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Environmental Exposures, Socioeconomics, Disparities, and the Kidneys
Environmental Exposures, Socioeconomics, Disparities, and the Kidneys Sarmad Said and German T. Hernandez Kidney disease disproportionately affects racial and ethnic minority populations, the poor, and the socially disadvantaged. The excess risk of kidney disease among minority and disadvantaged populations can only be partially explained by an excess of diabetes, hypertension, and poor access to preventive care. Disparities in the environmental exposure to nephrotoxicants have been documented in minority and disadvantaged populations and may explain some of the excess risk of kidney disease. High-level environmental and occupational exposure to lead, cadmium, and mercury are known to cause specific nephropathies. However, there is growing evidence that low-level exposures to heavy metals may contribute to the development of CKD and its progression. In this article, we summarize the excess risk of environmental exposures among minority and disadvantaged populations. We also review the epidemiologic and clinical data linking low-level environmental exposure to lead, cadmium, and mercury to CKD and its progression. Finally, we briefly describe Mesoamerican nephropathy, an epidemic of CKD affecting young men in Central America, which may have occupational and environmental exposures contributing to its development. Q 2015 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Cadmium, Chronic kidney disease, Health disparities, Lead, Mercury
Introduction
Kidney disease disproportionately affects racial and ethnic minority groups. Compared with whites, there is a 4-fold risk of ESRD among African Americans and nearly double the risk for Native Americans, Asian Americans, and Hispanics in the United States.1 Poverty and social disadvantage are associated with a higher risk of CKD and CKD progression.2-5 Additionally, it appears that the relationship between poverty, low socioeconomic status, and kidney disease may be different among racial and ethnic minorities compared with whites.6,7 Most cases of ESRD worldwide are due to diabetes mellitus and hypertension. However, the etiology of ESRD in a significant percentage of patients is never clearly established, and the diagnosis of kidney disease because of environmental or occupational nephrotoxicants is rarely considered.8-10 The kidneys are especially vulnerable to environmental exposures as approximately 20% of the cardiac output goes to the kidneys, and a fraction is then filtered. Along the nephron, the filtrate is largely reabsorbed, concentrated, and acidified. Thus, environmental toxins can be highly concentrated in the kidney, and some toxins can exist in ionic forms as the pH of the filtrate changes in different segments of the nephron. These factors help to explain the pathophysiologic mechanisms involved in certain toxins. For example, lead and cadmium cause much of their kidney ultrastructural damage in the proximal tubule, where two-thirds of the filtered load is reabsorbed.8 It is well known that high levels of exposure to occupational or environmental toxicants, such as lead, mercury, and cadmium, can cause specific nephropathies. However, more recent literature has examined low levels of environmental exposures to nephrotoxicants as risk factors for albuminuria and CKD.11-14 In the case of low-level lead exposure, there is growing evidence of its role as an independent risk factor for progression of CKD regardless of the cause of CKD.15-17 Race, ethnicity, low socioeconomic status, and poverty contribute to a higher burden of exposure to potential environmental nephrotoxicants
which in turn may partially explain the excess risk of kidney disease.12,13,18-21 In this overview, we discuss the available data showing potential socioeconomic, racial, and ethnic disparities in the burden of exposure to nephrotoxicant heavy metals. We also discuss the evidence linking exposure to lead, cadmium, and mercury and kidney disease. We also briefly describe Mesoamerican nephropathy, an epidemic affecting young and poor men working in lowland sugarcane cultivation in Central America.
Lead Exposure Pathophysiology and Mechanism of Kidney Injury Lead is a toxic metal with no known biologic function that can affect almost any organ system including the kidneys. Lead is absorbed from the lungs and the gastrointestinal tract and marginally through the skin. After absorption, lead is distributed approximately 4% in the blood (bound to erythrocytes) with a 30-day half-life and 2% in the soft tissues with a 40-day half-life, and more than 90% accumulates in both trabecular and cortical bone with a half-life of 1 to 16 and 10 to 30 years, respectively.22,23 The potential mechanisms of lead-induced kidney injury are shown in Figure 1.24
From the Division of Nephrology and Hypertension, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to German T. Hernandez, MD, FASN, FACP, Division of Nephrology and Hypertension, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, 4800 Alberta Avenue, El Paso, TX 79905. E-mail: drgermanhernandez@ gmail.com Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.09.003
Advances in Chronic Kidney Disease, Vol 22, No 1 (January), 2015: pp 39-45
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non-Hispanic white adults (0.6%; Fig 2).13 Similarly, adults with a low socioeconomic status had a higher burden of exposure. Specifically, after adjusting for age, race, ethnicity, and gender, the odds ratio of having a blood lead level of 5 mg/dL or more was 1.74 (95% confidence interval [CI], 1.23-2.46) for adults with an annual household income less than $20,000, 2.62 (95% CI, 1.95-3.52) for adults lacking health insurance, 2.17 (95% CI, 1.61-2.93) for adults living in housing built before 1978, and 2.67 (95% CI, 1.833.90) for adults with less than a high school education.13 Data from the New York City Health and Nutrition Examination Survey (NYC HANES) collected in 2004 sugHistorical Trends in Lead Exposure gests that Asian Americans have the highest mean blood Tetraethyl lead, a form of organic lead, was previously added lead levels, with foreign-born Chinese having the highest as an “antiknock” agent in gasoline, and its combustion prodlevels and the highest proportion of adults with a blood ucts represented the most important source of environmental lead level of 5 mg/dL or more.35 The NYC HANES 2004 lead exposure.8 The use of leaded paints and lead solder in also reported higher geometric mean blood lead levels food cans was also a significant source of environmental associated with lower income, lower levels of education, exposure to lead.27 With the removal of lead in gasoline, and shorter length of residence in the United States for paint, and can solder, there has a been a significant decline the foreign born (P , .004 for trend tests).35 in the overall US population’s blood lead levels over the During the period 2007 to 2010, the NHANES reported past 40 years; however, these sources of exposure continue similar disparities in lead to play a significant role in exposure among children poor and developing aged 1 to 5 years, with noncountries.13,21,27,28 Other CLINICAL SUMMARY Hispanic black children significant sources of having a significantly exposure include living Kidney disease disproportionately affects racial and ethnic higher geometric blood near or working in metal minority populations and poor and socially disadvantaged lead level (1.8 mg/dL [95% ore smelters, ceramic leadgroups. CI, 1.6-19]) compared with glazing shops, lead battery There is growing evidence that low-level environmental Mexican American (1.3 mg/ factories, or recycling exposure to lead, cadmium, and mercury may increase dL [95% CI, 1.2-1.4]) and plants, particularly in the risk for kidney disease. non-Hispanic white chilpoor countries without Race, ethnicity, low socioeconomic status, and poverty dren (1.3 mg/dL [95% CI, environmental or occupacontribute to a higher burden of exposure to 1.1-1.4]).21 Children living tional hygiene regulations 29-34 environmental nephrotoxicants and may explain some of in poverty had higher blood and active monitoring. the excess risk for kidney disease. lead levels compared with children not living in Mesoamerican nephropathy is a disease likely related to Disparities in Lead poverty (1.6 vs 1.2 mg/dL, occupational and environmental exposures affecting Exposure by Race, young men working in lowland sugarcane cultivation in respectively [P , .01]), and Ethnicity, and Central America. there was also a significant Socioeconomic difference comparing chilStatus dren enrolled in Medicaid Despite successful reducwith those not enrolled (1.6 mg/dL [95% CI, 1.5-1.7] vs 1.2 mg/dL [95% CI, 1.2-1.3], respections in the level of environmental exposure to lead in the overall US population, disparities persist. The National tively).21 Racial and ethnic minority groups, and those who have Health and Nutrition Examination Survey (NHANES) has recently