The Associations between Arsenic Concentration in Drinking Water and Chronic Kidney Disease: a Nationwide Study in Taiwan

The Associations between Arsenic in

Drinking Water and the Decline of

Chronic Kidney Disease (CKD): A

Nationwide Cohort Study in Taiwan

YA-YUN CHENG

Department of Environmental and Occupational Health

College of Medicine, National Cheng Kung University

27 Aug. 2014

Arsenic ^Important?

Nevertheless, epidemiology studies

on the association between arsenic

exposure and the progression of

CKD are still limited.

http://research.stevens.edu/index.php/sers-on-site-analysis

This graphic illustrates global occurrences of arsenic in groundwater

In TAIWAN 1/25

0.9 million / 23 million

were exposed to arsenic concentration

in drinking water above 0.05 mg/L

which was the regulatory standard at the time of survey.

(Lo et al. 1977, Guo et al. 1997; Guo et al. 1998)

As in well water: 350 to 1140 µg/L

1910s ~ the early 1970s

Arsenic-exposed areas in Taiwan

Fig. Map of southwestern and northeastern arsenic-exposed areas in Taiwan. There

are four townships in the southwestern exposed area: Putai (1), Ichu (2), Peimen

(3), and Hsuehchia (4); and four townships in the northeastern exposed area:

Chiaohsi (1), Chuangwei (2), Wuchieh (3), and Tungshan (4).

(Guo et al.,1998, 2008) 4

As in well water: 0.15μg/L ~3590μg/L

The late 1940s to the early 1990s

NCKU 5

Background- Arsenic

 Arsenic were the compounds that IARC

considered to have sufficient evidence for human

carcinogenicity, also for animal carcinogenicity.

(IARC, 2012a)

 Maximum permissible level (MPL) of arsenic

concentration 0.01 mg/L (ppm) in drinking water.

(WHO 2008)

 Several epidemiological studies have demonstrated

that there is increased risk for several types of

cancers and chronic diseases.

 DM, HTN, peripheral vascular disease, and

ischemic heart disease

(Wang et al. 2003;Walton et al. 2004; Meliker et al. 2007; Wu et al. 2011)

 Cancer: Bladder, lung, skin, liver, kidney

(Tseng et al. 1968, Chen et al., 1985; Guo et al., 1998, Guo 2004, Yuan et al. 2010) (IARC)，International Agency for Research on Cancer

60-75％

10-15％

10-20％

Blood

Liver

Liver

(Vahter M, 2000; Kitchin, 2001; Stýblo M et al., 2002; Hayakawa et al., 2005)

Monomethylarsonic Acid (MMA)

Dimethyarsinic Acid (DMA)

MMA3+＞As3+＞As5+＞MMA5+＝DMA5+

6

Arsenic concentrates in the kidney

during its urinary elimination that

affects the function of proximal tubules and glomerulus

Mechanisms pertaining to arsenic toxicity. Toxicol Int. 2011 Jul;18(2):87-93.

(Singh et al. 2011)

(Liao et al. 2009) ⁷

NCKU 8

Mechanisms pertaining to arsenic toxicity. Toxicol Int. 2011 Jul;18(2):87-93.

Arsenic-Induced Nephro-toxicity

By ROS (Reactive Oxygen Species)

Enhances lipid peroxidation and

cellular damage in renal tissue.

Acute renal dysfunction due

to arsenic exposure

is characterized by acute

tubular necrosis and cast

formation with increasing in

blood urea nitrogen (BUN)

and creatinine (Cr) levels.

(Giberson et al. 1976, Sasaki et al. 2007)

8

Epidemiology: As – kidney disease

Reference Design Arsenic exposure Main findings

(Chen et al. 2011) Chemosphere

Community-based cross-sectional study from central Taiwan

Urine As U-As might relate to renal

dysfunction even other important risk factors were taken into

account.

(B2MG > 0.154 mg/L) U-As > 35 lg/g

(eGFR < 90 mL/min/1.73 m2/year) U-As > 75 lg/g (Hsueh et al. 2009)

American Journal of Kidney Diseases

Hospital based Case- control study

125 CKD patients and 229 controls

Urine As Total arsenic level was

associated significantly with CKD in a dose-response relationship.

(Chiu and Yang 2005) Journal of Toxicology and Environmental Health - Part A

Standardized mortality ratios

(SMRs) for the years 1971–2000.

Residents BFD endemic area in the southwestern coast of Taiwan more than 50 yr.

(SMRs) for renal diseases were positively correlated.

(Chiou et al. 2005a) International Journal of Epidemiology

National Health Insurance (NHI) database.

1999-2000 prevalence

Residents BFD endemic area in the southwestern coast of Taiwan

An increased prevalence of microvascular diseases,

including neurological and renal disorders, is associated with arsenic ingestion.

NCKU 9

Arsenic level was associated significantly

with CKD in a dose-response relationship

9

NCKU 10

American Journal of Kidney Diseases, 2007 Vol 49, No 1 : pp 46-55

Epidemiology of

Chronic Kidney Disease

In NHIRD

(Kuo et al. 2007) (Wen et al. 2008)

They were significantly higher in

southwestern Taiwan with an

increasing trend.

