NELL-1 Associated Membranous Nephropathy: A case report of Lipoic Acid-Induced Nephrotic Syndrome

NELL-1 Associated Membranous Nephropathy: A case report of Lipoic Acid-Induced Nephrotic Syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report NELL-1 Associated Membranous Nephropathy: A case report of Lipoic Acid-Induced Nephrotic Syndrome Saman Rashid, Lakshiya Ramamoorthy, Bharath Duraisamy Swami Kannan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4920486/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Membranous nephropathy (MN) often arises from secondary causes such as hepatitis, HIV or heavy metal poisoning, but occasionally occurs without any identifiable underlying cause. Typically, more than 70% of cases are positive for phospholipaseA2 receptor 1(PLA2R1) and thromboplastin type 1 domain-containing protein 7 A (THSD7A). However, emerging evidence suggests associations with novel biomarkers. We present a case in which MN was associated with NELL-1 expression due to lipoic acid use (LA), highlighting the importance of identifying emerging biomarkers for MN diagnosis and timely initiation of appropriate treatment. Clinical Trial Number: Not applicabale Membranous nephropathy NELL-1 lipoic acid nephrotic syndrome. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Membranous nephropathy is an uncommon autoimmune disorder characterized by the subepithelial deposition of immune complexes formed by either circulating or in situ antibodies in the glomerulus of the kidney, leading to nephrotic syndrome. It is the leading cause of nephrotic syndrome in adults, with peak incidence in those aged 50–60 years and a male predominance [ 1 ]. MN is classified into primary and secondary types, with "idiopathic" reserved for cases with no known cause [ 2 ][ 3 ]. Novel biomarkers like NELL-1, NCAM-1, EXT1/2 along with PLA2R1 and THSD7A, are emerging in idiopathic MN. Additionally, lipoic acid, an over-the-counter supplement, has been identified as a potential cause of NELL-1 positive MN, further stressing the need to consider all possible etiological factors. This case report highlights a rare association of Membranous Nephropathy with the novel biomarker NELL-1 possibly due to lipoic acid as a potential contributing factor and draws attention to the necessity of complete diagnostic review in managing nephrotic syndrome to mitigate the progression of disease. Case presentation A 79-year-old man with a recent diagnosis of nephrotic syndrome complicated by renal vein thrombosis, reported a sudden onset of bilateral flank pain, peripheral edema, fatigue and malaise in the month since diagnosis. The pain was not preceded by known factors. He also had complaints of bilateral lower limb pain, with no associated fever, chills or dizziness. He had a history of previous hospitalization a few weeks prior with acute onset bilateral flank pain radiating to the groin, more to the left than to the right. Abdominal CT revealed focal wedge-shaped hypoattenuation in the left kidney consistent with a posterior renal infarct with perinephric stranding. A filling defect suggesting renal vein thrombosis was also noted on CT scan. Laboratory investigations revealed 24g of protein in 24 hours and an albumin concentration of 1.8 g, indicating nephrotic syndrome. Considering the renal vein thrombosis, APS (antiphospholipid syndrome) serology was ordered, which revealed positive titers for ANA (antinuclear antibodies). Moreover, the anti-phospholipase A2 receptor (PLAR2), hepatitis panel, and antineutrophil cytoplasmic antibody (ANCA) results were negative. The patient had a history of MGUS (monoclonal gammopathy of unknown significance) before admission; thus, SPEP (serum protein electrophoresis) was ordered, indicating a faint M spike of 0.3 IgG kappa monoclonal protein, which was unremarkable with respect to the ongoing problem. Kidney biopsy was ordered to determine the etiology of nephrotic syndrome. Both light and electron microscopy revealed features pertaining to membranous nephropathy with 10-20% underlying fibrosis (Figure 1). The PLA2R test was negative, whereas the NELL-1 neural epidermal growth factor test was positive (Figure 2). The patient was on lipoic acid due to its antioxidant properties, and with no other inciting agents identified as shown above, it was advised to discontinue lipoic acid due to its potential association with the development of membranous nephropathy. Discussion Membranous nephropathy (MN) is a rare autoimmune disorder marked by the deposition of immune complexes in the kidney's glomeruli, leading to nephrotic syndrome and potential complications such as thrombosis and kidney failure. While MN primarily affects adults, often presenting as primary MN with a peak incidence in middle age, it can also occur in children, usually associated with secondary conditions. The Heymann nephritis model back in 1959 paved the way for understanding the