Review Article

Environmental Exposures and Kidney Disease

Abhijit V. Kshirsagar ,1 Evan M. Zeitler ,1 Anne Weaver ,2 Nora Franceschini,3 and Lawrence S. Engel 3

Abstract
Accumulating evidence underscores the large role played by the environment in the health of communities and
individuals. We review the currently known contribution of environmental exposures and pollutants on kidney
disease and its associated morbidity. We review air pollutants, such as particulate matter; water pollutants, such
as trace elements, per- and polyfluoroalkyl substances, and pesticides; and extreme weather events and natural
disasters. We also discuss gaps in the evidence that presently relies heavily on observational studies and animal
models, and propose using recently developed analytic methods to help bridge the gaps. With the expected
increase in the intensity and frequency of many environmental exposures in the decades to come, an improved
understanding of their potential effect on kidney disease is crucial to mitigate potential morbidity and
mortality.
KIDNEY360 3: 2174–2182, 2022. doi: https://doi.org/10.34067/KID.0007962021

Introduction Cell culture and animal studies demonstrated that

There is growing understanding of how the environ- both short-term (days) and long-term (months to years)
ment affects the health of individuals and communities. exposure to PM2.5 induces oxidative stress, inflamma-
Exposure to human-made and naturally occurring tox- tion, cell autophagy, and cell apoptosis (5–10), whereas
ins in the air, water, and soil can lead to accumulation studies in humans demonstrated acute thrombus for-
in organs, and contribute to morbidity and mortality. mation and vascular dysfunction (11,12), which is pos-
Even transient events, such as extreme heat and natural tulated to eventually lead to clinical cardiovascular
disasters, may contribute to adverse health outcomes. events and mortality. Mechanisms of injury specific to
Patients with kidney disease may be especially sus- kidney disease are less clear. A recent study (13) of
ceptible to the effects of environmental exposures, given healthy volunteers demonstrated that inhaled inert
their innate frailty and high comorbidity burden. In this gold nanoparticles, a model for PM2.5, entering the
review, we discuss the potential contribution of envi- bloodstream, are detected in the urine within minutes
ronmental exposures to kidney disease and associated after exposure. The nanoparticle model suggests PM2.5
morbidity (Figure 1). We also discuss the current limita- can be filtered by the glomerulus and may thus lead to
tions in understanding and propose the use of recently indirect and direct kidney tissue injury.
developed analytic methods that may help to bridge Epidemiologic data about PM2.5 and kidney disease
some of these gaps. The intensity and frequency of can be divided into two categories: (1) PM2.5 as a risk
many environmental exposures are expected to increase factor for kidney disease and progression of CKD to
due to climate change while, at the same time, the global end stage kidney disease (ESKD), and (2) PM2.5 con-
burden of chronic kidney disease (CKD) is rising for all tributing to the morbidity and mortality of individuals
countries, including those with limited resources (1). with CKD, including ESKD.
A recent systematic review (14) identified 40 epide-
miologic studies examining the association of PM2.5 and
Air adverse kidney function. Most of the studies (36 of 40)
Particulate matter, an air pollutant that is a complex observed that PM2.5 exposure was associated with
mixture of small particles and liquid droplets arising adverse kidney function. The assessment of kidney
from the combustion of fossil fuels and biomass, has function was clinically diverse, and included outcomes
come into focus for its adverse effects (2,3). Particulate such as glomerular filtration rate (GFR), albuminuria,
matter with an aero-diameter ,2.5 mm (PM2.5) can and glomerulonephritis. We point out some of the
travel through the respiratory tract and enter the included studies to highlight the heterogeneity: (1)
bloodstream after inhalation; its components include long-term PM2.5 exposure was associated with the rise
sulfates, nitrates, ammonium, hydrogen ions, carbon, of a specific type of glomerular disease, membranous
volatile organic compounds, and trace metals. PM2.5 is nephropathy, in an 11-year series of .71,000 native kid-
one of the six criteria pollutants regulated by the US ney biopsy specimens across China (15); (2) among
Environmental Protection Agency (4). nearly 1 million US veterans, PM2.5 was associated with

1
UNC Kidney Center and Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, North Carolina
2
Center for Public Health and Environmental Assessment, Office of Research and Development, United States Environmental Protection
Agency, Chapel Hill, North Carolina
3
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina

Correspondence: Dr. Abhijit V. Kshirsagar, UNC Kidney Center and Division of Nephrology and Hypertension, University of North
Carolina, Room 7004 Burnett Womack Building, CB 7155, Chapel Hill, NC 27599-7155. Email: [email protected]

