Membranous nephropathy - an antigen-specific disease: a paradigm shift in the understanding of this disease

Membranous nephropathy (MN), called Membranous glomerulopathy, is a native kidney disease characterized by sub-epithelial immune complex deposits. Clinically, MN patients present with nephrotic syndrome, especially in the adolescent age group. MN has been traditionally divided into primary and secondary types based on the idiopathic nature and association with secondary causes. The vital breakthrough in understanding the pathogenesis of this disease was the discovery of the M type of phospholipase A2 receptor (PLA2R) antigen. It was found to be associated with 60-70% of primary/idiopathic MN. Thrombospondin type 1 domain-containing 7A (THSD7A) was the second discovered antigen associated with 7-10% of primary MN. PLA2R has become the gold standard for identification of primary MN and is documented as positive both at a tissue level and at a serological level. Later, with the help of laser dissection and mass spectrometry studies, many newer antigens have been discovered, such as NELL-1, Exostosin 1/2, Semaphorin 3B, and Netrin G1, etc., which were found to be associated with both primary and secondary MN. A few of these antigens were found to be specifically related to specific secondary causes, while other antigens had a lot of overlap. Given the substantial overlap associated with the latter, the dichotomy between primary and secondary MN will likely lose its importance. In addition, the need for a renal biopsy for a preliminary diagnosis becomes questionable. Hence, we speculate upon a paradigm shift in the understanding of pathogenesis and nomenclature of this disease since the antigen-based specificity has a potential impact on the therapeutic and prognostic aspects of the disease, which is the crux of this paper.