Estimation of biological half-life of urinary cadmium in inhabitants after cessation of environmental cadmium pollution using a mixed linear model.

We investigated the biological half-life of urinary cadmium concentration (U-Cd) based on a 22-year follow-up study after cessation of environmental Cd pollution. Spot urine samples were obtained from the inhabitants (32 men and 36 women) in the target area in 1986, 1991, 1999, 2003 and 2008. These inhabitants were divided into higher or lower baseline U-Cd group by the cut-off of 5 µg l(-1) or 5 µg g(-1) creatinine. Biological half-life of U-Cd was estimated using a linear mixed model adjusted for the baseline age. In the higher baseline U-Cd groups, the estimated half-life and 95% confidence intervals were 12.4 years (9.3-18.8 years) and 11.4 years (9.3-14.6 years) for unadjusted U-Cd in men and women, respectively. For creatinine-adjusted U-Cd, they were 16.0 years (13.0-20.7 years) and 20.4 years (16.6-26.2 years) in men and women, respectively. In the lower baseline U-Cd groups, biological half-life for unadjusted U-Cd in men was solely significant (23.4 years) and longer than the corresponding half-life in the higher baseline U-Cd group. The biological half-lives of U-Cd obtained in this study were identical with the values for U-Cd or total body burden determined by a different method.

Different association of cigarette smoking with GFR estimated from serum creatinine and that from serum cystatin C in the general population.

BACKGROUND: Previous studies have shown that GFR estimated from serum creatinine (eGFRcr) is higher in smokers although the implications remain unclear. We aimed to clarify the associations of smoking with eGFRcys (GFR estimated from serum cystatin C) and eGFRcr, cys (the surmised most precise GFR estimate based on serum creatinine and cystatin C) in a working population. METHODS: Cross-sectional observation in 1,587 male workers aged 25-64 years. For eGFRcr, JEQcr proposed by the Japanese Society of Nephrology (JSN) and jEPIcr by the Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) modified for Japanese, and for eGFRcys, JEQcys proposed by JSN and EPIcys by CKD-EPI were calculated together with eGFRcr,cys of JEQaver (the average of JEQcr and JEQcys) and jEPIcr,cys by CKD-EPI modified for Japanese. RESULTS: Mean JEQcys was 95.1 mL/min/1.73 m(2) in contrast to 80.9 in JEQcr, with this difference considerable. Serum cystatin C was higher in smokers and obese subjects while serum creatinine was lower in smokers and slender subjects. JEQcys and EPIcys were lower in smokers while JEQcr and jEPIcr were higher in smokers adjusting for body mass index (BMI). eGFRcr,cys (JEQaver and jEPIcr,cys) did not differ between the never smokers and current smokers. eGFRcr,cys predicted by the equations composed of eGFRcr, BMI, and smoking habits showed a good accordance with calculated eGFRcr,cys. CONCLUSIONS: Either eGFRcr, eGFRcys or both were not reliable indicators of renal function in workers who smoked. The possibly more precise estimate of eGFRcr,cys could be predicted by eGFRcr, BMI and smoking in such a generally healthy population.

Elevated Blood Pressure and Serum γ -Glutamyltransferase as Significant Characteristics of Smokers With Chronic Kidney Disease.

