Closing remarks from the <scp>IIGANN2023</scp> Tokyo symposium—40 years of study progress in <scp>IgA</scp> nephropathy

A successful round table that included patients representing several countries around the world (Argentina, Canada, Germany, Japan, UK and USA) brought an urgent need to improve health care procedures with patients and doctors working together for optimal patient care in IgAN. Discussions about IIGANN interaction with patient associations around the world were launched, notably to keep patients informed about new therapeutic advances and trials as well as to receive feedback from them about current problems on health care procedures. Since the 1980's it has been well-established that polymeric and abnormal IgA1 is the major form of IgA within mesangial deposits. IgA1 was shown extensively by several researchers worldwide to be de-glycosylated (dg) in its hinge region notably lacking galactose and sialic acids. A mucosa-kidney axis appeared to be crucial in IgAN pathogenesis. Altered mucosal immunity plays a pivotal role in the disease including altered mucosal microbiome. Genetic studies implicated genes involved in gut immunity, and the response to mucosa-directed immune modulating therapy. From this meeting, we learned from patient microbiome analysis of a French cohort that a gut dysbiosis of mucin-degrader commensals, that are able to de-glycosylate human IgA1 in the gut lumen in vivo in partly humanised mice, generate dg-IgA1 that are retro-transcytosed by enterocytes with consequent induction of systemic autoimmunity response anti-dg-IgA1 forming immune complexes that get deposited in the mesangial area. This data show that a microbiota dysbiosis can generate dg-IgA1 by a post-translational mechanism in the gut lumen, and consequently raised the hypothesis that environmental factors may play a causal role in IgAN pathogenesis, hence bringing some clues to better understand the worldwide heterogeneity of the disease. We also learned that plasmacytoid dendritic cells seem involved in the production of galactose-deficient (Gd) IgA1 and the existence of IgA autoantibodies to mesangial cells targeting β2 spectrin in a subpopulation of Japanese IgAN patients (Nihei et al Sci Adv 2023, 9:eadd6734). How these antibodies are produced remain unknown although a role of oral bacteria dysbiosis has been suspected. We also learned how important it will be to progress in glycomics analysis to better clarify complexed O-linked glycosylation of IgA1 and to gain insights in the structural basis of their interaction with anti-dg-IgA1 IgG autoantibodies. Many reports addressed the role of B cell modulators on dg-IgA1 production notably APRIL and BAFF as well the role of CD38+ plasma cells. Go to: IgAN Network President Lecture. The development of genome-wide associations studies (GWAS), and more recently whole-genome sequencing, are advancing the field substantially, and large multinational GWAS have been hypothesis-generating suggesting novel disease mechanisms to be explored. In this meeting, we learned from a recent IgAN GWAS study that the disease is multigenic with more than 30 loci being identified, confirming known players such as the FCAR locus already known to be involved in the disease, but also new ones such as loci for CFH variants and CFH/MCP haplotypes that are associated with IgAN severity, suggesting new therapeutic targets. Interestingly, an unpublished GWAS data on IgA vasculitis identified more restricted set of loci including HLA-DRB1, FCAR, SHIP1 and IL6R. Although mesangial complement deposition was soon detected when IgAN was described, it aroused limited interest. However recent GWAS suggest the importance of variations in complement regulatory proteins, and there is resurgence in the study of deposited and circulating complement using modern techniques. In this meeting, several studies presented data on complement fragments associated with IgAN progression and vascular lesions. Many questions remain unknown such as: Are C3 deposits underestimated? Is C3 locally activated in the mesangium? There has been, until the last 15 years, little or no consensus about the pathological features of IgAN, with several classifications being in use. The evidence-based Oxford classification, published in 2009, was rapidly adopted by the great majority of clinicians and investigators. Since that time this classification continues to be reviewed and refined. In this meeting, S and C scores were proposed be related to recurrence of IgA deposits in transplanted IgAN. S lesions with podocytes hypertrophy seems to be a bad prognosis in IgAN with data obtained from the VALIGA cohort. These data brought panel discussions about an unmet need to subclassify S lesions. It also clear from this meeting that machine learning is rapidly arising as new tool in pathology for diagnosis of IgAN. Next generation morphometry in pathomics data is already bringing new concepts as highlighted by Hölscher et al (Nat Commun 2023, 14:470). In Tokyo, three studies in cohorts from Japan and China brought promising machine learning data, such as, for example, clinical variables and T score to predict ESRD. A pilot study in the UK showed that digital spatial profiling (DSP) is able to reveal early evidence of complement activity associated with endocapillary hypercellularity in glomerular endothelial cells in IgAN. Thus, DSP method to analyse E1 inflammatory phenotype, notably for macrophages, appears to be a very promising tool to identify patients, which could benefit for specific therapy in IgAN. Role of complement and its inhibition in IgAN/Richard Lafayette. In the last 5 years, progress in IgAN therapy has been enormous with an increasing number of clinical trials ongoing. This is indeed an exciting time that certainly