MN in detail, which came with groundbreaking evidence that the circulating antibodies were the sole factor in play [ 4 ]. After years, in situ, autoantibodies were taken into account when there were cases of MN reported in the absence of circulating antibody complexes, which led to the description of PLA2R, a transmembrane glycoprotein confined to the podocytes as the main target in the majority of patients [ 5 ]. The mechanism behind MN is the deposition of immune complexes in the podocytes of the glomerular basement membranes, which leads to the activation of the complement pathway by three different pathways, leading to the formation of the C5-C9 complement attack complex (Fig. 3 ). Additionally, antibodies can directly affect podocytes, leading to podocyte damage, which impairs protein ultrafiltration [ 6 ]. PLA2R1 and THSD7A are the antigens on the glomerular podocytes, and symptoms of MN depend on the ability of the antibodies binding the basement membrane. Despite being found in other organs such as lung, testes, and placenta, MN is specific to the kidney due to epitope expression variations. PLA2R1 has a cysteine-rich domain similar to a bacterial cell wall enzyme, but no cases link it to bacterial strains like clostridia. Common secondary MN causes, such as hepatitis B or syphilis, lack this domain, not supporting a bacterial etiology. Overexpression of the THSD7A in malignancies explains secondary MN pathogenesis, IgG4 antibodies similar to primary MN. T17 helper cells are crucial in the pathogenesis, normalizing post-treatment. Environmental factors, like particulate matter (PM2.5), trigger PLA2R in lung tissue, inducing inflammation and increasing IL-1 and IL-6 causing vascular endothelial inflammation [ 7 ]. MN can be classified as PLA2R1-positive, THSD7A-positive, or double-negative, NELL-1 is a novel protein found predominantly in double-negative cases and exclusively in podocytes, as confirmed by immunohistochemistry, In NELL-1 positive MN, IgG1 is the main subclass, contrasting with the typical igG4 seen in MN [ 8 ]. NELL-1, named after Nel in the neural tissues, is expressed at low levels in non-neural tissues such as the liver and kidney. Since then 2 homologous genes NELL-1, and NELL-2 have been identified. It encodes an 810 amino-acid protein with terminal thromboplastin-1 like molecule (TSPN), 4 von Willebrand-type, and 6 EGF-like domains. In the kidney the gene expression is higher in the tubules. NELL-1 is the second most common antigen in MN [ 8 ]. Other MN antigens include NCAM1 (neural cell adhesion molecule 1), Sema3B (Semaphorin 3B), and NEP (Neural endopeptidase), the later linked to antenatal MN caused by alloimmunization [ 9 ][ 10 ][ 11 ]. Lipoic acid is an over-the-counter antioxidant and insulin-mimetic supplement which is used in various conditions such as multiple sclerosis (MS), diabetic neuropathy and schizophrenia. High grade proteinuria is an unexpected side effect of the supplementation. LA is still being investigated for its antioxidant and other therapeutic benefits (clinicaltrials.gov). Common side effects of LA use include GI upset, rash, and insulin autoimmune syndrome in rare cases. A large multi-institutional series conducted in 2024, LA (36%) being the most common associated cause for NELL-1 MN. NSAIDS (27%), autoimmune disease (23%) and malignancy (10% recent, 23% any) are among the other causes. Complete remission was achieved in patients without higher degree of tubular atrophy and interstitial fibrosis. NELL-1 MN is associated with thiol-containing medications particularly lipoic acid, tiopronin and bucillamine; and indigenous medications with high levels of mercury in it [ 12 ]. Interestingly, a case series documented the increasing number of NELL-1 MN seen in patients with fairness cream use which contained high levels of mercury [ 13 ]. This is also reported to be seen in graft versus host reaction. The underlying mechanism of LA causing is unclear, but there is a possible association between the sulfhydryl group and the disease development. NSAIDS use NELL-1 MN is thought to be associated with different antigen, specifically proprotein convertase subtilisin/kexin type 6 [ 12 ]. A MS clinical trial conducted to evaluate the use of lipoic acid in MS led to an observation on proteinuria being the common side effects in 5 patients. And on further investigation, biopsy results showed NELL-1 positivity. The onset of proteinuria was within 3 to 12 months of starting the LA supplementation. Workup for neoplasms, autoimmune and infectious diseases were negative. Thus, lipoic acid was discontinued following quantification of proteinuria with albumin-to-creatinine ratio, which improved the clinical and functional profile of the patient proving the cause behind the inciting event. None required immunosuppression [ 14 ]. A retrospective study conducted in 2022, showed out of 15 patients with NELL-1 positive biopsy, 