IgA Nephropathy—Should We Target the Gut?

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerular disease worldwide. Despite being initially described over 50 years ago by Dr. Jean Berger, there remains no disease-specific treatment. Its underlying pathogenesis is a dysregulation of the IgA immune system, which is characterized by elevated circulating levels of polymeric IgA1 that lack terminal galactose residues within the hinge region (termed “poorly galactosylated IgA1”) and the presence of IgA1-specific IgG and IgA antibodies (Figure 1). This leads to the formation of IgA-containing immune complexes that deposit within the glomerular mesangium, triggering mesangial cell proliferation, complement activation, inflammation, and subsequent damage (1). A number of trials have tested immunosuppressive strategies commonly employed in other immune-mediated glomerulonephritides, including cyclophosphamide, rituximab, mycophenolate, and azathioprine, but there is no clear evidence to support the efficacy of any of these agents in IgAN. Standard of care for the management of IgAN is currently focused on blood pressure control, weight loss, reduction of dietary sodium intake, smoking cessation, and use of renin-angiotensin system blockers. Current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines suggest the addition of corticosteroids only in cases where proteinuria persists despite the above measures, but the risk-benefit profile of their use has been brought into question by two recent randomized controlled trials: STOP-IgAN (Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy) (2) and TESTING (Therapeutic Evaluation of Steroids in IgA Nephropathy Global) (3).

Links between the gut and the kidney in IgA nephropathy

Citation: Kidney News 13, 4

(1) Dysregulation within the gut-associated lymphoid tissue (GALT), which may be potentiated by dynamic interactions with the gut microbiome, ultimately results in excess amounts of “mucosal-type” IgA1 entering the circulation through mis-homing of mucosal IgA1-producing B cells to systemic sites, including the bone marrow (2), and/or (3) direct passage of mucosal IgA1 from the GALT into the systemic circulation. The increase in circulating mucosal-type poorly galactosylated IgA1 (4) results in IgA immune complex formation due to self-aggregation of polymeric IgA1 molecules (5). Immune complex formation can be amplified by IgA1-specific IgG and IgA antibodies, which may be cross-reactive antimicrobial antibodies and/or true autoantibodies. Circulating IgA1 immune complexes subsequently deposit in the mesangium where they trigger a mesangioproliferative glomerulonephritis in susceptible individuals (6).

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Links between the gut and the kidney in IgA nephropathy

Citation: Kidney News 13, 4

(1) Dysregulation within the gut-associated lymphoid tissue (GALT), which may be potentiated by dynamic interactions with the gut microbiome, ultimately results in excess amounts of “mucosal-type” IgA1 entering the circulation through mis-homing of mucosal IgA1-producing B cells to systemic sites, including the bone marrow (2), and/or (3) direct passage of mucosal IgA1 from the GALT into the systemic circulation. The increase in circulating mucosal-type poorly galactosylated IgA1 (4) results in IgA immune complex formation due to self-aggregation of polymeric IgA1 molecules (5). Immune complex formation can be amplified by IgA1-specific IgG and IgA antibodies, which may be cross-reactive antimicrobial antibodies and/or true autoantibodies. Circulating IgA1 immune complexes subsequently deposit in the mesangium where they trigger a mesangioproliferative glomerulonephritis in susceptible individuals (6).

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Links between the gut and the kidney in IgA nephropathy

Citation: Kidney News 13, 4

(1) Dysregulation within the gut-associated lymphoid tissue (GALT), which may be potentiated by dynamic interactions with the gut microbiome, ultimately results in excess amounts of “mucosal-type” IgA1 entering the circulation through mis-homing of mucosal IgA1-producing B cells to systemic sites, including the bone marrow (2), and/or (3) direct passage of mucosal IgA1 from the GALT into the systemic circulation. The increase in circulating mucosal-type poorly galactosylated IgA1 (4) results in IgA immune complex formation due to self-aggregation of polymeric IgA1 molecules (5). Immune complex formation can be amplified by IgA1-specific IgG and IgA antibodies, which may be cross-reactive antimicrobial antibodies and/or true autoantibodies. Circulating IgA1 immune complexes subsequently deposit in the mesangium where they trigger a mesangioproliferative glomerulonephritis in susceptible individuals (6).

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Ever since its first description, there has been significant interest in a potential link between IgAN and the mucosal immune system due to the fact that approximately 30% of patients with IgAN experience episodes of visible hematuria coincident with upper respiratory tract or gastrointestinal infections (4). In addition, there are well-established associations between IgAN and other gastrointestinal diseases, including inflammatory bowel disease and celiac disease (5, 6). The exact mechanisms that link mucosal immune system activation and IgAN have been the focus of intense study, and over the past decade, a mucosal origin for IgAN has become more firmly established.