will show light at the end of the tunnel concerning health care progress for patients in IgAN. Although trials for childhood IgAN are still lacking, the number of high quality sufficiently powered RCTs for adult IgAN increased remarkably since the last meeting. Novel agents directed at manipulating the IgA1 molecules have emerged from pre-clinical assays as is the case of the IgA1 protease generated with a tolerogenic approach using mRNA-LNP strategy to reduce its immunogenicity in IgA1-humanised mice. Moreover, there are now emerging possibilities from therapies developed for other indications, for example, B cell modulators, complement inhibitors, tyrosine kinase inhibitors, hydroxychloroquine (HCQ) and so forth. Studies of treatments targeting B cells or the complement factors are currently underway and early data appear promising. Currently, different regimens targeting B/plasma cell pathway (i.e., telitacicept, atacicept, BION-1301, VIS649 and bortezomib) or complement pathway (i.e., Iptacopan, Avacopan and Nasoplimab), are in various stages of clinical development for IgAN. It is clear from preliminary data presented in Tokyo that anti-APRIL/BAFF monoclonal antibodies decreased Gd-IgA1 production and ameliorated proteinuria. Whether these agents can produce long-term kidney benefits at reduced risk of adverse events remain to be evaluated. Important progresses in IgAN treatment were presented and largely discussed in this symposium concerning renoprotectors and corticosteroids. Patients will certainly benefit in a near future of new classes of renoprotectors such as SGLT2i, a mineralocorticoid receptor antagonist and/or endothelin receptor antagonists for which trials are underway with encouraging preliminary data to reduce proteinuria. Concerning corticosteroids, there are now many RCT ongoing or already completed, not only for systemic corticosteroid therapy but also for local delivery of new formulations of corticosteroids that stay mainly at the mucosa surface with minor transport to systemic compartments. The data on systemic corticosteroid-based immunosuppression revealed some kidney protection in IgAN but is accompanied by substantial burden of adverse events (i.e., severe infections) that limit their use. TESTING, an international multi-centre double-blind RCT was initiated in 2012 and completed in 2022. This trial and an updated meta-analysis that included TESTING and STOP-IgAN studies have supported a kidney protective effect of glucocorticoid therapy in patients with severe IgAN but accompanied by serious adverse events. However, it is well-established now that a reduced-dose glucocorticoid therapy (0.4 mg/kg/d), as used in the TESTING study, seems at least as effective as full-dose treatment, with a much lower risk of adverse events. Nevertheless, the potential toxicity of a long-term therapy still highlights the need for safer therapies that target the disease pathophysiology. There were studies from several Japanese centres showing favourable associations of corticosteroid use and concurrent tonsillectomy with kidney survival (JNR-IgAN cohort). This therapeutic protocol should be evaluated in prospective studies and in other ethnicities. As a gut-kidney axis is now well-established in IgAN, an intestine-(ileum/colon) targeted and delayed release budesonide formulation, the Nefecon study, was the first conditionally approved treatment for IgAN based on proteinuria reduction and early eGFR data. This formulation is resistant to gastric acid pH thus releasing the drug in late small intestine (ileum) where Peyer patches are enriched targeting tissue IgA + B cells leading to downregulation of Gd-IgA1 production. The capsule disintegration occurred 1 h after encountering the small intestinal buffer phase thus releasing budesonide. In this meeting, we learned from data of a 2-year analysis of phase III NeflgArd trial, that Nefecon 16 mg/d significantly improved the UPCR, and slowed eGFR decline in patients with IgAN leading to clinically relevant and durable preservation of kidney function over 2 years regardless of the patients ethnic (Asian or Caucasian) origin. This treatment significantly reduced circulating levels of Gd-IgA1. Analysis of the NefIgArd (Part A) study population supports that suppression of circulating levels of BAFF, APRIL, and soluble BCMA in IgAN explained the mechanism of reduction of Gd-IgA1 and reinforce the central role of the gut-kidney axis in the pathogenesis of IgAN. The worldwide usage of this treatment in IgAN has been precluded by the extensive costs of the drug formulation. Generic forms of ileum/colon released budesonide formulation are expected to benefit patients worldwide, particularly in developing countries. Trials with mycophenolate mofetil (MMF), an immunosuppressive agent that is relatively selective for lymphocytes and inhibits antibody production by B cells, were also presented in the Tokyo meeting. While the efficiency of MMF remains controversial in the literature, two recent trials suggest a renal protection of MMF in the Chinese population. However, the efficacy of MMF in other ethnic groups remains unknown. HCQ appeared as a new therapeutic tool for IgAN. Pre-clinical studies in ddY mice showed that HCQ suppresses TLR9/TLR7 mediated cytokines. A Chinese centre conducted a single-centre randomised trial previously, including 60 patients with IgAN. The HCQ group demonstrated a greater reduction in proteinuria compared with placebo at 6 months in patients who have persistent proteinuria despite RAS blockade. An ongoing multi-centre RCT will evaluate the efficacy and safety of HCQ. CME workshop jointly held with JSN/ISN/APSN. 5. Current treatment and new insights in IgA nephropathy/Hong Zhang.

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