REVIEW ARTICLE
Chronic Kidney Disease Associated With
Environmental Toxins and Exposures
Peter Soderland,* Shachi Lovekar,* Daniel E. Weiner,†
Daniel R. Brooks,‡ and James S. Kaufman*{
People are exposed to various potentially toxic agents and conditions in their natural and occupational
environments. These agents may be physical or chemical, may enter the human body through oral, inhalational, or transdermal routes, and may exert effects on all organ systems. Several well-known as
well as lesser known associations exist between chronic kidney disease (CKD) and both environmental
agents and conditions, such as heavy metals, industrial chemicals, elevated ambient temperatures, and
infections. The effects of these agents may be modulated by genetic susceptibility and other comorbid
conditions and may lead to the development of acute and CKD. In this article, we present environmental
factors that are associated with CKD.
Published by the National Kidney Foundation, Inc.
Key Words: Heavy metals, Aristolochic acid, Environmental exposure, Infectious diseases, Acute kidney
injury, Heat
K
idney disease is receiving increased global
public health attention because of a significant increase in the prevalence of the disease,
the enormous cost of treatment, and the appreciation of its role as a risk factor for cardiovascular disease.1 For every patient on dialysis in
the United States, there are more than 200 with
stage 3 or 4 chronic kidney disease (CKD), and
almost 5000 with stage 1 or 2 disease.2 In the
United States, the majority of these patients
have diabetes and hypertension as a primary
cause of their kidney disease. Although
diabetes, hypertension, and other age and
obesity-associated conditions are increasingly
associated with CKD in developing nations,
chronic glomerulonephritis and interstitial
nephritis remain common causes of CKD in
the developing world, in part reflecting the
higher prevalence of bacterial, viral, and parasitic infections. In addition, environmental factors such as occupational exposures and
nephrotoxins may be an underappreciated
cause of CKD.
The establishment of a cause-and-effect link
between an environmental factor and kidney
disease requires exposure analysis. A potentially causal agent must have a plausible biologic association with kidney damage and
has to be present in an endemic area in sufficient quantities to induce health damage.
There must be a route of contamination for
the offending agent to affect susceptible individuals. Finally, this agent should cause a similar pattern of kidney injury when present in
disparate geographic regions.3 In the following review, we summarize toxins and environmental exposures that have been associated
with CKD. Some of these exposures, such as
industrial solvents, are more commonly associated with acute kidney injury (AKI) from
accidental exposure, but as they have also
been implicated as a cause of CKD, they are
included in this review.
From *Renal Section, Boston University School of Medicine,
Boston, MA;
†Division of Nephrology, Tufts Medical Center, Boston,
MA;
‡Department of Epidemiology, Boston University School of
Public Health, Boston, MA;
{Renal Section, VA Boston Healthcare System, Boston, MA.
Address correspondence to James S. Kaufman, MD, Renal
Section (111-RE), VA Boston Healthcare System, 150 S. Huntington Ave., Boston, MA 02130. E-mail: [email protected]
Published by the National Kidney Foundation, Inc.
1548-5595/10/1703-0007$36.00/0
doi:10.1053/j.ackd.2010.03.011
Heavy Metals
254
Among the common environmental toxins associated with CKD, heavy metals are the most
widely known (Table 1). Exposure may occur
at the workplace (eg, lead smelters), but
industrial environmental contamination of
groundwater is also recognized as an important source of exposure that may result in kidney disease in populations without direct
occupational exposure.
