Alpha-Lipoic Acid as a Reversible Trigger for NELL1-Associated Membranous Nephropathy: A Case Report

Introduction: Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults. Most “primary” cases are driven by autoantibodies to PLA2R or THSD7A. In 2019, neural epidermal growth factor-like protein 1 (NELL1) was described as another target antigen in MN, typically exhibiting IgG1-dominant, immune deposits. Although first linked to malignancy, NELL1 MN is increasingly associated with thiol-containing compounds such as bucillamine, tiopronin, and alpha lipoic acid (ALA). We present a well documented case of complete remission of nephrotic syndrome after ALA was withdrawn. Case Description: A 49 year old female with type 2 diabetes, obesity, and dyslipidemia noted foamy urine and increasing lower extremities edema one month after initiating ALA 600 mg/day. Her previous kidney function and urinalysis had been normal. Four months after initiation of ALA, her urine protein-to-creatinine ratio peaked at 8.4 g/g. Blood pressure was 115/70 mmHg; serum creatinine was 0.7 mg/dL with a bland urine sediment. She had significantly lower extremity edema. Serologic (HBV, HCV, HIV, ANA) and cancer screening (mammogram, vaginal ultrasound, colonoscopy, CT scan of chest and abdomen) were negative. A kidney biopsy showed MN and minimal interstitial fibrosis/tubular atrophy. Immunofluorescence showed 3+ granular IgG, trace C3, and negative PLA2R. Immunohistochemistry was positive for NELL1. Electron microscopy showed subepithelial and intramembranous deposits and diffuse foot process effacement. ALA was discontinued. Losartan, atorvastatin, and dapagliflozin were started. Over the following twelve months, her UPCR declined to 0.14 g/g, her edema resolved, and renal function remained normal. Discussion: Up to 40% of NELL1-MN cases are linked to malignancy, autoimmune disease, or drug exposure. Thiol groups, like those in ALA, can modify proteins and trigger autoantibodies. ALA, an over-the-counter antioxidant for diabetic neuropathy, has several reported cases related to NELL1-MN. In summary, ALA may be a reversible trigger for NELL1-associated MN. Clinicians should inquire about non-prescription supplements. Discontinuing ALA may allow remission without immunosuppressive therapy.