Use of a novel therapy for the treatment and understanding of autoimmune membranous nephropathy

UoM administered thesis: Phd

  • Authors:
  • Patrick Hamilton

Abstract

Background: Membranous nephropathy (MN) is amongst the most common causes of adult nephrotic syndrome worldwide. For the majority of patients, it is an autoimmune condition associated with anti-PLA2R autoantibodies. Despite recent advances in our understanding of the condition, much remains unknown and treatment has not changed in two decades. Here we use immunoadsorption therapy to directly remove IgG antibodies from patients with active autoimmune MN to induce remission. Methods: Using Peptide-GAM immunoadsorption we treated 12 patients with autoimmune MN for five consecutive days. Primary outcome was reduction of anti-PLA2R antibodies at day 14. Secondary outcomes were, change in anti- PLA2R level compared to baseline, uPCR, eGFR, EQ5D and adverse events at months 3, 6 and 12. Immune system modelling was carried out using flow cytometry to study cell populations of B cells, PLA2R specific B cells, T cell and monocytes. Results: At week 2 (day 14), median antibody level increased from a baseline of 679 U/mL (IQR 191-1070) to 902 U/mL (IQR 522-2665). Three patients have completed follow up with the first patient becoming antibody negative at week two and remaining negative at last follow up. Using flow cytometry, we demonstrated evidence for a new pathway in the pathogenesis of the disease in the role of natural T Regs and the potential involvement of IgM antibodies. Conclusion: Immunoadsorption therapy to directly remove the pathogenic anti- PLA2R antibody has potential efficacy in autoimmune MN and could avoid the need for toxic medications. We have also described for the first time important new components in the disease pathway to help further our understanding of the underlying mechanisms.

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Original languageEnglish
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Award date1 Aug 2019