Microplastics and IgA nephropathy: a novel environmental hypothesis of immune dysregulation.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by a 4-hit pathogenesis primarily driven by mucosal immune dysregulation in the gut-associated lymphoid tissue (GALT). However, the specific environmental triggers initiating this cascade remain elusive. We propose a novel hypothesis that chronic exposure to ubiquitous micro- and nano-plastics (MNPs) serves as a primary environmental catalyst for IgAN. Through a proposed 5-step cascade, we outline how ingested MNPs directly degrade intestinal tight junctions, precipitating a 'leaky gut' that permits the synergistic influx of plastics and commensal bacterial antigens into the GALT. Acting as a 'Trojan horse,' MNP-corona complexes evade immune detection but trigger chronic inflammation and B-cell dysregulation upon internalization by phagocytes. This persistent immune stimulation drives the aberrant production of galactose-deficient IgA1. Furthermore, we hypothesize that circulating MNPs co-deposit in the renal mesangium alongside immune complexes, acting as a dual generator of both systemic immune complexes and direct structural kidney injury. This potential gene-environment interaction is supported by the intersecting high prevalence of environmental MNPs and IgAN in Asia. Finally, we delineate future in vivo, observational, and epidemiological investigations required to establish this pathophysiological link.