5 achieved complete remission, 4 had partial and the others did not achieve remission; emphasizes further studies to deepen our knowledge about the relationship of LA and MN [ 15 ]. Our case underscores the clinical complexity of nephrotic syndrome with concurrent renal vein thrombosis, signifying the importance of interplay of other minor antigens in the pathogenesis of MN, which determines the appropriate prompt treatment for this patient. Patients with MN should be evaluated for associated conditions regardless of the presence of antibodies, such as cancer; iron deficiency anemia; HBV, HCV, HIV and treponemal infection on indication; chest X-ray is taken to rule out sarcoidosis; history of drug use such as NSAIDs, gold and penicillamine. All the workup turned out to be negative in our case. Only potential cause was lipoic acid, thus was advised to stop using it, and he was monitored appropriately for proteinuria. In MN, conservative management is essential for significant proteinuria. Data from literature suggests that discontinuation of LA and monitoring the patient for proteinuria should be considered as the first line management. Immunosuppressive therapy is reserved for moderate to very high-risk patients and is not usually required if eGFR is normal, unless serious complications are present (Fig. 4 ). Options include Calcineurin Inhibitors (CNI) for 6 months, either alone or with glucocorticoids, or extended therapy based on patient factors. Rituximab (1g IV twice within 2 weeks) has proven more effective than cyclosporine, while cyclophosphamide (2.5 mg/kg/day cyclically or 1.5 mg/kg/day continuously) is used with methylprednisolone. Kidney transplantation is considered for resistant cases. Conclusion This case highlights the role of emerging biomarkers like NELL-1 in Membranous Nephropathy and underscores the need for comprehensive diagnostic evaluation. Early recognition can guide diagnosis and prevent unnecessary treatments. Discontinuing lipoic acid was crucial in this patient’s management, emphasizing the importance of identifying the potential drug-related causes and tailoring treatment strategies accordingly. This case also reinforces the need for vigilant monitoring and individualized management to effectively address MN and associated complications. Declarations Ethical approval and consent to participate Informed consent was obtained or waived by all participants in this study. Consent for publication Authorized consent was obtained from the patient, according to the university standards. Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests. Funding No funding was used in this case study. Author contributions SR supervised the team, and acquired and analysed the data. LR was a major contributor to the drafting, conceptualization and design of the manuscript. B DSK contributed to the design, edited and critically reviewed the manuscript. Acknowledgement We would like to acknowledge Dr. Faizan Babar, the attending physician for the patient in this case report, for his significant role in data compilation and patient care. References Gu Y, Xu H, Tang D. Mechanisms of primary membranous nephropathy. Biomolecules. 2021;11(4):513. Ronco P, Beck L, Debiec H, Fervenza FC, Hou FF, Jha V, et al. Membranous nephropathy. Nat Rev Dis Primers. 2021;7(1):69. Safar-Boueri L, Piya A, Beck LH Jr, et al. Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era. Pediatr Nephrol. 2021;36:19–30. doi:10.1007/s00467-019-04425-1. Heymann W, Hackel DB, Harwood S, Wilson SG, Hunter JL. Production of nephrotic syndrome in rats by Freund's adjuvants and rat kidney suspensions. Proc Soc Exp Biol Med. 1959;100(4):660-4. Trujillo H, Alonso M, Praga M. New ways of understanding membranous nephropathy. Nephron. 2020;144(6):261-71. Ronco P, Debiec H. Molecular pathogenesis of membranous nephropathy. Annu Rev Pathol. 2020;15:287-313. Hoxha E, Reinhard L, Stahl RA. Membranous nephropathy: new pathogenic mechanisms and their clinical implications. Nat Rev Nephrol. 2022;18:466-78. doi:10.1038/s41581-022-00564-1. Sethi S, Debiec H, Madden B, Jadoul M, Fervenza FC, Ronco P. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int. 2020;98(6):1529-36. doi:10.1016/j.kint.2020.07.037. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277-87. doi:10.1056/NEJMoa1409354. Caza TN, Larsen CP. Lipoic acid in neural epidermal growth factor-like 1–associated membranous nephropathy: more than a coincidence? Kidney Int. 2022;101:418-9. doi:10.1016/j.kint.2021.12.001. Debiec H, Lefeu F, Kemper MJ, Niaudet P, Deschenes G, Ludwig M, et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N Engl J Med. 2004;348(23):2323-32. doi:10.1056/NEJMoa041703. Avasare RS, Clark S, Spain RI, Wusirika R, Rope R, Gurley S, et al. Characteristics and outcomes of NELL1 membranous nephropathy in lipoic acid users and nonusers. Kidney Int Rep. 2024;9:1379-86. Narayanan R, Sivadas S, Kurien AA. NELL-1–associated membranous nephropathy linked to skin fairness cream use: insights from an Indian case series. Kidney Int. 2024;105(6):1316-9. doi:10.1016/j.kint.2024.03.025. Spain RI, Andeen NK, Gibson PC, Samuels MH, Morris CD, Solomon AJ, et al. Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)–associated membranous nephropathy. Kidney Int. 2021;100:1208-13. doi:10.1016/j.kint.2021.10.010. Caza TN, Larsen CP. Lipoic acid in neural epidermal growth factor-like 1–associated membranous nephropathy: more than a coincidence? Kidney Int. 2022;101:418-9. doi:10.1016/j.kint.2021.12.001. Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, et al.; GEMRITUX Study Group. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. J Am Soc Nephrol. 2017;28(1):348-58. doi:10.1681/ASN.2016040449. Kadatz M, Klarenbach S, So H, Fervenza FC, Cattran DC, Barbour SJ. Rituximab or cyclosporine A for the treatment of membranous nephropathy: Economic evaluation of the MENTOR trial. Nephrol Dial Transplant. 2024. doi:10.1093/ndt/gfae084.of the MENTOR trial. Nephrol Dial Transplant. 2024. https://doi.org/10.1093/ndt/gfae084 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4920486","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":347238581,"identity":"8494ce18-6074-47c7-ab97-7a14424f34b5","order_by":0,"name":"Saman Rashid","email":"","orcid":"","institution":"University of Kentucky","correspondingAuthor":false,"prefix":"","firstName":"Saman","middleName":"","lastName":"Rashid","suffix":""},{"id":347238582,"identity":"569cfc91-caa9-44e5-a824-e283acf7b124","order_by":1,"name":"Lakshiya Ramamoorthy","email":"data:image/png;base64,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","orcid":"","institution":"Madras Medical College","correspondingAuthor":true,"prefix":"","firstName":"Lakshiya","middleName":"","lastName":"Ramamoorthy","suffix":""},{"id":347238584,"identity":"d3af47d4-0d8b-4783-a3b3-3805b910efd8","order_by":2,"name":"Bharath Duraisamy Swami Kannan","email":"","orcid":"","institution":"Sivagangai government medical college","correspondingAuthor":false,"prefix":"","firstName":"Bharath","middleName":"Duraisamy Swami","lastName":"Kannan","suffix":""}],"badges":[],"createdAt":"2024-08-15 16:21:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4920486/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4920486/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64285037,"identity":"245e09ab-1efb-4c89-89d9-2a293f0612a3","added_by":"auto","created_at":"2024-09-11 08:35:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":377165,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Low-power view of renal biopsy demonstrating extensive interstitial fibrosis and tubular atrophy, indicative of chronic kidney damage; (B) Renal biopsy showing thickening of the vascular walls, complicating membranous nephropathy; (C) High power view of renal biopsy under periodic acid Schiff (PAS) staining showing subepithelial immune complex deposits; (D) Immunofluorescence staining of renal biopsy showing IgG deposits.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4920486/v1/a8297df830e11580493b4d6e.png"},{"id":64285036,"identity":"04869a04-fb78-4093-b0c2-940c16466109","added_by":"auto","created_at":"2024-09-11 08:35:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":305290,"visible":true,"origin":"","legend":"\u003cp\u003e(A-C) Electron microscopy of renal biopsy revealing dense subepithelial electron-dense deposits characteristic of membranous nephropathy, detailing the damage in the glomerular basement membrane; (D) Immunohistochemical staining for NELL-1 in a renal biopsy sample showing positive expression, indicating the role of pathogenesis in MN.\u003c/p\u003e\n\u003cp\u003eThe patient was on lipoic acid due to its antioxidant properties, and with no other inciting agents identified as shown above, it was advised to discontinue lipoic acid due to its potential association with the development of membranous nephropathy.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4920486/v1/1e2f1899c81dd32d1eee73f7.png"},{"id":64285901,"identity":"2cbb45d8-92f3-48ae-b357-a05d51dce75b","added_by":"auto","created_at":"2024-09-11 08:43:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":80102,"visible":true,"origin":"","legend":"\u003cp\u003eKey pathways involved in the pathogenesis of membranous nephropathy.\u003c/p\u003e\n\u003cp\u003ePLA2R1 and THSD7A are antigens on the glomerular podocytes, and symptoms of MN depend on the ability of the antibodies to bind to the basement membrane. Despite being found in other organs such as the lung, testes, and placenta, MN is specific to the kidney due to epitope expression variations. PLA2R1 has a cysteine-rich domain similar to that of a bacterial cell wall enzyme, but no cases link it to bacterial strains such as clostridia. Common secondary MN causes, such as hepatitis B or syphilis, lack this domain, preventing a bacterial etiology. Overexpression of THSD7A in malignancies explains secondary MN pathogenesis, and IgG4 antibodies are similar to those in primary MN. T17 helper cells are crucial pathogenesis, and normalize post-treatment. Environmental factors, such as particulate matter (PM2.5), trigger PLA2R in lung tissue, inducing inflammation and increasing IL-1 and IL-6 causing vascular endothelial inflammation [7].