Cadmium Exposure Cause Kidney Damage: History
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The growing number of reports indicating unfavorable outcomes for human health upon environmental exposure to cadmium (Cd) have focused attention on the threat to the general population posed by this heavy metal. The kidney is a target organ during chronic Cd intoxication. The current levels of environmental exposure to Cd may increase the risk of clinically relevant kidney damage, resulting in, or at least contributing to, the development of chronic kidney disease (CKD).

  • cadmium
  • kidney
  • nephrotoxicity
  • chronic kidney disease

1. The Current Cd Exposure Level in Industrialized Countries

The technological progress in recent decades is the main reason for the increased use of Cd worldwide, contaminating the environment and dietary products and resulting in inevitable lifelong human exposure to this xenobiotic [2,9,26,53,54]. Naturally, Cd is present in the lithosphere at low concentrations (0.15 mg/kg in the Earth’s crust and 1.1 × 10−4 mg/L in seawater) [9], but numerous industrial activities (e.g., mining and smelting) have increased its presence in the environment and enhanced human exposure [9]. Every year, thousands of tons of Cd-contaminated wastes are discarded into the environment worldwide [9,21]. Despite the actions taken to remove Cd from and decrease the amount of Cd released into the lithosphere, the contamination of the natural environment with this xenobiotic shows an increasing trend, as this metal is not biodegradable and persists in the environment for hundreds of years [55].
Foods, especially plant products, are the main source of exposure to this heavy metal in the non-smoking portion of the general population [2,9,12], while for habitual tobacco smokers, tobacco smoke is a serious additional and often main source of intoxication with this xenobiotic [56,57]. The available data indicate that the current dietary intake of Cd worldwide sometimes exceeds the levels acknowledged to be safe [11,58,59]. The provisional tolerable monthly intake (PTMI) for this heavy metal is 25 μg/kg body weight (b.w.) [59], while its provisional tolerable weekly intake (PTWI) according to the European Food Safety Authority (EFSA) is 2.5 μg/kg b.w. [25]. Currently, the dietary intake of Cd in populations inhabiting areas considered to be non-polluted varies from 10 to 70 μg/day [25,26,29,54,60,61,62,63]. Assuming an average body weight of 70 kg, the weekly and monthly intake of this heavy metal would reach 1–7 and 4.2–30 μg/kg b.w., respectively. This proves that even for inhabitants of areas that are not polluted with Cd, the safe intake levels of this toxic element (the PTWI and PTMI) may be exceeded, in some cases by about threefold (PTWI). The lowest daily intake of Cd, with an arithmetic mean (AM) oscillating around 10 μg (1 μg/kg b.w./week; 99th percentile—2.1 μg/kg b.w./week), was noted in Sweden [61]. The highest oral exposure to this xenobiotic (exceeding the PTMI for this element by more than two-fold), which reached 55 μg/kg b.w./month in males and 53 μg/kg b.w./month in females (aged 18–39 years), was noted in industrialized regions of China [59]. The facts that the Cd concentration in commercially available dietary products sometimes exceeds the safe-limit values and that the dietary intake of this xenobiotic in some parts of the world or in certain groups exceeds the levels currently recognized as safe (the PTWI and PTMI) indicate a substantial risk of excessive intoxication with this element [54,59,62,64].
Numerous factors may increase the gastrointestinal absorption of Cd, simultaneously enhancing the burden of this xenobiotic in the body and exacerbating the risk of toxic effects. The efficiency of the absorption of this xenobiotic from the gastrointestinal tract is low, reaching only 1 to 8% in humans, and it depends mainly on diet, age, and sex [26,27,65,66,67,68]. Enhanced Cd absorption is noted particularly in women of reproductive age and children [67,68]. Among the nutritional factors influencing the gastrointestinal absorption of this heavy metal, the presence of essential elements (mainly zinc, magnesium, selenium, calcium, and iron); vitamins; and other bioactive compounds, such as polyphenols, phytates, and carotenoids, is the most important (for a review, see [69,70]). The bioavailability of Cd from the digestive tract may be increased by up to 20% due to the insufficient consumption of these nutritional factors [65,66].
Habitual tobacco smoking significantly increases the burden of Cd in the body, as each cigarette contains approximately 1 μg of this element, 25–35% of which undergoes absorption into the bloodstream [47]. Substantial data show that tobacco smoking is a source of exposure to large quantities of Cd. Concentrations of this heavy metal found in the blood and urine of active smokers were two to eight times higher compared to non-smokers who were gender- and ethnicity-matched and/or living in the same area (Table 2). Exposure to second-hand cigarette smoke also leads to (2–3-fold) higher Cd concentrations in the blood and urine compared to individuals who are neither active nor passive smokers [71,72].
