Drug-Induced Membranous Nephropathy: Piecing Together Clues to Understand Disease Mechanisms

There is a resurgence of interest in drug-induced membranous nephropathy because of the widespread availability of recently discovered culprit medications, such as lipoic acid supplements, mercury in skin-lightening creams, and nonsteroidal anti-inflammatory drugs, and the relationship between these drugs and newly described target antigens. The clinical syndromes associated with drug-induced membranous nephropathy are similar in that proteinuria ranges from low grade to nephrotic range and generally remits within months of drug cessation. Histology is notable for subepithelial deposits that are IgG1 subclass predominant, sometimes with a unique segmental distribution. The two antigens associated with drug-induced membranous nephropathy are neural epidermal growth factor-like 1 and proprotein convertase subtilisin/kexin type 6. Notably, several of the culprit drugs contain one or more sulfhydryl groups that may have potential mechanistic relevance. In this review, we explore past research investigations into mechanisms of membranous nephropathy associated with gold salts, penicillamine, and mercury and use these historical studies as the basis for formulating new hypotheses on how drugs might promote immune dysregulation and, ultimately, membranous nephropathy.