Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults and can lead to end stage kidney disease. This thesis reports on a number of investigative approaches to better understand the pathogenesis, heterogeneity, and responses to therapy in MN.
A database of all patients with MN diagnosed at Imperial College Healthcare NHS Trust from 2000 to 2020 was created and following the development of a staining protocol, all available renal biopsies were stained for PLA2R. The results demonstrated that PLA2R positive MN was common and confirmed by biopsy staining in 69% of cases. MN can be effectively treated with tacrolimus immunosuppression with good long term remission rates, but relapses occur after treatment cessation and are usually associated with PLA2R positivity on biopsy and return of circulating anti-PLA2R antibodies. A randomised controlled trial examining whether the addition of MMF to tacrolimus would reduce relapse rates after treatment cessation showed that the addition of MMF was not beneficial.
It has been suggested that the differentiation between primary and secondary MN should be based on the presence or absence of PLA2R in the glomerular immune deposits; however, anti-PLA2R antibodies can be found in cases of “secondary” MN associated with viral infection. PLA2R positive MN was found in 52% of cases of MN associated with viral infection. Although spontaneous remission was common, 80% of PLA2R positive MN cases associated with viral infection required immunosuppressive treatment to achieve remission. Crescentic MN can be associated with ANCA or anti-GBM antibodies, or less often with anti-PLA2R antibodies alone, and can be successfully treated as a necrotising and crescentic glomerulonephritis.
Complement has an important role in MN and in PLA2R positive cases glomerular deposition of complement components was significantly increased compared to PLA2R negative cases. Glomerular intensity for FHR5 was significantly increased in the PLA2R positive cases and correlated with intensity of glomerular C3c, C3d, C4d and C5b9 indicating a role for the alternative pathway in MN.
Anti-PLA2R antibodies can affect podocytes in the presence of complement leading to mild changes in the actin cytoskeleton that could be associated with progressive loss of podocyte architecture and function leading to effacement of the foot processes.
These data provide important information on the role of anti-PLA2R antibodies in MN, as well as clinical data supporting the use of tacrolimus for the treatment of MN, and experimental evidence indicating a role for complement in MN.