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Introduction and outline of the thesis   |   11



                Introduction

                Membranous nephropathy is the most common cause of nephrotic syndrome in Caucasian
                adults . In about one-third of patients an underlying cause, such as infection, malignancy,
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                systemic autoimmune disease, or use of drugs such as nonsteroidal anti-inflammatory   1
                agents, can be identified . In the remaining 70 % of patients there is no associated disease
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                and the term primary membranous nephropathy (pMN) is used. Most patients present
                with nephrotic syndrome defined by proteinuria of more than 3.5 grams/24 hours, low
                serum albumin level (< 30 g/l), edema and often high serum lipid levels. At presentation,
                most patients have preserved kidney function.

                Primary MN is an organ-specific disease characterized by the presence of subepithelial
                immune deposits, in the absence of proliferative lesions. In the early stages of disease the
                deposits are encased by protrusions of the GBM, the ‘spikes’, that are characteristic of MN.
                Granular capillary wall deposits of IgG and complement are seen on immunofluorescence,
                and subepithelial immune deposits on electronic microscopy with extensive effacement
                of the podocyte foot processes. In a later stage there is glomerular basement membrane
                thickening on silver stain. Studies in passive Heymann nephritis, a rat model that
                histopathologically mimics human MN, showed that the deposits in experimental
                MN formed in situ when circulating immunoglobulin bound to an intrinsic glomerular
                antigen. This rat model was induced by immunizing rats with an extract from proximal
                tubules. Auto-antibodies against megalin, a transporter protein expressed on the soles
                of the podocyte foot processes, turned out to be causative. However, human podocytes
                do not express megalin . The causative antigen in human MN remained unknown for
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                many years. In 2002 Debiec and colleagues described a remarkable case of neonatal MN
                in which transplacental passage of anti-neutrophil endopeptidase (NEP) antibodies from
                a presensitized NEP-deficient mother bound to NEP on the baby’s podocytes, proving
                the hypothesis of an autoantibody mediated disease . A major breakthrough came with
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                the discovery of circulating antibodies against the M-type phospholipase A2 receptor
                (aPLA2Rab) in 2009, in 70-80 % of patients with primary MN . Recently other antigens
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                in MN have been discovered, including other podocyte antigens; thrombospondin type-
                1 domain-containing 7A (THSD7A) , serine protease HTRA1  ,and semaphorin 3b . Also,
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                non-podocyte antigens including neural epidermal growth factor-like 1 protein (Nell-1)
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                and protocadherin 7 (PCDH7)  have been described. Besides, the following antigens
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                were recently encountered in membranous lupus nephritis; e.g. exostosin 1/2 (EXT 1/2) ,
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                neural cell adhesion molecule 1 (NCAM1) , and TGFBR3 .
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                The natural course of pMN is highly variable. Overall, up to 50 % of patients may
                develop a spontaneous remission of proteinuria , and therefore the unrestricted
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                use of immunosuppressive therapy will expose many patients unnecessarily to
                immunosuppressive drugs. The cornerstone in the treatment of MN is to initiate and
                optimize supportive care in the first six months after diagnosis (in case of stable renal
                function).  Blood  pressure  should  be  targeted  to  125/75  mmHg  with  angiotensin
                converting enzyme-inhibitors or angiotensin receptor blockers. Edema should be treated
                with sodium restriction and diuretics. Hypercholesterolaemia should be aggressively
                treated with lipid-lowering drugs and because of an increased incidence of venous and
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