\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4920486/v1/cb45c15e484c3375d8b916bd.png"},{"id":64285033,"identity":"300d977b-d8a7-46ae-a58e-63cc1f15b1a0","added_by":"auto","created_at":"2024-09-11 08:35:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":169686,"visible":true,"origin":"","legend":"\u003cp\u003eRisk categorization of membranous nephropathy.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4920486/v1/b459eea1b1bbcf1efa28f339.png"},{"id":67446459,"identity":"d1c32300-1364-460c-9ef7-24aca773733f","added_by":"auto","created_at":"2024-10-25 06:46:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1468774,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4920486/v1/61d8b949-2249-4bc0-b58c-f652b60f4e37.pdf"},{"id":64285035,"identity":"6957a424-216a-4cd8-9264-6efc306c49e7","added_by":"auto","created_at":"2024-09-11 08:35:46","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2612506,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFileMembranousNephropathy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4920486/v1/286a82d9edd5a577311b2d45.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"NELL-1 Associated Membranous Nephropathy: A case report of Lipoic Acid-Induced Nephrotic Syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMembranous nephropathy is an uncommon autoimmune disorder characterized by the subepithelial deposition of immune complexes formed by either circulating or in situ antibodies in the glomerulus of the kidney, leading to nephrotic syndrome. It is the leading cause of nephrotic syndrome in adults, with peak incidence in those aged 50\u0026ndash;60 years and a male predominance [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. MN is classified into primary and secondary types, with \"idiopathic\" reserved for cases with no known cause [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Novel biomarkers like NELL-1, NCAM-1, EXT1/2 along with PLA2R1 and THSD7A, are emerging in idiopathic MN. Additionally, lipoic acid, an over-the-counter supplement, has been identified as a potential cause of NELL-1 positive MN, further stressing the need to consider all possible etiological factors. This case report highlights a rare association of Membranous Nephropathy with the novel biomarker NELL-1 possibly due to lipoic acid as a potential contributing factor and draws attention to the necessity of complete diagnostic review in managing nephrotic syndrome to mitigate the progression of disease.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 79-year-old man with a recent diagnosis of nephrotic syndrome complicated by renal vein thrombosis, reported a sudden onset of\u0026nbsp;bilateral flank pain, peripheral edema, fatigue and malaise in the month since diagnosis. The pain was not preceded by known factors. He also had complaints of bilateral lower limb pain, with no associated fever, chills or dizziness. He had a history of previous hospitalization a few weeks prior with acute onset bilateral flank pain radiating to the groin, more to the left than to the right. Abdominal CT revealed focal wedge-shaped hypoattenuation in the left kidney consistent with a posterior renal infarct with perinephric stranding. A filling defect suggesting renal vein thrombosis was also noted on CT scan.\u003c/p\u003e\n\u003cp\u003eLaboratory investigations revealed 24g of protein in 24 hours and an albumin concentration of 1.8 g, indicating nephrotic syndrome. Considering the renal vein thrombosis, APS (antiphospholipid syndrome) serology was ordered, which revealed positive titers for ANA (antinuclear antibodies). Moreover, the anti-phospholipase A2 receptor (PLAR2), hepatitis panel, and antineutrophil cytoplasmic antibody (ANCA) results were negative. \u0026nbsp;The patient had a history of MGUS (monoclonal gammopathy of unknown significance) before admission; thus, SPEP (serum protein electrophoresis) was ordered, indicating a faint M spike of 0.3 IgG kappa monoclonal protein, which was unremarkable with respect to the ongoing problem.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKidney biopsy was ordered to determine the etiology of nephrotic syndrome. Both light and electron microscopy revealed features pertaining to membranous nephropathy with 10-20% underlying fibrosis (Figure 1). The PLA2R test was negative, whereas the NELL-1 neural epidermal growth factor test was positive (Figure 2).