Advances in Chronic Kidney Disease, Vol 17, No 3 (May), 2010: pp 254-264
Environmental CKD
255
Table 1. Heavy Metals Causing Kidney Disease and Their Environmental Sources
Metal
Lead
Cadmium
Arsenic
Mercury
Uranium
Sources of Exposure
Lead paint (pre-1977)
Lead pipes (in homes built before 1986)
Contamination of food during processing
Adulterated alcohol (moonshine)
Leaded gasoline (phased out in most of the world)
Contamination of air, water, and soil from occupational sources of lead (lead smelters,
garages and old mines)
Indoor firing ranges
Cigarette smoke
Occupational exposures (battery manufacturing, welders, use of lead solder)
Cigarettes
Combustion of industrial and household waste
Sewage
Contaminated food
Indian medicinal herbs
Contamination of air, water, and soil from industrial sources of lead
Occupational exposures (production of batteries, plating of steel, plastic
manufacturing, use of pigments)
Groundwater/drinking water
Pesticides (through contaminated food, now largely prohibited)
Seafood
Folk/alternative remedies
Wood preservation products
Occupational exposures (plywood and paperboard manufacture, manufacture of some
semiconductor devices, pharmaceutical and glass industries)
Edible fish (from contaminated water)
Fuel combustion
Whitening creams
Contaminated cereals (from use of ethyl mercury as pesticide)
Dental amalgam (controversial)
Occupational exposures (fluorescent bulb manufacturer, electrical switch
manufacturing, recyclers, industries that use caustic soda or sulfuric acid, battery
manufacturing)
Groundwater and food contamination
Contamination of soil, air, and plants from natural sources such as volcanic ash
Occupational exposures (uranium mining)
Lead
Environmental sources of lead exposure include lead paint (pre-1977), water from lead
pipes (common in homes built before 1986),
contamination of food during processing,
adulterated alcohol (moonshine), leaded gasoline (now phased out in most of the world),
and contamination of air, soil, and water in
areas close to lead smelters, old mines, or
garages.4 Environmental lead toxicity occurs
mainly through ingestion, although exposure
can also occur through cigarette smoke.5
Lead circulates in the blood, and can either be
excreted by the kidneys or can deposit in the
bone. The half-life of lead is approximately 35
days in the blood and 10 to 30 years in the
bone. Accordingly, blood lead levels may denote
both acute exposure and may also reflect equilibration with the bone pool, whereas bone stores
reflect the cumulative or chronic exposure and
account for 95% of total body lead burden.6
Body lead burden can be measured by x-ray
fluorescence or by chelation tests and measurement of urinary lead excretion, although abnormal values for this test are uncertain.
Nephrotoxicity associated with lead may
have acute and chronic manifestations. Acute
toxicity causes direct proximal tubular injury,
likely resulting from intranuclear, cytoplasmic,
and mitochondrial inclusion bodies composed
of a lead–protein complex7; acute toxicity most
commonly manifests with a Fanconi-type syndrome, including glucosuria, aminoaciduria,
and phosphate wasting, potentially caused by
mitochondrial dysfunction. Chronic lead
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Soderland et al
exposure may result in hypertension, gout, and
interstitial nephritis and fibrosis. Hypertension
is likely multifactorial in nature with causes
including disruptions in calcium-mediated
cell signaling and effects on the reninangiotensin-aldosterone system,8 whereas saturnine gout results from decreased clearance
of uric acid in the setting of lead toxicity.9 The
chronic nephrotoxicity of lead classically presents as decreased estimated glomerular filtration rate (eGFR), with minimal proteinuria
and bland urine sediment. Prolonged exposures, even if low level, may result in CKD by
causing interstitial nephritis, hypertension,
and hyperuricemia.10
Diagnosis is suspected in patients who present with the above symptoms and have a history
of occupational or environmental exposure to
lead. The prevalence of CKD attributable to
lead exposure is very difficult to determine,
given the unreliability of noninvasive tests to
make this diagnosis and the confounding relationship of hypertension and lead with CKD.
In the United States, blood lead levels are associated with higher serum creatinine in people
with CKD; fortunately, blood lead levels are progressively declining there, likely reflecting extensive public health efforts that have resulted
in removal of lead from fuels and paints.11
Interestingly, one placebo-controlled study
in individuals with creatinine levels consistent
with stage 3-4 CKD suggested that chelation
therapy with calcium disodium EDTA was associated with improved kidney outcomes in
individuals with only moderately elevated
blood lead levels, suggesting that even relatively low level lead exposure may be associated with ongoing kidney injury.12 Critically,
this study has not yet been reproduced in
other populations. Treatment of lead nephrotoxicity consists of minimizing exposure followed by chelation therapy, as indicated.
Importantly, although EDTA chelation treatment reduces lead levels in soft tissues, it is
not efficacious in reaching the bone lead deposits; thus, bone turnover may be a source
of long-term lead exposure.13
Cadmium
Environmental sources of cadmium toxicity
include combustion of fuels and industrial
and household waste, tobacco smoke, sewage,
foods such as sea food, vegetables and cereals,
residence in cadmium polluted areas,14 and
Indian medicinal herbs.15,16 Cadmium is also
a byproduct of mining and is used industrially
in plating of steel, plastics, and nickel–cadmium batteries. The oral route is the primary
route for environmental cadmium exposure
in the nonsmoking general population. The
best known example of environmental cadmium exposure is Itai-Itai disease, related to
dietary exposure to cadmium from the contaminated waters of the Jinzu River in Japan.