NCKU 11

（United States Renal Data System, USRDS 2012）

12% CKD 2.7 million in 2011

0.26% ESRD cost NHI: 7 % $

11

NCKU 12

Objective

1. To evaluate the associations between

arsenic exposure and the risks of CKD

and its rapid progression in Taiwan.

 We conducted a nationwide cohort

study including both the BFD endemic

area and other areas in Taiwan.

NCKU 13

Materials and methods

NCKU 14

Arsenic exposure index

 Data on well water arsenic were obtained

from a nationwide survey conducted by the

Taiwan Provincial Institute of Environmental

Sanitation using the standard mercuric

bromide stain method.

(Lo et al.,1977; APHA, 1985)

 There were more than 80,000 wells, mostly between

1974 and 1976, and were available for 311 townships.

 Arsenic levels were three categories: below 0.05 ppm

(similar to mg/L), 0.05-0.35 ppm, and above 0.35 ppm.

NCKU 15

Drinking history

Addresse

Evaluate the associations between possible arsenic

exposure and the risk of progression in CKD.

2000 2009

Addresses

MJ Health Management Institution 2000-2009:

A Nationwide Cohort Study in Taiwan (N=10,018)

(CP Wen, 2008)

End point:

Diagnosis of CKD3b-5

> 5 ml/min/1.73 m2/year

Follow up period

≥12 months ≤24 months

15

NCKU 16

Risk factors of CKD

 Epidemiological and clinical evidence have shown a

link between hypertension, diabetes, obesity, and

metabolic syndrome (Comorbidity) and the onset and

progression of CKD.



SEX, Age, Edu



High prevalence low awareness for CKD

(Hsu CC, 2006; Wen et al. 2008)



Western medicines



NSAID (non-steroidal anti-inflammatory drugs)



Acetaminophen

(Chiu et al. 2008; Wen et al. 2008; Lai et al. 2009; Lai et al. 2010)



Chinese herbal medicine ( Aristolochic acid)

(Vanherweghem JL, 1993; Yang CS, 2000; Chang CH, 2001; Yang HY, 2006)

Index of renal function and progression

 Subjects who had an eGFR of less than 60

mL/min/1.73 m

that continued for 3 months were

defined as having stages 3-5 CKD (Chronic Renal

Failure, CRF).



It was further divided into 3a with eGFR 45-59

mL/min/1.73 m

and 3b with eGFR 30-44 mL/min/1.73

m

National Kidney Foundation guidelines (NKF)].

 Rapid progression: is defined as a sustained decline

in eGFR of more than 5 ml/min/1.73 m

/ within 1

year according to KDIGO guideline and NICE

guideline.

NCKU 17

（K/DOQI）

NCKU 18

Statistic

• Chi-square test, T-test, ANOVA

• Logistic regression: CKD3b-5 / progression

• Odds Ratio 95% C.I

• Single, multiple, stepwise (include p<0.05;

exclude p>0.15)

• SAS 9.3 + SPSS1 17.0

• Two-side p<0.05

NCKU 19

We observed higher arsenic

concentration especially clustered

in endemic areas of southwestern

and northeastern Taiwan.

Fig. 1 Map of maximum arsenic concentration

categories in each township.

NCKU 20

Flow chart of the

nationwide cohort study

NCKU 21 21

NCKU 22

2-1

2-2

23

NCKU 24

2-3

24

25

b: CKD_3b~5: 19 factors15 factors

Male, ≥40 years, lower Educational, Residence (Middle+ South Taiwan),

smoker<10 year, Alcohol, NSAID, Herbal, As≥0.05, BMI≥27, SBP≥140,

FPS≥126, TG≥200, Anemia, HTN, DM, CVD, Gout, Nephritis

c: eGFR decline >5 ml/min/1.73 m

/year: 16 factors12 factors

Female, lower Educational, Residence (Middle+ South Taiwan), smoker≥10

year, Alcohol, Betel, Herbal, As_0.05_0.35, BMI≥27, SBP≥140, FPS≥126,

TG≥200, Anemia, HTN, DM, Nephritis

2-4

Conclusion

 Using either 0.05 or 0.35 mg/L as the cut-

off, we found most of the hot spots

clustered in the southwestern coast and

northeastern endemic areas in Taiwan.

 Furthermore, we found exposure to arsenic

in drinking water > 0.05 mg/L was

associated with both the prevalence of

CKD and the rapid progression of CKD

(eGFR decline>5 ml/min/1.73 m2/year),

independent of most documented risk

factors.

NCKU 26

Acknowledgements

 This work was supported by Grants

NSC102-2314-B-006 -026 -MY2 from the

Ministry of Science and Technology of

Taiwan, R.O.C.

 Co-author:

 Neng-Chyan Huang M.D

 How-Ran Guo M.D

NCKU 27

NCKU 28

Thank you for

your attention！

Q & A