Why Target the Gut to Treat IgA Nephropathy?

It is more than 50 years since the first description of IgA nephropathy (IgAN) by the Parisian pathologist, Jean Berger.1Berger J. Hinglais N. Intercapillary deposits of IgA-IgG.J Urol Nephrol (Paris). 1968; 74: 694-695PubMed Google Scholar Over this time, IgAN became recognized as the most common pattern of glomerular disease worldwide.2Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (614) Google Scholar Despite the significant global burden of chronic and end-stage kidney disease associated with IgAN, there are currently no approved treatments.3Thompson A. Carroll K. L A.I. et al.Proteinuria reduction as a surrogate end point in trials of IgA nephropathy.Clin J Am Soc Nephrol. 2019; 14: 469-481Crossref PubMed Scopus (38) Google Scholar Standard of care continues to be supportive therapy, which focuses on optimal blood pressure control, a low-sodium diet, and maximum tolerated blockade of the renin-angiotensin-aldosterone system (Kidney Disease Improving Global Outcomes Glomerulonephritis Work Group. KDIGO clinical practice guideline on glomerular diseases - public review draft, June 2020, personal communication).4Kidney Disease Improving Global Outcomes Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Google Scholar There is no evidence for the efficacy of traditional immunosuppressive agents, such as cyclophosphamide, azathioprine, mycophenolate mofetil, and rituximab.4Kidney Disease Improving Global Outcomes Glomerulonephritis Work GroupKDIGO clinical practice guideline for glomerulonephritis.Kidney Int Suppl. 2012; 2: 139-274Google Scholar,5Lafayette R.A. Canetta P.A. Rovin B.H. et al.A randomized, controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction.J Am Soc Nephrol. 2017; 28: 1306-1313Crossref PubMed Scopus (93) Google Scholar The safety and efficacy of systemic corticosteroids in IgAN have recently been challenged by the publication of the TESTING and the STOP-IgAN studies.6Lv J. Zhang H. Wong M.G. et al.Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: the TESTING randomized clinical trial.JAMA. 2017; 318: 432-442Crossref PubMed Scopus (174) Google Scholar,7Rauen T. Eitner F. Fitzner C. et al.Intensive supportive care plus immunosuppression in IgA nephropathy.N Engl J Med. 2015; 373: 2225-2236Crossref PubMed Scopus (273) Google Scholar There is a clear unmet need for safe and effective disease-modifying therapies in IgAN. This need may be met in the near future because a number of novel therapies are now being evaluated in phase 2 and phase 3 clinical trials.8Selvaskandan H. Cheung C.K. Muto M. et al.New strategies and perspectives on managing IgA nephropathy.Clin Exp Nephrol. 2019; 23: 577-588Crossref PubMed Scopus (18) Google Scholar Of these, the most advanced is the NefIgArd trial, which is evaluating the safety and efficacy of a targeted-release formulation of the corticosteroid, budesonide (NEFECON).S1 NEFECON is designed to release budesonide in the terminal ileum, a region of the gastrointestinal tract with a high density of lymphoid-rich Peyer’s patches.S2,S3 But why is one of the largest ever clinical trials for IgAN testing a drug that targets the gut? It was soon recognized after the first description of IgAN that there was a close association between mucosal inflammation, and episodes of nephritis in patients with IgAN.S4 The archetypal presentation is a young adult, commonly male, presenting with an episode of painless visible hematuria 24 to 48 hours after developing a mucosal infection, usually affecting the upper respiratory or gastrointestinal tract.S5,S6 We still do not completely understand the connection between mucosal inflammation and the kidney, but a number of important observations have led to the concept of a “gut–kidney” axis in IgAN.S7 The mucosal-associated lymphoid tissue is responsible for the synthesis of the bulk of IgA in the body, with more IgA produced at mucosal surfaces per day than all other types of antibody combined.S8,S9 The gut-associated lymphoid tissue (GALT) alone secretes between 3 and 5 g of IgA into the intestinal lumen every day, 15% of the body’s total Ig production.S10,S11 Furthermore, in the normal gut there are approximately 1 × 1010 IgA-producing lymphocytes per meter, which equates to at least 80% of all immunoglobulin-producing cells in the body.S8 Secreted IgA is an important first line of defense against microbial invasion. Secretory IgA attaches to the mucus layer covering epithelial surfaces, where it is available to bind to microbial pathogens and both prevent their attachment to epithelial cells by steric hinderance and crosslink the pathogens, trapping