Affected individuals presented with anemia,
severe bone pain and osteomalacia, and kidney toxicity including reduced kidney function and ultimately death attributable to
kidney failure.17
Cadmium has a long biological half-life,
ranging from 7.4 to 16 years.18 It induces the
synthesis of a protein called metallothionein
by the liver, which acts as cadmium scavenger.
Low metallothionein levels, iron deficiency,
older age, female gender, smoking history,
and place of residence (proximity to industrial
cadmium sources) are risk factors for cadmium toxicity.19 Clinically, cadmium nephrotoxicity presents with features of proximal
tubular dysfunction such as glucosuria, aminoaciduria, and low molecular weight proteinuria. These manifestations of toxicity
may occur at much lower levels of urinary
cadmium concentrations than those recognized as toxic by the World Health Organization. Other renal manifestations include
hypercalciuria and renal stones.20 There is no
specific treatment for cadmium nephrotoxicity, other than supportive care and removal
from exposure.
Arsenic
Environmental sources of arsenic include
groundwater, pesticides (by causing food contamination), seafood, folk or alternative
remedies, and products used for wood preservation.21 High drinking water arsenic levels
have been associated with increased mortality
from CKD.22 Arsenic levels in serum and
blood cells correlate with worsening kidney
disease,23 with the development and progression of CKD attributed to arsenic-induced
Environmental CKD
oxidative stress.24 A recent retrospective study
in Taiwan demonstrated a negative correlation
between urinary arsenic level and eGFR, and
a positive correlation between plasma lycopene (antioxidant) level and eGFR in the
same patients.25 Currently, no specific recommendations exist for treatment of nephrotoxicity from arsenic.
Mercury
Environmental sources of mercury include
contaminated water, fresh water fish from polluted waters and predatory ocean fish, fuel
combustion, and whitening creams.26 There
is conflicting evidence of nephrotoxicity
secondary to dental amalgam.27 The most
publicized mercury exposure occurred in the
mid-1950s in Japan; known as Minamata disease, mercury poisoning occurred after contamination of the waters of the Minamata
Bay of the Shiranui Sea from waste from
a chemical factory. This waste contaminated
the local food supply, predominantly comprised of locally caught fish. Although the
clinical picture of Minamata disease was dominated by neurologic symptoms, low molecular weight proteinuria was reported.28 Since
then, epidemics have also been reported in
Iraq, Ghana, and Sweden from consumption
of contaminated cereals treated with ethyl
mercury as pesticide.
Mercury causes both tubular and glomerular damage. It is filtered by the glomerulus
and reabsorbed in the proximal convoluted tubules, resulting in tubular toxicity with low
molecular weight proteinuria and enzymuria.
Mercury may also cause nephrotic syndrome,
either because of membranous nephropathy
or minimal change disease (described after
use of whitening creams).29 Both organic and
inorganic forms of mercury may cause toxicity, and the specific renal effects may be
dependent on the chemical form and valence.
Although chronically reduced GFR has not
been reported in association with mercury
toxicity, acute intoxication may result in acute
tubular necrosis with the potential for residual
interstitial nephritis. Because mercuryinduced nephrotoxicity is generally reversible,
treatment consists of preventing further
exposure.
257
Uranium
Uranium, the heaviest of the naturally occurring elements, is a metal the biological effects
of which were described in the published
data in as early as the 1820s. Animal studies,
as well as studies of occupationally exposed
persons, have shown that the major health
effect of uranium is chemical kidney toxicity,
rather than a radiation hazard.30 Exposure to
uranium is mainly oral, through groundwater
and food, although dermal exposure has been
reported for children playing in contaminated
areas.31 Elevated levels have been found in
uranium mining as well as in non-uraniumproducing communities. In the latter case,
the uranium has been introduced into drinking water, not through human activity, but
through natural activity, such as volcanoes,
wind, and streams. It can be found as dust in
the air, and this dust can dissolve in water
and settle on plants, and can be found in larger
particles in soil.
