NELL1 membranous nephropathy: clinical associations provide mechanistic clues

Abstract

Neural epidermal growth factor-like 1 (NELL1) membranous nephropathy (MN) is notable for its segmental deposit distribution, IgG1 dominant deposits, and comparatively high rate of spontaneous remission. It has been associated with a variety of exposures and secondary conditions, specifically use of thiol-containing medications - including lipoic acid, bucillamine, and tiopronin - as well as traditional indigenous medications (TIM) particularly those with high mercury content, and non-steroid anti-inflammatory drugs (NSAIDs). Malignancies, graft vs. host disease (GVHD), infection, and autoimmune conditions have also been associated with NELL1 MN. Herein, we provide a detailed summary of the clinicopathologic features of NELL1 and associations with underlying conditions, with a focus on treatment and outcomes. Rare cases of dual NELL1 and phospholipase A2 receptor (PLA2R) positive MN are reviewed. Genome-wide association study of NELL1, role of NELL1 in other physiologic and pathologic processes, and connection between NELL1 MN and malignancy with relevance of NELL1 tumor staining are examined. Finally, relationships and potential disease mechanisms of thiol- and mercury- associated NELL1 MN are discussed.

Keywords: NELL1; NSAID; drug-induced kidney disease; glomerular disease; lipoic acid; membranous nephropathy.

Figure 1

Neural epidermal growth factor-like 1 (NELL1) membranous nephropathy with (A) “stiff” appearing capillary loops with faint rarefactions of the glomerular basement membrane and subepithelial immune deposits (arrows, Jones stain 400x). (B) By immunofluorescence, there is segmentally distributed granular peripheral capillary wall staining for polyclonal IgG. (C) By electron microscopy, irregularly distributed subepithelial immune deposits are present, with associated podocyte foot process effacement (direct magnification 1900x). (D) By immunohistochemistry, there is corresponding incomplete capillary wall staining of immune deposits for NELL1.