Anti-glomerular Basement Membrane Antibody Glomerulonephritis Research Articles

Generation of Conditional KO Mice of CCN2 and Its Function in the Kidney.

CCN2 has been shown to be closely involved in the progression of renal fibrosis, indicating the potential of CCN2 inhibition as a therapeutic target. Although the examination of the renal disease phenotypes of adult CCN2 knockout mice has yielded valuable scientific insights, perinatal death has limited studies of CCN2 in vivo. Conditional knockout technology has become widely used to delete genes in the target cell populations or time points using cell-specific Cre recombinase-expressing mice. Therefore, several lines of CCN2-floxed mice have been developed to assess the functional role of CCN2 in adult mice.CCN2 levels are elevated in renal fibrosis and proliferative glomerulonephritis, making them suitable disease models for assessing the effects of CCN2 deletion on the kidney. Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis and transforming growth factor-β. CCN2 is increased in fibrosis and modulates a number of downstream signaling pathways involved in the fibrogenic properties of TGF-β. Unilateral ureteral obstruction is one of the most widely used models of renal tubulointerstitial fibrosis. In addition, anti-glomerular basement membrane antibody glomerulonephritis has become the most widely used model for evaluating the effect of increased renal CCN2 expression. Herein, we describe the construction of CCN2-floxed mice and inducible systemic CCN2 conditional knockout mice and methods for the operation of unilateral ureteral obstruction and the induction of anti-glomerular basement membrane antibody glomerulonephritis.

Therapeutic Apheresis and Immunosuppression in Renal Diseases

Therapeutic plasma exchange (TPE) with hollow fiber modules is used in different severe diseases since more than 40 years. The authors try to give an overview of therapeutic apheresis (TA) in renal diseases. The updated information on immunology and molecular biology of different renal diseases are discussed in relation to the rationale for apheresis therapy and its place in combination with other modern treatments. The different renal diseases can be treated by various apheresis methods such as TPE with substitution solution, or with online plasma or blood purification using adsorption columns, which contain biological or non-biological agents. The following diseases are discussed: rapidly progressive glomerulonephritis (RPGN) including anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM RPGN), RPGN with or without glomerular deposition (ANCA-ab), pauci-immune RPGN, immune complex nephritis (ICN), and various glomerulonephritis with nephrotic syndrome (NS), acute kidney injury (AKI), myoglobulinemic renal failure, hemolytic-uremic syndrome (HUS), and kidney transplant rejection. For the renal diseases, which can be treated with TA, the guidelines of the Apheresis Applications Committee (AAC) of the American Society for Apheresis (ASFA) are shown.

Rituximab use in adult glomerulopathies and its rationale

Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

A Case Report of Posterior Reversible Encephalopathy Syndrome with Rapidly Progressive Glomerulonephritis Combined with Membranous Nephropathy

Rapidly progressive glomerulonephritis is a group of clinical syndromes, in which renal function of patient progressively deteriorates with pathological manifestation of extensive glomerular crescent formation. Among which, anti-glomerular basement membrane antibody glomerulonephritis is the rarest but the most aggressive subtype. This paper discusses a case of rapidly progressive glomerulonephritis combined with membranous nephropathy. There were posterior reversible encephalopathy syndromes during diagnosis and treatment. Diagnosis was confirmed in time by laboratory examination and renal pathology. Condition of the patient was alleviated through close work between all departments. This allowed us to further understand the case characteristics of rapidly progressive glomerulonephritis combined with membranous nephropathy, importance of effective prevention, and significance of various complications during treatment, so as to alleviate pain and improve prognosis in patient.

Production and Analysis of Conditional KO Mice of CCN2 in Kidney.

CCN2 has been shown to be closely involved in the progression of renal fibrosis, indicating the potential of CCN2 inhibition as a therapeutic target. Although the examination of the phenotypes of adult CCN2 knockout mice with renal diseases has yielded valuable scientific insights, perinatal death has limited studies of CCN2 in vivo. Conditional knockout technology has become widely used for the deletion of genes in the desired cell populations and time points through the use of cell-specific Cre recombinase-expressing mice. Accordingly, several lines of CCN2 floxed mice have been developed for the assessment of the functional role of CCN2 in adult mice.CCN2 levels are increased in renal fibrosis and proliferative glomerulonephritis, which represent good disease models for evaluating the effects of CCN2 deletion on the kidney. Of these, anti-glomerular basement membrane antibody glomerulonephritis has become the most widely used model for evaluating the effect of increased renal CCN2 expression. Herein, we describe the construction of CCN2 floxed mice and inducible systemic CCN2 conditional knockout mice and methods for the induction of anti-glomerular basement membrane antibody glomerulonephritis.