them in the mucus layer for excretion in the feces.S12–S14 The GALT is highly organized and covers a surface area of 260 to 300 m2.S15 The most immunologically significant components of the GALT are the Peyer’s patches, which consist of at least 5 (but can contain up to 200) aggregated lymphoid follicles.S13,S16 Peyer’s patches are located in the mucosal layer of the intestine and extend into the submucosal layer, and they serve as the major antigen sampling and inductive sites of the GALT.S3,S17,S18 In humans, there are approximately 100 Peyer’s patches at birth, 225 in the mid-teens and approximately 100 in later years (≥70 years), at least 46% of these are concentrated in the distal 25 cm of the ileum.S3,S16 Human intestinal IgA is mostly dimeric and comprises both IgA1 and IgA2 subclasses. The ratio of plasma cells secreting the 2 subclasses of IgA is not the same throughout the gastrointestinal tract. Whereas most plasma cells in the small intestine secrete IgA1, the proportion secreting IgA2 increases from the duodenum through to the terminal ileum, and the subclasses are present in approximately equal proportions in the colon. In general, IgA2 is more resistant to bacterial proteases than IgA1 and may, therefore, have a longer half-life in the lumen of the distal intestinal tract.S19 Peyer’s patches are thought to be the main source of conventional surface IgA1-expressing primed mucosal B cells.S20 By contrast, the adjacent lamina propria is principally an effector site where surface IgA-expressing primed mucosal B cells terminally differentiate to plasma cells that produce IgA, which is then transported across the mucosal epithelium as secretory IgA (Figure 1).S21,S22 Supporting the importance of mucosal-derived IgA as a major source of pathogenic IgA, a number of studies have reported elevated serum levels of secretory IgA in IgAN, which increase after mucosal immunization, and perhaps more importantly suggests that secretory IgA contributes to the mesangial IgA deposits characteristic of IgAN.S23–S25 In parallel, a number of investigators have reported elevated levels of IgA antibodies specific for food antigens, mucosal vaccines, and gut-associated bacteria in the serum, suggesting a dysregulation of the mucosal-associated lymphoid tissue, and in particular the GALT.S26–S28 The most consistent finding is an increase in serum levels of poorly O-galactosylated IgA1 glycoforms (Gd-IgA1) and there is now convincing evidence that this IgA is derived from the mucosal-associated lymphoid tissue, predominantly the Peyer’s patches of the GALT.S13,S26,S29,S30 Indeed, multiple studies have reported that mucosally derived IgA has the same physicochemical properties as the IgA that forms circulating immune complexes and deposits in the mesangium.S31–S34 Mucosal IgA is polymeric, low affinity, poorly O-galactosylated, and found at increased concentrations in the serum in IgAN.S35 Two recent studies demonstrated that IgA1 O-galactosylation is in part determined by single nucleotide polymorphisms in the promoter region of the gene encoding core 1 ß1,3-galactosyltransferase (C1GALT1).S36,S37 This is consistent with earlier observations reporting that IgA1 O-galactosylation is modulated following class switch recombination and by the tissue microenvironment, in particular by cytokines and growth factors that are enriched in the Peyer’s patches.S38,S39 There are also intriguing data suggesting that gut bacteria may themselves be capable of modulating IgA class switching, the amount of mucosal IgA production, and IgA1 O-galactosylation in the GALT through activation of lymphoid Toll-like receptors.S40,S41 Moreover, there is early evidence that the composition of the gut microbiome may be different in patients with IgAN.S42 In addition, genome-wide association studies have identified a number of risk alleles, which are both strongly associated with age at disease onset and whose frequency increase sharply with eastward and northward distance from Africa, paralleling the known east–west gradient in disease risk.S43 Pathway analysis based on a large meta-analysis of genome-wide association studies identified the intestinal immune network for IgA production as the most enriched Kyoto Encyclopedia of Genes and Genomes pathway in IgAN.S44 Also, most of the identified risk alleles are either directly associated with risk of inflammatory bowel disease or maintenance of the intestinal epithelial barrier, as well as response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in the local gut pathogens, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.S44 These genetic observations are also