Research Renal Function after Reduction in Cadmium Exposure: An 8‑Year Follow‑ up of Residents in Cadmium‑Polluted Areas Yihuai Liang,1,2 Lijian Lei,1 Johan Nilsson,2 Huiqi Li,1 Monica Nordberg,3 Alfred Bernard,4 Gunnar F. Nordberg,2 Ingvar A. Bergdahl,2 and Taiyi Jin1 1Department of Occupational Health and Toxicology (Key Laboratory of Public Health Safety, Ministry of Education of China), School of Public Health, Fudan University, Shanghai, People’s Republic of China; 2Occupational and Environmental Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 3Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 4Unit of Toxicology, Université catholique de Louvain, Brussels, Belgium nad o Bjectiv Background : Long-term exposure to cadmium (Cd) causes renal dysfunction, but the change in renal function with exposure is unknown. We assessed the evolution of Cd-induced renal effects after a reduction in dietary exposure to Cd in rice. Methods : Four hundred twelve residents in previously Cd-polluted and nonpolluted areas were examined twice, in 1998 and in 2006. Changes in blood Cd, urinary Cd, and kidney function [N-acetyl-β-d-glucosaminidase (NAG), β2-microglobulin, and albumin in urine] were measured. r esult : In the most polluted area, mean blood Cd was 8.9 μg/L and 3.3 μg/L in 1998 and in 2006, respectively, and urinary Cd was 11.6 and 9.0 μg/g creatinine. Urinary albumin in 1998 increased with urinary Cd, but no such exposure–response relation appeared for 2006 albumin versus urinary Cd 1998, indicating recovery. Other biomarkers of kidney function were also elevated in 1998. Partial recovery was observed for NAG among women and was suggested for β2-microglobulin among young individuals. The probability of having β2-microglobulin levels above the 95th percentile in 2006 was high in those with elevated β2-microglobulin in 1998 [odds ratio (OR) = 24.8; 95% confidence interval (CI): 11.2, 55.3] compared with albumin (OR = 3.0; 95% CI: 1.2, 7.5) and NAG (OR = 2.6; 95% CI: 1.6, 4.4). c onclusi : Results suggest that a Cd-mediated increase in urinary albumin excretion is revers- ible upon substantial reduction of exposure. For markers of tubular effects, we observed a tendency toward improvement but not complete recovery. Data from repeated observations suggest that β2-microglobulin may be more informative than NAG as an indicator for an individual’s future tubular function. k ey words glucosaminidase, renal function. Environ Health Perspect 120:223–228 (2012). http://dx.doi. : albumin, β2-microglobulin, cadmium, environmental exposure, N-acetyl-β-d - org/10.1289/ehp.1103699 [Online 25 October 2011] Cadmium (Cd) has a very long biological half- life in humans (10–30 years). Occupational or environmental exposure to Cd can cause different health effects, one of the most promi- nent being kidney damage as a result of Cd accumulation in the kidney (Nordberg et al. 1971, 2007). The evolution of Cd-related renal effects after changes in exposure conditions (i.e., cessation of or reduction in Cd exposure) is now being discussed in the scientific litera- ture. An issue of major concern is whether renal effects of Cd are permanent, or whether renal function may recover after exposure ceases. Some authors have observed that severe renal tubular damage is irreversible in workers [urinary Cd (UCd) > 20 gμ/g creati- nine] previously exposed to high levels of Cd in the workplace (Jarup et al. 1993; Roels et al. 1997). Iwata et al. (1993) reported that renal dysfunction in individuals environmentally exposed to Cd via food became worse over time, even though exposure decreased from > 200 gμ/day to half that value 14 years later, with a corresponding reduction in UCd from 8.5 to 6 μg/g creatinine. Hotz et al. (1999), on the other hand, reported that mild and early forms of renal dysfunction improved in a population that had been environmentally exposed to Cd: mean UCd excretion and blood Cd (BCd) at baseline were 8.9 nmol/24 hr and 9.4 nmol/L (~ 1 μg/L), respectively, for men, and 8.8 nmol/24 hr and 10.9 nmol/L for women. We previously published data from a 3-year follow-up (1995–1998) of 148 individuals who stopped consuming rice with high Cd content, including biomarkers of kidney function at baseline and after exposure ceased (Wu et al. 2008). The geometric mean (GM) of UCd among these individuals was 3.7 μg/g creatinine at baseline and 5.5 μg/g creatinine 3 years later (p = 0.064). The results indicated that the Cd-induced renal dysfunction might be reversible if baseline exposure is relatively low (UCd < 10 μg/g creatinine) before exposure decrease but may be irreversible or increased among those with higher exposure at baseline. Here, we present data from 1998 and 2006 on 412 individuals from the same popu- lation as in the previous 3-year follow-up (Wu et al. 2008). Our aim was to evaluate changes in the prevalence of impaired kidney func- tion after cessation of exposure to contami- nated rice in relation to the initial exposure level and other characteristics such as age and Environmental Health Perspectives • volume 120 | number 2 | February 2012 sex. We measured three different biomarkers of kidney function [urinary N-acetyl-β-d - glucosaminidase (NAG), β2-microglobulin, and albumin] and also evaluated the ability of each biomarker to predict future impairment in the same individual. The present study was part of a larger pro- spective study that also evaluated bone effects after reduction in Cd exposure (Chen et al. 2009a, 2009b). Results of that study sug- gested that effects of Cd on bone persisted over an extended period, resulting in a decline in bone mineral density and an increased prevalence of osteoporosis. Materials and Methods Study area and subjects. The study area and subjects at baseline have been described previ- ously (Jin et al. 1999, 2002, 2004a, 2004b). In brief, three areas in the Zhejiang Province, China, were studied: Jiaoweibao (highly pol- luted), Nanbaixiang (moderately polluted), and Yantou, where no particular pollution had occurred (nonpolluted). In the polluted areas, water contaminated by Cd-containing waste from a local Cd refinery had been used to irrigate farming areas for about 30 years, resulting in the contamination of locally grown rice. This rice was the major source of Cd intake until 1995, when residents stopped consuming locally grown rice. In 1996 resi- dents of Jiaoweibao stopped producing rice and began eating commercially available rice from other (nonpolluted) areas. Although Address correspondence to T. Jin, Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Rd. Yixueyuan 138, 200032, Shanghai, P.R. China. Telephone: 86 21 5423 7214. Fax: 86 21 6417 8160. E-mail: tyjin@shmu.edu.cn Supplemental Material is available online (http:// dx.doi.org/10.1289/ehp.1103699). This work was supported by the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning; the European Union (Sixth Framework Programme; PHIME; FOOD-CT-2006- 016253); and the Key Laboratory of Public Health Safety (Ministry of Education of China). The article reflects only the authors’ views; the European Union is not liable for any use that may be made of the information. The authors declare they have no actual or potential competing financial interests. Received 20 March 2011; accepted 25 October 2011. 223