2174 Copyright # 2022 by the American Society of Nephrology www.kidney360.org Vol 3 December, 2022
KIDNEY360 3: 2174–2182, December, 2022 Environment and Kidney Disease, Kshirsagar et al. 2175

increased risk of all-cause and cardiovascular mortality

among patients receiving maintenance hemodialysis (21–23).
Short-term PM2.5 exposure is also associated with an in-
creased risk of hospital admissions and 30-day readmissions
among these patients (24).
In addition, limited evidence suggests an association
Air, water and soil pollutants between tropospheric or ground-level ozone, which is formed
by photochemical reactions between volatile organic com-

e
Ingestion

ur
pounds and nitrogen oxides in the atmosphere, and kidney
Inh

os
disease (25,26).
ala

p
ex
tio

in
n

Sk
Water
A range of heavy metals, perfluorinated compounds,
pesticides, industrial hydrocarbons, and pathogens are
common water contaminants. Human exposure to these
agents occurs through drinking the water, consumption of
animals (especially fish and mollusks) living in the water,
or dermal/mucosal contact with the water.
Metals, including arsenic, cadmium, lead, mercury, and ura-
Excessive heat Extreme nium, are among the most extensively studied waterborne
weather nephrotoxins. Arsenic is a naturally occurring metalloid found
in many parts of the world, especially in groundwater. Arsenic
can also be introduced into water via mining and metal smelt-
ing (27). Worldwide, .200 million people are estimated to be
chronically exposed to arsenic in drinking water at concentra-
tions above the World Health Organization provisional guide-
line value of 10 mg/L (27,28). Epidemiologic studies linked
high drinking water arsenic levels to increased CKD/ESKD
incidence (29,30), progression (31), and mortality (32).
Cadmium is released into water, soil, and air via (1) mining
and metal refining; (2) production and application of phos-
phate fertilizers; (3) burning of fossil fuels; and (4) waste
Indirect
effects (e.g. incineration, disposal, and recycling (33). Although drinking
DM, water contributes only a small proportion of total cadmium
hypertension) exposure in the general population, it can be an important
source of exposure for water in the vicinity of cadmium-
emitting industries (33,34). Historically, a major outbreak of
Figure 1. | Multiple routes of environmental exposures and their cadmium toxicity occurred in the Toyama Prefecture (Japan)
potential end-organ effects. Environmental exposures occur through a after contamination of the Jinzu River basin from a zinc mine
variety of routes that can directly and indirectly influence kidney health. in 1912. Local inhabitants termed the resulting disease
Pollutants in the air, water, and soil may be ingested, inhaled, or
“itai-itai” or “ouch-ouch” disease because of severe, diffuse
absorbed through the skin. To varying degrees, these pollutants cross
into the bloodstream, where they may travel to, and directly injure, the
bone pain from vitamin D–resistant rickets with osteomala-
kidneys. Some compounds will first be absorbed via the gastrointestinal cia; other manifestations included proximal tubular dysfunc-
tract, undergoing first-pass metabolism in the liver before returning to tion and hyperphosphaturia (35). Most studies of renal
the bloodstream. Some exposures may also indirectly contribute to kid- toxicity associated with cadmium have measured exposure
ney disease by causing conditions such as diabetes and hypertension— via blood or urine levels and have linked exposure with sev-
well-established risk factors for incident or progressive CKD. DM, diabe- eral molecular markers of kidney injury and CKD (33,36,37).
tes mellitus. The most common source of lead in drinking water is
from leaching of plumbing materials, including lead service
incident CKD and the progression of CKD to ESKD (16); (3) lines and residential pipes, lead solder, and certain fixtures
among a community-dwelling cohort of middle-aged indi- (38). However, it can also result from runoff or dumping
viduals, PM2.5 was associated with both increased urine from lead smelters, lead battery production or recycling
albumin and a decline in GFR (17); (4) modeling estimated 7 operations, and mining (38,39). In most countries, blood
million incident cases of CKD annually are attributable to lead levels are decreasing, but continue to be of concern
PM2.5 worldwide (18); and (5) among a US national cohort of (40). Most studies investigating kidney effects related to
kidney transplant recipients, PM2.5 was associated with lead exposure assessed exposure via blood lead levels;
increased risk of 1-year kidney rejection post-transplant, graft they identified associations with CKD incidence (41) and
failure, and all-cause death (19). prevalence (42,43), and increased serum creatinine (44) or
Short-term PM2.5 exposure during wildfires (20), and decreased eGFR (45,46). A recent study demonstrated that
short- and long-term ambient PM2.5, is associated with a 5% high lead levels were associated with a higher prevalence
2176 KIDNEY360

