REVIEWS

Environmental pollution and kidney

diseases
Xin Xu, Sheng Nie, Hanying Ding and Fan Fan Hou*
Abstract | The burden of disease and death attributable to environmental pollution is becoming a
public health challenge worldwide, especially in developing countries. The kidney is vulnerable to
environmental pollutants because most environmental toxins are concentrated by the kidney
during filtration. Given the high mortality and morbidity of kidney disease, environmental risk
factors and their effect on kidney disease need to be identified. In this Review, we highlight
epidemiological evidence for the association between kidney disease and environmental
pollutants, including air pollution, heavy metal pollution and other environmental risk factors.
We discuss the potential biological mechanisms that link exposure to environmental pollutants
to kidney damage and emphasize the contribution of environmental pollution to kidney disease.
Regulatory efforts should be made to control environmental pollution and limit individual
exposure to preventable or avoidable environmental risk. Population studies with accurate
quantification of environmental exposure in polluted regions, particularly in developing
countries, might aid our understanding of the dose–response relationship between pollutants
and kidney diseases.

National Clinical Research
Center for Kidney Disease,
State Key Laboratory of
Organ Failure Research,
Nanfang Hospital, Southern
Medical University, 1838
North Guangzhou Avenue,
Guangzhou 510515, China.
*e-mail:
ffhouguangzhou@163.com
doi:10.1038/nrneph.2018.11
Published online 26 Feb 2018
Kidney disease has been increasingly recognized as a
public health problem owing to its increasing prevalence,
the increased risk of cardiovascular disease (CVD) and
death in patients with kidney disease and the high cost
of treatment. A meta-analysis of 33 studies estimated
that the worldwide prevalence of chronic kidney disease
(CKD) in 2010 was 10.4% in men and 11.8% in women1,
with the majority of patients being from developing
countries. The Global Burden of Disease Study 2015
estimates that 1,234,900 deaths in 2010 were directly
attributable to CKD, which represents a 31.7% increase
from 2005 (REF. 2). The increasing prevalence of CKD
and the variation in the burden of kidney disease cannot
be fully explained by trends in traditional drivers, such
as diabetes mellitus and hypertension, suggesting that
other previously unappreciated risk factors contribute
to the disease process3–6.
The effects of increasing environmental pollution
(of air, water and soil, typically by chemical products
in daily use), which is a result of accelerated industri-
alization and urbanization worldwide, have become a
global health challenge. The World Health Organization
(WHO) reported that preventable environmental risks
accounted for 12.6 million deaths worldwide and 22%
of the global burden of disease in 2012 (REF. 7) (FIG. 1).
More than 1.7 million children younger than 5 years
of age die every year as a result of living in a polluted
environment. The kidney is especially vulnerable to
environmental pollutants, as almost 20% of the cardiac
output of blood is delivered to the kidneys, where the
blood is filtered and environmental toxins can be con-
centrated. Although diabetes, hypertension and primary
glomerulonephritis are major causes of CKD in most
middle-income and high-income countries, infectious
diseases and environmental and occupational exposure
to pollutants remain common causes of kidney disease
in the developing world.
In this Review, we summarize the epidemiological
evidence for the association between kidney disease
and exposure to environmental pollutants, including
air pollution, heavy metal pollution and other potential
environmental risk factors. We also discuss the poten-
tial biological mechanisms that might link exposure to
­environmental toxins to kidney damage.
Air pollution and kidney disease
The Global Burden of Disease Study estimates that
6.4 million deaths in 2015 were attributable to air pol-
lution2. Epidemiological and experimental studies have
clearly established that air pollution, and particulate mat-
ter from both pulmonary and extrapulmonary sources in
particular, contributes to cardiovascular morbidity and
mortality 8. Particulate matter is generally categorized
by its mean aerodynamic diameter as PM10 (particulate

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Key points In humans, most inhaled particles >5 μm in aero-

