The Phenotypic Difference of IgA Nephropathy and its Race/Gender-dependent Molecular Mechanisms

Abstract

IgA nephropathy (IgAn), defined by the pre dominant de position of IgA in the glomerular mesangium, is the most common form of GN throughout the world. However, its incidence, sex distribution, clinical presentation, and progression and pathogenic initiating factors are largely variable and do not fit such a simple definition. To assess the heterogeneity of this disease, we recently conducted a clinical survey on the presentation and clinical management of patients with IgAn in Europe and Japan. This clinical survey highlights similarities and differences in patients from different cont inents. The survey revealed obvious differences between nations in the frequency of gastrointestinal complications, including inflammatory bowel diseases (IBD) and celiac disease, which were more frequent in European patients. Such findings are compatible with susceptibility loci related to intestinal immunity and IBD in recent genome wide association studies (GWAS) on IgAn. However, most of the molecules in these mucosal-related loci fulfill the immunologic function not only of gut-associated lymphoid tissue (GALT), but also nasopharyngeal/bronchial-associated lymphoid tissues (NALT/BALT). Indeed, a similar frequency of macrohematuria coinciding with upper respiratory infection, a hallmark manifestation of this disease, was found in the survey, emphasizing the pathogenic roles of these molecules in the NALT/BALT of patients with IgAn. Recent experimental and clinical studies including GWAS on multiple common infections and IBD indicate immune crosstalk between GALT and NALT/BALT, and some related mediators, such as TNF superfamily ligands (APRIL/BAFF). This review explains the epidemiologic heterogeneity of this disease with the clinical survey, and discusses race and sex-dependent molecular mechanisms.

Keywords: APRIL; BAFF; HORMAD2; IgA nephropathy; glomerular and tubulointerstitial diseases; gut; mucosa; pIgR; race; sex; tonsil.

Figure 1.

The ratio of episodic hematuria coincident with an acute gastrointestinal disorder or upper respiratory tract infection. There are no clear differences between the ratio of episodic hematuria coincident with an acute gastrointestinal disorder between Europe and Japan. However, the ratio of episodic hematuria coincident with an upper respiratory tract infection was relatively high in both Europe and Japan (23% vs 30%, respectively). Euro, Europe.

Figure 2.

History of recurrent tonsillitis and tonsillectomy. Although recurrent tonsillitis is relatively common in Japanese patients with IgA nephropathy (IgAn), the ratio of tonsillectomy because of recurrent tonsillitis is similar between Europe and Japan. However, tonsillectomy is a common treatment option in Japan, and approximately 53% of Japanese patients with IgAn underwent a tonsillectomy.

Figure 3.

Differences in the status of treatment between Europe and Japan. Treatment with renin-angiotensin system (RAS) inhibitors is common in both Europe and Japan. There are major differences in the use of high-dose intravenous corticosteroids and oral corticosteroids between Europe and Japan.