Human IgA exists as two isoforms, IgA1 and IgA2, which in turn can exist as monomers or polymers. Polymeric IgA1, and in particular, poorly galactosylated polymeric IgA1, is mainly produced at respiratory and gut mucosal surfaces in the mucosa-associated lymphoid tissue (MALT) (7). Here, IgA plays an important role in the host defense against microbial invasion. The gut-associated lymphoid tissue (GALT) produces the most IgA of all MALT sites, and this is concentrated in specialized collections of lymphoid follicles called the Peyer’s patches, which are predominantly located in the distal ileum.

Not only is “mucosal-type” poorly galactosylated polymeric IgA1 elevated in the circulation in IgAN, but it is also a major component of mesangial IgA deposits (8). In addition, secretory IgA, which is mucosal IgA and bound to the 70-kDa secretory component from its passage across the mucosal epithelial cell layer, is also elevated in the circulation in IgAN and can be detected within mesangial IgA deposits (9). Collectively, these observations suggest that mucosal-type IgA is misdirected into the circulation in IgAN either directly from the MALT or from systemically located mucosal plasma cells that have mis-homed during normal lymphoid trafficking (10).

A number of other lines of evidence support an important link between the gut and kidney in IgAN. McCarthy et al. (11) developed a transgenic mouse that overexpresses the B cell survival cytokine BAFF (B cell activating factor). The mouse developed a hyper-IgA syndrome, driven by IgA production in the lamina propria of the gut, and an IgAN-like kidney phenotype. Raising these mice in a germ-free environment and therefore avoiding colonization of the gut by commensal flora prevented development of the kidney phenotype, until gut microbiota were introduced (11). Chemouny et al. (12) confirmed the importance of the interaction between the gut microbiome and the MALT by treating their humanized transgenic IgAN mouse model with antibiotics to deplete the gut microbiota and showing a significant reduction in mesangial IgA1 deposition. Genome-wide association studies have identified multiple risk alleles for IgAN that are also directly associated with synthesis of IgA within the gut, inflammatory bowel disease, integrity of the intestinal epithelial barrier, and response to mucosal pathogens (13). In keeping with this, a recent epidemiological study demonstrated that patients with IgAN are more likely to develop inflammatory bowel disease, and those who do have an increased risk of progression to end-stage kidney disease (5). There is also emerging evidence from cross-sectional studies that the composition of the gut microbiome may be altered in patients with progressive IgAN (14).

In the search for targeted therapies in IgAN, it is therefore logical that work has focused on GALT-directed treatments. A targeted release formulation of budesonide (Nefecon) has been developed to deliver the active drug to the distal ileum, targeting the Peyer’s patches of the GALT. The phase 2b NEFIGAN (The Effect of Nefecon® in Patients with Primary IgA Nephropathy at Risk of Developing End-stage Renal Disease) trial demonstrated that treatment with 16 mg Nefecon over 9 months significantly reduced proteinuria levels and stabilized kidney function compared to the placebo group where the estimated glomerular filtration rate (eGFR) fell by 4.7 mL/min/1.73 m² over the same time period (15). The phase 3 NefIgArd (Efficacy and Safety of Nefecon in Patients with Primary IgA [Immunoglobulin A] Nephropathy) trial is comparing 9 months’ treatment with 16 mg Nefecon vs. placebo in 360 patients with IgAN, with follow-up at 2 years (ClinicalTrials.gov: NCT03643965). This trial has closed to recruitment and recently reported 9-month outcomes in the first 199 patients, confirming that Nefecon treatment results in significant proteinuria reduction and less deterioration of eGFR than placebo. The elucidation of the mechanisms by which Nefecon modulates gut mucosal IgA production may shed additional light on the overall pathogenesis of IgAN.

Alternative strategies to target the GALT and mucosal IgA synthesis in IgAN have been proposed. Although there are interesting reports from mouse models of the impact of dietary modification, to date, there is no clear evidence that changes, such as a gluten-free diet, have a beneficial effect in IgAN (6). The influence of the gut microbiome on mucosal IgA production and ways in which this could be manipulated, for example, with probiotics, are areas of growing interest. The B cell survival cytokines BAFF and APRIL (a proliferation-inducing ligand) play key roles in IgA class-switch recombination and IgA synthesis in the GALT, and inhibition of BAFF and/or APRIL is the subject of ongoing phase 2 clinical trials in IgAN (16).

A better understanding of the links between the gut and the kidney in IgAN, including the composition of the gut microbiome, how the microbiota interact with the GALT to determine the mucosal IgA response, and factors involved in promoting the production of poorly galactosylated polymeric IgA1 and its passage into the circulation, will hopefully allow the development of additional targeted treatment strategies, with the aim of providing options to treat this disease at its various stages in order to prevent its progression.