• Up to 22% of the global burden of disease and 23% of deaths are attributable to
environmental pollution; the general public is inevitably exposed to environmental
pollutants
• The kidney is particularly vulnerable to toxic effects from environmental pollutants
owing to its filtration functions; environmental and occupational exposures to
pollutants remain common causes of kidney disease worldwide, especially in
developing countries
• Long-term exposure to particulate matter <2.5 μm in mean aerodynamic diameter
(PM2.5) is associated with increased risk of membranous nephropathy and more rapid
decline in renal function
• Exposure to heavy metals leads to acute and chronic kidney injury; tubular
dysfunction is the most common manifestation of nephrotoxicity from heavy metals
• Owing to the worldwide distribution of Aristolochia spp. and the still widespread use
of medicinal herbal remedies containing aristolochic acids, especially in east Asia, it is
possible that aristolochic acids might be the cause of unrecognized nephropathies
• Exposure to industrial and agricultural chemicals, biogenic toxins and secondhand
smoke are additional risk factors for kidney disease
matter <10 μm in diameter), PM2.5 (<2.5 μm) or ultra­
fine particles (UFPs, <0.1 μm) (FIG. 2). Exposure to PM2.5
caused 4.2 million deaths in 2015, which represents
7.6% of deaths worldwide, and contributed to 17.1% of
mortality from ischaemic heart disease, 14.2% of mortal-
ity from cerebrovascular disease and 16.5% of mortality
from lung cancer. Approximately 60% of PM2.5-related
deaths occurred in south and east Asia9,10.
Air pollution is a complex mixture of gaseous com-
ponents and solid and liquid particles suspended in the
air and can vary substantially in chemical composition
between different cities. Particulate matter, which pri-
marily comprises solid particulates that are derived
from the combustion of coal, gasoline and diesel fuels,
is the major element of air pollution that causes the
most adverse health effects in animals and humans8,11,12.
In large cities, the majority of particulate matter pro-
duction comes from road traffic and industrial burning
of fossil fuels13.
Gaseous compounds, such as nitrogen dioxide, car-
bon monoxide, ozone and sulfur oxides, are another
important component of air pollution. Nitric oxides and
carbon monoxide are mainly derived from road traffic
and the industrial burning of fuels14, whereas the indus-
trial production of sulfur-based products is the major
source of sulfur dioxide15. Exposure to these gaseous
pollutants is widely acknowledged to cause various
health problems in adults, including chronic obstruc-
tive pulmonary disease, asthma, cataracts and blind-
ness, whereas gaseous pollutants cause acute respiratory
­infections in both adults and children16.
Air quality varies markedly between different coun-
tries, different cities within a country and even different
locales within a city. In the decade from 2000 to 2010,
urban expansion in east Asia has exacerbated air pollu-
tion17. For example, the 1‑year average of PM2.5 exceeds
50 μg/m3 in developing countries such as China and India
compared with 10–14 μg/m3 in more-developed coun-
tries such as the USA, the UK and Japan18. The PM2.5 val-
ues ranged from 6 μg/m3 to 114 μg/m3 among 282 cities
in China, with an interquartile range of 41 μg/m3 (REF. 19).
dynamic diameter are trapped in the fluid that lines
the upper airways or larger lower airways, are moved
upwards by the mucociliary ladder and are excreted from
the body or swallowed. Particles <5 μm in aerodynamic
diameter are more likely to be deposited in the bron-
chioles and the alveoli of the lung 20. Particles deposited
beyond the terminal bronchioles are cleared by lung mac-
rophages that, in turn, transport the ingested particles
onto the mucociliary ladder or into the lymphatic sys-
tem. Alveolar phagocytes and pulmonary dendritic cells
engulf any extraneous materials deposited at the lung
epithelium, efficiently but slowly removing the foreign
particulate matter 21–23.
Adverse effects of particulate matter on the lungs
include disruption of the airway epithelial barrier and
cellular signalling pathways24–26, induction of oxidative
stress27–30, impairment of phagocytosis28, infiltration of
inflammatory cells, and dysregulation of cellular immu-
nity, epigenetic modifications and autophagy 27,28. The
pulmonary inflammatory mediators induced by PM2.5
could spill over into the circulation, resulting in systemic
inflammation, oxidative stress and damage to distant
organs8. PM2.5 deposited in alveoli activates an autonomic
nervous system reflex, which induces an autonomic nerv-
ous system imbalance31 and promotes systemic oxidative
stress and other organ damage. Furthermore, deposited
ultrafine particles may translocate directly into the circu-
lation or the lymphatic system, leading to dysfunction of
coagulation and/or fibrinolysis and, subsequently, cellu-
lar responses in nonpulmonary tissues32, which explains
why people with pre-existing disease are particularly
vulnerable when exposed to particulate matter 33,34 (FIG. 3).
Of note, inhaled particles <30 nm in diameter can trans­
locate from the lungs into the circulation, are filtered and
excreted by the kidneys and selectively accumulate at sites
of vascular inflammation in both animals and healthy
men35. Whether the deposition of inhaled nanoparticles
contributes to the progression of cardiovascular disease
in patients with CKD requires further investigation.
Mounting evidence implicates air pollution in the
pathogenesis of pulmonary and cardiovascular diseases,
including asthma, myocardial infarction, stroke, cardiac
arrhythmia and heart failure. A comprehensive review
of the likely biological mechanisms strongly supports
a causal relationship between air pollution and cardio­
vascular disease and mortality 4. Although currently limi­
ted, data on the link between air pollution and kidney
injury or disease in humans and in animal models are
also now beginning to emerge.
Epidemiological studies. A study of 1,103 consecutive
patients who were hospitalized with acute ischaemic
stroke in the Boston (MA, USA) metropolitan region
found an association between the proximity of a patient’s
home to a major roadway and their estimated glomer-
ular filtration rate (eGFR)36. Individuals living 50 m
from a major roadway had a 3.9 ml/min/1.73 m2 lower
eGFR than those who lived 1,000 m away. In another
cohort study that included 669 elderly men from the
Boston area, 1‑year PM2.5 exposure was associated with

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Disease burden (%)

9–14
15–16
17–18
19–22
23–31
Data not available
Not applicable
0 850 1,700 3,400
Kilometres

Figure 1 | Worldwide distribution of disease burden attributable to environmental risks in 2012. As a proportion of
Nature Reviews
total disease burden, the burden of disease attributable to environmental risks is higher in low-income | Nephrology
and middle-income
countries than in high-income countries. Reprinted from World Health Organization, Prüss-Ustün, A., Wolf, J., Corvalán, C.,
Bos, R. & Neira, M. Preventing disease through healthy environments: a global assessment of the burden of disease from
environmental risks, copyright (2016), REF. 7.