migrated to the United States, may also be at shown that although blood lead levels in the US adult pophigher risk of lead exposure from several sources ulation have decreased significantly from the periods 1988 including ayurvedic medicine, traditional Mexican to 1994 and 1999 to 2002, significant differences in exposure and Asian remedies, lead-glazed pottery, cosmetics, imremain among racial and ethnic minority groups, and the ported tamarind candy, and others.35-39 poor.13 The geometric mean blood lead levels in US adults decreased by 41% between 1988 to 1994 and 1999 to 2002 The Association between Lead Exposure and and the proportion of adults with a blood lead level of 10 CKD and Its Progression mg/dL or more decreased by 79%.13 However, the ageChronic high-level exposure to lead in the environment or adjusted prevalence of blood lead levels of 5 mg/dL or in the occupational setting is known to cause lead nephropmore for the 1999 to 2002 was higher for Mexican Ameriathy, a chronic tubulointerstitial nephritis.40,41 With the cans (8.7%) and non-Hispanic blacks (8.1%) compared advent of industrial hygiene regulations and the removal with non-Hispanic white adults (4.3%). A nearly 3-fold of lead as an additive to gasoline, paint, and can solder, higher prevalence of blood lead levels of 10 mg/dL or cases of overt lead nephropathy are exceedingly rare in more was also reported among non-Hispanic blacks developed countries. However, there is growing data (1.8%) and Mexican Americans (1.7%) compared with Whole-blood lead levels represent both exogenous exposure and endogenous exposure from the bioavailable lead stored in soft tissues and bone.8,25 Cumulative lead exposure and the bioavailable pool of lead in the body can be estimated by measuring cortical bone lead through in vivo X-ray fluorescence.25 Because bone lead is not easily measured, the pool of bioavailable body lead has also been estimated by measuring urine lead levels after the administration of a single dose of calcium disodium EDTA (EDTA-chelatable lead).26
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Figure 1. Potential mechanism of lead-induced kidney injury. Abbreviations: cGMP, cyclic guanosine monophosphate; NF-kb, nuclear factor kappa B. Reprinted with permission.24
suggesting that lower levels of lead exposure, previously thought to be acceptable (blood lead levels ,5-10 mg/dL), may be a risk factor for the development of CKD and the progression of established CKD. The NHANES 1999 to 2002 has shown that the prevalence of CKD (defined as an estimated glomerular filtration rate [GFR] ,60 mL/min/1.73 m2) among adults increases with higher blood lead levels. The prevalence of CKD was 1.8%, 3.4%, 5.6%, and 8.1% for adults in the lowest (,1.06 mg/dL), second (1.06-1.63 mg/dL), third (1.63-2.7 mg/dL), and the highest quartile of blood lead ($2.47 mg/dL), respectively (P , .001 for trend).13 After adjusting for age, race/ ethnicity, gender, diabetes mellitus, body mass index, smoking, alcohol consumption, educational attainment, and
Figure 2. Age-standardized prevalence of blood lead levels of 5 mg/dL or more (A) and 10 mg/dL or more (B) among adults by race/ethnicity during 1988 to 1994 (NHANES III) and 1999 to 2002. Abbreviations: MA, Mexican Americans; NHB, non-Hispanic blacks; NHW, non-Hispanic whites. Adapted and reprinted with permission.13
health insurance status, the odds ratio of prevalent CKD increased with increasing quartiles of blood lead levels (odds ratios [ORs] 1.49 [95% CI, 0.75-2.98], 1.89 [95% CI, 1.09-3.30], and 2.72 [95% CI, 1.47-5.04], respectively, for the second, third, and fourth increasing quartile of blood lead level [P , .01 for trend]).13 A more recent analysis of the NHANES, for the period of 1999 to 2006, reported that among adults with a blood lead level more than 2.4 mg/ dL, the OR for prevalent CKD was 1.56 (95% CI, 1.17-2.08) compared with adults with a blood lead level 1.1 mg/dL or less (P , .001 for trend).12 Although the NHANES studies were limited by their cross-sectional design, Tsaih and colleagues42 reported a significant longitudinal association between baseline tibial
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bone lead (measured by K X-ray fluorescence) and declining kidney function among middle-aged and elderly diabetic male veterans enrolled in the Normative Aging Study in the Greater Boston area. Comparing the predicted increases in serum creatinine over 10 years between participants in the highest tertile of tibial lead and the lowest tertile, the rate of rise in serum creatinine was 17-fold higher among diabetic participants compared with nondiabetics (1.08 mg/dL/10 y vs 0.062 mg/dL/10 y; P , .01).42 Several studies from Taiwan have reported low-level environmental lead exposure as a risk factor for the progression of CKD regardless of the etiology.15-17 Yu and others16 studied the effects of low-level environmental exposure among 121 patients with nondiabetic CKD. The participants had no identifiable source of overt lead exposure and at baseline had a mean GFR of 36 mL/min/1.73 m2 (range 14-56 mL/min/1.73 m2), mean blood lead level 4.2 mg/dL, and a mean body lead burden (estimated by 72hour urine lead after the administration of 1 g of intravenous calcium EDTA) of 99 mg. The body lead burden was between 80 and 599 mg in 63 patients (categorized as having “high-normal” body lead burden but still below the diagnostic criteria for overt lead nephropathy) and less than 80 mg in 58 patients (low normal) with a baseline mean GFR of 35.1 and 36.9 mL/min/1.73 m2, respectively (P ¼ .314). After 4 years of observation, 15 patients (23.8%) in the “high-normal” body lead burden group and only 2 (3.4%) in the “low-normal” group had a doubling of the baseline serum creatinine (P ¼ .001). Also, after adjusting for multiple factors, every increase of 1 mg/dL in the blood lead level at baseline was associated with a decrease in GFR of 4.0 mL/min/1.73 m2 (P ¼.0148).16 The same group of investigators in Taiwan has also shown that, among patients with low-level environmental lead exposure and nondiabetic or diabetic progressive CKD, the use of weekly calcium EDTA for 3 months reduces the body lead burden and ameliorates or reverses the progressive decline in GFR compared with placebo.15,17 In a study reported by Lin in 2003, 64 patients with nondiabetic CKD and high-normal body lead burden (with similar characteristics as in the observational study by Yu and others) were randomized to receive weekly infusions of calcium EDTA chelation or placebo.15 Twentyfour months after the initial infusion period was completed, the GFR improved by 2.1 mL/min/1.73 m2 in patients randomized to receive chelation compared with a decrease of 6 mL/min/1.73 m2 in patients who received placebo infusions (P ,.001).15 Similar results have been reported in patients with nondiabetic CKD and low-normal body lead burdens (post-calcium EDTA 72-hour urine lead levels between 20 and 79 mg) with an increase in GFR of 6.6 6 10.7 mL/min/1.73 m2 in the chelation patient group and a decrease in GFR of 4.6 6 4.3 mL/min/1.73 m2 in the placebo group (P , .001).43 The same investigator group in Taiwan has also performed similar chelation trials in patients with diabetic CKD. Among 50 patients with diabetic CKD and highnormal body lead burden who were randomized to receive calcium EDTA or placebo infusions, the decline in kidney function was attenuated in patients who received chelation.17 The yearly decrease in GFR was 5.6 6 5.0 mL/
min/1.73 m2/y in the calcium EDTA chelation group compared with a drop on GFR of 9.2 6 3.6 mL/min/ 1.73 m2/y in the placebo group (P ¼ .04).17
Cadmium Exposure
Cadmium is a relatively rare heavy metal found in ores of lead, copper, and zinc. In humans, cadmium exposure occurs primarily through gastrointestinal absorption and inhalation. Cadmium accumulation increases with age, mainly in the liver and kidneys where approximately 80% is stored, and reaches a biologic half-life of more than 10 to 40 years in the kidneys.8 Cadmium, especially at high levels of exposure, is a known nephrotoxicant.44 The dose and the duration of exposure determine the degree of kidney damage that is primarily tubulointerstitial in nature but can also include glomerular injury, lowmolecular weight proteinuria, albuminuria, decreased GFR, and ESRD.44,45 There is mounting evidence that environmental exposure to cadmium at low levels, previously thought to be acceptable, is associated with albuminuria, low GFR, and ESRD.12,46,47 Cadmium exposure in humans occurs primarily from tobacco smoke, ingestion of foods grown with cadmiumcontaining fertilizers or in polluted areas (especially rice, vegetables, grain, and seafood), and in the occupational settings such as in nickel-cadmium battery manufacturing.44 In the general population, blood and urine cadmium levels are usually highest among current cigarette smokers, intermediate in former smokers, and lowest in adults who have never smoked.48,49 Exposure to cadmium also appears to be higher for people living