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Human Idiopathic Membranous Nephropathy — a Mystery Solved? Richard J

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Human Idiopathic Membranous Nephropathy — a Mystery Solved? Richard J The new england journal of medicine editorials Human Idiopathic Membranous Nephropathy — A Mystery Solved? Richard J. Glassock, M.D. Just over 50 years ago, the late David Jones1 iden­ were fulfilled, defining the autoimmune nature tified (using the periodic acid–Schiff and meth­ of the disease in the rat model. enamine silver stains) the unique glomerular However, translation of the pathogenesis of pathologic features of membranous nephropathy, the rat model to idiopathic membranous nephrop­ thus distinguishing it from other causes of “ne­ athy in humans proved difficult. The target an­ phrotic glomerulonephritis.” Subsequent immuno­ tigen responsible for Heymann’s model appeared fluorescence and electron­microscopical studies to be absent in human kidneys.6 Diligent search­ established that membranous nephropathy was es for the autoantibody against the “Heymann” also characterized by striking granular aggrega­ antigen (now known to be megalin [glycoprotein tions of IgG and electron­dense deposits along 330]) were unrewarding.6 Thus, the true patho­ the outer (or subepithelial) aspect of the glomer­ genesis of human idiopathic membranous ne­ ular basement membrane. These glomerular IgG phropathy remained unresolved. deposits were initially believed to represent an Now, this long­lasting mystery may well have accumulation of immune complexes arising from been solved by Beck et al.,7 as reported in this the circulation, as is found with glomerulonephri­ issue of the Journal. Autoantibodies against an tis in a rabbit model (chronic serum sickness). antigen normally expressed on the podocyte cell In 1959, Heymann et al.2 described a rat mod­ membrane in humans, the M­type phospholipase el of membranous nephropathy, similar to the dis­ A2 receptor (PLA2R), appear to circulate and bind ease in humans, induced by active immunization to a conformational epitope (or epitopes) present with crude kidney extracts in complete Freund’s on PLA2R, producing in situ deposits character­ adjuvant. Initially, this model was also believed istic of those associated with membranous ne­ to be due to deposition of immune complexes phropathy. These autoantibodies are large ly, but from the circulation. Subsequently, however, Van not exclusively, immunoglobulins of the IgG4 sub­ Damme et al.3 and Couser et al.4 demonstrated class, similar to those seen in most instances of that a circulating antibody reacted with and bound idiopathic membranous nephropathy in patients. to the primary antigenic target located on podo­ Other renal diseases and secondary forms of cytes — the visceral epithelial cells of the glo­ membranous nephropathy (such as lupus mem­ merulus — indicating that the disease was caused branous nephropathy) do not appear to involve by the in situ formation of immune complexes. such autoantibodies. Others soon showed that additional antigens, nor­ Beck et al. also present preliminary indications mally extrinsic to the kidney, that were “planted” of an association between the clinical features of artificially in the glomeruli (the glomerular base­ the disease (proteinuria and the nephrotic syn­ ment membrane or podocyte) through biophys­ drome) and the presence and titer of the circu­ ical attraction to the capillary wall could provoke lating autoantibodies. If the disease can be trans­ an identical lesion (Fig. 1). ferred to nonhuman primates that express the Both the target antigen and the autoantibody PLA2R antigen on podocytes or if the subepithe­ operative in Heymann’s model were eventually lial deposits can be shown to recur rapidly in a characterized; thus, all of Witebsky’s postulates5 kidney transplanted from a normal donor to a n engl j med 361;1 nejm.org july 2, 2009 81 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF LOUISVILLE on May 22, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Figure 1. Possible Mechanisms of the Formation of Subepithelial Deposits in Experimental Models of, and Patients with, Membranous Nephropathy. Panel A shows the deposition of immune complexes from the circulation. Panel B shows the in situ formation of immune complexes through the reaction of circulating autoantibody to a native glomerular (podocyte) antigen. Panel C shows formation of immune com- plexes with a nonnative (extrinsic) antigen artificially bound to the capillary wall. recipient with membranous nephropathy whose of idiopathic membranous nephropathy are due 7 circulation contains auto–anti­PLA2R antibodies, to anti­PLA2R autoantibodies. Preliminary obser­ all of Witebsky’s postulates5 would be fulfilled vations