a lower eGFR and a faster annual decline of eGFR37.
Each 2.1 μg/m3 increase in PM2.5 exposure was associ-
ated with a 1.87 ml/min/1.73 m2 reduction in eGFR and a
0.60 ml/min/1.73 m2 per year additional decline in annual
renal function.
A nationwide study of renal biopsy samples obtained
during 2004–2014 included 71,151 native kidney biopsy
samples from 938 hospitals in 282 cities across China19.
During the study period, the level of PM2.5 exposure var-
ied from 6 μg/m3 to 114 μg/m3 (mean 52.6 μg/m3) among
the 282 cities. The researchers found that the prevalence
of membranous nephropathy increased from 12% to 24%
during the decade, whereas the prevalence of other major
glomerular diseases remained relatively stable. More strik-
ingly, long-term exposure to high levels of PM2.5 was asso-
ciated with an increased risk of membranous nephropathy
in a nonlinear pattern. Each 10 μg/m3 increase in PM2.5
concentration was associated with 14% higher odds of a
patient developing membranous nephropathy (OR 1.14,
95% CI 1.10–1.18) in regions with PM2.5 levels >70 μg/m3.
The effect size in regions with PM2.5 <60 μg/m3 was greatly
attenuated. The findings from this study suggest that
patients with long-term exposure to PM2.5 are more
likely to develop membranous nephropathy than they
are to develop other kidney diseases. However, the study
included only patients from whom renal biopsy samples
were taken and not the general population. Therefore,
without registry data for the biopsy samples, the aggre-
gated effect of PM2.5 on kidney disease in the general pop-
ulation cannot be estimated. Furthermore, the study
population is characterized by exposure to unusually high
levels of PM2.5, so the results might not be generalizable to
a population exposed to low levels of PM2.5.
A large cohort study of >2 million US veterans with no
previous history of kidney disease found that long-term
exposure to PM2.5, PM10, nitrogen dioxide and carbon
monoxide is associated with an increased risk of incident
CKD, CKD progression and development of end-stage
renal disease (ESRD)38. Each 10 μg/m3 increase in PM2.5
concentration was associated with 26–28% higher risk of
incident CKD, CKD progression and ESRD. The effect
sizes of different types of air pollutants (PM2.5, PM10,
nitrogen dioxide and carbon monoxide) were generally
comparable, and the relationship between the exposures
and the risk of CKD seemed to be linear in the range
studied. The researchers estimated that approximately
10–13% of the cases of CKD in the USA might be attrib-
utable to air pollution. Of note, the air quality in the
USA is relatively good compared to that of other coun-
tries, with a median exposure to PM2.5 of 10–11 μg/m3.
Establishing the dose–response relationship between
air pollution and the development and progression of
CKD across a wide range of exposure levels is of great
clinical importance.

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inflammatory signalling and endothelial dysfunction,

0 50 100
Particle size (μm)
PM2.5 (combustion particles, PM50–70 (human hair)
organic compounds, metals, etc.)
PM90 (fine beach sand)
PM10 (dust, pollen, mould, etc.)
Figure 2 | Size classification of particulate matter. Particulate matter
Nature (PM) in
Reviews airborne
| Nephrology
pollutants is classified based on the mean aerodynamic diameter of particles into PM10
(<10 μm), PM2.5 (<2.5 μm) and ultrafine particles (<0.1 μm). The sizes of various biological
entities are depicted for comparison.
Mechanical studies. The pathogenic mechanisms under-
lying the association between air pollution and kidney dis-
ease remain to be completely elucidated. Diesel exhaust
particles (DEPs) are the major source of PM2.5 and UFPs
in densely populated urban regions, contributing an esti-
mated 30% of the total particulate matter in the atmos-
phere39,40. In rodent models of acute kidney injury induced
by cisplatin, both single and repeated exposure to DEPs
in the lung aggravated cisplatin-induced nephrotoxicity,
resulting in increased urinary excretion of protein and
N‑acetyl-β‑d‑glucosaminidase, impaired renal func-
tion and increased severity of renal tubular necrosis41,42.
In rodents with adenine-induced CKD, exposure to DEPs
resulted in a substantial decrease in renal blood flow and
an increase in renal oxidative stress, inflammation
and DNA damage43–46. The nephrotoxicity of DEPs could
be partially abrogated by administration of the antioxidant
thymoquinone46. A pathogenic effect of DEPs in human
diseases, including diseases of the respiratory system and
distant organs such as the heart and the kidneys, has been
reported47, although the mechanism remains unclear.
Further study of the composition of different sources of
air pollution is required to improve our understanding
of the adverse health effects of air pollution on the kidney.
Ozone is a product of the interaction between ultra­
violet light and oxides of nitrogen and volatile hydro-
carbons. Short-term inhalation of ozone provokes an
inflammatory and metabolic response in the lungs
and also in extrapulmonary organs, such as the kid-
neys. Inhalation of ozone activates the hypothalamic–­
pituitary–adrenal axis in rats and increases plasma levels
of the glucocorticoid corticosterone. Several immuno­
suppressive and metabolic effects of ozone in the lungs,
heart, liver, kidneys and spleen are blocked by metyrapone
(an inhibitor of cortisol production) and are reproduced
through exogenous administration of corticosterone,
demonstrating glucocorticoid-dependent effects in tar-
get tissues48. In addition, gene expression analyses in rats
showed that inhalation of ozone (0.4 ppm and 0.8 ppm)
resulted in altered expression of genes that are involved
in various pathways, including the antioxidant response,
in the kidneys49. These results provide insights into the
potential mechanisms that underlie the health effects of
ozone inhalation and the susceptibility of the kidneys.
The risk of developing membranous nephropathy
has been associated with the level of exposure to PM2.5
(REF. 19), but the mechanisms underlying this association
remain to be elucidated. Membranous nephropathy is an
autoimmune disease that is characterized by the forma-
tion of circulating autoantibodies against secretory phos-
pholipase A2 receptor (PLA2R; encoded by PLA2R1) and
deposition of immune complexes at the glomerular base-
ment membrane50. M‑type PLA2R, which is expressed by
alveolar macrophages51 and glomerular podocytes52, has
been recognized as the major antigen that is implicated
in idiopathic membranous nephro­pathy, accounting for
~70% of cases of idiopathic membranous nephropathy 52.
Exposure to particulate matter might alter the structure
of PLA2R in the lung and stimulate the generation of
autoantibodies against PLA2R. The circulating auto­
antibodies interact with PLA2R on glomerular podo-
cytes, inducing the formation of immune complexes
that damage the cells, which then results in membra-
nous nephropathy. Animal studies support this mecha-
nism of particulate matter toxicity — exposure of mice
to fine particulate matter promotes formation of auto­
antibodies and immune complexes53. Interestingly, cir-
culating autoantibodies against PLA2R were detect­able
in approximately 80% of patients with membranous
nephropathy in a cohort study 19. It is important to exam-
ine whether the association between particulate matter
and ­membranous nephropathy is antigen-specific.
A study in traffic policemen demonstrated that expo-
sure to PM2.5 increased the circulating levels of inflam-
matory mediators such as tumour necrosis factor (TNF)
and IL‑6 (REF. 54). An explanation for this effect is that
cytokines generated in the airways in response to PM2.5
might spill over into the circulation, inducing systemic
inflammation and oxidative stress, and thus promote
distant organ damage.
Genetic factors have been implicated in suscepti­
bility to idiopathic membranous nephropathy. Several
risk alleles, such as the PLA2R1, HLADQA1 and
HLADRB1 loci, are strongly associated with an increased
risk of PLA2R‑related membranous nephropathy 55–57.
Additional studies are needed to determine the relation-
ship between genetic background and environment pol-
lutants and the role of genetic factors in the pathogenesis
of idiopathic membranous nephropathy.
Heavy metals and kidney disease
Human activities, such as mining, industry, urban
expansion and the use of fertilizers in agriculture, release
substantial quantities of pollutants into the environment
and ecosystems. Among all types of pollution in drink-
ing water and food, heavy metals are considered the
greatest threat to human health owing to their persis-
tence in the environment and their bioaccessibility, as
they can be absorbed into the human body from the diet
and drinking water, by inhalation and even by dermal
contact58,59.

