A recent study has indicated a causal relationship between environmental factors and both immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN).
IgAN is the most prevalent glomerulonephritis globally, carrying a considerable lifetime risk of kidney failure. Previous research has indicated a “four-hit” progression pattern for IgAN, although more recent studies have noted its failure to address the disease’s geographic distribution, racial diversity, and clinical heterogeneity.1
MN is an autoimmune disease triggered by autoantibodies attacking podocyte antigens, which leads to the in situ production of immune complexes. However, little is known about the pathogenesis or etiology. 40-60% of patients with nephrotic syndrome progress to end-stage renal disease or die from cardiovascular or thrombotic events.2,3
“Previous [Mendelian randomization (MR)] analyses have revealed that external environmental factors can influence disease progression by changing an individual’s internal environmental factors (e.g., personal behavior and metabolism),” wrote Chunmin Li, department of nephrology, Tongren Hospital of Wuhan University, and colleagues. “We performed a two-step MR analysis to dissect the mediating role of individual behavior, metabolism in the association of the external environment with disease, offering novel insights into their prevention.”1
Investigators collected data from the Genome-wide association study (GWAS) to investigate the relationships between a collective 68 environmental exposures and IgAN and MN. The risk factors were then divided into 5 main categories: socioeconomic factors, air pollution, metabolic factors, physical measurements, and behavioral factors. GWAS studies with larger sample sizes and greater recency were chosen as the source of instrumental variables (IVs) for exposure.1
The IgAN dataset was derived from a meta-analysis of 477,784 European samples (15,587 cases and 462,197 controls) and 24,182,646 single-nucleotide polymorphisms (SNPs) conducted by the UK Biobank and Finnish Genetics. The primary MN were acquired from 5 European cohorts totaling 7979 individuals (2150 primary MN cases and 5829 controls) and 5,327,688 SNPs conducted by the Kiryluk Lab.1
Causative connections were estimated using 3 different methods: weighted median (WM), MR-egger, and inverse variance weighted (IVW). Overall estimates using IVW were used as main effects, with WM and MR-egger as complements. All IVs in the study had F values >10, ranging from 27-808, and the number of SNPs ranged from 2-300.1
A total of 20 causal relationship pairs and 8 novel relationships were identified. IgAN exhibited novel relationships with cheese intake, fresh fruit consumption, transferrin saturation, cognitive performance, insomnia, and intelligence. A causal association also appeared between MN and beef intake, as well as moderate to vigorous physical activity.1
Li and colleagues also conducted reverse causality MR analysis, which indicated a negative causal relationship between IgAN and gluten-free (odds ratio [OR], .97; 95% CI, .947-.983; P <.001), cheese intake (OR, .970; 95% CI, .947-.993; P = .011), cognitive performance (OR, .928; 95% CI, .879-.98; P = .008), intelligence (OR, .949; 95% CI, .927-.972; P <.001), and hip circumference (OR, .937; 95% CI, .893-.984; P = .009). However, it predicted a positive causal relationship between IgAN and triglycerides (OR, 1.091; 95% CI, 1.026-1.16; P = .005).1
The team noted that the results from this study may provide clinicians with methods to forestall or prevent the development and prognosis of IgAN and MN. However, they also called for more research to be conducted into both the causal relationship between these external factors and nephropathy and the process of avoiding it.1
“This research provides a potential foundation for the establishment of precise etiological and risk assessment evidence for IgAN and MN,” Li and colleagues wrote.1
References
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Li C, Wen Q, Zhang Y, Wu J. Causal associations between environmental factors and risk of IgA nephropathy and membranous nephropathy: a bidirectional Mendelian randomization and mediation analysis. Ren Fail. 2025;47(1):2486620. doi:10.1080/0886022X.2025.2486620
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Stamellou E, Seikrit C, Tang SCW, et al. IgA nephropathy. Nat Rev Dis Primers. 2023;9(1):67. Published 2023 Nov 30. doi:10.1038/s41572-023-00476-9
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Claudio P. Primary membranous nephropathy: an endless story. J Nephrol. 2023;36(2):563-574. doi:10.1007/s40620-022-01461-3