Despite decades of research, our understanding of the pathophysiology of immunoglobulin A (IgA) nephropathy and the risk factors predicting progression to kidney failure remains incomplete. A multi-hit mechanism has been proposed, necessitating a trigger by certain bacterial or viral infections in a genetically predisposed individual (1).
Since galactose-deficient (Gd)-IgA production is believed to be related to mucosal immune dysfunction of the respiratory tract (2), an innovative clinical investigation recently published in Kidney International by Luo et al. examined the effect of air pollution, as measured by exposure to fine particulate matter <2.5 µm in diameter (PM2.5), on the risk of kidney failure in patients with IgA nephropathy (3).
This study enrolled 1979 patients with biopsy-proven IgA nephropathy in China. The investigators used satellite data to evaluate PM2.5 exposure in different Chinese regions from 1998 until 2016. The trends in PM2.5 exposure, incidence of end stage kidney disease (ESKD) at 5 years after study enrollment, and estimated glomerular filtration rate (eGFR) decline were compared between provinces. Patients residing in north provinces had a higher burden of exposure to PM2.5 compared with south residents. The provinces with the highest PM2.5 exposures clearly had faster rates of eGFR decline and higher incidence of ESKD. Each 10 μg/m3 increase in annual average concentration of PM2.5 exposure before study entry led to a 14% increase in risk of ESKD, and each 10 μg/m3 increase in time-varying PM2.5 exposure after study entry increased the risk of ESKD by 10%. Above-median PM2.5 pollution exposure both before and after study entry increased the risk of ESKD by 54%. The associations held after the authors adjusted the models for lab/clinicopathologic covariates known to affect outcomes in IgA nephropathy, as well as time period, city size, and cardiovascular risk factors. City size was used as a proxy for socioeconomic status, given their known correlation in China. The authors concluded that PM2.5 is an independent risk factor for kidney failure in patients with IgA nephropathy.
This study moves the field further by proposing that an incremental dose-response relationship exists between pollution and the progression of kidney diseases in IgA nephropathy, thus reinforcing similar findings in the general chronic kidney disease population (4) and in patients with membranous nephropathy (5).
This study has many limitations. First, there was a lack of ethnic diversity within the studied cohort. Socioeconomic status and access to health care were inferred by city size. Moreover, there are significant limitations that made it impossible to objectively measure an individual's actual particulate exposure, which depends on multiple factors such as the residence's proximity to air pollution sources, indoor air pollution, time spent outside, or potential change in address after enrollment, for example. Furthermore, the low number of participants with available serum Gd-IgA levels could explain the lack of effect of serum Gd-IgA1 levels on ESKD progression in either PM2.5 exposure group.
Although they would need to be confirmed in subsequent studies with multi-ethnic cohorts, the results of this clinical investigation are most certainly thought provoking. Future work should be directed to provide insight into the exact pathophysiology by which air pollution can alter mucosal IgA galactosylation and how this is influenced by an individual's genetic background. Other polluting toxins, such as heavy metals, industrial agricultural chemicals and pesticides, and secondhand smoke, also need to be examined. Such information may help guide regulatory strategies to reinforce pollution control and prevent exposure to populations at risk.
- 1. ↑
Knoppova B, et al. The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol 2016; 7:117. doi: 10.3389/fimmu.2016.00117
- 2. ↑
Emancipator SN. Immunoregulatory factors in the pathogenesis of IgA nephropathy. Kidney Int 1990; 38:1216–1229. doi: 10.1038/ki.1990.337
- 3. ↑
Luo C, et al. Particulate matter of air pollution may increase risk of kidney failure in IgA nephropathy. Kidney Int 2022; 102:1382–1391. doi: 10.1016/j.kint.2022.08.020
- 4. ↑
Bowe B, et al. Associations of ambient coarse particulate matter, nitrogen dioxide, and carbon monoxide with the risk of kidney disease: A cohort study. Lancet Planet Health 2017; 1:e267–e276. doi: 10.1016/S2542-5196(17)30117-1
- 5. ↑
Xu X, et al. Long-term exposure to air pollution and increased risk of membranous nephropathy in China. J Am Soc Nephrol 2016; 27:3739–3746. doi: 10.1681/ASN.2016010093