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A large proportion of the world’s water is polluted
with heavy metals, which in turn contaminates the soil
through irrigation, followed by contamination of the
crops planted in these soils and subsequently the animals
and humans further up the food chain. Accumulation
first occurs in plants, then in animals and eventu-
ally in humans, leading to disorders and diseases60,61.
Approximately 10% of farmland soil and 13.86% of
grain production in China is estimated to be contami-
nated with heavy metals through irrigation and the use

PM2.5 inhalation

Lung
• ↑ Oxidative stress and
inflammation
• Impairment of phagocytosis
• Dysregulated cell immunity
• Epigenetic modification
• Disruption of cellular
signalling pathways
Nervous system
PM2.5 • ANS imbalance
Alveolus • ↑ Sympathetic nervous system
Macrophage • ↓ Parasympathetic nervous system
Cytokine
release PM uptake Activation of
ANS reflex

Systemic Circulation PM transmitted

spillover into circulation

Systemic inflammation and oxidative

stress Coagulation and fibrinolysis
• ↑ Cellular response (activated dysfunction
leukocytes and platelets and increased • Altered rheology
MPO) • ↑ Coagulability
• ↑ Cytokine expression (IL-6, IL-8, IL-1β, • ↑ Peripheral thrombosis
TNF) • ↓ Oxygen saturation
• ↑ ROS-generating pathway (activation • ↓ Fibrinolysis
of NADPH oxidases) • ↑ Platelet aggregation
• ↓ Antioxidants

Kidney
• Inflammation and oxidative stress
• Circulating autoantibody
against PLA2R
• Formation of immune complexes
• Vascular (endothelial) injury
Vasculature
• Vasoconstriction
• Endothelial dysfunction
Heart • ↑ ROS
• ↑ Susceptibility to dysrhythmia
• Altered cardiac autonomic function
• Altered cardiac repolarization

Figure 3 | Potential mechanisms linking inhaled particles to pulmonary, cardiovascular, cerebral and kidney diseases.
Deposition of particulate matter (PM) with a mean aerodynamic diameter <2.5 μm (PM2.5) in the bronchioles and alveoli
Nature Reviews
leads to disruption of the airway epithelial barrier and to altered cellular signalling pathways, oxidative | Nephrology
stress and
inflammation. The pulmonary inflammatory mediators induced by PM2.5 might spill over into the circulation, resulting
in systemic inflammation, oxidative stress and damage to other distant organs. PM2.5 deposited in alveoli activates an
autonomic nervous system (ANS) reflex, inducing ANS imbalance and promoting damage to other organs. Furthermore,
ultrafine particles (<0.1 μm in diameter) might translocate directly into the circulation, leading to coagulation and/or
fibrinolysis dysfunction and, subsequently, to cellular responses in nonpulmonary tissues. MPO, myeloperoxidase;
PLA2R, secretory phospholipase A2 receptor; ROS, reactive oxygen species; TNF, tumour necrosis factor.

