https://www.zora.uzh.ch/id/eprint/78860/1/Eckardt_Lancet_2013.pdf

Evolving importance of kidney disease: from subspecialty to global health burden

142 Summary of Recommendation Statements 143 Chapter 1: Introduction 154 Chapter 2: General principles in the management of glomerular disease 156 Chapter 3: Steroid-sensitive nephrotic syndrome in children 163 Chapter 4: Steroid-resistant nephrotic syndrome in children 172 Chapter 5: Minimal-change disease in adults 177 Chapter 6: Idiopathic focal segmental glomerulosclerosis in adults 181 Chapter 7: Idiopathic membranous nephropathy 186 Chapter 8: Idiopathic membranoproliferative glomerulonephritis 198 Chapter 9: Infection-related glomerulonephritis 200 Chapter 10: Immunoglobulin A nephropathy 209 Chapter 11: Henoch-Schönlein purpura nephritis 218 Chapter 12: Lupus nephritis 221 Chapter 13: Pauci-immune focal and segmental necrotizing glomerulonephritis 233 Chapter 14: Anti-glomerular basement membrane antibody glomerulonephritis 240 Methods for guideline development 243 Biographic and Disclosure Information 252

KDIGO Clinical Practice Guideline for Glomerulonephritis

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-β(3) integrin interaction through antibodies and small molecules targeting either uPAR or β(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

/pdf/circulating-urokinase-receptor-as-a-cause-of-focal-segmental-4hscgr96p9.pdf

Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

https://www.nejm.org/doi/pdf/10.1056/NEJMra1104650

IgG4-related disease

Background Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown. Methods Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis. Results Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1–negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic memb...

/pdf/thrombospondin-type-1-domain-containing-7a-in-idiopathic-28zs66uz47.pdf

Thrombospondin Type-1 Domain-Containing 7A in Idiopathic Membranous Nephropathy

BACKGROUND Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown. METHODS We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody. RESULTS Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A 2 receptor (PLA 2 R). Reactive serum specimens recognized recombinant PLA 2 R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA 2 R antibody. Anti-PLA 2 R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA 2 R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA 2 R. CONCLUSIONS A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA 2 R. PLA 2 R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA 2 R is a major antigen in this disease.

/pdf/m-type-phospholipase-a2-receptor-as-target-antigen-in-3cz6d93aak.pdf

M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.

Autoantibodies to the M-type phospholipase A2 receptor (PLA2R) are sensitive and specific for idiopathic membranous nephropathy. The anti-B cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. Here, we investigated whether levels of anti-PLA2R correlate with the immunological activity of membranous nephropathy, potentially exhibiting a more rapid response to treatment than clinical parameters such as proteinuria. We measured the amount of anti-PLA2R using Western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti-PLA2R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab. Those who demonstrated this immunologic response fared better clinically: 59% and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0% and 33% among those with persistent anti-PLA2R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of anti-PLA2R. In summary, measuring anti-PLA2R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy.

Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.

Summary Background and objectives Circulating autoantibodies against the M-type phospholipase A2 receptor (anti-PLA2R) were recently identified in the majority of patients in the United States with idiopathic membranous nephropathy (iMN). The objectives of this study were to assess the prevalence of anti-PLA2R in a separate, European cohort of iMN patients and to correlate the presence of anti-PLA2R with clinical parameters reflective of disease activity. Design, setting, participants, & measurements Anti-PLA2R levels were blindly assessed by a Western blot immunoassay in 54 serum samples from 18 patients with iMN collected in various stages of clinical disease. Anti-PLA2R levels were correlated with other clinical parameters. Results 77.8% of iMN patients in our cohort had antibodies reactive with human PLA2R. The antibody levels in these patients correlated strongly with both clinical status and proteinuria (r = 0.73, P Conclusions The role of PLA2R as a major antigen in iMN was confirmed in an independent, European patient cohort, and levels of circulating anti-PLA2R revealed a strong correlation with clinical disease activity. We propose that detection and measurement of these autoantibodies may provide a tool for monitoring of disease activity and treatment efficacy.

Anti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.

Packed beds, such as those used in thermal energy storage (TES) systems, typically use flow from one end to the other. This axial flow configuration leads to inefficiencies due to dispersion effects and high pressure drop. Instead of axial flow, this work proposes radial flow in packed beds, where a central tube provides flow that transports fluid from the center to the bed’s wall. Radial flow could be a promising solution to increase the efficiency of charging/discharging processes in TES systems. For instance, studies have been conducted on the thermal behavior during the charging process using radial flow and axial flow, and it was found that radial flow is better than axial flow in terms of thermal performance, where more energy can be stored in the storage tank during the charging process. However, the design of the radial pipe should be optimized to improve even flow distribution. In this work, numerical investigations on different designs were analyzed to enhance even flow gas distribution in the porous media when using this radial technique. This work shows the impact of different parameters on the even flow distribution into the packed bed for two different designs: 1) one radial tube at the center to provide the radial flow along with an annular tube at the wall to receive the flow, and 2) one radial tube at the center and four radial tubes at the wall. Air was used as fluid and 6 mm alumina beads as packing materials. Computational fluid dynamics (CFD) models in COMSOL Multiphysics were used to simulate the behavior of air flow through the piping and packed bed. It was found that the flow into the bed from the radial tube can be affected by different parameters: space between the holes, size/diameter of the holes, number of segments/zones, number of the holes in each zone and the length of each zone. 

David M. Beck

Papers

M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.

Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.

Anti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.

Enhancing Even Gas Distribution in Porous Media with Radial Flow