Liang et al. Discussion In this study we observed that after cessation of exposure to contaminated rice, the Cd-related increase in urinary albumin was reversed. For the tubular markers after cessation of expo- sure, recovery was incomplete for NAG and there was little evidence of recovery of β2-microglobulin. In addition, the NAG sta- tus of an individual at baseline was a relatively weak predictor of elevated NAG at follow- up, whereas elevated β2-microglobulin at base- line was a strong predictor of renal tubular dysfunction 8 years later. Repeated observations were made for > 400 individuals, and the 8-year time period appeared to be sufficient to detect changes in kidney function in association with the decrease in Cd exposure. To assure analytical quality, we incorporated reference materials for blood and urine into the analyses and made dupli- cate measurements of all biological indicators. In addition, several samples from the 1998 study were selected randomly and analyzed again together with the newly collected samples in 2006. The agreement between 1998 and 2006 results was very good [see Supplemental Material, Figure 1 (http://dx.doi.org/10.1289/ ehp.1103699)]. The present study included > 50% of the original participants, and baseline character- istics of those who were lost to follow-up did not suggest that selection bias could explain the main findings of the study. A weakness of our study is that the prevalence analysis of renal dysfunction considered only whether individuals were above or below a cut point based on the distribution of biomarkers in the population with low exposure. In order to Age < 50 years Age ≥ 50 years 1998 2006 ( ( n n G G % % ( ( n n v v 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 UCd (µg/g creatinine) in 1998 UCd (µg/g creatinine) in 1998 ) ) e e l l r r m m extract as much information as possible from our observations, it would be better to use con- tinuous data for the kidney effect biomarkers. For example, Weaver et al. (2009) used gener- alized estimating equations to model change in renal effect markers and evaluated longitu- dinal associations between lead exposure and renal function in workers with occupational exposure. Although we reduced confounding by restricting the population according to age, blood pressure, and medication use, we did not perform multivariable models, and some residual confounding cannot be excluded. In the present study, the decrease in BCd in both the moderately and highly polluted areas confirmed that there was a very substan- tial decrease in exposure in the two areas. BCd responded more to the reduction in expo- sure than did UCd. This is consistent with well-known differences in the kinetics of the two Cd exposure biomarkers, such that BCd mainly reflects recent exposure, whereas UCd is a better indication of long-term exposure and is thus used as a marker of body burden (Nordberg et al. 2007). In the residents of the nonpolluted area, the GM of UCd was about 10 times higher and that of BCd about 2–3 times higher than values reported for adults in Germany (Becker et al. 2002, 2003) and the United States (Centers for Disease Control and Prevention 2009), indicating a relatively high baseline Cd exposure in these areas in China. Based on urinary NAG and β2-microglobulin, kidney tubular function of the residents appeared to decline over time, despite reduction in Cd exposure (Table 2). This is consistent with the findings of Japanese studies with repeated sampling, which were interpreted as evidence of irreversible renal tubular injury in individuals environmentally exposed to Cd (Cai et al. 2001; Fan et al. 1998; Iwata et al. 1993; Kido et al. 1988). Concerning blood pressure and the pos- sible effects of mild Cd exposure, a number of previous studies reported variable results (Nordberg et al. 2007). Gallagher and Meliker (2010) reported a positive associa- tion between BCd and blood pressure among women. According to Lee et al. (2011), BCd may be related to an increased risk for hyper- tension among men in a general Korean adult population. In a study by Kacar Kocak et al. (2011), a rat experiment suggested that Cd exposure affected blood pressure by increas- ing plasma viscosity. In the present study, we excluded participants with hypertension to reduce potential confounding effects of high blood pressure, which is a risk factor for renal dysfunction. The effect of age should be considered for kidney effect markers and has been taken into account in several epidemiological studies (Kobayashi et al. 2008; Moriguchi et al. 2003, 2005) and meta-analyses (Gamo et al. 2006; 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 UCd (µg/g creatinine) in 1998 UCd (µg/g creatinine) in 1998 80 70 )% 60 ce 50 lae 40 v e rp 30 AN 20 ) 60 ce 50 lae 40 rpe 30 Mβ2 20 10 0 80 70 10 0 80 70 (% 60 enc 50 vea 40 p in 30 lbu 20 A 10 0 80 70 ) 60 % ce 50 lvae 40 rpe 30 AN 20 ) 60 ce 50 lae 40 rpe 30 Mβ2 20 10 0 80 70 10 0 80 70 (% 60 nce 50 vea 40 inp 30 lbu 20 A 10 0 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 UCd (µg/g creatinine) in 1998 UCd (µg/g creatinine) in 1998 Figure 2. Prevalence of renal dysfunction in relation to 1998 UCd level in individuals < 50 years of age (A,C,E) and ≥ 50 years of age (B,D,F) shown by increased excretion of NAG (A, B), β2‑microglobulin (β2M; C,D), and albumin (E,F) above the cut points. 226 ovlume 120 | number 2 | February 2012 • Environmental Health Perspectives