Environmental uranium exposure from
drinking water has been associated with glucosuria, microalbuminuria, beta 2 microglobulinuria, phosphaturia, and hypercalciuria.32,33
Studies in occupationally exposed populations have also reported aminoaciduria and
low molecular weight proteinuria. An epidemiologic survey also reported statistically,
but not clinically significant, higher serum creatinine levels in individuals residing in close
proximity to a uranium processing plant in
Ohio, compared with the general US population.34 Treatment involves removal from the
source of exposure.
Other Environmental Nephrotoxins
Many occupational chemicals and substances
other than metals are associated with kidney
disease, mediated by either acute tubular
necrosis or specific kidney lesions. Kidney
failure caused by many of these toxins is often
acute and becomes manifest in conjunction
with hypotension, central nervous system
symptoms such as seizures and altered consciousness, or gastrointestinal symptoms
such as nausea, vomiting, diarrhea, and abdominal pain. Examples include arsine gas,35
carbon tetrachloride,36 methylene chloride,37
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Soderland et al
toluene,38 and trichloroethylene.39 When these
toxic agents are used for industrial purposes,
extensive precautions are generally taken to
avoid exposure. However, accidental inhalation, cutaneous absorption, or ingestion can
occur and can either be directly nephrotoxic
or cause hemolysis and rhabdomyolysis with
subsequent acute nephrotoxicity, although
CKD is rarely reported.
There is evidence that exposure to occupational solvents may affect the progression of
underlying kidney disease even if the primary
lesion is unrelated to the exposure. The GNPROGRESS cohort study evaluated 338 non–
end-stage renal disease (ESRD) patients, with
an initial biopsy for primary glomerulonephritis. Lifelong solvent exposures before
and after diagnosis were assessed. Subjects
were followed up for 5 years for progression
to ESRD. A graded relationship was observed
for membranous and for IgA nephropathy between increasing degree of exposure and
development of ESRD. Patients with membranous nephropathy, for example, had an
adjusted hazard ratio of 5.5 (1.3-23.9) for
high exposure, versus low exposure to solvents in the development of ESRD.40
Aristolochic Acid, Balkan Endemic
Nephropathy, and Chinese Herb
Nephropathy
In 1956, Tanchev41 first observed an unusual
clustering of chronic tubulointerstitial renal
disease in villages, families, and households
in northwest Bulgaria. The disease was so
focal that, within an affected town, there
would be individual households experiencing
the disease next to households that were not.
In addition, there was no racial, ethnic, or religious predilection for the disease. Another
feature of the disease is its long incubation period. Affected individuals must live in the area
for 15 to 20 years. Therefore, it has neither
been identified in children nor in adults who
leave the area before reaching the age of 20
years. Finally, those with the disease were at
a markedly increased risk of developing
upper urinary tract tumors. This disease was
initially called ‘‘endemic Vratza nephritis,’’
and was subsequently identified in Yugoslavia
and discrete regions of Romania. Reflecting
this wider geographic distribution, although
still confined to the alluvial plains of the
Danube Rivers, it was later renamed Balkan
endemic nephropathy.42 Balkan endemic nephropathy is a tubulointerstitial nephropathy
with a slow progression after an insidious
presentation. Early clinical manifestations
include low-grade tubular proteinuria without hypertension or edema.43 In addition to
kidney failure, late manifestations may also
include urothelial carcinomas; these are predominantly found in the upper urothelial
tract, but may also affect the bladder.44
The cause of Balkan endemic nephropathy
remains subject to debate.45 One early hypothesis was contamination of food in endemic
areas by ochratoxin A, a toxin produced by
molds that belong to the Aspergillus or Penicillium fungal genera. Ochratoxin A causes
mycotoxin-induced porcine nephropathy,
a similar pathological entity to Balkan endemic
nephropathy confined mainly to Northern
Europe. In addition, subjects in endemic areas
have been shown to have elevated blood levels
of ochratoxin A. However, ochratoxin A is an
unlikely cause as there is not a close correspondence between the geographic distribution of
food contamination with ochratoxin A and
Balkan endemic nephropathy, as well as
a lack of definitive proof for formation of
ochratoxin A-DNA adducts, pieces of DNA
covalently bonded to ochratoxin A and a sign
of chemical damage to the cell.46
In 1993, an outbreak of kidney failure was
identified among Belgian women who received a Chinese herbal medicine for weight
loss at a clinic in Brussels.47 The toxic product
was identified as aristolochic acid, produced
from the seeds of Aristolochia clematitis (birthwort). The clinical manifestations of the
disease in these women were remarkably similar to those seen in Balkan endemic nephropathy, with similar morphologic characteristics
and the occurrence of uroepithelial tumors.
