The mucosa–kidney axis in IgA nephropathy

Abstract

Links between IgA nephropathy (IgAN) and the mucosa have been recognized since the 1970s. In particular, the observation of visible haematuria induced by respiratory infections in patients with IgAN and the association of IgAN with diseases in which the mucosa plays a part, especially coeliac disease, have been taken as evidence of a mucosa-kidney axis. Here, we review current evidence that links the mucosa, in particular the gastrointestinal mucosa, and IgA produced by the bone marrow with IgAN. Genome-wide association studies in patients with IgAN have identified risk loci in genes involved in the intestinal mucosal integrity and immune network. Furthermore, the systemic immune response to mucosal antigens in IgAN is increased. Moreover, patients with IgAN have an increased reactivity to dietary proteins associated with subclinical intestinal mucosal inflammation. Associations between IgAN and gastrointestinal diseases have also been reported in a small number of patients, but whether these diseases share a common pathogenesis or whether gastrointestinal inflammation exacerbates IgAN is uncertain. Indeed, mucosal alterations such as infections could activate the innate immune system, aggravate a pre-existing IgAN and promote disease manifestations such as macrohaematuria. Various clinical interventions and trials targeting the mucosa or presumed mucosa-associated mechanisms have so far not yielded consistent findings and the results of ongoing trials are eagerly awaited.

<b><i>Campylobacter rectus</i></b> in the Oral Cavity Correlates with Proteinuria in Immunoglobulin A Nephropathy Patients

“…Some researchers have suggested a new hypothesis for the intestine – kidney connection when considering the possible mechanism for the pathogenesis of IgAN [31, 32]. Because C. rectus and S. mutans are oral bacterial species, our data provide evidence for a new concept of an oral – kidney association.…”

Effects of Hydroxychloroquine on Proteinuria in Immunoglobulin A Nephropathy

“…The synthesis and binding of antibodies directed against Gd-IgA1 lead to the formation of pathogenic IgA1-containing immune complexes, which activate mesangial cells, inducing the proliferation and expansion of the extracellular matrix and the production of cytokines and chemokines and activating the complement system through the alternative or lectin pathway, resulting in renal injury [13]. Additionally, mucosa-kidney axis disorders have been speculated to be involved in the pathogenesis of IgAN [8]. In a mouse model of IgAN, an association was observed between TLR9 polymorphisms and disease progression [14].…”

“…The efficacy of HCQ may result from its ability to inhibit the activation of toll-like receptors (TLRs) and numerous cytokines [7], which are also crucial in the abnormal mucosa-kidney axis in IgAN [8]. Gao et al [9] found that HCQ reduced proteinuria to 65.9 ± 25.5% ( p = 0.002) of the baseline level (0.90 ± 0.45 g/day) in patients with IgAN; however, there was no statistically significant difference in proteinuria levels between the HCQ and losartan groups.…”

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

“…The classical clinical picture in IgAN of recurrent episodes of visible hematuria coinciding with upper respiratory or intestinal tract infections indicate that mucosal immunity plays an important role in the pathogenesis of IgAN [18] . IgA1 is secreted by antibody-secreting B cells in distinct mucosal and systemic compartments with a characteristic site-specific phenotype [19] .…”