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-β-D-glucosaminidase (NAG) and β(2)-microglobulin (β(2)-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 β(2)-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

EFSA CEF Panel (Panel on Food Contac t Materials, Enzymes, Flavourings and Processing Aids , 2013. Scientific Opinion on Flavouring Group Evaluation 2 07 (FGE.2 07 )

International audienc

Comparison of Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Participants Enrolled in a Multinational Clinical Trial: HPTN 052

Objective: Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(2)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052). Method: HBV infection status at enrollment was compared between HIV(+) (N = 1241) and HIV(-) (N = 1232) from 7 HBV-endemic countries. Hepatitis B e antigen and plasma HBV DNA were determined in cHB. Median CD4, median plasma HIV RNA, and prevalence of transaminase elevation were compared in HIV(+) with and without cHB. Significance was assessed with x2 Fisher exact and median tests. Results: Among all participants, 33.6% had HBV exposure without cHB (8.9% isolated HBV core antibody, "HBcAb"; 24.7% HBcAb and anti-HB surface antibody positive, "recovered"), 4.3% had cHB, 8.9% were vaccinated, and 53.5% were uninfected. Data were similar among HIV(+) and HIV(2) except for isolated HBcAb, which was more prevalent in HIV(+) than HIV(2) [10.1% vs. 7.7%, P = 0.046]. Median HBV DNA trended higher in HIV(+) than in HIV(2). In HIV (+) with cHB versus those without cHB, transaminase elevations were more prevalent (alanine aminotransferase # grade 2, 12% vs. 5.2%, P = 0.037; aspartate aminotransferase # grade 2, 26% vs. 6.0%, P, 0.001), CD4 trended lower, and HIV RNA was similar. Conclusions: HBV infection status did not differ by HIV infection status. HIV co-infection was associated with isolated HBcAb and a trend of increased HBV DNA. In HIV, cHB was associated with mild transaminase elevations and a trend toward lower CD4

PhD

dissertation3-Methylindole (3MI), a highly selective pneumotoxin in ruminants, horses, sheep and rodents, is an anaerobic bacterial fermentation product of tryptophan formed in the rumen of ruminants and in the large intestine of man. Toxicity in humans is not known, despite significant human exposures to 3MI from intestinal absorption after tryptophan fermentation and from inhalation of cigarette smoke. Bioactivation of 3MI was investigated in human lung and liver tissues in order to provide information about the susceptibility of humans to 3MI toxicity. Human lung microsomes were prepared from eight organ transplantation donors. Human liver microsomes were prepared from one of the organ transplantation donors and three cadavers. Human liver cytochrome P-450 (CYP) content from the organ donor was 0.59 ± 0.13 nmol/mg. The CYP content in the livers from the cadavers (0.29 ± 0.17 nmol/mg) was lower than that of the organ donor. Even though the human lung CYP content was non-detectable, the 3MI turnover rate and covalent binding of radioactive 3MI to human lung microsomal proteins was measurable. The 3MI turnover rate with human lung microsomes was 0.23 ± 0.06 nmol/mg/min which was lower than the rate with the human liver microsomes (7.40 nmol/mg/min) from the organ donor. The activities were NADPH-dependent and inhibited by l-aminobenzotriazole (ABT), a potent CYP suicide substrate inhibitor. 3MI covalent binding to human lung microsomes was 2.74 ± 2.57 pmol/mg/min. The magnitude of this binding was only four percent of human liver microsomal binding. The covalent binding in human lung microsomes was NADPH- and protein-dependent and also was inhibited by ABT. Therefore, the bioactivation of 3MI to covalent-binding intermediates is catalyzed by CYP in human pulmonary tissues. Microsomal proteins from human and goat lung and liver were incubated with radioactive 3MI, and the radioactive alkylated proteins were analyzed by sodium dodecyl sulfate-polyacylamide gel electrophoresis and high pressure liquid chromatography (HPLC) and visualized by autoradiography and radiochromatography, respectively. The results showed that a 57 kDa protein in goat lung microsomes was clearly the most prominently alkylated target associated with 3MI reactive intermediates but a 53 kDa protein in human liver microsomes was the prominent target. A cysteinyl adduct of the methylene imine electrophilic intermediate of 3MI was analyzed by HPLC and identified by mass spectrometry. The results demonstrate that 3MI is bioactivated in vitro to an electrophilic methylene imine intermediate which covalently binds to the thiol group of pulmonary microsomal proteins, presumably to produce lung damage. The data from human tissues suggest that humans may be susceptible to 3MI-mediated toxicity. The specificity of 3MI covalent binding and the extent of binding to target proteins may play important roles in organ- and species-selective susceptibilities to 3MI-induced pneumotoxicity

