New approaches to get to the heart of membranous nephropathy A rare disease which affects the kidney, membranous nephropathy is the second-most common cause of nephrotic syndrome. The OSAI project is using novel technological approaches to shed new light on the disease, research which could lead to the development of rapidly acting new therapies, as Principal Investigator Professor Pierre Ronco explains A rare disease which affects structures inside the kidney, membranous nephropathy is caused by a thickening of the base membrane of the glomerulus, a filtering unit in the kidney. This thickening is caused by the accumulation of immune deposits, as Professor Pierre Ronco explains. “There are deposits of antibodies and of antigens. The consequence of that is the development of proteinuria – loss of proteins through the urine – and the decrease of the albumin serum in the blood,” he says. Based at the INSERM Institute and University Pierre et Marie Curie in Paris, Professor Ronco is the Principal Investigator of the OSAI project, an EC-backed initiative investigating the pathophysiology of membranous nephropathy, which he coordinates with his co-worker, Dr Hanna Debiec (Research Director at INSERM). “The disease can evolve in three ways; spontaneous remission, persistent proteinuria, or endstage renal failure,” he says. “It has been shown that this disease is auto-immune in nature – in most cases the antigen is localised in the glomerulus. The patient produces antibodies directed to this antigen, which become deposited in the glomerulus and this induces the disease.”
Triggering events The project’s primary objective is to understand the triggering events that lead to the disease and the pre-disposing factors behind positive or negative outcomes. This builds from the current understanding of how the disease develops and progresses. “The first step is the presentation of the antigens to the immune system by the HLA class 2 molecules – for instance HLA-DQA1,” explains Professor Ronco. The immune system produces antibodies which circulate in blood and are then deposited in the glomerulus, where Professor Ronco says they react with the antigens. “This activates a
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Figure 1. Mechanisms of immune mediated podocyte injury in MN and pathogenesis based therapeutic approach. complement cascade, leading to the formation of the membrane attack complex of complement. This induces injury to the podocyte, and to the capillary wall, which in turn induces proteinuria and can eventually lead to nephrotic syndrome,”
This forms a key element of the project’s research agenda. Membranous nephropathy is a complex disease, and typically develops as the result of a sequence of events. “We are interested in each step of the disease. We are interested
It has been shown that membranous nephropathy is auto-immune in nature – in most cases the antigen is localised in the glomerulus. The patient produces antibodies directed to this antigen, which becomes deposited in the glomerulus and induces the disease he outlines. “What is not known is the trigger event which induces the production of antibodies in patients with predisposing variants. Molecular mimicry with microbes or toxic agents could play an important role.”
in the first step, in the triggering event that stimulates the production of antibodies. We are also interested in the last step, the formation of the complex of complement, which attacks the podocyte membrane, and the development of
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