Table 2. The concentration of cadmium (Cd) in the blood and urine of tobacco smokers compared to people who have never smoked a.
The exposure of the general population to Cd may be monitored by evaluating the concentration of this xenobiotic in food and its total daily dietary intake [18,47]. However, due to the difficulty of precisely evaluating the daily intake of Cd, the influence of various factors on its absorption, the uncertainty as to whether a person is an active and/or passive tobacco smoker, and the possibility of additional exposure from sources other than the diet (i.e., the workplace or passive tobacco smoking), calculating the daily intake of this element is not considered a credible method for estimating Cd exposure. Measuring the Cd concentration in the blood and urine is the most reliable method for quantifying the exposure to this xenobiotic because its levels in these biological fluids reflect the exposure from all sources. The blood concentration of this element reflects the current exposure (within the last month), while the concentration in the urine is a more effective biomarker to monitor chronic intoxication [9,27,29,81]. Since Cd is a common contaminant of the environment and food, it is always present in the blood and urine of humans (Table 2 and Table 3). Concentrations of this element below 1 μg/g creatinine in the urine and 0.5 μg/L in the blood are recognized as “normal Cd concentrations” for the general population, defined as very low and safe concentrations resulting from inevitable exposure to low levels in the natural environment and in food [2]. The most recent comprehensive report on worldwide exposure to Cd was published in 2012 [82]. Moreover, there is no global system for monitoring environmental exposure to Cd in areas recognized as unpolluted by this heavy metal. Furthermore, the available data on the current concentrations of Cd in the blood and urine of inhabitants of unpolluted areas are incomplete, and originate from studies conducted in a limited number of countries (Table 3). In addition, the concentration of this element is expressed in various forms (AM, geometric mean (GM), or median), and its values in the urine are not always adjusted for the creatinine concentration (μg/g creatinine), sometimes being expressed as μg/L. Therefore, comparing data between studies is sometimes very difficult.
According to our review of the available data, the Cd concentration in the blood of the general population in industrialized countries worldwide ranges from 0.02 to 4.40 μg/L (0.02–2.88 μg/L in males and 0.02–4.40 μg/L in females), whereas its urinary concentration reaches 0.04–3.39 μg/g creatinine (0.04–2.34 μg/g creatinine in males and 0.09–3.39 μg/g creatinine in females) and 0.01–3.00 μg/L, and is generally higher in females than in males (Table 3). The higher concentration of Cd in the biological fluids of women compared to men may be explained by its higher rate of gastrointestinal absorption in women due to the smaller iron stores in the body and frequent deficiency of this bioelement. The blood and urinary concentrations of Cd in inhabitants of industrialized countries depend on several factors, mainly including smoking habits, age, and the pollution levels in the place of residence (Table 2 and Table 3). Due to the cumulative properties of this xenobiotic, its content in the body increases with age [47,57,83]. Available data in the literature show that the worldwide Cd concentration in the blood of non-smoking individuals reaches 0.09–1.88 μg/L, while in smokers it is higher, ranging from 0.22 to 3.75 μg/L (Table 2) and reaching 7 μg/L in heavy smokers (more than 20 cigarettes/day) [2]. The Cd concentration in the blood and urine increases with the extent of industrialization in the place of residence, as well as the degree of contamination with this xenobiotic [2,21,30,83,84,85,86]. According to the available data, the concentration of Cd in the blood and urine in the general population is lowest in countries such as Sweden and Canada, while the highest levels are found in South Korea and China (Table 3). According to this overview of recently published data, the current Cd exposure levels in industrialized countries worldwide, except for areas recognized as excessively polluted, are low to moderate.
Although the present article is focused on environmental exposure to Cd, one should not ignore that another source of intoxication with this element is the inhalation of airborne Cd particles in the workplace (e.g., in the production of alloys and batteries; the coating, enameling, and smelting of metals; and the printing of textiles) [87,88,89,90,91,92,93,94]. The concentration of Cd in the blood and urine of individuals occupationally exposed to this element exceeds the “normal concentration” of this heavy metal by many times, and is higher than that noted in persons who are not occupationally exposed, reaching 34 μg/L in the blood and 62 μg/g creatinine in the urine [90].
Table 3. The current concentration of cadmium (Cd) in the blood and urine of the general population a.

