Gut Connection in IgA Nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis world- wide and was identified over half a century ago. Appearance of transient gross haematuria during episodes of mucosal infections is the classical clinical presentation of IgAN. The research of the role of the gut in IgAN goes back as far as the 1980s. The emergence of corticosteroid therapies with promising efficacy for the survival of the kidneys of IgAN patients in the 1990s probably delayed study activity around the so-called gut-kidney axis for nearly two decades. Yet interest in this connection has resurfaced in international IgAN research in recent years.

The dissertation project focused on connections between diseases and processes of the intestine and kidney diseases. The prevalence of inflammatory bowel disease (IBD) was first evaluated among patients referred to kidney biopsy due to clinical indications. The focus was soon targeted to IgAN and phenomena in the intestines of biopsy-verified IgAN patients. The prevalence of coeliac disease (CeD) and IBD among IgAN patients was elucidated. Thereafter, presence of gastrointestinal symptoms and serum levels of indirect biomarkers of intestinal damage were studied in IgAN patients with no known diseases of the intestine. The dissertation consists of four sub-studies.

Study I investigated the prevalence and phenotypes of IBD in patients referred to kidney biopsy on a clinical basis from 2000 to 2012 at Tampere University Hospital (TAUH). Altogether 35 out of the 819 kidney-biopsied patients had IBD (4.3%). Crohn’s disease (CrD) and ulcerative colitis (UC) were equally common. The prevalence of IBD was 13.3% in patients diagnosed with tubulointerstitial nephritis and 4.6% in patients diagnosed with IgAN. In general population, prevalence of diagnosed IBD in 2008 was 0.6%. IBD was not associated with any increased risk of end-stage kidney disease during a median follow-up of nearly five years.

Study II evaluated the prevalence of diagnosed CeD, the prevalence of coeliac autoimmunity detected by serum levels of transglutaminase 2 targeted antibodies and the prevalence of IBD in 629 patients diagnosed with IgAN at TAUH from 1976 to 2012. The prevalence of CeD and coeliac autoimmunity decreased among IgAN patients from 5.6% in the 1980s to 1.4% by the beginning of the 21st century, whereas the prevalence of IBD increased from 2.0% to 4.4% over the same period of time.

Study III surveyed health-related quality of life and gastrointestinal (GI) symptoms experienced by 104 IgAN patients living in the TAUH catchment area in 2019. Conventionally, GI symptoms have been acknowledged to present in end- stage kidney disease. The questionnaires used were the self-administered, structured, well-validated Gastrointestinal Symptom Rating Scale (GSRS) and the Psychological General Well-Being Index. The results were compared with those of healthy people. IgAN patients reported more GI symptoms than did healthy people. The GSRS total score of the IgAN patients was about the same as in earlier studies on dialysis patients. Specifically, female patients and patients with preserved kidney function experienced an excess of GI symptoms. Health-related quality of life was likewise lower in IgAN patients than in healthy individuals.

Study IV used as its subjects 85 volunteer IgAN patients who had participated in Study III. Subclinical CeD was excluded with negative serum coeliac autoantibody tests from all participants and IBD with negative faecal calprotectin test from 57 volunteer patients. Thereafter, serum levels of three indirect biomarkers of intestinal damage were measured in all 85 patients. Test results were compared with those of healthy people and patients suffering from dyspepsia. Serum levels of a protein released into the circulation from enterocytes upon cell damage, intestinal fatty-acid binding protein, were higher in IgAN patients than in healthy people. Serum levels of soluble cluster of differentiation molecule 14, a biomarker likely representing increased intestinal permeability, did not differ between IgAN patients and healthy controls, but were lower in dyspepsia controls. Serum levels of another possible biomarker of intestinal permeability, lipopolysaccharide-binding protein, showed no difference between the groups. In none of the three biomarkers did the serum levels correlate with the GI symptoms measured by GSRS score.

In conclusion, IBD is present in a notable percentage of patients with clinical signs of a kidney disease. IBD should be kept in mind, especially when the kidney biopsy histology shows either tubulointerstitial nephritis or IgAN. The prevalence of IBD and especially that of Crohn’s disease is increasing in IgAN. Conversely, the prevalence of CeD in conjunction with IgAN is decreasing. IgAN patients and especially female IgAN patients experience more GI complaints than do healthy people. IgAN patients experience GI symptoms even without kidney failure. The finding of elevated serum levels of an indirect biomarker of intestinal damage among IgAN patients gives ground for further studies to explore gut phenomena in IgAN in more detail.