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of fertilizers62,63. Exposure to these pollutants via drink-
ing water represents a major health risk, especially for
people living in developing countries because of a lack
of sufficient water treatment facilities64–66. It is estimated
that >1.8 billion people in the world do not have access
to safe drinking water 67,68.
Cadmium. Cadmium is a by-product of mining and
is used industrially for the plating of steel and in the
production of plastics and nickel–cadmium batteries.
Repeated use of agrochemicals in agriculture, especially
phosphate fertilizers, causes deposition of cadmium
in intensively farmed soils, eventually resulting in its
transportation to and accumulation in the plant shoot 69.
In developing countries such as China, cadmium is one
of the major heavy metal pollutants in farmland70. Diet
is the primary source of cadmium exposure, followed by
tobacco smoke71,72. Cadmium has a long biological half-
life in the human body of 7–16 years73 and accumulates
in various organs and tissues, particularly in the renal
cortex 74. In Asian countries, rice is a staple food and cad-
mium accumulation in rice has been identified as the
leading source of cadmium burden, which is associated
with renal dysfunction in these areas75.
Studies of populations that are exposed to low levels
of cadmium showed that cadmium is present in children
and even in infants and that the cadmium concentra-
tion increases in adults and reaches its peak in elderly
individuals76. Urinary cadmium levels have been used as
a biomarker of the extent of ongoing and chronic cad-
mium exposure in the general population. Urinary
cadmium levels of 4–10 μg/g creatinine are associated
with increased microalbuminuria77. Accordingly, the
US Occupational Safety and Health Administration set
a urinary cadmium concentration of <3 μg/g creatinine
as the safety standard, whereas the WHO set the safe
threshold of urinary cadmium at 5.24 μg/g creatinine78.
The best-known case of cadmium poisoning is itai-
itai disease, which was caused by contamination of the
Jinzu River in Japan due to mining activity 79. The river
water was used for irrigation of rice fields, the rice plants
efficiently absorbed the cadmium, and ingestion of the
contaminated rice resulted in the accumulation of toxic
levels of cadmium in people. The affected individuals
suffered from anaemia, severe bone pain, osteomalacia
and kidney failure.
The proximal tubule and glomeruli are the major
targets in cadmium-induced nephropathy, as cadmium
is preferentially taken up by the proximal tubules and
mesangial cells in glomeruli80–82. The nephrotoxicity of
cadmium is dependent on the dose: one-time exposure
to cadmium induces reversible low-molecular-weight
proteinuria, whereas chronic repeated exposure causes
irreversible proteinuria83,84. Chronic cadmium exposure
results in kidney injury through several mechanisms,
including oxidative stress85, inhibition of the repair of
oxidative DNA damage86 and apoptosis87.
Mercury. Mercury is a widespread heavy metal pol-
lutant. Humans are exposed to mercuric compounds
predominantly from occupational, environmental and
dietary sources, including mining, fuel combustion,
drinking contaminated water, eating freshwater fish
species from polluted waters, eating predatory ocean
fish species and the use of skin-whitening creams88.
Although the major toxicity associated with mercury
exposure is neurological and digestive, nephrotoxicity
has also been reported89. As inorganic mercury is pre-
dominantly reabsorbed in the proximal tubules, they
are the sites that are most sensitive to mercury nephro­
toxicity. Acute effects of mercury, including mitochon-
drial injury and DNA damage, have been observed in
human proximal tubular cells90,91. Acute exposure to
mercury can cause tubular epithelial cell necrosis and
low-molecular-weight proteinuria92.
Of note, chronic exposure to mercury also has detri­
mental effects on glomeruli. In a systematic review of
27 case reports of 42 patients with mercury-associated
nephrotic syndrome, 26 patients underwent a renal
biopsy 93. Among these 26 patients, 21 (80.7%) had
glomerular diseases, which included membranous
nephropathy (15/26), minimal change disease (4/26),
focal segmental glomerulosclerosis (1/26) and chronic
proliferative glomerulonephritis (1/26). Another case
series from China enrolled 11 patients with mercury-­
induced membranous nephropathy 94. The duration
of exposure to mercury in these patients ranged from
2 months to 5 years, and the urinary mercury concen-
trations were 1.5–50 times higher than in individuals
without exposure to mercury. Unlike in patients with
idiopathic membranous nephropathy, patients
with  mercury-­induced membranous nephropathy
were nega­tive for the PLA2R‑specific autoantibody in
serum95. In addition, immunoglobulin G1 (IgG1) is the
predominant immunoglobulin in glomerular deposits
in patients with mercury-induced membranous nephro­
pathy, whereas IgG4 is the primary glomerular deposit
in patients with idiopathic membranous nephropathy 94,
suggesting that the pathogenesis differs between the
two forms of membranous nephropathy. Interestingly,
>80% of the patients achieved complete remission after
­withdrawal from m ­ ercury exposure.
The pathogenic mechanisms of mercury-induced
glomerular disease have not been fully elucidated. In
animal models, mercury induces autoimmune dys-
function that is characterized by activation of T cell-­
dependent polyclonal B cells, increased serum levels of
IgG and IgE, production of antinuclear autoantibodies
(ANAs) and formation of immune complex deposits in
the kidneys96–100. A higher prevalence of detectable ANAs
and increased serum concentration of inflammatory
cytokines, such as IL‑1β, TNF and IFNγ, are observed
in gold miners with chronic exposure to mercury 101.
Several autoantibodies have been identified as novel
potential biomarkers of mercury-induced immuno­
toxicity, including those that react with glutathione
S‑transferase α1 (GSTA1), TNF ligand superfamily mem-
ber 13 (TNFSF13) and linker for activation of T cells fam-
ily member 1 (LAT)102. Mercury-induced auto­immunity
and inflammation might result in the formation of
circulating immune complexes that deposit in the kid-
neys, or it might lead to the production of antibodies

