New insights into membranous glomerulonephritis: from bench to bedside.

Idiopathic membranous nephropathy (IMN) is responsible for most cases of nephrotic syndrome in adults [1]. Although spontaneous remission may occur in some cases and several therapeutic options are now available [2–4], in a significant number of patients the response to therapy is poor and the risk of cardiovascular events or kidney disease progression remains high. Prognostic markers in IMN would help clinicians identify potential candidates to early intervention and specific strategies. In general, the development of biomarkers largely depends on the understanding of the pathogenesis of the disease. Until recently, the mechanisms of IMN in humans were translated from animal models, mainly from Heymann nephritis. However, basic differences in autoantigens glomerular expression among mice, rabbits and humans represented the main roadblock to the understanding of mechanisms of IMN in humans [5]. In fact, megalin, the autoantigen of Heymann nephritis, is not expressed in human glomeruli. The finding that neutral endopeptidase (NEP) is the target antigen of the autoimmune response in neonatal forms of the disease represents a breakthrough in the identification of glomerular autoantigen in human IMN. Elegant works by Debiec et al. [6, 7] showed the presence of anti-NEP antibodies in a woman carrying a homozygous deletion in MME (the gene coding for NEP). After alloimmunization occurred during a former pregnancy, anti-NEP antibodies were transferred to the fetus during a successive pregnancy. This rare form of IMN first proved the role of circulating antibodies against a podocyte protein in determining human IMN. More recently, new podocyte autoantigens have been identified [8–10] and research is now focused on the development and validation of a panel of antibodies to risk stratify patients and assist clinical decision making. Direct analysis of antibodies eluted from human glomeruli are now possible thanks to advances in technologies of recent application to human pathology, such as laser capture microdissection and proteomics. Potential biomarkers are identified in a three-step process. Firstly, IgG4 eluted from laser-captured glomeruli of IMN patients are tested for binding to podocyte extracts. Proteins recognized by eluted antibodies become autoantigens candidates [11]. Secondly, these candidate molecules are considered autoantigens if 2428 Nephrol Dial Transphant (2011): Editorial Comments