reduced as long as the renal burden of Cd (as reflected by UCd) continues to be elevated. The limited but statistically significant decrease in UCd in the highly exposed area (Table 2) may be partly related to the decrease in urinary albumin excretion, because Cd in blood plasma of animals has been shown to bind to albumin to a large extent (Nordberg et al. 1971). Obviously, when albumin excre- tion is changed, excretion of plasma Cd bound to this protein would be expected to change accordingly. Hotz et al. (1999) reported that baseline levels of β2-microglobulin and NAG were not significant predictors of changes in urinary albumin 5 years after slightly reduced Cd expo- sure. Nishijo et al. (1994) identified urinary β2-microglobulin as an important prognos- tic factor, that is, an early index predictive of 1998 2006 Males Renal function after reduction in Cd exposure mortality. In our study we tested how strongly elevated levels of markers of renal tubular injury in 1998 predicted elevated levels of the same markers in 2006. The status of kidney function, as graded by dichotomous cut points, indicated for NAG that 2006 values were dependent on values in 1998 only to a limited degree (OR = 2.6). β2-Microglobulin, however, served as a good predictor for future results (OR = 24.8). The difference could be explained by the origins of urinary β2-microglobulin and NAG. β2-Microglobulin (11.8 kDa), normally found on the surface of nearly all nucleated cells and in small amounts in the blood and urine, is readily filtered through the glomerular membrane and almost completely resorbed by the renal proximal tubules (Wu et al. 2008). Impaired reabsorption leads to increased excre- tion of β2-microglobulin in urine. NAG, a Females Omarova and Phillips 2007) of Cd. We used age-adjusted cut points to define abnormal kidney function to reduce the effect of age on our analysis of changes in kidney function over time. In our stratified analyses for age ≥ 50 years versus < 50 years and for sex, we observed indications of a slight recovery in NAG and β2-microglobulin for some groups, whereas albumin showed a clear recovery (Figures 2 and 3). Disease status is known to have great influence on GFR (Cirillo 2010). A community- based Japanese study (not related to Cd) revealed that individuals with baseline urinary β2-microglobulin > 300 μg/g creatinine had a greater decline in eGFR after 5 years (Kudo et al. 2011). Earlier studies of Cd-exposed workers indicated a relationship between BCd and decreased GFR. Jarup et al. (1995) found such a relationship among workers with BCd up to 14 μg/L, which is of the same magnitude as that found in the present study (interquartile range of 5–14 μg/L in the highly polluted area before reduction in exposure). In the present study, the renal filtration function of individuals in polluted areas in 2006 was at the levels of controls in that year, as indicated by eGFR (Table 2), but the individuals with the highest UCd in 1998 (> 20 gμ/g creatinine) had a decreased eGFR in 2006 (Table 3). Unfortunately, we do not have eGFR data for 1998. Mean levels of urinary albumin in 2006 decreased significantly from baseline levels among both men and women in the highly polluted area (p < 0.01; Table 2). Hotz et al. (1999) reported that urinary albu- min decreased significantly in men, but not in women, after Cd body burden decreased slightly during a 5-year follow-up. Previous studies on experimental animals (Bernard et al. 1992) and Cd-exposed workers (Bernard et al. 1988) have suggested that Cd-induced albuminuria might be due to loss of the glomerular polyanion charge and thus reduced electrostatic repulsion of negatively charged plasma proteins by the glomerular capillary wall. These studies and the study by Cardenas et al. (1991) have shown that loss of glomerular barrier function is reflected by a parallel loss of red blood cell charge and that these two phenomena are probably caused by a decrease of the sialic acid content of glomerular and red blood cell membranes. This is suggestive of a biochemical mechanism linked to circulating levels of Cd that might be reversible with a decrease in BCd, consistent with our findings. In contrast, effects of Cd on urinary excretion of β2-microglobulin and NAG are directly related to the accumulation of Cd in the proximal tubular cells, and there is no reason to believe that effects would be reversible after environmental exposure is Environmental Health Perspectives • volume 120 | number 2 | February 2012 35 35 80 70 ) 60 % ( ce 50 n lae 40 v rpe 30 G AN 20 10 0 80 70 10 0 80 70 0 0 0 ) 60 % ( ce 50 n lae 40 v e rp 30 Mβ2 20 ) (% 60 e c len 50 a rve 40 p in 30 m lbu 20 A 10 0 5 10 15 20 25 30 UCd (µg/g creatinine) in 1998 5 10 15 20 25 30 UCd (µg/g creatinine) in 1998 Figure 3. Prevalence of renal dysfunction in relation to 1998 UCd level in males (A,C,E) and females (B,D,F) shown by increased excretion of NAG (A,B), β2‑microglobulin ( β2M; C,D), and albumin (E,F) above the cut points. 5 10 15 20 25 30 UCd (µg/g creatinine) in 1998 35 5 10 15 20 25 30 UCd (µg/g creatinine) in 1998 35 5 10 15 20 25 30 UCd (µg/g creatinine) in 1998 5 10 15 20 25 30 UCd (µg/g creatinine) in 1998 80 70 ) 60 % ( ce 50 n lae 40 v e rp 30 G AN 20 ) 60 % ( ce 50 n lae 40 v e rp 30 Mβ2 20 10 0 80 70 10 0 80 70 ) (% 60 e c len 50 a rve 40 p in 30 m lbu 20 A 10 0 0 0 0 35 35 227