Unmet challenges in membranous nephropathy

Abstract

Purpose of review: Despite major advances in since the discovery of the phospholipase A2 receptor (PLA2R) as the major autoantigen on podocytes in primary membranous nephropathy (MN), there are still several unanswered questions as highlighted here. Recent findings: A substantial body of literature, included in more than 680 papers since 2009, has documented genetic susceptibility to primary MN involving PLA2R1 and class II MHC alleles, the clinical value of anti-PLA2R assays, the significance of epitope spreading of the anti-PLA2R response, discovery of thrombospondin type I domain containing 7A (THSD7A) as a minor antigen in primary MN, and the ability to transfer disease into mice by infusion of anti-THSD7A sera. However, the normal physiology and pathophysiology of PLA2R and THSD7A in podocytes is still unknown and the genetic influence on disease susceptibility is unexplained. We still don’t know what causes loss of self-tolerance to PLA2R and THSD7A or how the autoantibodies, which are predominantly of the IgG4 subclass, cause podocyte injury and proteinuria. Complement deposits are prominent in MN, but we are still uncertain how the complement system is activated and whether or not it plays a role in podocyte damage. Notwithstanding the advances over the past decade, our treatments have not changed substantially. Summary: This review identifies opportunities to extend the advances that have been made to better understand the immunopathogenesis and genetic basis of primary MN and apply the knowledge to design more specific therapies.

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

“…MN, a leading cause of nephrotic syndrome in adults, is characterized by the deposition of immune complexes between podocytes and the glomerular basement membrane. The phospholipase A2 receptor (PLA2R) has been identified as the major autoantigen on podocytes in primary MN, and thrombospondin type I domain-containing 7A (THSD7A) is a minor antigen [75]. Autoantibodies to PLA2R and THSD7A are considered to be predominantly of the IgG4 subclass [75].…”

“…The phospholipase A2 receptor (PLA2R) has been identified as the major autoantigen on podocytes in primary MN, and thrombospondin type I domain-containing 7A (THSD7A) is a minor antigen [75]. Autoantibodies to PLA2R and THSD7A are considered to be predominantly of the IgG4 subclass [75]. Increased glomerular mitochondrial fission proteins, DRP1, phosphorylated-DRP1 (Ser-616), and FIS1, were observed in patients with MN [76].…”

Proteomic Analysis of Complement Proteins in Membranous Nephropathy

“…A detailed analysis of the contribution of complement in MN has the potential to inform our understanding of the role played by glomerular deposition of complement proteins and their cleavage products in both causing and amplifying injury to glomerular endothelial cells and podocytes. [9][10][11] In this study, we sought to address this knowledge gap by identifying which complement proteins are deposited in MN, as this insight may establish whether specific complement pathways are triggered in this disease. This knowledge is relevant as numerous anticomplement drugs are being developed, and their targeted use requires a detailed understanding of specific disease processes.…”

Advances in Pathogenesis of Idiopathic Membranous Nephropathy

“…Nonetheless, the ability of thrombo­spondin type 1 repeats to engage in cell-cell and cell-matrix interactions, as well as the studies with THSD7A in human umbilical vein endothelial cells and zebrafish, suggests that THSD7A may contribute to podocytes’ adhesion to the GBM. Moreover, it is possible that proteolytic cleavage and release of soluble THSD7A during antibody-mediated injury may influence such adhesion and, thereby, cause effacement of the podocyte foot process [13].…”