\u003c/p\u003e\n\u003cp\u003eThe patient was on lipoic acid due to its antioxidant properties, and with no other inciting agents identified as shown above, it was advised to discontinue lipoic acid due to its potential association with the development of membranous nephropathy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMembranous nephropathy (MN) is a rare autoimmune disorder marked by the deposition of immune complexes in the kidney's glomeruli, leading to nephrotic syndrome and potential complications such as thrombosis and kidney failure. While MN primarily affects adults, often presenting as primary MN with a peak incidence in middle age, it can also occur in children, usually associated with secondary conditions. The Heymann nephritis model back in 1959 paved the way for understanding the MN in detail, which came with groundbreaking evidence that the circulating antibodies were the sole factor in play [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. After years, in situ, autoantibodies were taken into account when there were cases of MN reported in the absence of circulating antibody complexes, which led to the description of PLA2R, a transmembrane glycoprotein confined to the podocytes as the main target in the majority of patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mechanism behind MN is the deposition of immune complexes in the podocytes of the glomerular basement membranes, which leads to the activation of the complement pathway by three different pathways, leading to the formation of the C5-C9 complement attack complex (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Additionally, antibodies can directly affect podocytes, leading to podocyte damage, which impairs protein ultrafiltration [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePLA2R1 and THSD7A are the antigens on the glomerular podocytes, and symptoms of MN depend on the ability of the antibodies binding the basement membrane. Despite being found in other organs such as lung, testes, and placenta, MN is specific to the kidney due to epitope expression variations. PLA2R1 has a cysteine-rich domain similar to a bacterial cell wall enzyme, but no cases link it to bacterial strains like clostridia. Common secondary MN causes, such as hepatitis B or syphilis, lack this domain, not supporting a bacterial etiology. Overexpression of the THSD7A in malignancies explains secondary MN pathogenesis, IgG4 antibodies similar to primary MN. T17 helper cells are crucial in the pathogenesis, normalizing post-treatment. Environmental factors, like particulate matter (PM2.5), trigger PLA2R in lung tissue, inducing inflammation and increasing IL-1 and IL-6 causing vascular endothelial inflammation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMN can be classified as PLA2R1-positive, THSD7A-positive, or double-negative, NELL-1 is a novel protein found predominantly in double-negative cases and exclusively in podocytes, as confirmed by immunohistochemistry, In NELL-1 positive MN, IgG1 is the main subclass, contrasting with the typical igG4 seen in MN [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. NELL-1, named after Nel in the neural tissues, is expressed at low levels in non-neural tissues such as the liver and kidney. Since then 2 homologous genes \u003cem\u003eNELL-1, and NELL-2\u003c/em\u003e have been identified. It encodes an 810 amino-acid protein with terminal thromboplastin-1 like molecule (TSPN), 4 von Willebrand-type, and 6 EGF-like domains. In the kidney the gene expression is higher in the tubules. NELL-1 is the second most common antigen in MN [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Other MN antigens include NCAM1 (neural cell adhesion molecule 1), Sema3B (Semaphorin 3B), and NEP (Neural endopeptidase), the later linked to antenatal MN caused by alloimmunization [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e][\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLipoic acid is an over-the-counter antioxidant and insulin-mimetic supplement which is used in various conditions such as multiple sclerosis (MS), diabetic neuropathy and schizophrenia. High grade proteinuria is an unexpected side effect of the supplementation. LA is still being investigated for its antioxidant and other therapeutic benefits (clinicaltrials.gov). Common side effects of LA use include GI upset, rash, and insulin autoimmune syndrome in rare cases. A large multi-institutional series conducted in 2024, LA (36%) being the most common associated cause for NELL-1 MN. NSAIDS (27%), autoimmune disease (23%) and malignancy (10% recent, 23% any) are among the other causes. Complete remission was achieved in patients without higher degree of tubular atrophy and interstitial fibrosis.