The Role of B-Cell Differentiation and Gut Microbiome in the Pathogenesis and Progression of IgA Nephropathy. Doctoral Thesis

Abstract

Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerular disease in numerous countries and continues to be a significant contributor to chronic kidney disease and end-stage kidney disease (ESKD). The clinical course can vary, but on average 30–40 % of patients reach ESKD within 20–30 years of diagnosis, and the disease may recur in the kidney graft. As the prognosis of this disease varies depending on its clinical presentation, the International IgAN Prediction Tool (IIgANPT) was developed in 2019 to integrate clinicopathological prognostic factors at the time of diagnosis and generate an individualised risk of disease progression. According to existing evidence, IgAN is believed to result from a combination of various pathogenic factors rather than a singular cause. This study was conducted to evaluate the risk of disease progression in IgAN patients and to analyse B-cell differentiation and the gut microbiome as potential factors in the pathogenesis of the disease. During a median follow-up of 18 months, 14.7 % of IgAN patients progressed to ESKD, corresponding to an incidence rate of 0.11 episodes per patient-year. Gender, MEST-T score and increased diastolic blood pressure were identified as significant risk factors for reduced kidney survival. We carried out flow cytometry analysis of peripheral blood B cells in IgAN patients and healthy controls (HC) to investigate how B cells are activated to produce pathogenic IgA. Expansion of na?ve and reduction in memory B cells was seen in IgAN patients with an increased frequency of IgA-expressing B cells that lacked the classical memory marker CD27, but were CD21+. IgAN patients furthermore had an expanded population of IgA+ antibody-secreting cells, which correlated with serum IgA levels. Both IgA+ plasmabalsts and CD27? B cells co-expressed galactose-deficient IgA1 (Gd-IgA1). Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide in the serum and IgA+CD27? B cell frequency. Metagenomic analysis and functional profiling of the gut microbiome were performed in IgAN patients categorised either as progressors (defined by an estimated glomerular filtration rate decline > 5? ml/min/1.73?m²/year), or non-progressors, and HC. Compared to HC, IgAN patients showed a reduced abundance of butyrate-producing bacteria. In addition, pathways related to nucleotide and nucleoside biosynthesis were more pronounced in IgAN patients, suggesting underlying immune activation and inflammation. Variations in these metabolic pathways were, in part, explained by Gd-IgA1 levels. Notably, the progressor group exhibited functional microbial changes linked to the stabilisation of bacterial cell membranes.