Is renal tubular cadmium toxicity clinically relevant?

Abstract

BackgroundExposure to cadmium (Cd) has been associated with the development of hypertension, especially in women, but the mechanism of such an association is not understood. We hypothesize that Cd exposure alters renal production of 20-hydroxyeicosatetraenoic acid (20-HETE), which plays an indispensable role in renal salt balance and blood pressure control.MethodsWe examined long-term Cd exposure in relation to urinary 20-HETE excretion levels, tubular dysfunction and blood pressure measures, using data from a population-based, cross-sectional study that included 115 normotensive and 110 hypertensive women, 33–55 years of age, who lived in Cd contamination areas in Thailand.ResultsThe mean [standard deviation (SD)] blood Cd level of the study subjects was 3.57 (3.3) µg/L, while the mean (SD) urinary Cd and urinary 20-HETE levels were 0.58 (0.47) µg/g creatinine and 1651 (4793) pg/mL, respectively. Elevated 20-HETE levels were associated with a 90% increase in prevalence odds of hypertension (P = 0.029), four times greater odds of having higher urinary Cd levels (P = 0.030) and a 53% increase in odds of having higher levels of tubular dysfunction (P = 0.049), evident from an increase in urinary excretion of β2-microglobulin. In normotensive subjects, an increase in urinary 20-HETE levels from tertile 1 to tertile 3 was associated with a systolic blood pressure increase of 6 mmHg (95% confidence interval 0.3–12, P = 0.040).ConclusionsThis is the first report that links urinary 20-HETE levels to blood pressure increases in Cd-exposed women, thereby providing a plausible mechanism for associated development of hypertension.

An updated systematic review on the association between Cd exposure, blood pressure and hypertension

“…Eight studies reported an association between urine Cd levels and hypertension ( Ikeda et al, 2013 ; Oliver-Williams et al, 2018 ; Swaddiwudhipong et al, 2012 , 2010b , 2015b ; Tangvarasittichai et al, 2015 ; Van Larebeke et al, 2015 ; Wu et al, 2019 ). Two other studies reported an association between urinary Cd levels and an increase in both systolic and diastolic blood pressure ( Boonprasert et al, 2018 ; Franceschini et al, 2017 ). Urine Cd levels were associated with increase in both blood pressure and hypertension in one study ( Wang and Wei, 2018 ).…”

“…For the general population, the most frequently reported effect of Cd exposure is injury to tubular epithelial cells that actively reabsorb Cd from the glomerular filtrate ( Satarug et al, 2017 ). Boonprasert et al (2018) showed that exposure to Cd is a predictor of urinary 20-hydroxyeicosatetraenoic acid (20-HETE) levels; 20-HETE levels, in turn, are associated with increased odds of hypertension and tubular dysfunction. As noted above, renal function may modify the association between urinary Cd levels with blood pressure ( Gao et al, 2018 ).…”

Chronic exposure to cadmium is associated with a marked reduction in glomerular filtration rate

“…After exclusion of subjects with an incomplete dataset, 309 persons (84 men and 225 women) formed the study subjects in the present study. All women ( n = 225) were the same as in our previous report [14]. However, a coding error was rectified for one treated hypertensive woman who had previously been classified as normotensive.…”

“…Of further concern, Cd exposure has been implicated in the development of hypertension either as a direct effect or as a consequence of CKD [9–13]. We have previously reported an association between the prevalence of hypertension in Thai women with elevated urinary levels of Cd and the eicosanoid, 20-hydroxyeicosatetraenoic acid (20-HETE) [14–17]. In human kidneys, the majority of 20-HETE is derived from catalytic activity of enzymes of the cytochrome P450 (CYP) superfamily, notably CYP4A11 and CYP4F2 that are differentially expressed in the kidney glomeruli, proximal and distal tubules [15].…”

Evidence Linking Cadmium Exposure and β2-Microglobulin to Increased Risk of Hypertension in Diabetes Type 2

“…Hypertension is defined as systolic blood pressure ≥ 140 mmHg, or diastolic blood pressure ≥90 mmHg, and is both a cause and a consequence of chronic kidney disease (CKD) [ 1 , 2 , 3 ]. An increased risk of hypertension has been linked to environmental exposure to cadmium (Cd), a widespread metal pollutant, in the general population in many countries, including the U.S. [ 4 , 5 ], Korea [ 6 ], China [ 7 , 8 ], Canada [ 9 ], Japan [ 10 ], and Thailand [ 11 ]. A cross-sectional study of the U.S. population observed an increased risk of hypertension in Caucasian and Mexican-American women who had blood Cd levels ≥0.4 µg/L [ 4 ].…”