Daniel C. Cattran

It has been clear for several decades from comparison with the rodent model disease Heymann nephritis that membranous glomerulonephritis (MGN) is an immune condition in which antibodies, usually autoantibodies, bind to targets on the surface of podocytes. However, the antigen in Heymann nephritis, megalin, is not present on human podocytes. The first potential antigen was identified by studying rare examples of maternal alloimmunization, leading to congenital membranous nephropathy in the infant caused by antibodies to neutral endopeptidase. More recently, the target of autoantibody formation in most patients with primary MGN has been identified to be the phospholipase A2 receptor, PLA2R. Genome-wide association studies identify predisposing genetic loci at HLADQ and at the locus encoding the autoantigen itself. So antibodies to at least two different molecular targets can cause MGN, and it seems likely that there may be other targets in secondary types of MGN, and possibly haptenized or otherwise modified molecules are implicated in drug- and toxin-induced MGN. Once antibodies are fixed, animal models and human observations suggest that complement is involved in mediating tissue damage. However, immunoglobulin G4, not thought to fix complement, is the predominant isotype in human MGN, and the mechanisms are not fully unravelled. Podocyte injury is known to cause proteinuria. In MGN, antibody fixation or cell damage may stimulate production of extracellular matrix to account for the increased GBM thickness with ‘podocyte type’ basement membrane collagen isoforms, and ultimately cell death and glomerulosclerosis.

FSGS is a lesion, not a disease. The separation into primary FSGS (a result of immunologic-mediated injury) versus secondary FSGS (related to a variety of causes) is often difficult. Even when this particular issue is carefully evaluated, the therapeutic implications are not always apparent. Newer literature on both biomarker discovery and on the genetic basis of FSGS is reviewed in this context. In addition, the thorny implications of obesity as it relates to the FSGS lesion are discussed. An overall practical algorithmic approach to the management and treatment of the FSGS lesion that integrates these controversial overlap areas is suggested.

Summary Background and objectives The long-term effect of immunosuppressive therapy (IS) on kidney survival in idiopathic membranous nephropathy (MGN) is debated. The introduction of renin angiotensin blockade, rigorous BP control, and the increasing age at presentation of patients with MGN adds further uncertainty. Given these important changes, we sought to determine whether implementation of IS has altered outcome. Design, setting, participants, & methods We prospectively evaluated 280 incident MGN patients from three distinct 10-year periods starting from 1975. Results We found expected changes in treatment regimens but also variations in age, renal function, severity of proteinuria, and BP at presentation over this time. Outcomes did not differ over time if these significant variations in clinical characteristics were not accounted for across the eras. The effect of IS in the 57 patients treated with currently recommended regimens was assessed using propensity adjustment to address selection bias and the effect of newer, conservative therapies. A propensity score estimating the probability of receiving IS permitted the pairing of 39 treated patients with controls with similar high risk of progression of clinical features. Using this approach, IS was associated not only with remissions in proteinuria but also with substantially improved renal survival. Conclusions The study confirms that patient presenting characteristics and management regimens have changed significantly over time and the natural history of MGN has been altered. A study of propensity-matched patients confirms that current recommendations for IS have improved outcomes in MGN patients at high risk of progression.