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against membrane proteins on podocytes. Testing of
these hypotheses of mercury-induced immunotoxicity
is crucial for understanding the role of ­mercury in the
pathogenesis of autoimmune renal diseases.
Lead. Lead is a chemically stable heavy metal with a
low melting point and poor electrical conductivity, and
thus it is widely used in industrial products. Exposure to
lead primarily occurs through diet and drinking water,
and to a lesser extent by inhalation, and occasionally by
dermal contact with organic lead compounds. In adults,
most of the lead that enters the body is excreted in the
urine, whereas children excrete only 32% of internalized
lead. Lead is one of the most toxic heavy metals, as it can
remain in the soil for over 150 years. A portion of the lead
that enters the body cannot be excreted in the urine and
is deposited in bone, where its half-life is 10–30 years.
Of note, lead can cross the blood–placenta barrier freely,
and thus maternal lead exposure can affect a fetus103.
Exposure to even a low dose of lead in infancy and
early childhood can result in impairment of c­ ognitive,
­neurochemical and behavioural development104–106.
Data from population-based studies showed that
chronic exposure to lead increases the incidence of CKD
and nephrolithiasis107–109. Lead exposure causes injury
in proximal tubular cells, glomerular dysfunction and
interstitial fibrosis, with clinical manifestations such as
albuminuria and reduced GFR110–113. Lead-induced mito-
chondrial swelling and energy metabolism dysfunction
in tubular cells also contribute to the pathogenesis of
kidney disease114. The accumulation of lead in the kid-
ney results in upregulated transforming growth factor-β
(TGFβ) expression and lipid peroxidation, leading to the
development of tubulointerstitial lesions and fibrosis115,116.
Other heavy metals. Arsenic is an element that occurs
naturally in soil, food and water. Humans are exposed to
inorganic arsenic from mining and smelting metal ores,
pesticide manufacture, wood preservatives and medi­
cines. Food may contain both organic and i­norganic
arsenic, whereas drinking water contains primarily
inorganic arsenic 117–119. People living in areas with
major arsenic contamination usually have an increased
incidence of arsenic-related cancers, such as carcino-
mas of the liver, lung, skin, bladder and kidney 120,121.
Studies of arsenic-induced nephrotoxicity are rare, but
one study reported an increased risk of kidney disease in
individuals exposed to arsenic-contaminated drinking
water in MI, USA122.
Although copper is an essential trace element,
excessive intake of copper can be toxic owing to its
redox-­active nature, which induces oxidative stress
and thereby cellular injury in organs in which copper is
deposited123. Copper in water and soil enters the human
body through food intake and reaches the kidneys via
the circulation124. Copper nephrotoxicity is characterized
by proximal tubule necrosis that results from oxidative
stress, which is induced by copper catalysing the forma-
tion of highly reactive hydroxyl radicals125,126. Nickel is
an essential element, as it is a constituent of enzymes,
proteins and nucleic acids. Nickel is abundant in the
Earth’s crust, with an average concentration of 75 μg/g
(REF. 127). Compounds containing nickel are widely used
in industrial and commercial areas, and extensive indus-
trialization has resulted in the release of excess nickel into
ecosystems. Nickel has genotoxic, immunotoxic, muta-
genic and carcinogenic effects in humans128. The kidney
is the major organ for nickel accumulation and excretion.
Excess nickel triggers an inflammatory response via acti-
vation of nuclear factor‑κB (NF‑κB) and tubular apopto-
sis through the phosphoinositide 3‑kinase (PI3K)–RAC
serine/threonine-protein kinase (AKT) pathway 129,130.
Sources of heavy metal pollutants, the clinical features
of pollution-related kidney diseases and possible patho­
genic mechanisms have been reviewed elsewhere131–143
(summarized in TABLE 1).
Other environmental pollutants
Biogenic toxins. Aristolochic acids are a family of
carcinogenic and nephrotoxic compounds that are
commonly present in members of the birthwort
(Aristolochiaceae) family of plants. The family includes
the Aristolochia and Asarum (wild ginger) genera.
Aristolochic acids are the causative agents of Balkan
endemic nephropathy, which is a chronic, progressive
tubulointerstitial disease that is clustered in the residents
of rural farming villages located along tributaries of the
Danube River in southeastern Europe144. An unusual
feature of Balkan endemic nephropathy is the strikingly
high incidence (>50%) of upper urinary tract cancers
in patients145. Balkan endemic nephropathy was first
described in the 1950s and exhibits a familial but not
inherited association, suggesting the importance of envi-
ronmental factors. Members of the Aristolochiaceae fam-
ily grow abundantly as weeds in local wheat fields around
the towns affected by Balkan endemic nephro­pathy, and
their seeds are co‑mingled with wheat grain during the
harvesting process. Balkan endemic nephro­pathy is
now believed to be caused primarily by consumption of
aristolochic acids present in flour obtained from wheat
grown in fields contaminated with Aristolochia clema-
titis146. Kidney failure also occurred among hundreds
of Belgian women who received a Chinese herbal rem-
edy containing aristolochic acids, which confirmed the
nephrotoxicity of these compounds 147. Owing to
the worldwide distribution of Aristolochia spp. and the
still widespread use of medicinal herbal remedies con-
taining aristolochic acids, especially in east Asia, it is
possible that aristolochic acids might be the cause of
­nephropathies of unrecognized aetiology148.
The pathogenic mechanisms of aristolochic acid-­
induced nephropathy are not fully understood. In both
acute and chronic aristolochic acid-induced nephro­
pathy, autophagy can be activated via upregulation of
the extracellular signal-regulated kinase 1 (ERK1; also
known as MAPK3) and ERK2 (also known as MAPK1)
pathways149 and by induction of autophagy protein 5
(ATG5) and microtubule-associated proteins 1A/1B
light chain 3B (MAPILC3B; also known as LC3) expres-
sion 150. In addition, administration of aristolochic
acid triggers the upregulation of proteins involved in
mitochondrial and endoplasmic reticulum stress149–151.