\u003c/p\u003e \u003cp\u003eNELL-1 MN is associated with thiol-containing medications particularly lipoic acid, tiopronin and bucillamine; and indigenous medications with high levels of mercury in it [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Interestingly, a case series documented the increasing number of NELL-1 MN seen in patients with fairness cream use which contained high levels of mercury [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This is also reported to be seen in graft versus host reaction. The underlying mechanism of LA causing is unclear, but there is a possible association between the sulfhydryl group and the disease development. NSAIDS use NELL-1 MN is thought to be associated with different antigen, specifically proprotein convertase subtilisin/kexin type 6 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA MS clinical trial conducted to evaluate the use of lipoic acid in MS led to an observation on proteinuria being the common side effects in 5 patients. And on further investigation, biopsy results showed NELL-1 positivity. The onset of proteinuria was within 3 to 12 months of starting the LA supplementation. Workup for neoplasms, autoimmune and infectious diseases were negative. Thus, lipoic acid was discontinued following quantification of proteinuria with albumin-to-creatinine ratio, which improved the clinical and functional profile of the patient proving the cause behind the inciting event. None required immunosuppression [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A retrospective study conducted in 2022, showed out of 15 patients with NELL-1 positive biopsy, 5 achieved complete remission, 4 had partial and the others did not achieve remission; emphasizes further studies to deepen our knowledge about the relationship of LA and MN [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur case underscores the clinical complexity of nephrotic syndrome with concurrent renal vein thrombosis, signifying the importance of interplay of other minor antigens in the pathogenesis of MN, which determines the appropriate prompt treatment for this patient. Patients with MN should be evaluated for associated conditions regardless of the presence of antibodies, such as cancer; iron deficiency anemia; HBV, HCV, HIV and treponemal infection on indication; chest X-ray is taken to rule out sarcoidosis; history of drug use such as NSAIDs, gold and penicillamine. All the workup turned out to be negative in our case. Only potential cause was lipoic acid, thus was advised to stop using it, and he was monitored appropriately for proteinuria.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn MN, conservative management is essential for significant proteinuria. Data from literature suggests that discontinuation of LA and monitoring the patient for proteinuria should be considered as the first line management. Immunosuppressive therapy is reserved for moderate to very high-risk patients and is not usually required if eGFR is normal, unless serious complications are present (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Options include Calcineurin Inhibitors (CNI) for 6 months, either alone or with glucocorticoids, or extended therapy based on patient factors. Rituximab (1g IV twice within 2 weeks) has proven more effective than cyclosporine, while cyclophosphamide (2.5 mg/kg/day cyclically or 1.5 mg/kg/day continuously) is used with methylprednisolone. Kidney transplantation is considered for resistant cases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the role of emerging biomarkers like NELL-1 in Membranous Nephropathy and underscores the need for comprehensive diagnostic evaluation. Early recognition can guide diagnosis and prevent unnecessary treatments. Discontinuing lipoic acid was crucial in this patient\u0026rsquo;s management, emphasizing the importance of identifying the potential drug-related causes and tailoring treatment strategies accordingly. This case also reinforces the need for vigilant monitoring and individualized management to effectively address MN and associated complications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained or waived by all participants in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthorized consent was obtained from the patient, according to the university standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was used in this case study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSR supervised the team, and acquired and analysed the data.\u003c/p\u003e\n\u003cp\u003eLR was a major contributor to the drafting, conceptualization and design of the manuscript.\u003c/p\u003e\n\u003cp\u003eB DSK contributed to the design, edited and critically reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge Dr. Faizan Babar, the attending physician for the patient in this case report, for his significant role in data compilation and patient care.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGu Y, Xu H, Tang D. Mechanisms of primary membranous nephropathy. Biomolecules. 2021;11(4):513.\u003c/li\u003e\n \u003cli\u003eRonco P, Beck L, Debiec H, Fervenza FC, Hou FF, Jha V, et al. Membranous nephropathy. Nat Rev Dis Primers. 2021;7(1):69.