in or near areas with contaminated soil.50 A higher burden of cadmium exposure also exists among the poor and some racial and ethnic minority groups. A study by Tyrrekk and colleagues18 reported an association between poverty (defined as a low poverty income ratio) and higher levels of both blood and urine cadmium among adult participants in several waves of the NHANES. The association between poverty and higher cadmium exposure was only partially mediated by smoking status, occupation, and dietary habits.18 A separate analysis of the NHANES 1999 to 2006 reported a higher risk of cadmium exposure among Mexican American and non-Hispanic black women of childbearing age who had never smoked compared with non-Hispanic white women who had never smoked (adjusted ORs 1.77 [95% CI, 10.6-2.96] and 2.96 [95% CI, 1.96-4.47]), respectively.51 A report from the NYC HANES also found a differential burden of exposure to cadmium across different groups of income, education, and race/ethnicity. The adjusted proportional change in mean blood cadmium was significantly higher among adults with lower income, lower levels of education, smokers, and Asian and nonHispanic black New Yorkers.35 Cadmium exposure was highest among foreign-born Chinese adults with a mean blood cadmium level of 1.34 compared with 1.22 mg/L for current smokers. Current smoking did not explain the higher levels of cadmium exposure among Asian New Yorkers.35 A report from the NHANES 1999 to 2006 found a significant association between cadmium exposure and reduced
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GFR and albuminuria. Among more than 14,000 adults, the adjusted prevalence odds ratio for reduced GFR (,60 mL/min/1.73 m2) was 1.32 (95% CI, 1.04-1.68) when comparing individuals in the highest quartile of blood cadmium (.0.6 mg/L) with the lowest quartile (#0.2 mg/L).12 The OR for albuminuria (defined as an urine albumin/ creatinine ratio $ 30 mg/g) was 1.92 (95% CI, 1.53-2.43), and the OR for concomitant albuminuria and reduced GFR was 2.91 (95% CI, 1.76-4.81)12 More importantly, the authors adjusted for multiple risk factors for kidney disease including blood lead levels. Furthermore, when comparing the risk of prevalent kidney disease for individuals in the highest quartile for both cadmium and lead with those in the lowest quartile for both metals, the risk was magnified (OR 1.98 [95% CI, 1.27-3.10], OR 2.34 [95% CI, 1.72-3.18], and OR 4.10 [95% CI, 1.58-10.65] for reduced GFR, albuminuria, and for both outcomes, respectively).12 Individuals with environmental exposure to cadmium living in or near polluted regions appear to have a €m and others47 calculated higher risk of ESRD. Hellstro the level of environmental exposure to cadmium and the incidence of ESRD between 1978 and 1995 among people living in Kalmar County, Sweden, a region with known cadmium pollution from nickel-cadmium battery manufacturing. The age-standardized rate ratios for ESRD were 1.4 (95% CI, 0.8-2.0), 1.9 (95% CI, 1.3-2.5), and 2.3 (95% CI, 0.6-6.0) in the low-level, moderate-level, and high-level cadmium exposure groups, respectively.47
Mercury Exposure
Mercury is a toxic metal with elemental, inorganic, and organic forms. Elemental mercury is released into the environment as a result of coal combustion, mining, and smelting.50 Exposure to mercury can occur by inhalation of elemental mercury vapor in the atmosphere and from dental amalgams.52 Exposure to organic mercury, mainly methyl mercury, occurs from a diet rich in long-lived predatory fish with bioconcentrated methyl mercury in their tissues (shark, swordfish, and tuna) or fish from contaminated lakes.53,54 Inorganic mercury exposure can cause tubular damage ranging from low-molecular weight proteinuria and enzymuria to acute tubular necrosis.8 Both inorganic and organic mercury exposures have also been reported to cause secondary membranous glomerulonephritis and minimal change disease.55,56 An analysis of the NHANES 2001 to 2010 reported an association between poverty and lower levels of both blood and urine mercury among American adults.18 A similar relationship between poverty and mercury exposure was also reported in the NYC HANES with lower blood mercury levels in individuals with lower income.35 Higher levels of mercury exposure among adults with higher income were mediated by higher fish and shellfish consumption, a finding consistent with other studies.18,35,53,54 When examining differences in mercury exposure by race and ethnicity, a report from the NHANES 1999-2002 found that among women of childbearing age, those who self-identified as Asian, Pacific Islander, Native American, or multiracial had a higher prevalence of
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elevated mercury blood levels compared with Mexican Americans, non-Hispanic blacks, and non-Hispanic whites.20 The NYC HANES also found that Asian participants had higher geometric mean blood mercury levels (4.11 mg/L) compared with non-Hispanic whites (2.83 mg/L), non-Hispanic blacks (2.61 mg/L), and Hispanics (2.27 mg/L); the highest levels were reported among foreign-born Chinese New Yorkers (7.26 mg/L).35 There is conflicting data reported on the association between low-level mercury exposure and kidney disease. Lin and others14 reported that among NHANES adult participants in the 2003 to 2004 wave, there was a higher adjusted prevalence odds ratio of reduced GFR (,60 mL/min/1.73 m2) with increasing tertiles of blood mercury levels. The odds ratios for reduced GFR were 2.09 (95% CI, 1.11-3.96) and 2.94 (95% CI, 1.04-8.33) for tertile 2 (blood mercury 0.66-1.64 mg/L) and tertile 3 (blood mercury .1.64 mg/L), respectively, compared with the lowest tertile (blood mercury ,0.66 mg/L; P ¼ .03 for trend). However, there was not a significant relationship between increasing blood mercury levels and the prevalence of albuminuria.14 Despite the association between low-level mercury exposure and reduced kidney function, there is no data showing an increased risk of ESRD. In fact, a Swedish population-based case-control study nested in 2 prospective cohort studies found an inverse relationship between blood mercury levels and the risk of developing ESRD. The adjusted odds ratio for ESRD associated with every increase of 1 mg/L in blood mercury was 0.81 (95% CI, 0.680.99).57
Mesoamerican Nephropathy
For the last 20 years, there has been an epidemic of CKD across the pacific coast of Central America.58-60 The recently named disease, Mesoamerican nephropathy, affects primarily young rural poor men who work in sugarcane cultivation and other farming activities in low altitude regions.61,62 The clinical manifestations include minimal proteinuria, slow progression, and small echogenic kidneys.62 The kidney biopsies feature extensive glomerulosclerosis, chronic glomerular ischemia, tubulointerstitial fibrosis, and only mild vascular lesions.61 The etiology of Mesoamerican nephropathy has not yet been fully elucidated. Potential causes include repeated occupation-related episodes of volume depletion associated with an increase in serum osmolarity and activation of the polyol pathway in the kidneys, heat-related acute kidney injury, recurrent rhabdomyolysis, toxins (agrochemicals, heavy metals, and medications, such as nonsteroidal anti-inflammatory drugs), infections, and genetic causes.63 Recently, Roncal Jimenez and colleagues64 have reported that mice subjected to severe and recurrent dehydration without access to water during the day showed activation of the kidney aldose reductase pathway with increased sorbitol and fructose kidney levels and subsequent early fibrosis and elevated serum creatinine levels. The authors postulated that the increase in kidney fructose generation, associated with recurrent dehydration and delayed rehydration, subsequently leads to its metabolism by
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fructokinase with production of inflammatory mediators and oxidants that cause kidney injury.64 However, it has not yet been established if the proposed mechanism of fructokinase-related kidney injury plays a primary role among sugarcane workers with Mesoamerican nephropathy. To our knowledge, a description of water accessibility and fluid intake patterns during the workday has not been reported for sugarcane workers at risk for Mesoamerican nephropathy. If present, differences in access to rehydration during the work day may explain why acute kidney injury or CKD has not been observed in similar populations of agricultural workers at risk for dehydration in different geographic regions. Kidney replacement therapy is not a feasible option for many in Central America, especially for the working poor, and many of the men with Mesoamerican nephropathy die an early death because of untreated ESRD.60 It is estimated that the mortality from Mesoamerican nephropathy has doubled in Nicaragua between 2000 and 2009.65 Further research efforts are needed to firmly establish the etiology of Mesoamerican nephropathy and to develop prevention strategies.