entirely consistent with known secondary causes of IgAN, which include a range of gastrointestinal disorders, including inflammatory bowel disease and celiac disease.S45 Due to the increasing recognition of the role of the GALT, in particular the Peyer’s patches, in the generation of pathogenic IgA, a novel, oral, targeted-release formulation of the glucocorticoid, budesonide was developed to release the drug in the Peyer’s patch–rich distal ileum. An initial exploratory phase 2a trial of NEFECON in 16 patients with IgAN was performed and showed a statistically significant reduction in proteinuria.S46 NEFECON was also well tolerated.S46 A second phase 2b trial, the NEFIGAN trial, assessed the safety and efficacy of 2 different doses of NEFECON in patients who were at risk of progression to end-stage kidney disease due to persistent proteinuria despite optimized renin-angiotensin-aldosterone system blockade therapy.S2 After 9 months of treatment, the urine protein-to-creatinine ratio was reduced by approximately 30% in the 16 mg NEFECON treatment group compared with placebo. In addition, the estimated glomerular filtration rate showed no deterioration in the 16 mg NEFECON group compared with a drop of 4.7 ml/min per 1.73 m2 in the placebo group. The incidence of patients reporting adverse events was similar in all groups. These data led to the design of the ongoing phase 3 NefIgArd study (Supplementary Introduction). NefIgArd is a randomized, double-blind, placebo-controlled phase 3 trial, composed of 2 parts (Supplementary Methods). Part A of the trial comprises a 15- to 35-day screening period, 9-month treatment, and a 3-month follow-up period. Part B contains a 12-month no-treatment follow-up period (see Supplemental Methods for full protocol). The study is recruiting 360 patients across 150 nephrology clinics in 20 countries (Supplementary Results). Patients must be at least 18 years old with biopsy-confirmed primary IgAN and persistent proteinuria >1 g/24 hours, and an estimated glomerular filtration rate of ≥35 and ≤90 ml/min per 1.73 m2 despite optimized renin-angiotensin-aldosterone system blockade. Patients are randomized in a 1:1 ratio to 16 mg/day NEFECON or placebo, stratified by baseline 24-hour urine protein-to-creatinine ratio. The primary outcome of Part A is to assess the effect of NEFECON 16 mg treatment on 24-hour urine protein-to-creatinine ratio over 9 months compared with placebo. This is consistent with a recent article indicating that proteinuria reduction can be used as a surrogate endpoint in trials of IgAN.3Thompson A. Carroll K. L A.I. et al.Proteinuria reduction as a surrogate end point in trials of IgA nephropathy.Clin J Am Soc Nephrol. 2019; 14: 469-481Crossref PubMed Scopus (38) Google Scholar The Part B primary outcome is based on data presented at the National Kidney Foundation/Food and Drug Administration/European Medicines Agency workshop in March 2018 that supported estimated glomerular filtration rate slope as an endpoint for full approval, and is to assess the effect of NEFECON 16 mg treatment on a 2-year estimated glomerular filtration rate–based endpoint compared with placebo.S47 In comparison with other currently recruiting studies, it is expected that the relatively short period required to provide validation of the surrogacy of proteinuria reduction will significantly reduce the risks of nonprotocol treatments and loss of patients from the study that could dilute the true treatment effect of the drug. In contrast to the earlier studies of NEFECON,S2 NefIgArd is including Asian patients to expand the generalizability of the trial. The NefIgArd study will be the largest commercially sponsored study ever completed in IgAN, and could provide us with the first specific disease-modifying therapy that works by downregulating the production of pathogenic IgA in the Peyer’s patches of the GALT (Supplementary Discussion). JB is Chair of the Study Steering Committee for the NefIgArd trial. BHR, DC, JF, RL, VT, HZ, and HT are members of the Study Steering Committee for the NefIgArd trial. Medical writing assistance was provided by Chameleon Communications International Ltd. This article was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP3 Guidelines.” Trial Registrations: EudraCT number: 2017-004902-16; ClinicalTrials.gov identifier: NCT03643965 All authors were involved in the preparation, critical revision, and final approval of this editorial. All authors were involved in the decision to submit this editorial and will take public responsibility for all aspects of the publication. Download .pdf (.46 MB) Help with pdf files Supplementary File (PDF)