of anemia among patients with ESKD (47). Overall, lead- the widespread presence and stability of aristolochic acids in
induced kidney disease may be underdiagnosed or mis- groundwater in Serbia (69); however, the prevalence and
diagnosed as hypertensive kidney disease without accurate levels of such groundwater contamination worldwide are
assessment of lead exposure from patient histories. unknown.
Globally, artisanal and small-scale gold mining and coal Exposure to pesticides occurs through several routes,
combustion are the primary sources of anthropogenic mer- including consumption of contaminated surface or well
cury emissions (48). General population exposure to mer- water. Most studies examining pesticides and CKD have
cury, primarily in the form of methylmercury, occurs been conducted among farmers or agricultural workers.
mostly through consumption of fish, shellfish, and marine They have assessed exposure via self-report in terms of
mammals from contaminated fresh- or seawater (48). applications, i.e., either direct from handling of the pesti-
Although chronic exposure to mercury has been shown to cides or indirect from being in the vicinity of applications.
induce renal dysfunction, there is limited epidemiologic Pesticides that have been linked to CKD/ESKD in one or
evidence of an association specifically between methylmer- more epidemiologic studies include the herbicides alachlor,
cury and CKD (49). Methylmercury toxicity manifests atrazine, butylate, glyphosate, metolachlor, paraquat, and
primarily in neurologic changes (Minamata disease) (50) pendimethalin, and the insecticides methyl parathion and
and less commonly in markers of kidney disease, such as permethrin (70–75). The organochlorine insecticides hexa-
proteinuria (51). chlorocyclohexane and endosulfan have also been associ-
For the general population, drinking water is an impor- ated with CKD (76,77). The herbicide dicamba has been
tant source of uranium exposure (52). Contamination of associated with reduced eGFR (76), whereas the organo-
ground- and surface water arises largely from redistribu- chlorine insecticide dichlorodiphenyltrichloroethane (DDT)
tion of uranium and uranium progeny through the natural and its primary metabolite have been linked to insulin
erosion of rock and soil, although elevated levels can be resistance and increased diabetes risk, which may indi-
found near mining operations. Epidemiologic studies have rectly impair renal function (78).
reported associations between uranium levels in drinking
water and molecular markers of renal dysfunction, with
stronger evidence from animal studies (52).
Extreme Weather Events and Natural Disasters
Per- and polyfluoroalkyl substances, known as PFAS, are
An extreme weather event is defined as “time and place
a large family of manmade, persistent chemicals widely
in which weather, climate, or environmental conditions—
used in everyday products and widespread drinking water
such as temperature, precipitation, drought, or flooding—
contaminants. PFAS are used in firefighting foam, food
rank above a threshold value near the upper or lower ends
packaging, personal care products, nonstick cookware, car-
of the range of historical measurements” (79). Natural
pet, upholstery, and many other applications. Two of these,
disasters are weather conditions “ … that have the potential
perfluorooctanoic acid and perfluorooctane sulfonate, were
to pose a significant threat to human health and safety,
manufactured and released into the environment for deca-
property, [and] critical infrastructure … ” (80).
des, but are no longer produced or used in the United
To date, the primary epidemiologic focus has been
States or most other industrialized countries (53). However,
they and the PFAS that replaced them continue to be found extreme heat, especially in the context of CKD of unknown
in surface and groundwater sources. These legacy PFAS etiology (CKDu) or CKD of nontraditional origin. CKDu/
have been associated directly with increased risk of CKD in CKD of nontraditional origin occurs among individuals
some (54–57), but not all (58–60), studies, and inversely engaged in intense manual labor in hot environments. The
with GFR in several studies (56,61,62). The exact nature of described kidney injury is tubulointerstitial, associated with
the association of PFAS and CKD is ambiguous because increased levels of urinary neutrophil gelatinase-associated
serum concentrations of PFAS may increase with decreased lipocalin (NGAL) (81–83) and urinary IGF binding protein
kidney function (63). PFAS exposure has also been linked 7 in some studies (82), and renal biopsy specimens demon-
to obesity, diabetes mellitus, hyperlipidemia, and cardio- strate acute tubular cell injury and chronic tubulointerstitial
vascular conditions that are direct and indirect risk factors nephritis (84). An increase in urinary markers of kidney
for kidney disease. injury after physical work in the heat has been shown to be
For the general population, the primary routes of expo- exacerbated by longer work durations (85) and the magni-
sure to trichloroethylene and tetrachloroethylene, used as tude of hyperthermia and/or dehydration (82). The kidney
industrial degreasers and in dry cleaning, are inhalation injury may be exacerbated by the occurrence of muscle-
from ambient or indoor air and ingestion of contaminated damaging exercise (83) and/or the intake of sugar-
drinking water (64,65). These chemicals have been shown sweetened beverages high in fructose (81) that are common
to have nephrotoxic effects in epidemiologic and animal in these workplaces (86) and associated with increased uri-
studies (64,65). nary neutrophil gelatinase-associated lipocalin. The National
In addition to chemical pollutants often found in drinking Institutes of Health has started a multicenter study of CKDu
water, biologic contaminants, including the bacteria Lepto- focused on hot-spot regions in Central America and India,
spira (66) and parasitic worms from the genus Schistosoma with the intent of characterizing CKDu clinical features and
(67,68), have been implicated in the pathogenesis of CKD. identifying biomarkers for early disease, environmental
Aristolochic acids, potent nephrotoxins produced by the exposures, and other risk factors.
Aristolochia plant, were first identified in relation to Balkan A recent study demonstrated an association of extreme
endemic nephropathy among individuals using Aristolochia- heat events, defined as temperature .95th percentile for
based herbal remedies (69). A recent study demonstrated the day and location over 30 years, and hospitalizations
KIDNEY360 3: 2174–2182, December, 2022 Environment and Kidney Disease, Kshirsagar et al. 2177

