Renal adverse effects and Diffuse Podocytopathy Associated With Semaglutide

Diffuse podocytopathy Associated With Semaglutide adverse effects

Publication: Annals of Internal Medicine: Clinical Cases Volume 3, Number 5

Abstract: We observed three cases in which minimal change kidney disease occurred after exposure to semaglutide, a medication for type 2 diabetes. Two out of the three cases showed the formation of new antinephrin antibodies. All patients fully recovered after stopping semaglutide and receiving immunosuppressive therapy. This report sheds light on a new association that prescribers should be mindful of, especially considering the increasing use of semaglutide. Introduction: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are innovative medications for diabetes that not only improve diabetes management but also provide various benefits, such as heart protection, weight loss, and kidney protection. Recent trials have shown promising results, leading to the anticipation of a surge in the use of GLP-1RAs. However, there is a need for further research to confirm the potential adverse effects associated with these drugs. Murine models have suggested that GLP-1RAs might influence the immune system and autoimmune diseases, but more evidence is required. We present three cases of biopsy-proven diffuse podocytopathy–minimal change disease (MCD) associated with exposure to semaglutide.

Case Report –

A 60-year-old woman with a previous medical history of hypothyroidism was referred for the evaluation of anasarca. She had been only taking l-thyroxine at a stable dose for many years until approximately 2.5 months before her presentation when she began receiving subcutaneous injections of semaglutide at a dose of 0.25 mg weekly for weight loss. Three weeks before her presentation, her semaglutide dosage was increased to 1 mg per week. After this dose adjustment, she began experiencing symptoms such as headaches, nausea, and bloating, and she gained 10 kg in weight over the following 2 weeks. She self-discontinued the semaglutide at that point. Notably, she had no history of viral infections and no exposure to nonsteroidal anti-inflammatory drugs, contrast agents, or nephrotoxic substances. Her initial work-up included a urinalysis, which revealed 100 mg/dL of protein, UPCR 2.9 g/g, UACR 2 g/g, serum albumin 2.9 g/dL, creatinine 0.64 mg/dL, low-density lipoprotein 233 mg/dL, and thyroid-stimulating hormone 6.8 uIU/mL. Additional tests for ANCA, double-stranded DNA, antiphospholipase a2 receptor, serum protein electrophoresis, serum immunofixation electrophoresis, HIV, syphilis, and hepatitis B and C serologies all returned negative results. C3 and C4 were within the normal range. A kidney biopsy was performed, revealing diffuse effacement of podocyte foot processes, consistent with MCD. IF did not reveal fine dusting by IgG staining. Consequently, the patient was initiated on prednisone treatment, starting at a dose of 60 mg, daily for 4 weeks, followed by a gradual taper of 10 mg per week until discontinuation. Two months into her prednisone course, her proteinuria decreased to 0.3 g/g. Her low-density lipoprotein cholesterol levels also improved, decreasing to 94 mg/dL, and her weight returned to baseline.

Our report is the first to document an association with glomerulopathy. When we searched the Food and Drug Administration Adverse Event Reporting System database, we found 17 cases of proteinuria and 1 of glomerulonephritis (GN) associated with semaglutide. A query of the European Database of Suspected Adverse Drug Reaction Reports (Eudravigilance) also revealed 1 report of GN and 8 reports of proteinuria related to semaglutide. Similar adverse kidney events were also identified with other GLP1-RAs, such as liraglutide and dulaglutide. These findings suggest a class effect of GLP1-RA rather than a specific side effect attributed solely to semaglutide. Although these databases cannot confirm definitive causality, our observations support the association between GLP1-RA and glomerulopathy and suggest that such cases may be underdiagnosed. All kidney biopsies displayed diffuse podocytopathy, with some showing fine IgG podocyte dusting on immunofluorescence (IF), indicating an antinephrin antibody-mediated process. A circulating anti-nephrin antibody was detected in one case, and nephrin co-localization with IgG was also observed on biopsy. These findings imply that semaglutide-associated podocytopathy may be linked to the de novo formation of antinephrin antibodies, potentially contributing to the pathogenesis of podocytopathy. Furthermore, although GLP1-RA is known for its anti-inflammatory effects, some reports have indicated an association with autoimmune diseases, such as autoimmune hepatitis and rheumatoid arthritis. This suggests a potential involvement of GLP1-RA in triggering autoimmunity in certain patients. Several hypotheses can be proposed to elucidate the mechanism by which semaglutide induces the formation of antinephrin antibodies. These include a type 2 systemic hypersensitivity reaction, the development of antisemaglutide antibodies leading to an immune response against nephrin, or semaglutide acting as a triggering factor for disease development in individuals with an underlying genetic predisposition.