Human idiopathic membranous nephropathy--a mystery solved?

Just over 50 years ago, the late David Jones1 iden­ tified (using the periodic acid–Schiff and meth­ enamine silver stains) the unique glomerular pathologic features of membranous nephropathy, thus distinguishing it from other causes of “ne­ phrotic glomerulonephritis.” Subsequent immuno­ fluorescence and electron­microscopical studies established that membranous nephropathy was also characterized by striking granular aggrega­ tions of IgG and electron­dense deposits along the outer (or subepithelial) aspect of the glomer­ ular basement membrane. These glomerular IgG deposits were initially believed to represent an accumulation of immune complexes arising from the circulation, as is found with glomerulonephri­ tis in a rabbit model (chronic serum sickness). In 1959, Heymann et al.2 described a rat mod­ el of membranous nephropathy, similar to the dis­ ease in humans, induced by active immunization with crude kidney extracts in complete Freund’s adjuvant. Initially, this model was also believed to be due to deposition of immune complexes from the circulation. Subsequently, however, Van Damme et al.3 and Couser et al.4 demonstrated that a circulating antibody reacted with and bound to the primary antigenic target located on podo­ cytes — the visceral epithelial cells of the glo­ merulus — indicating that the disease was caused by the in situ formation of immune complexes. Others soon showed that additional antigens, nor­ mally extrinsic to the kidney, that were “planted” artificially in the glomeruli (the glomerular base­ ment membrane or podocyte) through biophys­ ical attraction to the capillary wall could provoke an identical lesion (Fig. 1). Both the target antigen and the autoantibody operative in Heymann’s model were eventually characterized; thus, all of Witebsky’s postulates5 were fulfilled, defining the autoimmune nature of the disease in the rat model. However, translation of the pathogenesis of the rat model to idiopathic membranous nephrop­ athy in humans proved difficult. The target an­ tigen responsible for Heymann’s model appeared to be absent in human kidneys.6 Diligent search­ es for the autoantibody against the “Heymann” antigen (now known to be megalin [glycoprotein 330]) were unrewarding.6 Thus, the true patho­ genesis of human idiopathic membranous ne­ phropathy remained unresolved. Now, this long­lasting mystery may well have been solved by Beck et al.,7 as reported in this issue of the Journal. Autoantibodies against an antigen normally expressed on the podocyte cell membrane in humans, the M­type phospholipase A2 receptor (PLA2R), appear to circulate and bind to a conformational epitope (or epitopes) present on PLA2R, producing in situ deposits character­ istic of those associated with membranous ne­ phropathy. These autoantibodies are large ly, but not exclusively, immunoglobulins of the IgG4 sub­ class, similar to those seen in most instances of idiopathic membranous nephropathy in patients. Other renal diseases and secondary forms of membranous nephropathy (such as lupus mem­ branous nephropathy) do not appear to involve such autoantibodies. Beck et al. also present preliminary indications of an association between the clinical features of the disease (proteinuria and the nephrotic syn­ drome) and the presence and titer of the circu­ lating autoantibodies. If the disease can be trans­ ferred to nonhuman primates that express the PLA2R antigen on podocytes or if the subepithe­ lial deposits can be shown to recur rapidly in a kidney transplanted from a normal donor to a