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Aristolactam, a metabolite of aristolochic acid, forms
DNA adducts in  the kidney and causes mutations
in TP53, which encodes the tumour suppressor p53
(REF. 152). Furthermore, the TP53 mutations caused by
aristolochic acid are dominated by A>T to T>A trans-
versions, and the TP53 gene contains several unique hot
spots (‘mutation signatures’) that are highly specific for
aristolochic acid-induced carcinogenicity 153–156.
Ochratoxin A (OTA) is one of the most common
mycotoxins and is a ubiquitous natural contaminant of
food, including wheat, nuts, spices, dried meats, milk,
fruit juices, wine and cocoa. Removing or reducing
the level of OTA in food processing is difficult. Animal
studies from the US National Cancer Institute–National
Toxicological Program (NCI–NTP) have established that
OTA is nephrotoxic and has renal carcinogenic effects157.
Exposure to OTA can lead to renal disorders, such as
acute kidney injury and upper urothelial carcinoma.
OTA is also considered to be a potential cause of Balkan
endemic nephropathy in the Balkan peninsula and of
chronic interstitial nephropathy in northern African
countries158,159. The mechanisms of OTA nephrotoxicity
include inhibition of protein synthesis, lipoperoxidation
and modulation of the mitogen activated protein kinase
(MAPK) cascade160.
Agricultural pesticides. Pesticides are chemicals that are
used to destroy destructive pests or to prevent or control
their growth. Approximately 3 million tons of pesticides,
mainly herbicides, insecticides and fungicides, are used
globally every year. Exposure to pesticides might cause
various health problems, ranging from irritation of the
skin and eyes to more severe effects, such as nervous
system disorders, reproductive problems and cancer 161.
A number of widely used pesticides are established
human nephrotoxins, including paraquat 162, glypho-
sate163 and some organochlorine insecticides164. Paraquat
is a widely used herbicide that induces glomerular
lesions and renal tubular necrosis in animal studies165.
In a large prospective study of individuals involved in
applying pesticides in the USA166, exposure to six pesti­
cides, including five herbicides (paraquat, alachlor,
atrazine, metolachlor and pendimethalin) and an insec-
ticide (permethrin), was associated with increased risk
of ESRD. Intriguingly, risk of ESRD was also increased
among the spouses of those applying the paraquat, who
do not come in direct contact with the pesticides167.
Chronic exposure to an ultra-low dose of glyphosate in
an established animal toxicity model system can result
in kidney damage168. In a case–control study of patients
with CKD, deficiencies in the activity of the glutathione
S‑transferases GSTθ1 and GSTμ1 were associ­ated
with accumulation of organochlorine pesticides and
­aggravation of kidney dysfunction169.
Only a limited number of the thousands of pesticides
used worldwide have been tested for nephrotoxicity. The
heterogeneity in study design and unquantified assess-
ment of pesticide exposure limit the interpretation of
results from published studies. Additional studies are
needed to characterize the nephrotoxicity of pesticides
and their pathogenic mechanisms.
Industrial chemicals. The general public is unknow-
ingly exposed to industrial chemicals, such as phtha-
lates, bisphenol A and perfluoroalkyl acids, during daily
consumer activities. These chemicals are widely used
in shampoo, cosmetics and food packaging. Numerous
cross-sectional studies have linked exposure to these
industrial chemicals with an increased incidence of
kidney disease170. The melamine poisoning incident in
2009 exemplifies the devastating effect of widespread
exposure to chemical contaminants on human health
and, in particular, kidney disease. Exposure of >300,000
infants and children in China to milk-based formulas

Table 1 | Effects of heavy metal pollution on the kidney

Metal Source of exposure
Cadmium Contaminated food (rice);
cigarette smoke; industrial waste;
occupational exposure (mining,
production of batteries, plating of
steel and plastic manufacturing)
Lead Contaminated food; petroleum;
contaminated air, water and soil
polluted with industrial waste;
cigarette smoke; occupational
exposure (mining, production of
batteries, welding and lead soldering)
Mercury Contaminated water; fish from
polluted waters; fuel combustion;
skin-whitening creams; mining
Arsenic Occupational exposure (mining,
wood preservatives, smelting metal
ores and pesticides); contaminated
seafood and water; specific
medication
GFR, glomerular filtration rate; RKIP, RAF kinase inhibitor protein; TGFβ, transforming growth factor‑β.
Kidney injury
Proximal tubular dysfunction
(glucosuria, aminoaciduria
and low-molecular-weight
proteinuria)83,84,131; reduced GFR
Proximal tubular
dysfunction110–113; interstitial
fibrosis132; tubular atrophy133;
reduced GFR
Secondary membranous
nephropathy136; interstitial
nephritis; acute tubular
necrosis137; reduced GFR
Tubular interstitial nephritis;
acute tubular necrosis140;
reduced GFR
Mechanisms
Oxidative stress85; impaired
DNA repair86; reduced
antioxidant ability; cellular
apoptosis87
Oxidative stress134; increased
TGFβ expression and lipid
oxidation115,116; mitochondrial
dysfunction114; DNA
fragmentation135
DNA damage90,91; mitochondrial
dysfunction138; reduced
enzymatic activity139
Oxidative stress; reduced
expression of RKIP141; DNA
methylation and histone
acetylation142; DNA oxidation;
reduced antioxidant defences143