Epidemiologic Biological
data samples

15
–log10(P)

10
5
0
Environment-wide association studies Metabolomic/proteomic analysis

Markers Predictors
of exposure of outcome

Disease-associated
exposures

Figure 2. | Integration of epidemiologic data with metabolomic/proteomic analyses to bridge the information gap. Integrating large data-
sets from previously disparate fields, such as epidemiology and metabolomics, may be key to connecting environmental exposures to biologic
outcomes. In the proposed framework, epidemiologic data contribute to epigenome-wide association studies (EWAS), which identify putative
disease-associated exposures. Concurrently, metabolomic and proteomic studies can identify signals in biologic samples that are associated with
exposure to pollutants, are predictors of outcome, or both. Exposures identified via EWAS can then be compared with these signals, and candi-
date compounds tested in preclinical models to confirm causality.

and mortality for patients receiving in-center hemodialysis interspecies differences in toxicant uptake, metabolism, and
in the northeastern United States (87). response may limit the utility of some animal models.
A systematic review evaluated the effects of natural disas- Observational studies often generate and test hypotheses,
ters on dialysis populations in the Americas, assessing but they cannot alone establish causation. Furthermore,
15 original research articles published in the English lan- existing banked specimens from established cohort studies
guage from 2009 to 2019. They found that disasters have have varying longitudinal follow-up, storage quality, and
immediate, direct effects related to the ability to receive assay repeatability.
maintenance dialysis from loss of electricity and other infra- Advances in the “omic” technologies and new study
structure, such as water. Additionally, the disasters exacer- designs may help address some of the limitations. Multiple
bate depression and post-traumatic stress disorder in the omic approaches may offer a better picture of the different
long term (88). The effect of such extreme heat events and aspects related to the “exposome”—the measure of all
natural disasters (e.g., hurricanes), is expected to increase in exposures across a person’s lifespan related to health (90).
the coming years because of climate change. Genomics encompass the study of the DNA structure and
its epigenetic regulation, and proteomics include the evalua-
tion of gene products and protein post-translational modifi-
Mind the Gap cations (91). Metabolomics measure intermediate metabolic
The current literature on the potential role of environmen- chemical processes in biologic tissues and fluids (92). These
tal exposures in kidney disease has important limitations. omic assays have been applied in studies of patients with
First, national and international agencies have different kidney disease and in healthy individuals (93) and, taken
accepted levels for pollutants, preventing the establishment together, they can analyze the flow of biologic information
of standard toxicity thresholds. Second, we rely either on from exposure to gene, protein, and function (and back).
cell and animal models or on epidemiologic studies—each New study designs include meeting-in-the-middle (MITM)
with their respective challenges. Although in vitro and ani- (94) and environment-wide association studies. As an exam-
mal experiments can test highly specific exposures, quantify ple, exposure to PM2.5 is associated with epigenetic changes
outcomes, and control conditions, they may not replicate the in DNA methylation (95,96), and exposure to PFAS is associ-
effects of exposures profiles (dose, duration) seen in the real ated with plasma metabolites related to kidney injury (97).
world. For example, an individual’s PM2.5 exposure is influ- Alone, these findings are suggestive of associations between
enced by both environmental and behavioral factors (e.g., air exposures and outcomes. MITM studies use advanced
filtration and duration of time outdoors) (89). Furthermore, regression techniques and mediation analysis to find overlap
an individual’s potential effective exposure dose is governed between proteomic or metabolomic profiles resulting from
by particle deposition, clearance, and retention within the exposure and those that are predictive of disease (94). This
respiratory tract and extrapulmonary tissues. In addition, model is particularly useful in prospective cohorts with
2178 KIDNEY360