The defining kidney lesion in these women
was severe tubulointerstitial fibrosis with
minimal glomerular injury and negative immunofluorescent staining, and the kidney
survival rate at 2-years was only 17% in the
original population.
In 1967, Kazantis had proposed that Balkan
nephropathy was caused by the contamination
Environmental CKD
of the baking flour in endemic areas by seeds of
A clematitis, but this hypothesis had not garnered much attention.48 However, after the
identification of Chinese herbal nephropathy,
there was increasing interest in this toxin as
a cause of Balkan nephropathy, with the subsequent identification of covalent aristolactamDNA adducts in affected tissues of patients
with the disease,46 and the finding of ‘‘signature’’ mutations known to be associated with
aristolochic acid in tissue of patients affected
by Balkan endemic nephropathy and urothelial tumors.45 Finally, a specific Balkan endemic
nephropathy–associated locus was identified
in 3q25 combined with instability of the long
arm of chromosome 3. These genetic alterations may determine the susceptibility for
the development of the disease in people
exposed to aristolochic acid and relatives of
patients with Balkan endemic nephropathy.49
To date, however, genome-wide scans have
not been performed to identify single nucleotide polymorphisms associated with Balkan
endemic nephropathy susceptibility.
Although it seems likely that contamination
of flour with aristolochic acid is a likely cause
of Balkan nephropathy, a final hypothesis that
continues to be explored is the proximity of
Pliocene age lignites, polycyclic aromatic hydrocarbons in water originating from Pliocene
age coal beds, to the communities affected by
Balkan endemic nephropathy. Weathering of
the low-rank coals could lead to toxic substances leaking into groundwater and trans-
259
ported into the drinking water of the shallow
farm wells. Settlements where inhabitants
use the same limited number of wells have
a greater incidence of Balkan endemic nephropathy. The presence of small concentrations of organic toxic materials is compatible
with a low-level, chronic poisoning of Balkan
endemic nephropathy patients. The lignite
hypothesis can be used to develop a predictive
model; an area of Serbia without prior Balkan
endemic nephropathy was identified as an endemic area after characterizing that it lay close
to a low-rank coal field.
Endemic Infections as Causes of Kidney
Disease
Although human immunodeficiency virus
and both hepatitis B and C are associated
with significant kidney lesions, there are several other infectious etiologies of kidney disease that are related to specific environments
(Table 2). Although these infections are more
commonly associated with AKI, they have
been implicated in the development of CKD,
perhaps through the development of severe
AKI, but also possibly from chronic exposure.
Leptospirosis
Leptospirosis, a spirochete, is exceedingly common in warm and humid climates. Infected animals shed organisms through urine, with
human infection occurring through consumption of contaminated water or mucosal contact
Table 2. Geographical Distribution of Endemic Infections Causing Kidney Disease
Infectious Agent
Leptospirosis
Hantavirus
Malaria
Leprosy
Endemic Geographical Areas
South East Asia
Central America
Peru (Amazon basin)
Hawaii
Old World strains—China, Korea, Japan, Europe, Russia, Syria, Lebanon, Israel
New World strains—Central and South America, United States,
particularly the Southeast and Southwest
Africa (P falciparum, P vivax, P malariae in sub Saharan Africa)
Indian subcontinent and South East Asia (P vivax, P falciparum)
China (P vivax)
Russia (P vivax)
South and Central America (P vivax)
Middle Eastern countries
Philippine Archipelago (P ovale)
New Guinea (P falciparum, P ovale)
India, Bangladesh, Indonesia
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Soderland et al
with contaminated water or soil. A broad spectrum of clinical syndromes is caused by leptospirosis, ranging from subclinical infection
and self-limited anicteric febrile illness to fatal
disease. Weil’s syndrome is the most severe
form of infection, presenting as a febrile illness
with hemorrhagic tendencies, hepatic dysfunction, and acute renal failure. Tubulointerstitial
nephritis is the main cause of AKI. Polyuria
and hypokalemia with an elevated urinary
fractional excretion of potassium may be seen
because of proximal tubule damage. Thrombocytopenia may be associated with severe endotoxin injury and may appear in association with
acute renal failure. Kidney sonography typically reveals swollen, edematous kidneys that
may indicate tubulointerstitial edema by the
invasion of leptospira.50 Penicillin and tetracycline are the drugs of choice for treatment and
may significantly improve morbidity and mortality from the infection. If left untreated, the infection can lead to a chronic carrier state in
which leptospira localize to the kidney and
remain viable in the tubules despite the presence of host immunity,51 although there is no
evidence that leptospirosis can lead to CKD in
the absence of AKI.