BACKGROUND: Smoking is a risk factor for chronic kidney disease (CKD). However, it is speculated that only a small subset of sensitive smokers develop CKD. OBJECTIVES: We aimed to reveal the characteristics of such smokers sensitive to the renal effects of smoking with respect to cardiovascular (CV) risk factors associated with smoking and/or CKD. PATIENTS AND METHODS: Renal functions and CVD risk factors were assessed in middle-aged male workers. The patients were comprised of 336 nonsmokers, 332 smokers currently smoking up to one pack per day, and 38 who smoked more than one pack per day. CKD was determined by estimated glomerular filtration rate (eGFR) from serum creatinine and urinary albumin to creatinine ratio (ACR). The independent and interactive effects of smoking and CKD on the CVD risk factors adjusted for age, body mass index, alcohol consumption, and physical activity were statistically analyzed. RESULTS: In comparison to nonsmokers, smokers had significantly higher waist circumference, white blood cells (WBC), serum triglycerides, γ-glutamyltransferase (GGT), and C-reactive protein (CRP) and lower serum high-density lipoprotein cholesterol and uric acid. On the other hand, blood pressure (BP) and WBC tended to be higher in those showing CKD than others. Serum GGT and fasting plasma glucose were significantly higher, and insulin resistance index of homeostatic model assessment (HOMA-IR) tended to be higher in those with CKD. Serum CRP was especially high in those with moderate to severe CKD. A significant interactive effect of smoking and CKD on BP and serum GGT levels was detected, i.e. BP and GGT were not different in the subjects among nonsmokers with and without CKD, but were conspicuously high among smokers with CKD. No significant interactive effect was found on either HOMA-IR or serum CRP. CONCLUSIONS: Smokers with a higher BP and/or serum GGT may be at a higher risk of developing CKD. The associations of BP and serum GGT with CKD in smokers are not entirely mediated by increased insulin resistance or chronic inflammation caused by smoking.

Use of the kidney injury molecule-1 as a biomarker for early detection of renal tubular dysfunction in a population chronically exposed to cadmium in the environment.

Cadmium (Cd) has been found as an environmental pollutant in Mae Sot district, Tak province, Thailand. Prolong exposure to high levels of Cd of the resident increases high risk of Cd toxicity especially to kidney which is the primary target of Cd. In order to investigate the early effect of Cd induced renal dysfunction, a kidney injury molecule-1 (KIM-1), a novel biomarker of renal tubular dysfunction, was measured using an enzyme linked immunosorbent assay (ELISA). The method was validated and used to quantify the KIM-1 concentrations in the urine of 700 subjects (260 men, 440 women) who lived in the Cd contaminated area. The KIM-1 concentrations were compared to the concentrations of two conventional renal tubular dysfunction biomarkers, N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG). Urinary KIM-1 was correlated with urinary and blood Cd as well as NAG. After adjustment of age and smoking, urinary KIM-1 was correlated with blood Cd more than urinary NAG did. Clear dose response relationships of urinary KIM-1 with urinary Cd were shown in both men and women. These results indicate that the urinary KIM-1 might be more sensitive biomarker than urinary NAG and ß2-MG for an early detection of renal tubular dysfunction. It is useful as a tool to detect renal effect of toxicity due to chronic Cd exposure at high level.

Distribution of and factors contributing to chronic kidney disease in a middle-aged working population.

OBJECTIVES: To clarify the distribution of chronic kidney disease (CKD) and the factors contributing to its development and progression in middle-aged Japanese workers/employees. METHODS: This was a retrospective study involving 3,964 men and 2,698 women aged 35-64 years in 2009 who had been followed-up until 2003. Data on proteinuria determined with a dipstick and glomerular filtration rate estimated from serum creatinine concentration (eGFR) were collected in the annual health check-ups. RESULTS: Proteinuria was detected in 2.9 and 1.1 % of the men and women, respectively, and total CKD was detected in 16.0 and 16.1 % of the men and women respectively. Moderate or severe CKD associated a high risk of cardiovascular diseases and end-stage kidney disease was found mostly in the male subjects [2.0 (men) vs. 0.6 % (women)]. High-risk CKD was found in 3.3 % of the men aged 55-64 years. A body mass index (BMI) of ≥30, hypertension, diabetes mellitus (DM), current smoking and some job types were independently related to the development of proteinuria, while age, BMI, hypertriglyceridemia, and job types were related to total CKD. The development of high-risk CKD was related to preceding mild CKD signs of reduced eGFR and proteinuria as well as to hypertension, DM, smoking, and job type. CONCLUSIONS: Chronic kidney disease was found in 16 % of middle-aged workers with an equal prevalence in both sexes, while high-risk CKD was found mostly in men, of whom 3.3 % were aged 55-64 years. Obesity, hypertension, DM, smoking and some job types were related to the development and progression of CKD.