suggest that many patients with idiopath­ for the disease in humans. In addition, anti­ ic membranous nephropathy also have circulating PLA2R autoantibodies would be proven as the autoantibodies reactive with neutral endopepti­ circulating vector, and podocyte PLA2R would be dase, another podocyte antigen previously impli­ proven as the target autoantigen, in membranous cated in alloimmune congenital membranous nephropathy. Even without this proof, the pres­ nephropathy.8,9 Sorting out this apparent conun­ ent observations of Beck et al. represent a major drum will require the sharing of serum samples breakthrough that will almost certainly initiate between laboratories studying membranous ne­ a new era of investigation into human membra­ phropathy and independent confirmation in an­ nous nephropathy. other population of patients with idiopathic However, several additional mysteries remain membranous nephropathy, with the use of both to be resolved. First, what proportion of cases of anti­PLA2R and anti–neutral endopeptidase as­ what we call “idiopathic” membranous nephrop­ says simultaneously. In addition, an older obser­ athy is caused by anti­PLA2R autoantibodies? Next, vation regarding a putative role for anti–α­enolase what triggers the production of these autoanti­ autoantibodies found in Japanese patients with bodies? Third, how do the autoantibodies pro­ membranous nephropathy should be reexam­ duce the enhanced glomerular permeability to ined.10 The variety of autoantibodies seen in pa­ protein? tients with idiopathic membranous nephropathy Beck et al. suggest that at least 70% of cases may represent the phenomenon of epitope spread­ 82 n engl j med 361;1 nejm.org july 2, 2009 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF LOUISVILLE on May 22, 2012. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved. editorials ing, as observed in other chronic autoimmune activity of the disease in response to treatment. diseases.11 Serial examination of serum samples Five decades after its initial recognition, mem­ obtained and stored years before the apparent branous nephropathy is now entering an exciting onset and diagnosis of membranous nephropa­ and dynamic new era. thy should be enlightening in testing this hy­ Dr. Glassock reports receiving consulting fees from Genentech pothesis.12 (Roche), FibroGen, Novartis, QuestCor, Gilead Sciences, Keryx, and As preva (Vifor), and lecture fees from QuestCor. No other poten­ Better understanding of the potential autolo­ tial conflict of interest relevant to this article was reported. gous or environmental triggers of autoantibody production in patients with membranous nephrop­ From the David Geffen School of Medicine at UCLA, Los Angeles. athy may uncover possible targets for preventing 1. Jones DB. Nephrotic glomerulonephritis. Am J Pathol 1957; the disease. The binding of the autoantibody to 33:313­29. 2. Heymann W, Hackel DB, Harwood S, Wilson SG, Hunter HL. its relevant antigen on the podocyte cell surface Production of nephrotic syndrome in rats by Freund’s adjuvant may be sufficient to initiate the disease process. and rat kidney suspensions. Proc Soc Exp Biol Med 1959;100: However, much data from experimental and clin­ 660­4. 3. Van Damme BJ, Fleuren GJ, Bakker WW, Vernier RL, Hoede­ ical investigations suggest that in situ activation maeker PJ. Experimental glomerulonephritis in the rat induced of the complement cascade and generation of the by antibodies directed against tubular antigens. V. Fixed glomer­ membrane­attack complex of complement in the ular antigens in the pathogenesis of heterologous immune com­ plex glomerulonephritis. Lab Invest 1978;38:502­10. capillary wall play important roles in the ensuing 4. Couser WG, Steinmuller DR, Stilmant MM, Salant DJ, Lowen­ glomerular permeability defects that lead to pro­ stein LM. Experimental glomerulonephritis in the isolated per­ teinuria. This poses a dilemma, since the IgG4 fused rat kidney. J Clin Invest 1978;62:1275­87. 5. Rose NR, Bona C. Defining criteria for autoimmune diseases subclass is known to activate complement only (Witebsky’s postulates revisited). Immunol Today 1993;14:426­30. poorly, if at all, yet the dominant autoantibodies 6. Whitworth JA, Leibowitz S, Kennedy MC, et al. Absence of in the circulation and in the deposits are of the glomerular renal tubular epithelial antigen in membranous glo­ 7 merulonephritis. Clin Nephrol 1976;5:159­62. IgG4 subclass. Perhaps the concomitant produc­ 7. Beck LH Jr, Bonegio RGB, Lambeau G, et al. M­type phos­ tion of IgG1 or IgG2 autoantibodies is required pholipase A2 receptor as target antigen in idiopathic membra­ for the full expression of the abnormal glomer­ nous nephropathy. N Engl J Med 2009;361:11­21. 8. Debiec H, Guigonis
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