Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers

NELL1 membranous nephropathy: clinical associations provide mechanistic clues

“…In 2019, two groups identified neural epidermal growth factorlike 1 (NELL1) podocyte antigen in a subset of MN with distinct histologic and immunologic features, generally segmental glomerular capillary loop subepithelial deposits with IgG1 dominant staining (12,13). Although initially suggested to be largely a primary MN comprising 16% of PLA2R negative MN (12), secondary associations were subsequently discovered and account for the majority of cases in some studies (up 89% in our recent series) (26). The strength of these associations, disease prevalence and epidemiologic characteristics, and clinical outcomes vary by study and location, and are summarized in Table 1.…”

“…Notably, NELL1 MN has relatively similar pathologic features regardless of underlying etiology. However, clinical outcomes are impacted by the details of – or discovery of – the underlying exposure or condition ( 26 ), as discussed below.…”

“…The largest series of TIM-associated MN was reported from India, where NELL1 MN comprised 34% of all MN and 88% of TIM-MN ( 36 ), again suggesting that auto-reactivity to the NELL1 antigen specifically may account for most historically reported mercury-associated MN. The remission rate of NELL1 MN in patients on TIM (74% at 3.5 months) ( 36 ) or lipoic acid (88% at 11 months, without immunosuppression) ( 26 ) is quite high, and significantly higher than other NELL1 MN associations ( 26 ), likely related to relative simplicity of discontinuing the exposure (i.e. compared with treating a complex underlying condition).…”

“…MN in the setting of hematopoietic stem cell transplant and graft-versus-host disease (GVHD) can occur with the NELL1 antigen ( 29 ) although is much more commonly associated with the protocadherin FAT1 antigen ( 18 ). Autoimmune disease, seen in 0-31% of reported patients ( 13 , 26 , 36 , 37 ), including sarcoidosis ( 40 , 41 ), rheumatoid arthritis (especially patients treated with bucillamine) ( 37 – 39 ) and others may also be associated with NELL1 MN. Finally, NSAIDs have also been associated with NELL1 MN ( 26 , 34 , 40 ) (up to 27%), though are also associated with the PCSK 6 antigen ( 21 ) and clinical correlations between NSAID cessation and remission are currently less well-documented than for thiol- or mercury- associated NELL1 MN.…”

“…Lipoic acid is chiral and natural forms exist as the R enantiomer, whereas ex vivo synthesized lipoic acid supplements contain a racemic mixture of both R and S enantiomers ( 71 – 73 ), which have potentially differing biologic effects. Neither specific dose toxicity nor specific manufacturers have been connected to lipoic acid associated NELL1 MN ( 26 , 31 ). Adverse immune events associated with thiol compounds also include pemphigus, rash, oral mucosal ulcers, and, for lipoic acid, insulin autoimmune syndrome in genetically susceptible individuals (HLA-DRB1*0406 and DRB1*0403) ( 42 , 74 – 77 ).…”