The mucosa–kidney axis in IgA nephropathy

Key Points

  • Genome-wide association studies in patients with IgA nephropathy (IgAN) have identified risk loci in genes involved in the intestinal mucosal integrity and immune network

  • Immune responses to mucosal antigens and immunization studies suggest that the systemic response to mucosal antigens is exaggerated in patients with IgAN

  • Patients with IgAN have increased reactivity to dietary proteins associated with subclinical intestinal mucosal inflammation, although in general they do not have overt dietary intolerance

  • Very rarely, IgAN is associated with gastrointestinal diseases; whether these diseases indeed share a common pathogenesis or whether gastrointestinal inflammation exacerbates IgAN is uncertain

  • Mucosal alterations such as respiratory tract infections could activate the innate immune system, aggravate a pre-existing IgAN and promote disease manifestations such as macrohaematuria, rather than a share a pathogenetic link with IgAN

  • Intervention studies targeting the mucosae in IgAN have been inconclusive so far, but new studies are ongoing

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.

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Figure 1: Mechanisms of normal IgA production in the mucosal and systemic arms of the IgA immune system in humans.
Figure 2: A comparison of duodenal histology in IgA nephropathy (IgAN) and coeliac disease.

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The authors contributed equally to researching data for the article, discussing its content, writing and reviewing/editing the manuscript before submission.

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Correspondence to Jürgen Floege.

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J. Floege has received honoraria from Pharmalink, Sweden. J. Feehally declares no competing interests.

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Floege, J., Feehally, J. The mucosa–kidney axis in IgA nephropathy. Nat Rev Nephrol 12, 147–156 (2016). https://doi.org/10.1038/nrneph.2015.208

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