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containing melamine resulted in kidney stone forma- Conclusions

tion, renal dysfunction and retarded renal growth in
these children171,172.
Secondhand smoke in children. Tobacco smoke contains
>4,000 toxic chemicals and particles that are nephrotoxic,
including nicotine, carbon monoxide, arsenic, cadmium
and lead. Cigarette smoking is associated with increased
risk of CKD and ESRD in adults. A meta-­analysis of
15 prospective cohorts including 65,064 patients with
incident CKD showed that current smoking is an inde-
pendent risk factor for incident CKD (OR 1.34, 95% CI
1.23–1.47), compared with never smokers173. Although
the prevalence of smoking is decreasing in adults, up
to 20–40% of children are still exposed to a living envi-
ronment that contains secondhand smoke174,175. In chil-
dren, exposure to secondhand smoke is associated with
increased blood pressure, dyslipidaemia176, increased
C‑reactive protein levels and endothelial dysfunction177.
A study reported an association between exposure to
second­hand smoke and nephrotic-range proteinuria in
children with mild to moderate CKD, even after a­ djusting
for other known risk factors178.
Chronic kidney disease of unknown aetiology. Diabetes
and hypertension are the leading causes of CKD in devel-
oped countries, whereas glomerulonephritis remains
the main cause of CKD in the developing world179. In the
past two decades, outbreaks of CKD of unknown aeti-
ology (CKDu) have been reported in several developing
countries, including Sri Lanka, India, Egypt and sev-
eral countries in Central America180. Patients with CKDu
are mainly young male farmers, and the clinical mani­
festations of CKDu are similar to those of interstitial
nephritis. The major histological lesions in the biopsy
samples from patients with CKDu include interstitial
fibrosis, tubular atrophy and interstitial mononuclear
cell infiltration. Environmental pollutants in contami-
nated water and food, including heavy metals, indus-
trial chemicals, fertilizers and pesticides, are suspected
potential causes of CKDu179. In a study carried out in
Sri Lanka, exposure to glyphosate was associated with
substantially increased risk of CKDu among male farm-
workers and residents who drank water polluted with
glyphosate181. To identify the aetiologies of CKDu, the
design of consistent and comparative multisite studies
across high-risk populations might help to elucidate the
importance of region-specific versus global risk factors.
Environmental pollutants, such as particulate matter,
heavy metals and industrial and agricultural chemicals,
are important risk factors for kidney disease, especially
in developing countries in which environmental pollu-
tion is prevalent. The causes of CKDu and the patho-
genic mechanisms of most environmental nephrotoxins
remain to be elucidated. As mentioned earlier, approxi-
mately 10–13% of CKD cases in the USA are estimated
to be attributable to air pollution38. As the air quality and
extent of environmental pollution is far worse in most
developing countries than in the USA, air and/or envi-
ronmental pollution may have a substantial role in the
aetiology of CKDu in developing countries. It is crucial
to raise awareness among policy makers, industry repre-
sentatives and the public in developing countries about
environmental pollutants as a public health threat. Many
of the strategies for environmental protection that have
been successfully applied in developed countries, such as
establishing and strictly enforcing air quality standards,
mandating vehicle and industrial emissions controls,
adopting policies against heavily polluting industries,
promoting the use of greener energy and public trans-
portation and prioritizing clinical and health-care
research into the effects of pollutants, could also be
applied in developing countries.
Most of the epidemiological evidence linking envi-
ronmental pollution to kidney diseases discussed here
are from cross-sectional studies. To establish a causal
relationship between exposure to environment pol-
lutants and kidney disease, longitudinal studies with
specific and quantified measurement of environmental
exposures are required. It is important to investigate the
toxic effects of each constituent of various sources of
pollution and to establish the dose–response relation-
ship between a pollutant and kidney disease for a wide
range of exposure levels. Most studies on the pathogenic
mechanisms of pollutants focus on their effects on gen-
eral pathways, such as systemic inflammation and oxida-
tive stress, and study of the detailed mechanisms of the
pathogenesis of specific kidney diseases is particularly
lacking. In addition, studying the genetic background of
patients and the interaction between environment pol-
lutants and genetic factors may provide valuable insights
into disease susceptibility. Finally, data from high-quality
population-based studies will inform regulatory strat­
egies for the control of pollution and reduce or prevent
the exposure of people to environmental health risks.

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Acknowledgements
The authors are supported by the National Key Technology
S u p p o r t P ro g ra m o f C h i n a ( 2 01 3 BA I 0 9 B 0 6 a n d
2015BAI12B07 to F.F.H.), the National Natural Science
Foundation of China (81770683 to X.X.), the National
Natural Science Foundation of China (Key Program)
(81430016 to F.F.H.), the Major Scientific and Technological
Planning Project of Guangzhou (201504010027 to F.F.H.)
and the Major International (Regional) Joint Research Project
(81620108003 to F.F.H.).
Author contributions
All authors researched data for the article, contributed sub-
stantially to discussion of the article’s content, wrote the arti-
cle and reviewed and/or edited the manuscript before
submission.
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

324 | MAY 2018 | VOLUME 14 www.nature.com/nrneph

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