Case report on pathogenetic link between gluten and IgA nephropathy
A relationship between IgA nephropathy (IgAN) and celiac disease (CD) has been reported. We show the pathogenetic link for the first time.
A 39-year-old man with cystic fibrosis (CF) and CF-related diabetes started to present gross hematuria, back pain and headache. At admission, laboratory analysis showed increase in serum creatinine of 1.5 mg/dl, together with hematuria and mild proteinuria (1 g/24 h). He underwent a renal biopsy to investigate the cause of hematuria and renal failure. Biopsy was consistent with IgAN. In view of patient reported dyspepsia, an upper gastrointestinal endoscopy with duodenal biopsies was undertaken and was normal. We looked for mucosal deposits of tTG-2 in the duodenum and the renal mesangium. tTG-2 deposits were found both in the duodenum and in renal biopsies, where they topographically replicated mesangial IgA deposits. After one year on a continued gluten containing diet, the patient developed a Marsh 2 type duodenal pathology.
Our findings suggest a connection between CD and IgAN in terms of an immune-mediated gluten-induced pathogenesis even in the absence of villous atrophy and serum celiac autoantibodies.
KeywordsIGA nephropathy Celiac disease Tissue transglutaminase Immunofluorescence technique Pathogenesis
IgA-tissue antitransglutaminase antibodies
A relationship between celiac disease and other autoimmune inflammatory disorders is known . With regardto IgA nephropathy (IgAN), some studies report an increased incidence of celiac disease  and postulate a role of gluten in the pathogenesis of this disorder [3, 4]. A double immunofluorescence technique to detect intestinal deposits of anti-tissue transglutaminase IgA was successfully performed in patients with dermatitis herpetiformis (DH)  and gluten ataxia (GA)  showing a link between gluten and these diseases even in absence of duodenal atrophy or positive celiac serology.
We used this technique to detect anti-TG2 in the mesangium and duodenum of a patient with IgAN.
Given the morphological features of IgAN, and the presence of proteinuria, steroid therapy was started according to a standardized six month’s protocol . After one month, proteinuria decreased to 100 mg/24 h and hematuria resolved. Steroids were stopped after six months of treatment. The patient continued on a gluten containing diet.
Discussion and conclusions
To our knowledge, this is the first demonstration of the pathogenetic role of gluten in IgAN. IgAN is a rare complication of CF . In these cases, it is supposed that aninfectious stimulus acts as a trigger. On the other hand, a relationship between CD and IgAN has previously been suggested. In 2002, Collin et al. demonstrated an incidence of 3.6% of biopsy proven CD in IgAN . On the other hand, a recent study demonstrated an increased risk of biopsy-verified IgAN among individuals with CD . Another link between these two diseases is represented by the ability of gliadin to act as a lectin and to form immunocomplexes with IgA1N (oligosaccharide-containing IgA). Coppo et al. were able to induce experimental IgAN in mice immunized with gliadin . The same authors showed a positive effect of a gluten free diet on proteinuria and on progression of renal failure in patients with IgAN. Berthelot et al. showed how activation of transglutaminase 2 is crucial for the deposition of immune-complexes in the mesangium of patients with IgAN . Lechner et al. showed that the removal of IgA deposits by a proteases led to a decrease of TG2 staining thus confirming the presence of the enzyme in mesangial immunocomplexes .
In several case reports, an improvement of IgAN is described following a gluten free diet [15, 16, 17]. All these cases are characterized by the presence of a biopsy proven CD and in no caseis a contemporary immune activation in intestine and kidney reported before the development of duodenal atrophy.