Urinary cadmium threshold to prevent kidney disease development

The frequently observed association between kidney toxicity and long-term cadmium (Cd) exposure has long been dismissed and deemed not to be of clinical relevance. However, Cd exposure has now been associated with increased risk of developing chronic kidney disease (CKD). We investigated the link that may exist between kidney Cd toxicity markers and clinical kidney function measure such as estimated glomerular filtration rates (eGFR). We analyzed data from 193 men to 202 women, aged 16&minus;87 years [mean age 48.8 years], who lived in a low- and high-Cd exposure areas in Thailand. The mean (range) urinary Cd level was 5.93 (0.05⁻57) &mu;g/g creatinine. The mean (range) for estimated GFR was 86.9 (19.6&minus;137.8) mL/min/1.73 m². Kidney pathology reflected by urinary &beta;2-microglobulin (&beta;2-MG) levels &ge; 300 &mu;g/g creatinine showed an association with 5.32-fold increase in prevalence odds of CKD ( = 0.001), while urinary Cd levels showed an association with a 2.98-fold greater odds of CKD prevalence ( = 0.037). In non-smoking women, Cd in the highest urinary Cd quartile was associated with 18.3 mL/min/1.73 m² lower eGFR value, compared to the lowest quartile ( < 0.001). Evidence for Cd-induced kidney pathology could thus be linked to GFR reduction, and CKD development in Cd-exposed people. These findings may help prioritize efforts to reassess Cd exposure and its impact on population health, given the rising prevalence of CKD globally

Monitoring of cadmium toxicity in a Thai population with high-level environmental exposure

This study evaluated the utility of single and combined measurements of cadmium toxicity markers for surveillance purposes, using a sample of 224 individuals, 30–87 years of age, who were residents of cadmium polluted area in Mae Sot District, Tak Province, Thailand. Urinary cadmium levels excreted by them ranged between 1 and 58 μg/g creatinine with geometric mean of 8.2 μg/g creatinine which was 16-fold greater than the average for the general Thai population of 0.5 μg/g creatinine. The urinary markers evaluated were total protein, albumin, N-acetyl-β-d-glucosaminidase (NAG), lysozyme, β2-microglobulin (β2-MG) and 1-microblobulin (1-MG). Among these markers, only NAG showed a positive correlation with urinary cadmium in both male and female subjects with and without disease (r = 0.43–0.71). Further, the prevalence rates for urinary NAG above 8 units/g creatinine (NAG-uria) increased with exposure levels in a dose dependent manner (p = 0.05) among subjects with disease. In contrast, however, increased prevalence of β2-MG above 0.4 mg/g creatinine (β2-MG-uria) was associated with cadmium above 5 μg/g creatinine only in those without disease (POR = 10.6 and 7.8 for 6–10 and >10 μg/g creatinine). Prevalence rates for abnormal excretion of all other markers, except albumin, were markedly increased among those having β2-MG-uria with and without disease (χ2-test, p ≤ 0.001–0.02). Thus, urinary β2-MG and NAG should be used together with urinary cadmium in the monitoring of renal toxicity in a population exposed to high-level cadmium coupled with high prevalence of chronic diseases

The inverse association of glomerular function and urinary β2-MG excretion and its implications for cadmium health risk assessment

Urinary β2-microgroblin (β2-MG) excretion levels above 300 μg/g creatinine are used to indicate defective tubular reabsorption. Arguably, increased urinary β2-MG excretion could also reflect glomerular filtration rate decline. Thus, we investigated an association between urinary β2-MG and estimated glomerular filtration rate (eGFR). We studied 527 subjects, aged 30–87 years (mean 51.2), who lived in a rural area of Thailand polluted with cadmium (Cd). Of this cohort, 10.3% had urinary Cd level

Gender-Specific Impact of Cadmium Exposure on Bone Metabolism in Older People Living in a Cadmium-Polluted Area in Thailand

To elucidate the influence of cadmium exposure on bone metabolism, associations between urinary/blood cadmium and bone resorption/formation markers were investigated in older cadmium exposed men and women. Increased urinary cross-linked N-telopeptide of type I collagen (NTx), a bone resorption marker, was found to be associated with increased levels of parathyroid hormone, fractional excretion of calcium, and urinary/blood cadmium after adjusting for confounding factors in men. In women, urinary NTx was significantly associated with only urinary cadmium and a strong relationship with increased fractional excretion of calcium. Risk for bone metabolic disorders, indicated by high urinary NTx, significantly increased in men with blood cadmium ≥ 10 μg/L or urinary cadmium ≥ 10 μg/g creatinine. Increased osteocalcin level was significantly associated with increased blood cadmium in men. In conclusion, cadmium exposure appeared to have an influence on bone remodeling both bone resorption and formation in this population of older Thai men, and blood cadmium was more closely associated with bone metabolism than urinary cadmium

A Biomarker Found in Cadmium Exposed Residents of Thailand by Metabolome Analysis

First, the urinary metabolic profiling by gas chromatography-mass spectrometry (GC-MS), was performed to compare ten cadmium (Cd) toxicosis cases from a Cd-polluted area in Mae Sot (Thailand) with gender-matched healthy controls. Orthogonal partial list square-discrimination analysis was used to identify new biomarker candidates in highly Cd exposed toxicosis cases with remarkable renal tubular dysfunction. The results of the first step of this study showed that urinary citrate was a negative marker and myo-inositol was a positive marker for Cd toxicosis in Thailand. In the second step, we measured urinary citrate in the residents (168 Cd-exposed subjects and 100 controls) and found significantly lower levels of urinary citrate and higher ratios of calcium/citrate and magnesium/citrate, which are risk factors for nephrolithiasis, in highly Cd-exposed residents. Additionally, this inverse association of urinary citrate with urinary Cd was observed after adjustment for age, smoking and renal tubular dysfunction, suggesting a direct effect of Cd on citrate metabolism. These results indicate that urinary citrate is a useful biomarker for the adverse health effects of Cd exposure in a Thai population with a high prevalence of nephrolithiasis