To Örebro University

Background and Aims: IgA nephropathy (IgAN) is the most common global kidney disease with a highly variable clinical presentation. Diagnosis IgAN requires a biopsy, and the immunohistologic examination is dominated by depositions of aberrant IgA1 antibodies. Since IgA antibodies are mainly produced by the mucosal associated lymphoid tissue the relationship between the mucosal immune system and IgAN has long been considered. The current theories on the origin of the disease involve genetic and environmental factors, with mucosal infections potentially playing a role. In some IgAN patients gastrointestinal and/or upper respiratory infections can aggravate the disease with episodic macrohematuria and/or increased proteinuria. Coincidently, these infections are also more common among patients with selective IgA deficiency. The aim of this study was to investigate whether the presence of IgAN confers an increased risk of infections in general to the IgAN patient.

Method: IgAN was defined by a computerized biopsy record from 1997 to 2011 in Sweden. Each IgAN patient was matched with up to five reference individuals based on age, sex, calendar year, and county of residence. Exclusions included those with organ transplants, HIV, immunodeficiency, or end-stage kidney disease before study entry, and follow-up data were censored for subsequent occurrences. Linear and Cox regressions, adjusted for age, sex, and education, were performed to analyze total infections and antimicrobial treatments in both patient and reference groups. Sibling analyses were also performed, adjusted for baseline age, sex and educational attainment.

Results: The linear regression analysis revealed a significant association between IgA nephropathy (IgAN) and the overall frequency of infections compared to the general population (β = 0.45; 95% CI: 0.37–0.54), women (β = 0.35; 95% CI: 0.19–0.50), men (β = 0.50; 95% CI: 0.40–0.60), and siblings (β = 0.37; 95% CI: 0.25–0.49) for women (β = 0.24; 95% CI: 0.06–0.41) and men (β = 0.43; 95% CI: 0.27–0.60). Similarly, a significant association was found for the frequency of prescribed antimicrobial agents compared to the general population (β = 0.66; 95% CI: 0.51–0.82), women (β = 0.92; 95% CI: 0.56–1.27), men (β = 0.55; 95% CI: 0.39–0.71), with similar estimates in the sibling analyses. The subtypes with the strongest association were urinary tract infections (β = 0.09; 95% CI: 0.07–0.11), ENT (ear, nose, and throat) infections (β = 0.08; 95% CI: 0.04–0.12), muscular infections (β = 0.08; 95% CI: 0.05–0.12), and infections in the GI (gastrointestinal) tract (β = 0.06; 95% CI: 0.04–0.09). Infections in the lower respiratory tract, skin and mycoses also had a significant positive association, however, no associations to infections in the central nervous system or infections caused by helminths and protozoans were identified. Cox regression showed an elevated risk of any infection with an adjusted hazard ratio (HR) of 2.05 (95% CI: 1.88–2.23), especially for sepsis (aHR = 3.13; 95% CI: 2.14–4.59), and time to the first prescription of antimicrobials with an aHR of 1.37 (95% CI: 1.30–1.45). Linear regression of prescribed antimicrobial treatments showed an overall β = 0.67; 95% CI: 0.51–0.82, and specifically for antibiotics (β = 0.64; 95% CI: 0.49–0.78).

Conclusion: Our study demonstrates an increased prevalence of infections and antibiotic prescriptions in IgAN patients compared to the general population and their siblings. Further studies on the potential impact of IgAN and its immunological aberrations on overall infection susceptibility is warranted.