The effects of continuing and discontinuing smoking on the development of chronic kidney disease (CKD) in the healthy middle-aged working population in Japan.

OBJECTIVES: The strength of the association between smoking and the development of chronic kidney disease (CKD) in the healthy middle-aged working age population has not been established. METHODS: This was a retrospective 6-year observational study involving 4,121 male and 2,877 female workers who were free of primary kidney disease, diabetes mellitus, severe hypertension, and the signs and symptoms of CKD. Proteinuria was detected by a dipstick method, and glomerular filtration rate (GFR) was estimated by the equation of the Japan Society of Nephrology. RESULTS: Sixty men (1.5 %) and 21 women (0.7 %) developed proteinuria over the 6 years of the study. Irrespective of sex, in comparison with non-smokers, those who continued smoking showed an odds ratio (OR) of 2.52 with a 95 % confidence interval (CI) of 1.50-4.25 for developing proteinuria while those who quit smoking showed an OR of 1.29 (95 % CI 0.48-3.42), following adjustment for confounders. Among the study population, 443 men (10.7 %) and 356 women (12.4 %) developed a GFR of <60 mL/min/1.73 m(2), corresponding to stage III CKD. Continuing smokers had a low OR (0.74, 95 % CI 0.60-0.90) for developing a low GFR, as well as a higher mean GFR than non-smokers. The reduction in GFR during the 6-year study period was not different between smokers and non-smokers, but it was larger in those who developed proteinuria than in those who did not, irrespective of smoking. CONCLUSIONS: Continuing smokers showed a twofold or more higher risk of developing proteinuria. Discontinuation of smoking substantially reduced the risk. A longer observational period may be required to detect the smoking-induced risk of developing stage III CKD in the middle-aged working population.

Elevated Serum Gamma-Glutamyltransferase (GGT) Activity and the Development of Chronic Kidney Disease (CKD) in Cigarette Smokers.

BACKGROUND: Elevated serum gamma-glutamyltransferase (GGT) is predictive of various cardiovascular (CV) risk factors including chronic kidney disease (CKD). Elevated serum GGT has been recognized in smokers who are likely to develop CKD, but no study has focused on serum GGT and CKD in smokers. OBJECTIVES: The aim of this study was to clarify the associations between cigarette consumption, elevation of serum GGT and the development of proteinuria and CKD. PATIENTS AND METHODS: A retrospective 6-year observational study was conducted on 2,603 male workers aged between 40 and 64 years. Incidences of proteinuria detected by dipstick and CKD defined by proteinuria and/or reduced estimated glomerular filtration rate (eGFR) measured in health check-ups were determined 6 years later for those who had been free of them at baseline. RESULTS: Higher means of serum GGT in smokers than in nonsmokers at baseline, and a higher incidence of elevated serum GGT in smokers than in nonsmokers during the 6-year period were recognized only for alcohol consumers. Incidences of proteinuria and moderate or severe CKD which has a high risk of future renal failure or CV disease were higher in the subjects with greater cigarette consumption or a higher serum GGT level. Multiple logistic regression analyses adjusting for major CV risk factors showed a significant interactive effect between smoking and elevated serum GGT on the development of proteinuria and an additive effect of smoking and serum GGT on the development of high-risk CKD. CONCLUSIONS: Elevation of serum GGT in smokers, to a large extent, depends on the associated alcohol consumption. Elevated GGT in smokers plays at least a partial role in the development of CKD, mainly proteinuria, and the underlying mechanisms remain to be elucidated.

Cigarette smoking, proteinuria, and renal function in middle-aged Japanese men from an occupational population.

