Editorial

Is Arsenic a Contributor to CKD?

Related Article, p. 385

Arsenic has a fascinating and checkered history. Ithas been a popular poison for at least 2,000

years because it is colorless and tasteless, yet it alsocommonly was used therapeutically in the 19th andearly 20th century in Fowler’s solution (1% potas-sium arsenite), Donovan’s solution (arsenic iodide),and deValagin’s solution (arsenic trichloride) to treata range of maladies,1 and arsenic trioxide currently isprescribed as part of many leukemia treatments. Sto-ries about arsenic appear periodically in the publicsphere as a result of accidental poisonings from inges-tion of old arsenical herbicides or use of arsenic intreated wood, although this use of chromated copperarsenate ceased in 2003. However, for the vast major-ity of the world’s population, the dominant route ofexposure is ingestion of naturally occurring arsenic indrinking water or in food cooked or irrigated withcontaminated water. There are estimated to be morethan 100,000,000 people worldwide exposed to arse-nic levels �10 �g/L in drinking water (the recom-mended maximum level by the United States and theWorld Health Organization), with the largest popula-tion of concern in Bangladesh.2 Inorganic arsenicexposure through drinking water has been a publichealth concern since we first began testing for it in the1940s; however, it is only in the past few decades thatepidemiologic studies have been able to quantify therisk due to exposure.

Research in high-exposure populations (occupa-tional settings or regions with naturally contaminatedgroundwater) has identified increased risk for a rangeof adverse health outcomes. Long-term exposure toinorganic arsenic in drinking water is a well-establishedrisk factor for cardiovascular disease,3 diabetes,4 can-cer,5 and skin disease,6 with some suggestion of anassociation with chronic kidney disease (CKD),7-9 amongother adverse health outcomes. Given the known risksat higher levels of exposure, investigators now areturning to understanding associations from lower levelexposures (�50 �g/L in drinking water) for whichrisk is equivocal.

In this issue of AJKD, Zheng et al10 look to build onfindings from areas with high arsenic exposure by

Address correspondence to Jaymie Meliker, PhD, Program inPublic Health, Stony Brook University, HSC L3, Rm 071, StonyBrook, NY 11794-8338. E-mail: jrmeliker@gmail.com

© 2013 by the National Kidney Foundation, Inc.0272-6386/$36.00

http://dx.doi.org/10.1053/j.ajkd.2012.12.004

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being the first to use a cohort to investigate theassociation between arsenic exposure and CKD in alow-to-moderate arsenic-exposure area. Zheng et al10

conducted a cross-sectional study in a well-poweredcohort derived from the Strong Heart Study, a prospec-tive study of risk factors for cardiovascular disease inAmerican Indian men and women. The outcome mea-sure, albuminuria, was defined as urine albumin levelcorrected for creatinine �30 mg/g. Exposure to arse-nic was based on urine arsenic species concentrationrelevant to inorganic arsenic exposure (As3�, As5�,monomethylarsonic acid, and dimethylarsenic acid).After adjusting extensively for potential risk factorsfor kidney disease, regression models showed increas-ing prevalence with increasing creatinine-correctedurine arsenic levels (prevalence ratios of 1.16 [95%CI, 1.00-1.34], 1.24 [95% CI, 1.07-1.43], and 1.55[95% CI, 1.35-1.78] for concentrations in the rangesof 5.8-9.7, 9.7-15.6, and �15.6 �g/g, respectively).These results were robust in analyses stratified byseveral covariates,10 indicating a consistent associa-tion across many subsets of their study population.Importantly, these findings are significant at relativelylow urine arsenic levels similar to those commonlyseen in the upper quartile of the US population per theNational Health and Nutrition Examination Survey(NHANES),11 which suggests that inorganic arsenicexposure at low to moderate levels may have adversekidney effects. If one were to assume a causal relation-ship, the attributable fraction of albuminuria due toarsenic exposure would be �25% in this study popu-lation and �6% in the total US population, for which�25% of the population has urine arsenic concentra-tions (As3� � As5� � monomethylarsonic acid �dimethylarsenic acid) higher than �8 �g per gram ofcreatinine.

The study by Zheng et al10 had several limitations.Most importantly, it is cross-sectional in design andalso did not associate urinary arsenic concentrationsto measured arsenic concentrations in drinking waterdirectly. Scientific literature confirms a strong correla-tion between urine arsenic species and drinking waterarsenic, especially in populations that do not smoke ordo not have occupational exposures.12-15 However,inorganic arsenic levels in groundwater in the 4 statesof the Strong Heart Study are highly variable, withranges from nondetectable to �50 �g/L, and urinearsenic concentrations cannot be linked directly withdrinking water levels to inform public health policy.

Results from this study quantify the dose-responserelationships of inorganic arsenic at low exposure,

which supports research in areas with high exposure,

Am J Kidney Dis. 2013;61(3):364-365

Editorial

including a recent case-control study in Taiwan8 thatshowed that patients with CKD had significantlygreater total urinary arsenic levels compared withcontrols. This stratagem in arsenic research of deter-mining adverse outcomes in high-exposure areas andthen testing the association in moderate to low areasalso has been seen in cardiovascular disease, cancer,and diabetes. As more physiologic systems are identi-fied as being adversely affected by inorganic arsenicexposure through drinking water, the premise thatarsenic is a systemic toxin and that there is no safelevel of long-term exposure becomes more authenti-cated. However, substantially more research in low tomoderate areas needs to be conducted in the future.

Future research of inorganic arsenic exposure, espe-cially related to nephrotoxicity, can follow severaldirections. Experimental research to discern the com-plex mechanistic pathway is necessary to understandthe nephrotoxicity of inorganic arsenic and answerquestions such as whether inorganic arsenic is actingon the kidneys directly or perhaps also through diabe-togenic effects. Epidemiologic studies need to con-tinue to replicate and quantify associations at lowlevels of exposure, seeking to eliminate possible con-founding factors. Exposure science research needs todevelop methodology that can discern the additive orsynergistic effects of other metals with known nephro-toxic effects, such as cadmium, thallium, and lead.Although Zheng et al10 did not identify an interactionbetween urine arsenic and cadmium levels and uri-nary albumin levels, another study in an area withhigh exposure found possible interactions with bio-markers for kidney disease.16 Last, research needs todetermine the biologically relevant exposure period.Kidney disease is a complex syndrome with manymechanisms for initiation; determining when expo-sure to inorganic arsenic initiates disease action isimportant to assess exposure, and therefore risk, accu-rately.

In closing, Zheng et al10 made commendable ef-forts to ensure the strongest analytic plan to addressthe main hypothesis given the cross-sectional studydesign. This research is the first to identify an associa-tion between urinary arsenic concentrations and abiomarker for kidney disease, albuminuria, in a popu-lation with moderate to low exposure, thereby identi-fying another physiologic system adversely affectedby long-term exposure to inorganic arsenic.

Kathy James, PhDUniversity of Colorado

Aurora, Colorado

Jaymie R. Meliker, PhD

Am J Kidney Dis. 2013;61(3):364-365

Stony Brook UniversityStony Brook, New York

ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: The authors declare that they have no

relevant financial interests.

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