Membranous nephropathy (MN, also membranous glomerulonephritis) is a chronic inflammatory disease of the kidney glomeruli and characterised by subepithelial deposits of immune complexes at the glomerular basement membrane (see illustration). Due to the deposits, the permeability of the capillary wall of the glomeruli is disturbed, which leads to proteinuria and very frequently to nephrotic syndrome. Besides a strongly increased protein exretion via the urine (>3.5 g/24 h), this is characterised by reduced protein concentrations in the blood (hypoproteinaemia), increased blood lipid levels (hyperlipidaemia) and oedema.1
Approximately 20 to 30% of MN cases occur as secondary conditions as a consequence of different underlying diseases or the use of specific drugs.2,3,4 They must be differentiated from primary MN for which no underlying disease is known and which is caused by autoantibodies (see tables). In 2009, David J. Salant and colleagues first discovered PLA2R as the antigen, followed by the second antigen, THSD7A, in 2014. If neither an underlying disease nor detectable autoantibodies are present, the condition is referred to as idiopathic MN.5
|Causes of pMN|
|Causes of sMN (for a complete list, see KDIGO4)|
|Infections (e.g. hepatitis B virus, hepatitis C virus, syphilis, malaria)|
|Autoimmune diseases (e.g. rheumatoid arthritis, Sjögren´s Syndrome, bullous pemphigoid)|
|Other diseases (e.g. sickle cell anaemia, Guillain-Barré syndrome)|
|Drugs (e.g. nonsteroidal anti-inflammatory drugs (NSAID), gold, mercury, penicillamine)|
CONCLUSION: Since the treatment of the two disease forms differs significantly, the diagnostic differentiation between primary and secondary MN is of greatest clinical importance.4 In sMN, the therapy focuses on the underlying disease, whereas patients with pMN are mainly treated with immunosuppressives. Therefore, correct and fast diagnosis may prevent unnescessary diagnostic procedures or drug treatment.
In 2009, David J. Salant and colleagues discovered PLA2R, a185-kDa glycoprotein, as a specific autoantigen for antibodies, which were detected in 70-80% of all patients with MN without secondary cause.5 In 2014, a second antigen was described in connection with primary MN6, THSD7A. In patients with sMN, no corresponding autoantibodies were detected.
The antigens are expressed on the surface of the podocytes and bind circulating autoantibodies.
Even though the exact pathogenic mechanisms for the development of pMN are still unknown, it is assumed that in-situ immune complexes form in the area of the glomerular basement membrane due to the binding of the autoantibodies. These possibly cause a local complement activation which, via the formation of different mediators, lead to a rearrangement of the cytoskeleton.3,7 This causes damage in the podocytes, resulting in a disturbed filtering function and the symptoms of nephrotic syndrome: an increased transfer of proteins into the primary urine (proteinuria), accompanied by oedema and compensatory increase of lipoprotein synthesis.
For THSD7A it could be shown in a mouse model in 2017, that THSD7A antibodies are directly involved in the pathogenesis of MN. An injection of antibodies led to severe nephrotic syndrome with proteinuria and hyperlipidaemia in the mice.8
1Schmidt et al., Internist 43, 749–759 (2002)
2Pavenstädt, Nephrologe 3, 220–230 (2011)
3Ronco et Debiec, Nat Rev Nephr 8, 203-213 (2012)
4KDIGO, Kidney inter., Suppl. 2: 139–274 (2012)
5Beck et al., N Engl J Med 361, 11-21 (2009)
6Tomas et al., N Engl J Med 371, 2277-2287 (2014)
7Ma et al., Semin Nephrol 33, 531-542 (2013)
8Tomas et al., J Am Soc Nephrol 28, 3262-3277 (2017)