Conclusions
Kidney disease disproportionately affects racial and ethnic minority populations, the poor, and the socially disadvantaged. Although the excess risk of kidney disease among minorities and the poor is partially explained by an excess of diabetes, hypertension, and poor access to care, a significant unexplained risk remains. High-level environmental and occupational exposures to nephrotoxicants, such as lead, cadmium, and mercury, are known to cause specific nephropathies. Racial and ethnic minorities and the poor shoulder a higher burden of environmental exposures. Mexican Americans, non-Hispanic blacks, Asians, and the poor have a higher burden of environmental exposure to lead and cadmium. Although Asians, Pacific Islanders, and Native Americans have a higher environmental exposure to mercury, the poor appear to have lower levels of exposure compared with individuals with higher income. There is growing epidemiologic evidence showing a link between low levels of exposure to lead, cadmium, and mercury and a higher risk of CKD and its progression. The differential risk of environmental exposures among minority populations and the poor may contribute to some of the unexplained excess risk of kidney disease. Mesoamerican nephropathy is an epidemic of CKD affecting mainly young and poor men working in sugarcane cultivation in the lowlands of Central America. Although the etiology of Mesoamerican nephropathy has not been fully elucidated, it appears that occupational and environmental exposures may be contributing to the epidemic, especially exposure to recurrent dehydration.
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3. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382(9888):260-272. 4. Merkin SS, Coresh J, Diez Roux AV, Taylor HA, Powe NR. Area socioeconomic status and progressive CKD: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2005;46(2):203-213. 5. Merkin SS, Diez Roux AV, Coresh J, Fried LF, Jackson SA, Powe NR. Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: the Cardiovascular Health Study. Soc Sci Med. 2007;65(4):809-821. 6. Feehally J. Ethnicity and renal disease. Kidney Int. 2005;68(1): 414-424. 7. Crews DC, Pfaff T, Powe NR. Socioeconomic factors and racial disparities in kidney disease outcomes. Semin Nephrol. 2013;33(5): 468-475. 8. Hernandez GT, Rodriguez RA. Renal toxicology. In: LaDou J, Harrison R, eds. Current Occupational and Environmental Medicine. 5th ed. New York, NY: McGraw Hill; 2014:413-422. 9. Ball S, Lloyd J, Cairns T, et al. Why is there so much end-stage renal failure of undetermined cause in UK Indo-Asians? QJM. 2001;94(4):187-193. 10. Lightstone L, Rees AJ, Tomson C, Walls J, Winearls CG, Feehally J. High incidence of end-stage renal disease in Indo-Asians in the UK. QJM. 1995;88(3):191-195. 11. Wedeen RP. Occupational and environmental renal disease. Semin Nephrol. 1997;17(1):46-53. 12. Navas-Acien A, Tellez-Plaza M, Guallar E, et al. Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am J Epidemiol. 2009;170(9):1156-1164. 13. Muntner P, Menke A, DeSalvo KB, Rabito FA, Batuman V. Continued decline in blood lead levels among adults in the United States: the National Health and Nutrition Examination Surveys. Arch Intern Med. 2005;165(18):2155-2161. 14. Lin YS, Ginsberg G, Lin JW, Sonawane B. Mercury exposure and omega-3 fatty acid intake in relation to renal function in the US population. Int J Hyg Environ Health. 2014;217(4-5):465-472. 15. Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med. 2003;348(4):277-286. 16. Yu CC, Lin JL, Lin-Tan DT. Environmental exposure to lead and progression of chronic renal diseases: a four-year prospective longitudinal study. J Am Soc Nephrol. 2004;15(4):1016-1022. 17. Chen KH, Lin JL, Lin-Tan DT, et al. Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. Am J Kidney Dis. 2012;60(4):530-538. 18. Tyrrell J, Melzer D, Henley W, Galloway TS, Osborne NJ. Associations between socioeconomic status and environmental toxicant concentrations in adults in the USA: NHANES 2001-2010. Environ Int. 2013;59:328-335. 19. Brown P. Race, class, and environmental health: a review and systematization of the literature. Environ Res. 1995;69(1):15-30. 20. Hightower JM, O’Hare A, Hernandez GT. Blood mercury reporting in NHANES: identifying Asian, Pacific Islander, Native American, and multiracial groups. Environ Health Perspect. 2006;114(2):173-175. 21. Centers for Disease Control and Prevention. Blood lead levels in children aged 1-5 years—United States, 1999-2010. MMWR Morb Mortal Wkly Rep. 2013;62(13):245-248. 22. Rabinowitz MB, Wetherill GW, Kopple JD. Kinetic analysis of lead metabolism in healthy humans. J Clin Invest. 1976;58(2):260-270. 23. Rabinowitz MB. Toxicokinetics of bone lead. Environ Health Perspect. 1991;91:33-37. 24. Sabath E, Robles-Osorio ML. Renal health and the environment: heavy metal nephrotoxicity. Nefrologia. 2012;32(3):279-286. 25. Barbosa F Jr, Tanus-Santos JE, Gerlach RF, Parsons PJ. A critical review of biomarkers used for monitoring human exposure to lead: advantages, limitations, and future needs. Environ Health Perspect. 2005;113(12):1669-1674.