Table 1. Summary of environmental pollutants and their potential effect on kidney disease

Pollutants Source Kidney Effect

Particulate matter ,2.5 mm Air Associated with kidney function decline, and
with CKD and ESKD morbidity/mortality
Ozone Air Limited association with CKD
Heavy metals
Arsenic Water, soil, diet Associated with incident CKD and ESKD, and with
CKD progression and mortality
Cadmium Water, soil, air Bone disease (itai-itai), proximal tubular
dysfunction, AKI
Lead Water, soil, air Associated with incident and prevalent CKD, and
with anemia of ESKD
Mercury Seafood, air Limited association with CKD
Uranium Water Associated with markers of kidney injury
Per- and polyfluoralkyl substances
Perfluorooctanoic acid Water, diet Limited association with kidney disease
Perfluorooctane sulfonate Water, diet Limited association with kidney disease
Industrial degreasers
Trichloroethylene Air/water Both cause nephrotoxicity in animal studies,
Tetrachloroethylene limited association with CKD
Organisms and plants
Leptospira Water Associated with CKD
Schistosoma Water Associated with CKD
Aristolochia Water, diet Chronic tubulointerstitial nephritis
Insecticides
Methyl parathion, permethrin, Water, diet, dermal All associated with CKD,
hexachlorocyclohexane, endosulfan, contact dichlorodiphenyltrichloroethane specifically
dichlorodiphenyltrichloroethane associated with insulin resistance and increase
risk for diabetes
Herbicides
Alachlor, atrazine, butylate, glycophosate, Water, diet, dermal All associated with CKD
metolachlor, paraquat, pendimethalin, contact
dicamba
Heat N/A Associated with CKD of unknown cause, and with
morbidity for patients with ESKD receiving dialysis
Natural disasters N/A Associated with increased morbidity for patients with
ESKD receiving dialysis

N/A, not applicable.

longitudinal sample collection, such that biologic samples are By integrating multiple environmental exposures, MITM
available before disease onset. One such study examined the designs could help make connections from environmental
relationship between exposure to PFAS during pregnancy exposure to intermediate markers, then to biologic effects,
and fetal growth restriction (98), combining a metabolome- and finally to clinical outcomes in a stepwise fashion. Metab-
wide association study of PFAS exposure with a olome- and proteome-wide association studies of environ
metabolome-wide association study of fetal growth to iden- mental exposures can target metabolic pathways and iden-
tify metabolites that were associated with both exposure and tify biomarkers of exposure. These “exposure/early effect
outcome. This study identified altered amino acid and lipid markers” can then be evaluated for their association with the
metabolism, linking exposure and outcome. Thus, incorpo- outcome of interest (Figure 2). Although this type of study is
rating the MITM approach can strengthen causal inference ambitious, the infrastructure to perform it now exists. Multi-
from these data. ple large cohorts (including participants with and without
Studies examining multiple exposures present an oppor- kidney disease) would lend themselves to such investigations,
tunity to expand the scope of MITM studies. These studies including NHANES, the Chronic Renal Insufficiency Study,
aim to identify environmental factors associated with the the Atherosclerosis Risk in Communities study, and the Cure
disease of interest that are examined individually or as Glomerulopathy Network. Targets identified through these
combined exposures (99). Although few such studies are analyses could then be investigated in existing preclinical
related to kidney disease, recent work in the National models to confirm their role in the pathogenesis of kidney dis-
Health and Nutritional Examination Survey (NHANES) ease. Such preclinical models already exist for exposures such
identified that blood cadmium, lead, and volatile organic as PM2.5 and have helped to elucidate the mechanisms by
compound exposures are associated with CKD (100). This which particulate matter may directly affect kidney function
study used biomarkers and additional studies, using sur- (101), illustrating how hypotheses generated by examining
vey or geospatial data, are needed to complement these exposures in observational epidemiologic studies may be
findings. tested in vivo.
KIDNEY360 3: 2174–2182, December, 2022 Environment and Kidney Disease, Kshirsagar et al. 2179

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