OBJECTIVES: To clarify the renal effects of cigarette smoking in a middle-aged occupational population because the effects have previously been demonstrated mainly in community populations that included many elderly people who are thought to be vulnerable to such effects. METHODS: In 990 middle-aged men recruited from a chemical plant, proteinuria was measured by a dipstick method and the glomerular filtration rate was estimated (eGFR) using a formula proposed by the Japanese Society of Nephrology. RESULTS: Proteinuria was found in 4.6% of the current smokers and 1.5% of the never-smokers. It was found in 4.8% of the subjects having a Brinkman index (BI) of 400-599 and 6.3% of those having a BI of 600 or above. The odds ratio for proteinuria in them was 2.94 (CI: 1.01-8.55) and 3.61 (CI: 1.29-10.1), respectively, adjusting for possible confounders. The mean eGFR was higher in smokers than in nonsmokers throughout middle age up to 64 years. Normal but high eGFR was found in 6.7% of the current heavy smokers and subnormal eGFR in 5.7% of the largest cumulative cigarette consumers in contrast to 3.0% or less of the never-smokers. Proteinuria was found in 13.3% of the subjects showing subnormal eGFR, specifically in 16.7% of the smokers and 8.3% of the nonsmokers. CONCLUSIONS: Smoking causes proteinuria in working middle-aged men. Smokers tend to have a high eGFR, but those with subnormal eGFR showed proteinuria most frequently. Whether the high eGFR in smokers will eventually decrease and cause proteinuria remains an important focus for further studies.

Long-term natural history of acquired cystic disease of the kidney.

Patients with acquired cystic disease of the kidney (ACDK) were followed longitudinally over an average of 21.7 +/- 5.4 years to determine the natural history of the disease; that is, how big the kidneys become, when the kidney size reaches a plateau, and when the size regresses. Twenty-seven male and 20 female patients with chronic glomerulonephritis treated at our hospital were investigated. CT scans were performed once a year and kidney volume was measured. Two different quadratic curves with a node of 5.2 years for males and 2.5 years for females after the start of hemodialysis were fitted to log-transformed kidney volume to the duration of hemodialysis using a linear mixed model. The maximum kidney volume in male patients was obtained 21.1 years after the start of hemodialysis using this model. Peak values of kidney volume were demonstrated in 19 of 26 cases during the observation period. The median peak value (interquartile range) of bilateral kidney volumes was 274 (165-849) mL/1.73 m(2) occurring 19.1 +/- 4.5 years after the start of dialysis. In one male patient who had undergone nephrectomy due to renal cell carcinoma and in two of the remaining 26 male patients, the maximum kidney volume of 782 (residual kidney), 1151, and 1129 mL regressed to 428, 616, and 847 mL (reduction rate: 45.3, 46.5, and 25.0%) at 20.6, 25.4, and 23.1 years after the start of hemodialysis, respectively. Kidney enlargement due to ACDK reached a plateau after 21.1 years of hemodialysis in the male patients. Partial regression of severe ACDK may occur naturally after long-term hemodialysis without renal transplantation.

Cadmium induced renal dysfunction among residents of rice farming area downstream from a zinc-mineralized belt in Thailand.

High levels of cadmium (Cd) in paddy soil and rice, and a concurrent increase in urinary Cd of inhabitants in the Mae Sot District, Tak Province, Thailand first emerged in 2003. Risk factors such as occupation, sources of staple food and drinking water as well as biomarkers of adverse renal effects of the increased body burden of Cd were investigated in 795 residents, 30 years or older, whose urinary Cd levels were between 0.02 and 106mug/g creatinine. Farmers who consumed their own rice and residents who sourced drinking water from wells and/or the river demonstrated increased urinary Cd. Age-adjusted mean urinary cadmium for male and female subjects who consumed well water was 5.7mug/g vs. 6.1mug/g creatinine while the corresponding value for male and female subjects who did not consume well water was 3.7mug/g vs. 4.8mug/g creatinine, respectively. Increased urinary levels of beta(2)-microglobulin and N-acetyl-beta-d-glucosaminidase were observed with the increase in urinary Cd, indicating tubular dysfunction and renal damage associated with increase in Cd body burden. Consumption of well water and rice grown in the contaminated area increase the body burden of Cd. Cessation of exposure is essential to prevent and possibly recover from Cd toxicity, especially among the residents whose kidney damage and malfunction may be reversible.

Cadmium-exposed population in Mae Sot district, Tak province: 3. Associations between urinary cadmium and renal dysfunction, hypertension, diabetes, and urinary stones.