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26. Wedeen RP. Use of the CaNa2 EDTA Pb-mobilization test to detect occult lead nephropathy. Uremia Invest. 1985;9(2):127-130. 27. Pirkle JL, Brody DJ, Gunter EW, et al. The decline in blood lead levels in the United States. The National Health and Nutrition Examination Surveys (NHANES). JAMA. 1994;272(4):284-291. 28. Kaiser R, Henderson AK, Daley WR, et al. Blood lead levels of primary school children in Dhaka, Bangladesh. Environ Health Perspect. 2001;109(6):563-566. 29. Morse DL, Landrigan PJ, Rosenblum BF, Hubert JS, Housworth J. El Paso revisited. Epidemiologic follow-up of an environmental lead problem. JAMA. 1979;242(8):739-741. 30. Garcia-Vargas GG, Rothenberg SJ, Silbergeld EK, et al. Spatial clustering of toxic trace elements in adolescents around the Torreon, Mexico lead-zinc smelter. J Expo Sci Environ Epidemiol. 2014;24(6):634-642. 31. Ortega F, Counter SA, Buchanan LH, Parra AM, Collaguaso MA, Jacobs AB. Tracking blood lead and zinc protoporphyrin levels in Andean adults working in a lead contaminated environment. J Toxicol Environ Health A. 2013;76(19):1111-1120. 32. Haefliger P, Mathieu-Nolf M, Lociciro S, et al. Mass lead intoxication from informal used lead-acid battery recycling in Dakar, Senegal. Environ Health Perspect. 2009;117(10):1535-1540. 33. Moszynski P. Lead poisoning in Nigeria causes “unprecedented” emergency. BMJ. 2010;341:c4031. 34. Gottesfeld P, Pokhrel AK. Review: lead exposure in battery manufacturing and recycling in developing countries and among children in nearby communities. J Occup Environ Hyg. 2011;8(9): 520-532. 35. McKelvey W, Gwynn RC, Jeffery N, et al. A biomonitoring study of lead, cadmium, and mercury in the blood of New York City adults. Environ Health Perspect. 2007;115(10):1435-1441. 36. Prakash S, Hernandez GT, Dujaili I, Bhalla V. Lead poisoning from an ayurvedic herbal medicine in a patient with chronic kidney disease. Nat Rev Nephrol. 2009;5(5):297-300. 37. Centers for Disease Control and Prevention. Lead poisoning associated with use of traditional ethnic remedies—California, 1991-1992. MMWR Morb Mortal Wkly Rep. 1993;42(27):521-524. 38. Centers for Disease Control and Prevention. Childhood lead poisoning associated with tamarind candy and folk remedies—California, 1999-2000. MMWR Morb Mortal Wkly Rep. 2002;51(31):684-686. 39. Centers for Disease Control and Prevention. Infant lead poisoning associated with use of tiro, an eye cosmetic from Nigeria—Boston, Massachusetts, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(30):574-576. 40. Inglis JA, Henderson DA, Emmerson BT. The pathology and pathogenesis of chronic lead nephropathy occurring in Queensland. J Pathol. 1978;124(2):65-76. 41. Wedeen RP, Malik DK, Batuman V. Detection and treatment of occupational lead nephropathy. Arch Intern Med. 1979;139(1):53-57. 42. Tsaih SW, Korrick S, Schwartz J, et al. Lead, diabetes, hypertension, and renal function: the normative aging study. Environ Health Perspect. 2004;112(11):1178-1182. 43. Lin JL, Lin-Tan DT, Li YJ, Chen KH, Huang YL. Low-level environmental exposure to lead and progressive chronic kidney diseases. Am J Med. 2006;119(8):707.e1-707.e9. 44. Elinder CG, J€ aup L. Cadmium exposure and health risks: recent findings. Ambio. 1996;25(5):370-373. 45. Prozialeck WC, Edwards JR. Early biomarkers of cadmium exposure and nephrotoxicity. Biometals. 2010;23(5):793-809.
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46. Hwangbo Y, Weaver VM, Tellez-Plaza M, Guallar E, Lee BK, NavasAcien A. Blood cadmium and estimated glomerular filtration rate in Korean adults. Environ Health Perspect. 2011;119(12):1800-1805. 47. Hellstrom L, Elinder CG, Dahlberg B, et al. Cadmium exposure and end-stage renal disease. Am J Kidney Dis. 2001;38(5):1001-1008. 48. Becker K, Kaus S, Krause C, et al. German Environmental Survey 1998 (GerES III): environmental pollutants in blood of the German population. Int J Hyg Environ Health. 2002;205(4):297-308. 49. Mannino DM, Holguin F, Greves HM, Savage-Brown A, Stock AL, Jones RL. Urinary cadmium levels predict lower lung function in current and former smokers: data from the Third National Health and Nutrition Examination Survey. Thorax. 2004;59(3):194-198. 50. Centers for Disease Control and Prevention (CDC). Fourth National Report on Human Exposure to Environmental Chemicals. Atlanta, GA: Department of Health and Human Services Centers for Disease Control and Prevention; 1999. 51. Mijal RS, Holzman CB. Blood cadmium levels in women of childbearing age vary by race/ethnicity. Environ Res. 2010;110(5):505-512. 52. Park JD, Zheng W. Human exposure and health effects of inorganic and elemental mercury. J Prev Med Public Health. 2012;45(6):344-352. 53. Hightower JM, Moore D. Mercury levels in high-end consumers of fish. Environ Health Perspect. 2003;111(4):604-608. 54. Mahaffey KR, Clickner RP, Jeffries RA. Adult women’s blood mercury concentrations vary regionally in the United States: association with patterns of fish consumption (NHANES 1999-2004). Environ Health Perspect. 2009;117(1):47-53. 55. Li SJ, Zhang SH, Chen HP, et al. Mercury-induced membranous nephropathy: clinical and pathological features. Clin J Am Soc Nephrol. 2010;5(3):439-444. 56. Tang HL, Chu KH, Mak YF, et al. Minimal change disease following exposure to mercury-containing skin lightening cream. Hong Kong Med J. 2006;12(4):316-318. 57. Sommar JN, Svensson MK, Bjor BM, et al. End-stage renal disease and low level exposure to lead, cadmium and mercury; a population-based, prospective nested case-referent study in Sweden. Environ Health. 2013;12:9. 58. Brooks DR, Ramirez-Rubio O, Amador JJ. CKD in Central America: a hot issue. Am J Kidney Dis. 2012;59(4):481-484. 59. Peraza S, Wesseling C, Aragon A, et al. Decreased kidney function among agricultural workers in El Salvador. Am J Kidney Dis. 2012;59(4):531-540. 60. Torres C, Aragon A, Gonzalez M, et al. Decreased kidney function of unknown cause in Nicaragua: a community-based survey. Am J Kidney Dis. 2010;55(3):485-496. 61. Wijkstrom J, Leiva R, Elinder CG, et al. Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America. Am J Kidney Dis. 2013;62(5):908-918. 62. Weiner DE, McClean MD, Kaufman JS, Brooks DR. The Central American epidemic of CKD. Clin J Am Soc Nephrol. 2013;8(3):504511. 63. Wesseling C, Crowe J, Hogstedt C, et al. Resolving the enigma of the Mesoamerican nephropathy: a research workshop summary. Am J Kidney Dis. 2014;63(3):396-404. 64. Roncal Jimenez CA, Ishimoto T, Lanaspa MA, et al. Fructokinase activity mediates dehydration-induced renal injury. Kidney Int. 2014;86(2):294-302. 65. Krinsky LM, Levine WJ. An island of widows: the human face of Mesoamerican endemic nephropathy. Kidney Int. 2014;86(2):221-223.
Introduction
Kidney disease disproportionately affects racial and ethnic minority groups. Compared with whites, there is a 4-fold risk of ESRD among African Americans and nearly double the risk for Native Americans, Asian Americans, and Hispanics in the United States.1 Poverty and social disadvantage are associated with a higher risk of CKD and CKD progression.2-5 Additionally, it appears that the relationship between poverty, low socioeconomic status, and kidney disease may be different among racial and ethnic minorities compared with whites.6,7 Most cases of ESRD worldwide are due to diabetes mellitus and hypertension. However, the etiology of ESRD in a significant percentage of patients is never clearly established, and the diagnosis of kidney disease because of environmental or occupational nephrotoxicants is rarely considered.8-10 The kidneys are especially vulnerable to environmental exposures as approximately 20% of the cardiac output goes to the kidneys, and a fraction is then filtered. Along the nephron, the filtrate is largely reabsorbed, concentrated, and acidified. Thus, environmental toxins can be highly concentrated in the kidney, and some toxins can exist in ionic forms as the pH of the filtrate changes in different segments of the nephron. These factors help to explain the pathophysiologic mechanisms involved in certain toxins. For example, lead and cadmium cause much of their kidney ultrastructural damage in the proximal tubule, where two-thirds of the filtered load is reabsorbed.8 It is well known that high levels of exposure to occupational or environmental toxicants, such as lead, mercury, and cadmium, can cause specific nephropathies. However, more recent literature has examined low levels of environmental exposures to nephrotoxicants as risk factors for albuminuria and CKD.11-14 In the case of low-level lead exposure, there is growing evidence of its role as an independent risk factor for progression of CKD regardless of the cause of CKD.15-17 Race, ethnicity, low socioeconomic status, and poverty contribute to a higher burden of exposure to potential environmental nephrotoxicants
which in turn may partially explain the excess risk of kidney disease.12,13,18-21 In this overview, we discuss the available data showing potential socioeconomic, racial, and ethnic disparities in the burden of exposure to nephrotoxicant heavy metals. We also discuss the evidence linking exposure to lead, cadmium, and mercury and kidney disease. We also briefly describe Mesoamerican nephropathy, an epidemic affecting young and poor men working in lowland sugarcane cultivation in Central America.