ICER controls Th17 cell differentiation and autoimmune pathology (IRM15P.600)

Abstract Inducible cAMP early repressor (ICER) is a splice variant of cAMP-responsive element modulator (CREM). Because ICER lacks transcriptional activation domains, ICER acts as a repressor of various genes involved in immune cell function and inhibits T cell activation by suppressing the induction of pro-inflammatory cytokines including IL-2. However, little is known about ICER involvement in IL-17 production and Th17 differentiation. Culture of murine naïve CD4 T cells under Th17 skewing conditions showed surprisingly high expression of ICER indicating and important role in these cells. T cells from animals in which the CREM gene had been deleted were cultured under these conditions, which revealed less IL-17 than T cells from CREM sufficient mice. Because ICER induction is abrogated in T cells from STAT3-deficient mice, we considered the possibility that IL6-STAT3 signaling plays a crucial role in ICER induction in Th17 T cells. We expanded our observations in vivo. We induced experimental anti-glomerular basement membrane antibody glomerulonephritis (AIGN) and experimental autoimmune encephalomyelitis model (EAE) in CREM-deficient and sufficient animals and found that CREM-deficient had diminished nephritis and encephalomyelitis. Collectively, our results suggest that the transcription factor ICER supports Th17 differentiation and promotes Th17-dependent autoimmune pathology.

P–585 - Cloning of a novel cDNA, AGN-1 that is up-regulated in anti-glomerular basement membrane antibody glomerulonephritis in rats.

P–585 - Cloning of a novel cDNA, AGN-1 that is up-regulated in anti-glomerular basement membrane antibody glomerulonephritis in rats.

Purification and characterization of human nephritogenic antigen that induces anti-GBM nephritis in rats.

Human nephritogenic antigen induces anti-glomerular basement membrane antibody glomerulonephritis in rats. This antigen was purified from collagenase-solubilized renal basement membrane by means of gel filtration and affinity chromatography using a rabbit antibody. Western blots of the purified nephritogenic antigen using epitope-defined monoclonal antibodies showed that it contains the NC1 domains of the a1 to a6 chains of type IV collagen. Nephritogenicity was thought to be a feature of the NC1 domains of the a3 to a5 chains, because the a6 chain is not located in the glomerular basement membrane, and because an NC1 fraction consisting of the NC1 domains of the a1 and a2 chains was poorly nephritogenic. Autoantibodies in the sera of patients with Goodpasture's syndrome were detected by ELISA using the purified nephritogenic antigen. These results indicate that the nephritogenic antigen contains the Goodpasture antigen, defined as the antigen reactive with sera from patients with Goodpasture's syndrome.

Recurrence of anti-glomerular basement membrane antibody glomerulonephritis.

Recurrence of anti-glomerular membrane antibody glomerulonephritis seems to be an unusual clinical phenomenon. We report a 57-year-old man with recurrence of anti-glomerular basement membrane antibody glomerulonephritis. He developed a rapidly progressive glomerulonephritis with anti-glomerular basement membrane antibody (anti-GBM Ab), and recovered with a combined treatment of prednisolone, anticoagulant and antiplatelet agents. After a 2-year remission, hematuria and proteinuria followed by renal functional deterioration occurred without any obvious cause. The second renal biopsy revealed cellular crescents with linear IgG deposition along GBM, a finding similar to the first one. The aforementioned combined treatment resulted in a gradual recovery from proteinuria and renal functional derangement.

Glomerular Effects of Pregnancy in a Model of Glomerulonephritis in the Rat

These studies were designed to investigate the functional and morphologic glomerular effects of pregnancy in a model of experimentally induced glomerulonephritis (GN) in the Munich-Wistar rat. Virgin and midterm (day 12) pregnant rats were studied during the autologous phase of anti-glomerular basement membrane antibody GN and were compared with normal control virgin and pregnant rats. In this model of moderately intense GN, glomerular filtration rate (GFR) and single-nephron GFR were not different from normal controls; however, glomerular micropuncture revealed that glomerular capillary blood pressure was elevated and the glomerular capillary ultrafiltration coefficient, Kfi, was reduced in rats with GN compared with normal rats. In addition a substantial proteinuria was present, and there was morphologic evidence of a moderate and fairly uniform GN. The superimposition of pregnancy to midterm (11 to 13 days) had no effects on the proteinuria or glomerular morphology in rats with GN. Also, pregnancy did not further alter the increased glomerular blood pressure or reduced Kf that occur in this model of GN. Despite the presence of an underlying glomerular disease, the maternal kidney was able to increase renal plasma flow. When underlying mild GN is present, 11 to 13 days of pregnancy does not appear to worsen the disease in the short term. Other studies are needed to determine the long-term renal effects of repeated pregnancy when underlying GN is present.

Difference in susceptibility to experimental immune glomerulonephritis among rat strains

Rats of Sprague-Dawley and two Wistar strains were injected fortnightly for 100 days with isolated human glomerular basement membrane emulsified in Freund's adjuvant and then slaughtered. Renal function was monitored by weekly urine protein estimations, and kidneys taken by unilateral nephrectomy and at slaughter were examined by light and electron microscopy and by immunofluorescence. Proteinuria began after 4 wk in Sprague-Dawley rats and continued until slaughter. Glomerular lesions, ranging from focal cellular proliferation and hypertrophy to widespread adhesions and sclerosis, were seen in these rats. By contrast, rats of both Wistar strains failed to develop proteinuria and no glomerular lesions were found. Sections stained with fluorescein-tagged anti-rat IgG antibody revealed intense and consistent linear fluorescence characteristic of anti-glomerular basement membrane antibody along the glomerular capillary walls of Sprague-Dawley rats. Such staining was either weak or absent in the other rats. This observed strain difference in susceptibility to experimental autologous antiglomerular basement membrane antibody glomerulonephritis is thought to be due to genetic variation in the capacity to produce antibody against the introduced foreign glomerular basement membrane.