\u003c/li\u003e\n \u003cli\u003eSafar-Boueri L, Piya A, Beck LH Jr, et al. Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era. Pediatr Nephrol. 2021;36:19\u0026ndash;30. doi:10.1007/s00467-019-04425-1.\u003c/li\u003e\n \u003cli\u003eHeymann W, Hackel DB, Harwood S, Wilson SG, Hunter JL. Production of nephrotic syndrome in rats by Freund\u0026apos;s adjuvants and rat kidney suspensions. Proc Soc Exp Biol Med. 1959;100(4):660-4.\u003c/li\u003e\n \u003cli\u003eTrujillo H, Alonso M, Praga M. New ways of understanding membranous nephropathy. Nephron. 2020;144(6):261-71.\u003c/li\u003e\n \u003cli\u003eRonco P, Debiec H. Molecular pathogenesis of membranous nephropathy. Annu Rev Pathol. 2020;15:287-313.\u003c/li\u003e\n \u003cli\u003eHoxha E, Reinhard L, Stahl RA. Membranous nephropathy: new pathogenic mechanisms and their clinical implications. Nat Rev Nephrol. 2022;18:466-78. doi:10.1038/s41581-022-00564-1.\u003c/li\u003e\n \u003cli\u003eSethi S, Debiec H, Madden B, Jadoul M, Fervenza FC, Ronco P. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int. 2020;98(6):1529-36. doi:10.1016/j.kint.2020.07.037.\u003c/li\u003e\n \u003cli\u003eTomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277-87. doi:10.1056/NEJMoa1409354.\u003c/li\u003e\n \u003cli\u003eCaza TN, Larsen CP. Lipoic acid in neural epidermal growth factor-like 1\u0026ndash;associated membranous nephropathy: more than a coincidence? Kidney Int. 2022;101:418-9. doi:10.1016/j.kint.2021.12.001.\u003c/li\u003e\n \u003cli\u003eDebiec H, Lefeu F, Kemper MJ, Niaudet P, Deschenes G, Ludwig M, et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N Engl J Med. 2004;348(23):2323-32. doi:10.1056/NEJMoa041703.\u003c/li\u003e\n \u003cli\u003eAvasare RS, Clark S, Spain RI, Wusirika R, Rope R, Gurley S, et al. Characteristics and outcomes of NELL1 membranous nephropathy in lipoic acid users and nonusers. Kidney Int Rep. 2024;9:1379-86.\u003c/li\u003e\n \u003cli\u003eNarayanan R, Sivadas S, Kurien AA. NELL-1\u0026ndash;associated membranous nephropathy linked to skin fairness cream use: insights from an Indian case series. Kidney Int. 2024;105(6):1316-9. doi:10.1016/j.kint.2024.03.025.\u003c/li\u003e\n \u003cli\u003eSpain RI, Andeen NK, Gibson PC, Samuels MH, Morris CD, Solomon AJ, et al. Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)\u0026ndash;associated membranous nephropathy. Kidney Int. 2021;100:1208-13. doi:10.1016/j.kint.2021.10.010.\u003c/li\u003e\n \u003cli\u003eCaza TN, Larsen CP. Lipoic acid in neural epidermal growth factor-like 1\u0026ndash;associated membranous nephropathy: more than a coincidence? Kidney Int. 2022;101:418-9. doi:10.1016/j.kint.2021.12.001.\u003c/li\u003e\n \u003cli\u003eDahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, et al.; GEMRITUX Study Group. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. J Am Soc Nephrol. 2017;28(1):348-58. doi:10.1681/ASN.2016040449.\u003c/li\u003e\n \u003cli\u003eKadatz M, Klarenbach S, So H, Fervenza FC, Cattran DC, Barbour SJ. Rituximab or cyclosporine A for the treatment of membranous nephropathy: Economic evaluation of the MENTOR trial. Nephrol Dial Transplant. 2024. doi:10.1093/ndt/gfae084.of the MENTOR trial. Nephrol Dial Transplant. 2024.\u0026nbsp;\u003ca\u003ehttps://doi.org/10.1093/ndt/gfae084\u003c/a\u003e.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Membranous nephropathy, NELL-1, lipoic acid, nephrotic syndrome.","lastPublishedDoi":"10.21203/rs.3.rs-4920486/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4920486/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMembranous nephropathy (MN) often arises from secondary causes such as hepatitis, HIV or heavy metal poisoning, but occasionally occurs without any identifiable underlying cause. Typically, more than 70% of cases are positive for phospholipaseA2 receptor 1(PLA2R1) and thromboplastin type 1 domain-containing protein 7 A (THSD7A). However, emerging evidence suggests associations with novel biomarkers. We present a case in which MN was associated with NELL-1 expression due to lipoic acid use (LA), highlighting the importance of identifying emerging biomarkers for MN diagnosis and timely initiation of appropriate treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number: \u003c/strong\u003eNot applicabale\u003c/p\u003e","manuscriptTitle":"NELL-1 Associated Membranous Nephropathy: A case report of Lipoic Acid-Induced Nephrotic Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-11 08:35:41","doi":"10.21203/rs.3.rs-4920486/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c76200e2-42f0-4bfc-b71e-9b4485e4fef4","owner":[],"postedDate":"September 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-25T06:38:38+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-11 08:35:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4920486","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4920486","identity":"rs-4920486","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}