Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people (i.e., those of European, Middle Eastern, or North African ancestry.).
It is the second most common cause of nephrotic syndrome in adults, with focal segmental glomerulosclerosis (FSGS) recently becoming the most common.
Signs and symptoms Most people will present as nephrotic syndrome, with the triad of albuminuria, edema and low serum albumin (with or without kidney failure). High blood pressure and high cholesterol are often also present. Others may not have symptoms and may be picked up on screening, with urinalysis finding high amounts of protein loss in the urine. A definitive diagnosis of membranous nephropathy requires a kidney biopsy, though given the very high specificity of anti-PLA2R antibody positivity this can sometimes be avoided in patients with nephrotic syndrome and preserved kidney function
Causes Traditional definitions split membranous nephropathy into 'primary/idiopathic' or 'secondary'. It is likely that instead the field will move to novel classification on the basis of the specific autoantigen detected, though given the current lack of clinical assays (other than for PLA2R autoantibodies) this may be several years off still.
Primary/idiopathic Traditionally 85% of MGN cases are classified as primary membranous glomerulonephritis—that is to say, the cause of the disease is idiopathic (of unknown origin or cause). This can also be referred to as idiopathic membranous nephropathy. Antibodies to an M-type phospholipase A2 receptor are responsible around 60% of cases of membranous nephropathy. Testing for these anti-PLA2R has revolutionised diagnosis and treatment of this disease in antibody positive patients, and tracking titre level over time allows you to predict risk of disease progression and chance of spontaneous remission There is little secondary disease association with PLA2R autoantibodies. In 2014, a second autoantigen was discovered, the thrombospondin type 1 domain-containing 7A (THSD7A) system that might account for an additional 1% of membranous nephropathy cases, and appears to be associated with malignancies. Further studies have identified more novel auto-antigens responsible for causing a membranous nephropathy pattern of injury continue to be published, with antibodies discovered against:
NELL-1 likely the second most common autoantibody with prevalence in MN of 5-10%. It has a heterogenous pattern of secondary association, from none to sarcoidosis, malignancy, drugs such as bucillamine, and infections. Like PLA2R, antibody titres go into remission with treatment. EXT1/EXT2 was reported in 2019. It is predominantly found in younger, female patients, and indeed 1/3 of patients with class V lupus nephritis are EXT positive In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes. Prognosis is good. A less common target antigen in lupus nephritis is NCAM1. Semaphorin3B predominates in children, esp <2 years old. there can be a family history of MN in these patients, it frequently causes progressive disease and it can recur in kidney transplants. Protocadherin 7 (PCDH7) in 2020. It is generally described in older patients, who have less complement on renal biopsy and frequently have spontaneous remission.Journal of the American Society of Nephrology FAT1 is associated with haemopoetic stem cell transplant, and responds to treatment Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1. NDNF is associated with syphilis (close to 100% of membranous nephrology is NDNF positive). HTRA1, often in older persons.
Secondary We include the traditional list of secondary causes, though as above nomenclature is moving towards an autoantibody specific approach. Membranous nephropathy is associated with the following:
autoimmune conditions (e.g., systemic lupus erythematosus). infections (e.g., syphilis, malaria, hepatitis B, hepatitis C, HIV). drugs (e.g., captopril, NSAIDs, penicillamine, probenecid, Bucillamine, Anti-TNF therapy, Tiopronin). inorganic salts (e.g. gold, mercury). tumors, frequently solid tumors of the lung and colon; melanomas; hematological malignancies such as chronic lymphocytic leukemia are less common.
Pathogenesis
MGN is caused by immune complex formation in the glomerulus. The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane. The antigens may be part of the basement membrane, or deposited from elsewhere by the systemic circulation. The immune complex serves as an activator that triggers a response from the C5b - C9 complements, which form a membrane attack complex (MAC) on the glomerular epithelial cells. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". In addition, the epithelial cells also seem to secrete an unknown mediator that reduces nephrin synthesis and distribution. Within membranous glomerulonephritis, especially in cases caused by viral hepatitis, serum C3 levels are low. Similar to other causes of nephrotic syndrome (e.g., focal segmental glomerulosclerosis or minimal change disease), membranous nephropathy is known to predispose affected individuals to develop blood clots such as pulmonary emboli. Membranous nephropathy in particular is known to increase this risk more than other causes of nephrotic syndrome though the reason for this is not yet clear.
Morphology The defining point of MGN is the presence of subepithelial immunoglobulin-containing deposits along the glomerular basement membrane (GBM).
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