Malaria
There are 2 renal syndromes associated with
malaria: (1) chronic, progressive glomerular lesions complicating quartan malaria because of
Plasmodium malariae, and (2) AKI associated
with falciparum malaria. Chronic malarial nephropathy typically affects children aged 4 to
8 and is a steroid resistant nephrotic syndrome.
The pathologic lesion is mesangiocapillary glomerulonephritis with subendothelial immune
complexes containing IgG, C3, and malarial
antigens. The disease progresses to renal failure even after eradication of the infection.
Acute malarial nephropathy is more frequent
in nonimmune Europeans compared with
residents of endemic areas.53 Most cases are
oliguric and associated with additional manifestations of malarial infection. Jaundice, anemia, thrombocytopenia, and peripheral blood
pooling are common with malaria-associated
acute renal failure. Proteinuria is usually less
than 1 g a day, and typically resolves with recovery of kidney function.54 Hyponatremia
and severe hyperkalemia are common. Histopathologic evaluation reveals a variable mixture of acute tubular necrosis, interstitial
nephritis, and glomerulonephritis.
Hantavirus
Leprosy
There are more than 30 different strains of hantavirus that have coevolved with a specific rodent in specific geographic regions. Human
infection occurs through inhalation of aerosolized rodent excrement. All Old World hantaviruses cause hemorrhagic fever with renal
syndrome, a generalized infection with hantavirus nephropathy. All pathologic New World
hantaviruses belong to a second lineage and
cause hantavirus pulmonary syndrome, affecting primarily the lungs. Peripheral vascular injury with severely affected permeability is
generalized with the kidneys as the primary target in hemorrhagic fever with renal syndrome.
Hantavirus is present in the endothelial cells
of the interstitial capillaries of the medulla, but
rarely in tubular interstitial cells. Clinically patients present with fever, loin or abdominal
pain, proteinuria, hematuria, and reduced glomerular filtration rate, although presentation
and severity depends on the particular strain
of hantavirus and may progress to CKD.52
Leprosy is a multisystem, granulomatous disease caused by Mycobacterium leprae that primarily involves the skin and peripheral
nervous system. The typical clinical picture
includes anesthetic skin lesions, peripheral neuropathy, and palpable enlargement of peripheral nerves. The disease remains prevalent in
Asia, Africa, and Latin America, with over 5
million cases worldwide. The kidney is a target
organ during the splanchnic localization of the
disease with a broad spectrum of pathologies.
Diffuse endocapillary proliferative, membranoproliferative, focal proliferative, membranous
and crescentic glomerulonephritis, renal amyloidosis, and interstitial nephritis have all been
associated with the infection.55 Duration of the
disease has a significant correlation with renal
involvement.
Schistosomiasis
Schistosomiasis is caused by a parasitic trematode worm that lives in the abdominal veins of
Environmental CKD
the host. The urogenital system is the primary
target of Schistosoma haematobium and occasionally Schistosoma mansoni infestation, with
the main initial lesion being pseudotubercles,
polyps, and ulcers of the urinary bladder.
When these lesions heal, they lead to a wide
spectrum of bladder pathology including
chronic cystitis, calcification, cystitis cystica,
and villous squamous cell carcinoma. Several
patterns of glomerular pathology have been
described with schistosomiasis, including mesangioproliferative, exudative, membranoproliferative, and sclerosing glomerulonephritis
and amyloidosis. Current evidence suggests
that the pathogenesis of schistosomal glomerulopathy is triphasic. Mesangial deposition of
antigens of different schistosomal species
induces the initial glomerular injury usually
manifesting as a mesangioproliferative lesion.
Further progression into overt renal disease
involves a multiplicity of agent and host factors. Finally, the disease may progress to
ESRD.56
Exertion, Heat Stroke, and Recurrent
AKI
In epidemiologic studies, it is apparent that
AKI is a risk factor for development of
CKD.57 The pathophysiology supporting this
association was reviewed in depth by Venkatachalam and colleagues,58 where it is stressed
that recovery from AKI is often not complete
and is marked by residual structural damage,
with interstitial fibrosis the most notable
feature. This was elegantly demonstrated in
a rat model by Nath and colleagues,59 where
repeated exposure to a heme proteininstigated, oxidant-mediated kidney injury resulted in significant chronic tubulointerstitial
disease, marked by interstitial cellular
infiltration, tubular atrophy, tubular dilation,
and tubular casts.
