Alpha Lipoic Acid- and NELL1-Associated Membranous Nephropathy

Introduction: Membranous nephropathy (MN) is a leading cause of nephrotic syndrome, representing a spectrum of diseases with a common histological pattern of Immunoglobulin and complement-containing immune deposits in the subepithelial position. 75% of cases are primary to some response to a normal podocyte antigen antigen (of which PLA2R is most common) whereas the other cases are secondary to a systemic process. Neural Epidermal Growth Factor-Like 1 (NELL-1) has been implicated as a target antigen in MN. Alpha Lipoic Acid (ALA), a common over the counter supplement, is often recommended for diabetic neuropathy. We describe a rare case of ALA associated NELL-1 positive MN with complete resolution of proteinuria when the drug was stopped. Case Description: A 69 year-old female with prediabetes and controlled hypertension presented to clinic for proteinuria in 2022. The patient had no history of CKD. She was prescribed 1200 mg of ALA in October 2020 for peripheral neuropathy. Urinalysis in 2017 was normal. UA in January 2022 revealed an Albumin:Cr 1774 and Serum Creatinine 0.70. 24 hour total protein excretion was 1,625 mg, albumin 1,160 mg and Creatinine clearance of 79. SPEP, UPEP, and Serum Immunofixation were normal. Although the patient had a positive ANA (1:1280), further workup was negative, and rheumatology evaluated the positive lab value to not be clinically significant. Hepatitis panel was negative. Renal biopsy showed segmental membranous nephropathy with diffuse staining for IgG3 and NELL-1. ALA was stopped in June 2022, and in June 2023 there was complete resolution of proteinuria (135 mg 24 hour total protein). She was up to date with all age-appropriate cancer-related screening exams. Discussion: Recent advances in serologic testing have allowed for a biopsy-sparing approach in diagnosis and treatment of PLA2R associated MN. NELL-1 is the second most common antigen identified in MN. There is an opportunity to expand upon this diagnostic approach to include other target antigens such as NELL-1. ALA associated NELL-1 MN is rarely reported upon in literature. Furthermore, there is only one retrospective review of this association. The growing recognition of the interplay between ALA and NELL-1 MN should prompt research into the unclear mechanism behind how this association occurs. Understanding this relationship will guide intervention to both treat and prevent ALA associated MN.