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Unmet challenges in membranous nephropathy

Salant, David J.

Current Opinion in Nephrology and Hypertension: January 2019 - Volume 28 - Issue 1 - p 70–76
doi: 10.1097/MNH.0000000000000459

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, there are still several unanswered questions as highlighted here.

Recent findings A substantial body of literature, included in more than 680 articles since 2009, has documented genetic susceptibility to primary membranous nephropathy 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 membranous nephropathy, 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 do not 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 membranous nephropathy 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 membranous nephropathy and apply the knowledge to design more specific therapies.

Department of Medicine, Boston University School of Medicine and Section of Nephrology, Boston Medical Center, Boston, Massachusetts, USA

Correspondence to David J. Salant, MD, Renal Section, Evans Biomedical Research Center, X504, Boston Medical Center, 650 Albany Street, Boston, MA 02118, USA. Tel: +1 617 638 7330; e-mail:

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