Lead Exposure Pathophysiology and Mechanism of Kidney Injury Lead is a toxic metal with no known biologic function that can affect almost any organ system including the kidneys. Lead is absorbed from the lungs and the gastrointestinal tract and marginally through the skin. After absorption, lead is distributed approximately 4% in the blood (bound to erythrocytes) with a 30-day half-life and 2% in the soft tissues with a 40-day half-life, and more than 90% accumulates in both trabecular and cortical bone with a half-life of 1 to 16 and 10 to 30 years, respectively.22,23 The potential mechanisms of lead-induced kidney injury are shown in Figure 1.24
From the Division of Nephrology and Hypertension, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to German T. Hernandez, MD, FASN, FACP, Division of Nephrology and Hypertension, Department of Internal Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center at El Paso, 4800 Alberta Avenue, El Paso, TX 79905. E-mail: drgermanhernandez@ gmail.com Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.09.003
Advances in Chronic Kidney Disease, Vol 22, No 1 (January), 2015: pp 39-45
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non-Hispanic white adults (0.6%; Fig 2).13 Similarly, adults with a low socioeconomic status had a higher burden of exposure. Specifically, after adjusting for age, race, ethnicity, and gender, the odds ratio of having a blood lead level of 5 mg/dL or more was 1.74 (95% confidence interval [CI], 1.23-2.46) for adults with an annual household income less than $20,000, 2.62 (95% CI, 1.95-3.52) for adults lacking health insurance, 2.17 (95% CI, 1.61-2.93) for adults living in housing built before 1978, and 2.67 (95% CI, 1.833.90) for adults with less than a high school education.13 Data from the New York City Health and Nutrition Examination Survey (NYC HANES) collected in 2004 sugHistorical Trends in Lead Exposure gests that Asian Americans have the highest mean blood Tetraethyl lead, a form of organic lead, was previously added lead levels, with foreign-born Chinese having the highest as an “antiknock” agent in gasoline, and its combustion prodlevels and the highest proportion of adults with a blood ucts represented the most important source of environmental lead level of 5 mg/dL or more.35 The NYC HANES 2004 lead exposure.8 The use of leaded paints and lead solder in also reported higher geometric mean blood lead levels food cans was also a significant source of environmental associated with lower income, lower levels of education, exposure to lead.27 With the removal of lead in gasoline, and shorter length of residence in the United States for paint, and can solder, there has a been a significant decline the foreign born (P , .004 for trend tests).35 in the overall US population’s blood lead levels over the During the period 2007 to 2010, the NHANES reported past 40 years; however, these sources of exposure continue similar disparities in lead to play a significant role in exposure among children poor and developing aged 1 to 5 years, with noncountries.13,21,27,28 Other CLINICAL SUMMARY Hispanic black children significant sources of having a significantly exposure include living Kidney disease disproportionately affects racial and ethnic higher geometric blood near or working in metal minority populations and poor and socially disadvantaged lead level (1.8 mg/dL [95% ore smelters, ceramic leadgroups. CI, 1.6-19]) compared with glazing shops, lead battery There is growing evidence that low-level environmental Mexican American (1.3 mg/ factories, or recycling exposure to lead, cadmium, and mercury may increase dL [95% CI, 1.2-1.4]) and plants, particularly in the risk for kidney disease. non-Hispanic white chilpoor countries without Race, ethnicity, low socioeconomic status, and poverty dren (1.3 mg/dL [95% CI, environmental or occupacontribute to a higher burden of exposure to 1.1-1.4]).21 Children living tional hygiene regulations 29-34 environmental nephrotoxicants and may explain some of in poverty had higher blood and active monitoring. the excess risk for kidney disease. lead levels compared with children not living in Mesoamerican nephropathy is a disease likely related to Disparities in Lead poverty (1.6 vs 1.2 mg/dL, occupational and environmental exposures affecting Exposure by Race, young men working in lowland sugarcane cultivation in respectively [P , .01]), and Ethnicity, and Central America. there was also a significant Socioeconomic difference comparing chilStatus dren enrolled in Medicaid Despite successful reducwith those not enrolled (1.6 mg/dL [95% CI, 1.5-1.7] vs 1.2 mg/dL [95% CI, 1.2-1.3], respections in the level of environmental exposure to lead in the overall US population, disparities persist. The National tively).21 Racial and ethnic minority groups, and those who have Health and Nutrition Examination Survey (NHANES) has recently migrated to the United States, may also be at shown that although blood lead levels in the US adult pophigher risk of lead exposure from several sources ulation have decreased significantly from the periods 1988 including ayurvedic medicine, traditional Mexican to 1994 and 1999 to 2002, significant differences in exposure and Asian remedies, lead-glazed pottery, cosmetics, imremain among racial and ethnic minority groups, and the ported tamarind candy, and others.35-39 poor.13 The geometric mean blood lead levels in US adults decreased by 41% between 1988 to 1994 and 1999 to 2002 The Association between Lead Exposure and and the proportion of adults with a blood lead level of 10 CKD and Its Progression mg/dL or more decreased by 79%.13 However, the ageChronic high-level exposure to lead in the environment or adjusted prevalence of blood lead levels of 5 mg/dL or in the occupational setting is known to cause lead nephropmore for the 1999 to 2002 was higher for Mexican Ameriathy, a chronic tubulointerstitial nephritis.40,41 With the cans (8.7%) and non-Hispanic blacks (8.1%) compared advent of industrial hygiene regulations and the removal with non-Hispanic white adults (4.3%). A nearly 3-fold of lead as an additive to gasoline, paint, and can solder, higher prevalence of blood lead levels of 10 mg/dL or cases of overt lead nephropathy are exceedingly rare in more was also reported among non-Hispanic blacks developed countries. However, there is growing data (1.8%) and Mexican Americans (1.7%) compared with Whole-blood lead levels represent both exogenous exposure and endogenous exposure from the bioavailable lead stored in soft tissues and bone.8,25 Cumulative lead exposure and the bioavailable pool of lead in the body can be estimated by measuring cortical bone lead through in vivo X-ray fluorescence.25 Because bone lead is not easily measured, the pool of bioavailable body lead has also been estimated by measuring urine lead levels after the administration of a single dose of calcium disodium EDTA (EDTA-chelatable lead).26
Environmental Exposures and the Kidneys
41
Figure 1. Potential mechanism of lead-induced kidney injury. Abbreviations: cGMP, cyclic guanosine monophosphate; NF-kb, nuclear factor kappa B. Reprinted with permission.24
suggesting that lower levels of lead exposure, previously thought to be acceptable (blood lead levels ,5-10 mg/dL), may be a risk factor for the development of CKD and the progression of established CKD. The NHANES 1999 to 2002 has shown that the prevalence of CKD (defined as an estimated glomerular filtration rate [GFR] ,60 mL/min/1.73 m2) among adults increases with higher blood lead levels. The prevalence of CKD was 1.8%, 3.4%, 5.6%, and 8.1% for adults in the lowest (,1.06 mg/dL), second (1.06-1.63 mg/dL), third (1.63-2.7 mg/dL), and the highest quartile of blood lead ($2.47 mg/dL), respectively (P , .001 for trend).13 After adjusting for age, race/ ethnicity, gender, diabetes mellitus, body mass index, smoking, alcohol consumption, educational attainment, and
Figure 2. Age-standardized prevalence of blood lead levels of 5 mg/dL or more (A) and 10 mg/dL or more (B) among adults by race/ethnicity during 1988 to 1994 (NHANES III) and 1999 to 2002. Abbreviations: MA, Mexican Americans; NHB, non-Hispanic blacks; NHW, non-Hispanic whites. Adapted and reprinted with permission.13
