Gut Microbiome in IgA Nephropathy: Associations with Baseline Disease Presentation and Longitudinal Clinical Outcomes in South Asians

IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally and a leading cause of chronic kidney disease in South Asia. Gut dysbiosis plays a crucial role in the pathogenesis of IgAN. South Asians have an aggressive disease presentation and progression, and the impact of gut dysbiosis has not been addressed in this population. This study investigated gut microbiome alterations in IgAN and their associations with clinical presentation and disease progression in the longitudinal prospective GRACE-IgANI cohort.

Consecutive patients in the GRACE-IgANI cohort were recruited at the time of kidney biopsy after obtaining written informed consent. Inclusion criteria included age > 18 years with biopsy-proven IgAN and no use of antibiotics or immunosuppressants in the preceding 12 weeks. Those with secondary IgAN and those with estimated glomerular filtration rate (eGFR) estimated by the CKD-EPI equation <10 ml/min/1.73 m2 were excluded. The disease controls included all patients other than IgAN (matched by age and gender) who underwent kidney biopsy during the same period. The baseline and three-year longitudinal outcomes were analysed for IgAN cohort and compared with age and gender matched healthy controls. 

Microbiome profiling was performed using 16S rRNA gene sequencing. The primary outcomes assessed the difference in gut microbiome composition between IgAN patients and disease- and healthy controls, as measured by α- and β-diversity metrics and the relative abundance of bacterial taxa. Secondary outcomes included correlations between microbial profiles and clinical parameters—such as 24-hour proteinuria, eGFR, and other biomarkers associated with disease severity and progression. 

Alpha diversity was assessed using Shannon and Faith’s phylogenetic metrics, while Bray-Curtis, weighted, and unweighted UniFrac measured beta diversity. Random forest prediction models were used to analyse the differences in microbiome composition. Statistical analyses were conducted in R 4.2.0 using relevant packages for data reduction, analysis and visualisation.

Stool samples from 111 biopsy-proven IgAN patients, 140 disease controls and 120 healthy controls were analysed using 16S rRNA gene sequencing to determine bacterial diversity and composition. The mean age of the IgAN cohort was 36.26 (10.30) years, with 71.2 % being males. The median eGFR and proteinuria were 41.6 (30.4, 71.8) mL/minute/sq.m and 1790 (980, 3600) mg/g, respectively. Other baseline clinical characteristics of IgAN patients and controls were summarised below. The IgAN cohort and disease controls were comparable in terms of alpha and beta diversity. Bacillota and Pseudomonadota were more abundant in both IgAN and disease controls. Rombustia, Bacteroides, Faecalibacterium and Segatella differentiated IgAN patients from controls. Higher serum IgA levels were associated with lower alpha diversity as per the Chao1 index. Gemmiger species showed a negative correlation with C3 deposition in the glomerulus. Significant Difference in Alpha Diversity using Chao1 index between rapid progressors and non-progressors. Among the top taxa, the increased abundance of Escherichia and Shigella, and the decreased abundance of Segatella and Faecalibacterium, were associated with unfavourable clinical outcomes. Data on healthy controls and comparisons with the IgAN cohort are being analysed.

This well-characterised immunosuppression-naïve clinical cohort, with stool samples collected at the time of diagnosis, is the first study from South Asia to explore the gut microbiome in primary IgAN and its relationship with longitudinal clinical outcomes.