Our finding can explain how CD and IgAN are related. As we found deposits of IgA anti-tissue transglutaminase both in the duodenum and glomerular mesangium we can argue that an autoimmune activation, triggered by gluten in intestinal mucosa and involving tissue transglutaminase, mayoccur in extraintestinal target sites. This kind of association has been demonstrated in other diseases such as GA and in DH, where the role of gluten is well recognized, and a gluten free diet is beneficial [5, 6]. Duodenal atrophy can be absentalso in these diseases, as auto-antibodies production is directed against specific transglutaminase isotypes represented, in dermis, by isotype 3, and in myelin by isotype 6, in DH and GA, respectively, In particular, in GA a contemporary presence of anti-tTG2 deposits was found in jejunal mucosa and within the muscular layer of brain vessels and brain parenchyma particularly of the cerebellum, regardless of the presence of duodenal atrophy or positive celiac serology. In our case the strength of pathogeneticassociation between CD and IgAN depends on the diagnostic power of the technique we adopted to detect a gluten dependent immune activation. Duodenal deposits oftTG2 are very sensitive and specific for diagnosis of celiac disease, even in the absence of duodenal atrophy and positive celiac serology . Moreover, Salmi et al.  showed how mucosal anti-tTG2 deposits strongly predict forthcoming duodenal atrophy.
Actually, after one year, the patient developed a duodenal pathology, thus confirming that intestinal deposits of anti-tTG2 were the initial manifestation of a gluten driven inflammation. As transglutaminase 2 is the most represented isoform in the mesangium, we suggest that mesangial deposition of anti-tTG-2 may play a determinant role in pathogenesis of the disease even in the absence of other signs suggesting celiac disease.
Our findings suggest an immune-mediated gluten-induced pathogenetic link between CD and IgAN even in the absence of villous atrophy and serum celiac autoantibodies. Searching for mesangial deposits of anti-tTG2 in a large series of new cases of IgAN will allow to define how many cases are caused by this autoimmune mechanism and if a gluten free diet can really improve renal outcome of these patients.
The authors thank Trays Macdonnell for the English language revision of the article.
Availability of data and materials
Raw data are available upon request to the corresponding author.
SC, GC, SP, DS and GM planned the study, analyzed data and drafted the article. MCL, AI, GT and GV gave substantial contributions to conception and design, acquisition and interpretation of data, revising the article critically for important intellectual content. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
Written informed consent for publication of clinical details and clinical images was obtained from the patient.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- 4.Papista C, Lechner S, Ben Mkaddem S, LeStang MB, Abbad L, Bex-Coudrat J, Pillebout E, Chemouny JM, Jablonski M, Flamant M, Daugas E, Vrtovsnik F, Yiangou M, Berthelot L, Monteiro RC. Gluten exacerbates IgA nephropathy in humanized micethrough gliadin-CD89 interaction. Kidney Int. 2015;88(2):276–85.CrossRefPubMedGoogle Scholar
- 10.Salmi TT, Collin P, Järvinen O, Haimila K, Partanen J, Laurila K, Korponay-Szabo IR, Huhtala H, Reunala T, Mäki M, Kaukinen K. Immunoglobulin Aautoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease. Aliment Pharmacol Ther. 2006;24(3):541–52.CrossRefPubMedGoogle Scholar
- 13.Berthelot L, Papista C, Maciel TT, Biarnes-Pelicot M, Tissandie E, Wang PH, Tamouza H, Jamin A, Bex-Coudrat J, Gestin A, Boumediene A, Arcos-Fajardo M, England P, Pillebout E, Walker F, Daugas E, Vrtosvnik F, Flamant M, Benhamou M, Cogné M, Moura IC, Monteiro RC. Transglutaminase is essential for IgA nephropathydevelopment acting through IgA receptors. J Exp Med. 2012;209(4):793–806.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Lechner SM, Abbad L, Boedec E, Papista C, Le Stang MB, Moal C, Maillard J, Jamin A, Bex-Coudrat J, Wang Y, Li A, Martini PG, Monteiro RC, Berthelot L. IgA1 protease treatment reverses mesangial deposits and hematuria in a model of IgA Nephropathy. J Am Soc Nephrol. 2016;27(9):2622–9.PubMedPubMedCentralGoogle Scholar
- 18.Kaukinen K, Peräaho M, Collin P, Partanen J, Woolley N, Kaartinen T, Nuutinen T, Halttunen T, Mäki M, Korponay-Szabo I. Small-bowel mucosal transglutaminase2-specific IgA deposits in coeliac disease without villous atrophy: a prospectiveand randomized clinical study. Scand J Gastroenterol. 2005;40(5):564–72.CrossRefPubMedGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.