health insurance status, the odds ratio of prevalent CKD increased with increasing quartiles of blood lead levels (odds ratios [ORs] 1.49 [95% CI, 0.75-2.98], 1.89 [95% CI, 1.09-3.30], and 2.72 [95% CI, 1.47-5.04], respectively, for the second, third, and fourth increasing quartile of blood lead level [P , .01 for trend]).13 A more recent analysis of the NHANES, for the period of 1999 to 2006, reported that among adults with a blood lead level more than 2.4 mg/ dL, the OR for prevalent CKD was 1.56 (95% CI, 1.17-2.08) compared with adults with a blood lead level 1.1 mg/dL or less (P , .001 for trend).12 Although the NHANES studies were limited by their cross-sectional design, Tsaih and colleagues42 reported a significant longitudinal association between baseline tibial
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bone lead (measured by K X-ray fluorescence) and declining kidney function among middle-aged and elderly diabetic male veterans enrolled in the Normative Aging Study in the Greater Boston area. Comparing the predicted increases in serum creatinine over 10 years between participants in the highest tertile of tibial lead and the lowest tertile, the rate of rise in serum creatinine was 17-fold higher among diabetic participants compared with nondiabetics (1.08 mg/dL/10 y vs 0.062 mg/dL/10 y; P , .01).42 Several studies from Taiwan have reported low-level environmental lead exposure as a risk factor for the progression of CKD regardless of the etiology.15-17 Yu and others16 studied the effects of low-level environmental exposure among 121 patients with nondiabetic CKD. The participants had no identifiable source of overt lead exposure and at baseline had a mean GFR of 36 mL/min/1.73 m2 (range 14-56 mL/min/1.73 m2), mean blood lead level 4.2 mg/dL, and a mean body lead burden (estimated by 72hour urine lead after the administration of 1 g of intravenous calcium EDTA) of 99 mg. The body lead burden was between 80 and 599 mg in 63 patients (categorized as having “high-normal” body lead burden but still below the diagnostic criteria for overt lead nephropathy) and less than 80 mg in 58 patients (low normal) with a baseline mean GFR of 35.1 and 36.9 mL/min/1.73 m2, respectively (P ¼ .314). After 4 years of observation, 15 patients (23.8%) in the “high-normal” body lead burden group and only 2 (3.4%) in the “low-normal” group had a doubling of the baseline serum creatinine (P ¼ .001). Also, after adjusting for multiple factors, every increase of 1 mg/dL in the blood lead level at baseline was associated with a decrease in GFR of 4.0 mL/min/1.73 m2 (P ¼.0148).16 The same group of investigators in Taiwan has also shown that, among patients with low-level environmental lead exposure and nondiabetic or diabetic progressive CKD, the use of weekly calcium EDTA for 3 months reduces the body lead burden and ameliorates or reverses the progressive decline in GFR compared with placebo.15,17 In a study reported by Lin in 2003, 64 patients with nondiabetic CKD and high-normal body lead burden (with similar characteristics as in the observational study by Yu and others) were randomized to receive weekly infusions of calcium EDTA chelation or placebo.15 Twentyfour months after the initial infusion period was completed, the GFR improved by 2.1 mL/min/1.73 m2 in patients randomized to receive chelation compared with a decrease of 6 mL/min/1.73 m2 in patients who received placebo infusions (P ,.001).15 Similar results have been reported in patients with nondiabetic CKD and low-normal body lead burdens (post-calcium EDTA 72-hour urine lead levels between 20 and 79 mg) with an increase in GFR of 6.6 6 10.7 mL/min/1.73 m2 in the chelation patient group and a decrease in GFR of 4.6 6 4.3 mL/min/1.73 m2 in the placebo group (P , .001).43 The same investigator group in Taiwan has also performed similar chelation trials in patients with diabetic CKD. Among 50 patients with diabetic CKD and highnormal body lead burden who were randomized to receive calcium EDTA or placebo infusions, the decline in kidney function was attenuated in patients who received chelation.17 The yearly decrease in GFR was 5.6 6 5.0 mL/
min/1.73 m2/y in the calcium EDTA chelation group compared with a drop on GFR of 9.2 6 3.6 mL/min/ 1.73 m2/y in the placebo group (P ¼ .04).17
Cadmium Exposure
Cadmium is a relatively rare heavy metal found in ores of lead, copper, and zinc. In humans, cadmium exposure occurs primarily through gastrointestinal absorption and inhalation. Cadmium accumulation increases with age, mainly in the liver and kidneys where approximately 80% is stored, and reaches a biologic half-life of more than 10 to 40 years in the kidneys.8 Cadmium, especially at high levels of exposure, is a known nephrotoxicant.44 The dose and the duration of exposure determine the degree of kidney damage that is primarily tubulointerstitial in nature but can also include glomerular injury, lowmolecular weight proteinuria, albuminuria, decreased GFR, and ESRD.44,45 There is mounting evidence that environmental exposure to cadmium at low levels, previously thought to be acceptable, is associated with albuminuria, low GFR, and ESRD.12,46,47 Cadmium exposure in humans occurs primarily from tobacco smoke, ingestion of foods grown with cadmiumcontaining fertilizers or in polluted areas (especially rice, vegetables, grain, and seafood), and in the occupational settings such as in nickel-cadmium battery manufacturing.44 In the general population, blood and urine cadmium levels are usually highest among current cigarette smokers, intermediate in former smokers, and lowest in adults who have never smoked.48,49 Exposure to cadmium also appears to be higher for people living in or near areas with contaminated soil.50 A higher burden of cadmium exposure also exists among the poor and some racial and ethnic minority groups. A study by Tyrrekk and colleagues18 reported an association between poverty (defined as a low poverty income ratio) and higher levels of both blood and urine cadmium among adult participants in several waves of the NHANES. The association between poverty and higher cadmium exposure was only partially mediated by smoking status, occupation, and dietary habits.18 A separate analysis of the NHANES 1999 to 2006 reported a higher risk of cadmium exposure among Mexican American and non-Hispanic black women of childbearing age who had never smoked compared with non-Hispanic white women who had never smoked (adjusted ORs 1.77 [95% CI, 10.6-2.96] and 2.96 [95% CI, 1.96-4.47]), respectively.51 A report from the NYC HANES also found a differential burden of exposure to cadmium across different groups of income, education, and race/ethnicity. The adjusted proportional change in mean blood cadmium was significantly higher among adults with lower income, lower levels of education, smokers, and Asian and nonHispanic black New Yorkers.35 Cadmium exposure was highest among foreign-born Chinese adults with a mean blood cadmium level of 1.34 compared with 1.22 mg/L for current smokers. Current smoking did not explain the higher levels of cadmium exposure among Asian New Yorkers.35 A report from the NHANES 1999 to 2006 found a significant association between cadmium exposure and reduced
Environmental Exposures and the Kidneys
GFR and albuminuria. Among more than 14,000 adults, the adjusted prevalence odds ratio for reduced GFR (,60 mL/min/1.73 m2) was 1.32 (95% CI, 1.04-1.68) when comparing individuals in the highest quartile of blood cadmium (.0.6 mg/L) with the lowest quartile (#0.2 mg/L).12 The OR for albuminuria (defined as an urine albumin/ creatinine ratio $ 30 mg/g) was 1.92 (95% CI, 1.53-2.43), and the OR for concomitant albuminuria and reduced GFR was 2.91 (95% CI, 1.76-4.81)12 More importantly, the authors adjusted for multiple risk factors for kidney disease including blood lead levels. Furthermore, when comparing the risk of prevalent kidney disease for individuals in the highest quartile for both cadmium and lead with those in the lowest quartile for both metals, the risk was magnified (OR 1.98 [95% CI, 1.27-3.10], OR 2.34 [95% CI, 1.72-3.18], and OR 4.10 [95% CI, 1.58-10.65] for reduced GFR, albuminuria, and for both outcomes, respectively).12 Individuals with environmental exposure to cadmium living in or near polluted regions appear to have a €m and others47 calculated higher risk of ESRD. Hellstro the level of environmental exposure to cadmium and the incidence of ESRD between 1978 and 1995 among people living in Kalmar County, Sweden, a region with known cadmium pollution from nickel-cadmium battery manufacturing. The age-standardized rate ratios for ESRD were 1.4 (95% CI, 0.8-2.0), 1.9 (95% CI, 1.3-2.5), and 2.3 (95% CI, 0.6-6.0) in the low-level, moderate-level, and high-level cadmium exposure groups, respectively.47