OBJECTIVE: To study the associations between urinary cadmium and renal dysfunction, hypertension, diabetes, and urinary stones in an adult population living in cadmium-contaminated areas in Mae Sot District, Tak Province, Thailand. MATERIAL AND METHOD: Seven hundred ninety five cadmium-exposed adults were screened for urinary cadmium, renal dysfunction, hypertension, diabetes, and urinary stones in 2005. Six selected markers of renal function in the present study were urinary excretion of beta2-microglobulin (beta2-MG), N-acetyl-beta-D-glucosaminidase (NAG), total protein and calcium, serum creatinine, and glomerular filtration rate (GFR). RESULTS: The mean age of the study persons was 50-years-old. The overall prevalence rates of hypertension, diabetes, and urinary stones were 33.3%, 6.2%, and 8.9% respectively. The prevalence of increased proteinuria was greatest in those with urinary cadmium levels > or = 15 microg/g creatinine. Urinary excretion of beta2-MG, NAG, and total protein significantly increased with increasing urinary cadmium levels, after adjusting for other co-variables by multiple linear regression analysis. However, urinary cadmium was not significantly associated with urinary calcium, serum creatinine, and GFR. The prevalence rates of hypertension, diabetes, and urinary stones did not significantly increase with increasing urinary cadmium levels. Hypertension, diabetes, and urinary stones were also significant predictors of impaired renal function. CONCLUSION: In this population, increasing levels of urinary cadmium are associated with increasing urinary excretion of beta2-MG, NAG, and total protein. Risk for hypertension, diabetes, and urinary stones remains uncertain in relation to cadmium exposure.

Seventeen-year observation on urinary cadmium and beta2-microglobulin in inhabitants after cessation of cadmium-exposure in Japan.

The purpose of this study was to clarify the change and relationship of urinary cadmium (Cd) and beta(2)-microglobulin (beta(2)-MG) concentrations of inhabitants in Cd-polluted areas after soil restoration. The urinary Cd and beta(2)-MG concentrations of 25 males and 28 females did not show a significant change, 22 years after the Cd-polluted soil was restored. Once exposed to Cd, it was found to remain in the body, 22 years after the Cd -polluted soil was restored. However, this did not influence renal tubular dysfunction in most of the younger generation compared with elders heavily exposed to Cd.

Cadmium-exposed population in Mae Sot District, Tak Province: 4 bone mineral density in persons with high cadmium exposure.

OBJECTIVE: To measure bone mineral density in cadmium-exposed persons aged 40 years and older that lived in the 12 contaminated villages in northwestern Thailand. MATERIAL AND METHOD: Five hundred seventy three persons with urinary cadmium levels > or = 5 microg/g creatinine during the 2004-2006 surveys were screened in 2007 for urinary excretion of cadmium, bone formation and resorption markers, and renalfunction markers. Calcaneus bone density was measured in each person by a dual-energy X-ray absorptiometry bone scanner. RESULTS: The mean age of the study persons was 57 years old. The geometric mean level of urinary cadmium for women was significantly higher than that for men. Women had a lower mean of calcaneus bone density than men. The rate of osteoporosis in women (21.5%) was significantly higher than that for men (14.7%). Calcaneus bone density was negatively correlated with urinary excretion of calcium (in both genders) and crosslinked N-telopeptide of type I collagen (in women), after adjusting for other co-variables. Increasing urinary cadmium levels appeared to correlate with reduced bone density in women, but not in men. In both genders, urinary excretion of beta2-microglobulin and N-acetyl-beta-D-glucosaminidase was higher in persons with osteoporosis than those without. CONCLUSION: Bone mineral loss is correlated with urinary cadmium levels and renal dysfunction in this female population.

Estimation of benchmark rice cadmium doses as threshold values for abnormal urinary findings with adjustment for consumption of Jinzu River water.

