In Vitro Immunomodulation in Membranous Nephropathy Relapses

Membranous Nephropathy (MN) is a rare autoimmune renal disease and the first cause of nephrotic syndrome in adults. In one third of cases, it progresses to end-stage renal failure. Rituximab has shown very good efficacy (60-80%) and excellent safety in this indication. However, one third of MN patients relapse after a course of rituximab, raising the question of maintenance treatment or repeated courses of rituximab whose long-term impact is unknown.

The investigators studied the cytokine profile of MN patients and demonstrated, after non-specific stimulation of innate immunity cells and T cells, a Th17 profile (increased levels of interleukin-6 (Il-6) and interleukin-17A (Il-17A) compared to healthy subjects), and inhibition of the Th1 (decreased IL-12p70 and Interferon-γ (IFN-γ)) and T regulatory T reg pathways (decreased IL-10) (doi: 10. 3389/fimmu.2020.574997).

Th17 cells and Treg cells with interconnected development have opposite roles. Th17 cells induce inflammation to initiate a reaction against a pathogen, while Treg cells control an inflammatory reaction.

The investigators showed that high Il-17A levels were associated with a risk of thrombotic events (p = 0.03) and relapse (p = 0.0006). A patient with an IL-17A level > 73 pg/ml had a 10.5-fold increased risk of relapse.

Rituximab-induced remission leads to an increase in Treg and Th1 pathway cytokines but has no impact on IL-17A production, which remains important even in remission.

Thus, in this group of patients with high IL-17A levels, targeted action on B lymphocytes is probably not sufficient to avoid relapse and the addition of a treatment aimed at inhibiting the Th17 pathway and promoting Treg induction seems legitimate.

Various potential treatment exist: anti-Il-6 antibodies (tocilizumab), anti-Il-17 antibodies (secukinumab), low-dose Il-2 (a few studies have demonstrated its ability to induce Treg in various autoimmune diseases), hydroxychloroquine in low doses (used in lupus to limit relapses and having an anti-inflammatory effect), the plant extract Alphanosos (anti-Th1) or Levamizole (validated in nephrotic syndrome in children).

In order to propose the best therapeutic option to relapsed MN patients with a strong activation of the Th17 pathway, the investigators propose to study in vitro the effect of these different immunomodulators on the Th17/Treg balance evaluated by cytokine profile and lymphocyte phenotyping in flow cytometry.

Inclusion criteria

• Age ≥ 18 years
• Patient with MN proven on renal biopsy or by the presence of anti-PLA2R1 or anti-THDS71 antibodies
• Relapsed MN, defined as proteinuria > 3.5g/g after achieving remission (partial or complete, definitions according to KDIGO 2012 guidelines)
• At a distance from any immunosuppressive treatment (at least 6 months)
• Freely given informed consent signed by the patient after clear, fair and appropriate information
• Affiliated to a social security system

Exclusion criteria

• Pregnant or breastfeeding woman
• Patient under 18 years of age
• Persons of legal age