Mercury Exposure
Mercury is a toxic metal with elemental, inorganic, and organic forms. Elemental mercury is released into the environment as a result of coal combustion, mining, and smelting.50 Exposure to mercury can occur by inhalation of elemental mercury vapor in the atmosphere and from dental amalgams.52 Exposure to organic mercury, mainly methyl mercury, occurs from a diet rich in long-lived predatory fish with bioconcentrated methyl mercury in their tissues (shark, swordfish, and tuna) or fish from contaminated lakes.53,54 Inorganic mercury exposure can cause tubular damage ranging from low-molecular weight proteinuria and enzymuria to acute tubular necrosis.8 Both inorganic and organic mercury exposures have also been reported to cause secondary membranous glomerulonephritis and minimal change disease.55,56 An analysis of the NHANES 2001 to 2010 reported an association between poverty and lower levels of both blood and urine mercury among American adults.18 A similar relationship between poverty and mercury exposure was also reported in the NYC HANES with lower blood mercury levels in individuals with lower income.35 Higher levels of mercury exposure among adults with higher income were mediated by higher fish and shellfish consumption, a finding consistent with other studies.18,35,53,54 When examining differences in mercury exposure by race and ethnicity, a report from the NHANES 1999-2002 found that among women of childbearing age, those who self-identified as Asian, Pacific Islander, Native American, or multiracial had a higher prevalence of
43
elevated mercury blood levels compared with Mexican Americans, non-Hispanic blacks, and non-Hispanic whites.20 The NYC HANES also found that Asian participants had higher geometric mean blood mercury levels (4.11 mg/L) compared with non-Hispanic whites (2.83 mg/L), non-Hispanic blacks (2.61 mg/L), and Hispanics (2.27 mg/L); the highest levels were reported among foreign-born Chinese New Yorkers (7.26 mg/L).35 There is conflicting data reported on the association between low-level mercury exposure and kidney disease. Lin and others14 reported that among NHANES adult participants in the 2003 to 2004 wave, there was a higher adjusted prevalence odds ratio of reduced GFR (,60 mL/min/1.73 m2) with increasing tertiles of blood mercury levels. The odds ratios for reduced GFR were 2.09 (95% CI, 1.11-3.96) and 2.94 (95% CI, 1.04-8.33) for tertile 2 (blood mercury 0.66-1.64 mg/L) and tertile 3 (blood mercury .1.64 mg/L), respectively, compared with the lowest tertile (blood mercury ,0.66 mg/L; P ¼ .03 for trend). However, there was not a significant relationship between increasing blood mercury levels and the prevalence of albuminuria.14 Despite the association between low-level mercury exposure and reduced kidney function, there is no data showing an increased risk of ESRD. In fact, a Swedish population-based case-control study nested in 2 prospective cohort studies found an inverse relationship between blood mercury levels and the risk of developing ESRD. The adjusted odds ratio for ESRD associated with every increase of 1 mg/L in blood mercury was 0.81 (95% CI, 0.680.99).57
Mesoamerican Nephropathy
For the last 20 years, there has been an epidemic of CKD across the pacific coast of Central America.58-60 The recently named disease, Mesoamerican nephropathy, affects primarily young rural poor men who work in sugarcane cultivation and other farming activities in low altitude regions.61,62 The clinical manifestations include minimal proteinuria, slow progression, and small echogenic kidneys.62 The kidney biopsies feature extensive glomerulosclerosis, chronic glomerular ischemia, tubulointerstitial fibrosis, and only mild vascular lesions.61 The etiology of Mesoamerican nephropathy has not yet been fully elucidated. Potential causes include repeated occupation-related episodes of volume depletion associated with an increase in serum osmolarity and activation of the polyol pathway in the kidneys, heat-related acute kidney injury, recurrent rhabdomyolysis, toxins (agrochemicals, heavy metals, and medications, such as nonsteroidal anti-inflammatory drugs), infections, and genetic causes.63 Recently, Roncal Jimenez and colleagues64 have reported that mice subjected to severe and recurrent dehydration without access to water during the day showed activation of the kidney aldose reductase pathway with increased sorbitol and fructose kidney levels and subsequent early fibrosis and elevated serum creatinine levels. The authors postulated that the increase in kidney fructose generation, associated with recurrent dehydration and delayed rehydration, subsequently leads to its metabolism by
44
Said and Hernandez
fructokinase with production of inflammatory mediators and oxidants that cause kidney injury.64 However, it has not yet been established if the proposed mechanism of fructokinase-related kidney injury plays a primary role among sugarcane workers with Mesoamerican nephropathy. To our knowledge, a description of water accessibility and fluid intake patterns during the workday has not been reported for sugarcane workers at risk for Mesoamerican nephropathy. If present, differences in access to rehydration during the work day may explain why acute kidney injury or CKD has not been observed in similar populations of agricultural workers at risk for dehydration in different geographic regions. Kidney replacement therapy is not a feasible option for many in Central America, especially for the working poor, and many of the men with Mesoamerican nephropathy die an early death because of untreated ESRD.60 It is estimated that the mortality from Mesoamerican nephropathy has doubled in Nicaragua between 2000 and 2009.65 Further research efforts are needed to firmly establish the etiology of Mesoamerican nephropathy and to develop prevention strategies.
Conclusions
Kidney disease disproportionately affects racial and ethnic minority populations, the poor, and the socially disadvantaged. Although the excess risk of kidney disease among minorities and the poor is partially explained by an excess of diabetes, hypertension, and poor access to care, a significant unexplained risk remains. High-level environmental and occupational exposures to nephrotoxicants, such as lead, cadmium, and mercury, are known to cause specific nephropathies. Racial and ethnic minorities and the poor shoulder a higher burden of environmental exposures. Mexican Americans, non-Hispanic blacks, Asians, and the poor have a higher burden of environmental exposure to lead and cadmium. Although Asians, Pacific Islanders, and Native Americans have a higher environmental exposure to mercury, the poor appear to have lower levels of exposure compared with individuals with higher income. There is growing epidemiologic evidence showing a link between low levels of exposure to lead, cadmium, and mercury and a higher risk of CKD and its progression. The differential risk of environmental exposures among minority populations and the poor may contribute to some of the unexplained excess risk of kidney disease. Mesoamerican nephropathy is an epidemic of CKD affecting mainly young and poor men working in sugarcane cultivation in the lowlands of Central America. Although the etiology of Mesoamerican nephropathy has not been fully elucidated, it appears that occupational and environmental exposures may be contributing to the epidemic, especially exposure to recurrent dehydration.
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