We performed this study to determine whether both eating cadmium (Cd)-polluted rice and drinking and/or cooking with Jinzu River water are associated with renal tubular dysfunction. A multiple logistic regression analysis of retrospective data indicated that both factors may contribute to this condition. Estimated threshold values of rice Cd concentration in men were 0.13-0.27 ppm and 0.09-0.18 ppm in women, without adjustment for use of Jinzu River water. The additional influence of drinking and/or cooking with Jinzu River water was estimated to be about 0.008 ppm.

Biological half-life of cadmium in the urine of inhabitants after cessation of cadmium exposure.

We investigated the biological half-life of the urinary cadmium concentration (U-Cd) based on a 24-year follow-up study after cessation of cadmium exposure in a cadmium-polluted area. Spot urine samples were obtained from all inhabitants in this area in 1979, 1986, 1991, 1999 and 2003. Biological half-life was calculated in the inhabitants whose U-Cd was more than 5 microg l(-1) (9 men and 12 women) or 5 microg g(-1) creatinine (9 men and 19 women) using a one-compartment model. The estimated half-life and 95% confidence intervals were 13.6 years (9.0-28.2 years) and 13.9 years (9.6-25.6 years) for unadjusted U-Cd in men and women, respectively. For creatinine-adjusted U-Cd, they were 14.2 years (11.2-19.4 years) and 23.5 years (17.7-35.0 years) in men and women, respectively. The biological half-lives of U-Cd obtained in this study were identical with the values of total body burden determined by a different method.

Association of lifetime cadmium intake or drinking Jinzu River water with the occurrence of renal tubular dysfunction.

This study was performed to clarify whether lifetime cadmium (Cd) intake (LCd) calculated from consumption of Cd-polluted rice and other foods, or drinking and/or cooking with Jinzu River water is associated with the occurrence of renal tubular dysfunction and to estimate the threshold level of LCd using a benchmark dose procedure. From participants in the 1967 and 1968 health examinations, the 2607 subjects (1430 men and 1177 women) who were aged 50 years or more, and who had either resided in the current hamlet since birth or moved there from a nonpolluted area and resided for a total of 30 years or longer were chosen as the target population. Based on a multiple logistic regression analysis performed for abnormal urinary findings (proteinuria, glucosuria, or proteinuria with glucosuria) using LCd as the explanatory variable with or without consideration of use of the river water for drinking and/or cooking, it was inferred that both factors of LCd and use of the river water influenced the occurrence of renal tubular dysfunction, with LCd appearing to exert a greater impact compared to drinking/cooking with the river water. Moreover, the threshold values of LCd for proteinuria with glucosuria were estimated to be 2.91 g in men and 1.79 g in women, without adjustment for use of the river water. After adjustment for its use, the values of proteinuria were calculated to be 0.93 g in women. When assuming user/nonuser status of the river water, the threshold level was calculated as 0.75/0.93 g in women. The difference of 0.18 g was interpreted as representing the influence of drinking/cooking with the river water.

Influence of consumption of cadmium-polluted rice or Jinzu River water on occurrence of renal tubular dysfunction and/or Itai-itai disease.

The aim of this study was to clarify whether consumption of cadmium (Cd)-polluted rice or Jinzu River water exerted any influence on the occurrence of renal tubular dysfunction and/or Itai-itai disease. From the participants of health examinations conducted in 1967 and 1968, 3,078 subjects who had resided for >30 years in the present hamlet and were aged >50 years were selected as the target population and were divided according to their residence in 55 hamlets. In a multiple regression analysis, the regression coefficients between rice-Cd concentration and prevalence of abnormal urinary findings (proteinuria, glucosuria, or proteinuria with glucosuria) or patients with Itai-itai disease were statistically significant between both sexes. The correlation between the prevalence of users of Jinzu River water and the occurrence of glucosuria in men as well as abnormal urinary findings in women was not statistically significant. We surmise that eating Cd-polluted rice and drinking and/or cooking with Jinzu River water influenced the occurrence of Itai-itai disease. The occurrence of renal tubular dysfunction is likely to have also been influenced by both factors, with eating Cd-polluted rice having a greater impact on the occurrence of renal tubular dysfunction as compared to drinking and/or cooking with Jinzu River water.