characteristics are not well established. Here, we measured anti-PLA(2)R (aPLA(2)R) antibody titer and subclass in a well defined cohort of 117 Caucasian patients with idiopathic membranous nephropathy and nephrotic-range proteinuria using both indirect immunofluorescence testing (IIFT) and ELISA.

Development of novel single-stranded nucleic acid aptamers against the pro-angiogenic and metastatic enzyme heparanase (HPSE1).

Heparanase is an enzyme involved in extracellular matrix remodelling and heparan sulphate proteoglycan catabolism. It is secreted by metastatic tumour cells, allowing them to penetrate the endothelial cell layer and basement membrane to invade target organs. The release of growth factors at the site of cleaved heparan sulphate chains further enhance the potential of the tumour by encouraging the process of angiogenesis.

Pharmacology, efficacy and safety of oral phosphate binders.

The ideal serum level of phosphate in patients on dialysis, and the benefits of controlling levels of phosphate in serum remain unclear despite observational studies that associate phosphate levels with mortality. In the absence of robust data from trials, current guidelines are necessarily based on opinion. Oral phosphate binders are required by the majority of patients on dialysis, and all of these binders can control serum levels of phosphate to similar degrees.

Encapsulating peritoneal sclerosis following renal transplantation despite tamoxifen and immunosuppressive therapy.

Encapsulating peritoneal sclerosis (EPS) is a rare disease in patients who have undergone peritoneal dialysis (PD). We report a case of EPS following renal transplantation that highlights important clinical issues. Initially, a presumptive diagnosis of EPS was made following surgical and pathological findings at the time of cholecystectomy.

Nutritional management of patients undergoing surgery following diagnosis with encapsulating peritoneal sclerosis.

Background: Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). Gastrointestinal (GI) symptoms affect appetite and dietary intake. Adequate nutrition is especially important if surgical interventions are required.

VEGF polymorphisms are associated with severity of diabetic retinopathy.

Purpose: To determine whether single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor (VEGF) gene are associated with severity of diabetic retinopathy.

Methods: A case-control study was conducted in which 45 individuals with type 1 or 2 diabetes with proliferative diabetic retinopathy (PDR) and 61 individuals with type 1 or 2 diabetes without retinopathy (DWR) were genotyped for 14 SNPs in the VEGF promoter and gene.

Results: Three of the promoter SNP genotypes, -160C, -152A (rs13207351), and -116A (rs1570360), showed significant independent associations with PDR, as well as the minihaplotype CAA (P = 0.