It is possible that similar repetitive kidney
injury may occur in people subjected to severe
working environments, particularly in developing nations where workplace protection
laws are less prevalent and/or less stringent
and in the setting of other nephrotoxins (eg,
non-steroidal inflammatory drugs). Clinically,
acute exertional rhabdomyolysis is described
in populations who experience extremes of
261
exertion, including Marine Corps recruits
and Olympic athletes,60 although few individuals with single episodes of exertional rhabdomyolysis develop acute and chronic kidney
failure.61 However, in theory, the long-term
consequences of repeated episodes of exertional rhabdomyolysis on kidney function
may be an unrecognized medical burden to
worker populations in high heat environments, a setting in which a preponderance of
kidney disease has been described. To date,
the most extensive evaluation is of gold
miners in South Dakota who had a standard
incidence ratio of ESRD as high as 7.7 for
workers with 10 years or more experience.
Although the increased risk was attributed to
silica exposure, extremes of heat may be an
important factor.62 In addition, another report
describes chronic interstitial nephritis as a consequence of heatstroke in South African gold
miners.63
Nicaragua and Sri Lanka—Case
Examples
An illustration of the environmental influences on kidney disease can be seen in the
Central American country of Nicaragua,
where an excess prevalence of CKD has been
described in young, male agricultural
workers, clustered in the northwestern regions of Leon and Chinandega.64 CKD is the
leading cause of death among men in these
regions, and, based on data from the Nicaragua Ministry of Health, the prevalence of
CKD in this region appears far higher than
that seen in other regions.
Although incompletely studied, pyuria,
minimal or low-grade proteinuria, and small
shrunken kidneys on imaging appear to characterize the CKD. Some observers also note
a high prevalence of kidney stones, whereas
the prevalence of diabetes mellitus and hypertension is insufficient to explain the prevalence of CKD. The predominance of cases
among males and its occurrence among younger age groups also differ from the typical patterns seen in developed countries. Several
unpublished studies have found associations
between presence of CKD and pesticide exposure, dehydration, residence at lower altitude,
heavy metal exposure, alcohol consumption
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Soderland et al
and smoking, whereas other potential associations include urinary tract infections, nonsteroidal anti-inflammatory use, and family
history. The role of exposure to volcanic ash,
heat, and infections such as malaria, Chagas
disease, hantavirus, leptospirosis, and
schistosomiasis have been suggested as possible causal or potentiating factors worth
investigation.
A similar increase in the incidence of ESRD
has occurred in males from rural farming
communities in Sri Lanka. As in Nicaragua,
pesticide use has been suggested as a possible
cause.65 However, other than paraquat and diaquat which cause AKI associated with intentional or accidental ingestion, agrichemicals
and pesticides have had limited study as
causes of CKD. In a study from Sri Lanka,
acetylcholinesterase-inhibiting pesticides exposure has been associated with CKD.66 In
a study from an unidentified Latin American
country, agricultural workers with reported
exposure to dibromochloropropane were
more likely to have elevated serum creatinine
levels, although exposure to the chemical was
not clearly documented nor was it detectable
in water samples from the work environment.67 Because of the short half-life in the
environment and the possibility that remote
exposure may lead to toxicity, establishing
a link between agrichemical use and CKD
will be difficult.
Conclusion
Environmental factors are an important cause
of acute and CKD, especially in the developing world. It is important to note that most
environmental renal disease is in fact multifactorial. As an example, only 2% to 5% of the residents in an endemic area for Balkan Endemic
Nephropathy progress to the disease. Furthermore, even residents of nonendemic foci who
are found to have this nephropathy belong to
families with other individuals with the disease. This potential genetic link is strengthened by the observation that the proportion
of sick offspring increases according to the
number of parents affected, and the risk of
developing the disease is much greater in
first-degree compared with second-degree relatives. It is, therefore, highly likely that renal
lesions associated with an environmental
exposure will be superimposed on a certain
genetic background to create the phenotype
of the disease. Further evaluation of important
genetic markers such as MYH9 will provide
valuable insight into the intersection of environment and genetics.
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