2. Kidneys as the Main Organ of Cd Accumulation in the Body

After entering the bloodstream, the absorbed Cd binds with thiol groups (sulfhydryl groups, -SH groups) of proteins in the erythrocyte membranes and plasma (mainly with albumins), and most of it is transported with the blood into the liver. In this organ, ions of Cd (Cd2+) induce the synthesis of MT and form complexes with this protein (Cd-MT complexes). Some of these complexes are released from the liver into the bloodstream and pass into the tubular fluid [43,52,106]. Moreover, small amounts of this element bound to thiol-containing compounds (e.g., GSH, L-cysteine, L-homocysteine, and N-acetyl-L-cysteine) in the plasma are carried to the kidneys and can be absorbed via the cells of the renal proximal tubules [107].
The main locations of Cd accumulation in both human and animal bodies are the liver and kidneys. During short-term intoxication, Cd is retained mainly in the liver, while long-term exposure results in the accumulation of this xenobiotic mainly in the kidneys, due to their inability to eliminate it from the renal tissues [32,42,108]. The average half-life of Cd in the kidney is 14 years (9–28 years), but some data suggest that it may reach 45 years [18,109]. Thus, the kidney Cd content increases with age, peaking at around 60 years [71,110].
The concentration of this element in the kidneys of the general population (Table 4) has not yet been precisely estimated because of the substantial difficulty of obtaining such data. The only method that allows for the determination of the Cd content in the kidney in vivo, i.e., neutron activation analysis [111], has not been used in epidemiological studies. The burden of Cd on the kidneys has not been evaluated using this method in humans. Data on the Cd concentration in the kidney usually originate from studies carried out post mortem or in living donors. According to the available data, the Cd concentrations detected in the kidneys of the general population represent a wide range of values, from 1.45 to 93 μg/g wet weight (w.w.) (Table 4). The very limited data from the last 10 years show that the mean concentration of this heavy metal in this organ is 16.0 ± 13.2 μg/g w.w. in subjects aged 37.1 ± 18.7 [112]. The concentration of Cd in the kidneys of individuals occupationally exposed to this xenobiotic [2,88,89,90,94] may be many times higher (150–395 μg/g w.w.) than in the general population (Table 4).
Table 4. The concentration of cadmium (Cd) in the kidneys of different populations non-occupationally exposed to this heavy metal.
Cd accumulates in the body mainly in the form of complexes with MT. The MT family is a group of cysteine-rich proteins that have a high affinity to various elements, including both necessary and toxic elements, due to the abundance of -SH groups in their cysteine residues. The physiological role of MT is to regulate the metabolism of bioelements such as copper, zinc, and selenium. Furthermore, this protein protects against the toxicity of heavy metals, including Cd, mercury, and lead [56,107,121]. MT binds Cd2+ ions in the kidney cells, forming Cd-MT complexes, which are non-toxic; however, their presence in the extracellular space is dangerous [122].

3. Cd as a Nephrotoxic Factor

Both acute and chronic intoxication with Cd may result in kidney dysfunction in humans and experimental animals (for a review, see [15,27,88]). Since acute poisoning with this toxic element is very rare nowadays, the risk of acute kidney damage is negligible on a global scale. Chronic occupational [90,93,94] and environmental [7,16,40,126,127] exposure to Cd may cause or contribute to kidney injury; however, the risk of damage to this organ in the general population at the low and moderately low exposure levels that currently occur in many developed and developing countries has not been fully estimated.
The fact that Cd damages the kidneys of humans and experimental animals has been known for a long time. The first cases of this xenobiotic exerting a harmful impact on the kidneys as an outcome of environmental exposure were reported in Japan in the mid-1950s in areas around the Jinzu River, which were polluted by this heavy metal due to the operations of the Kamioka Mine, located upriver [53,128,129,130]. The water of this river was used for both the irrigation of rice fields and fishing. The long-term consumption of food (mainly rice) contaminated with this heavy metal caused chronic Cd poisoning, later called “Itai-Itai” disease. Patients suffering from this disease had a mean Cd concentration of 26.4 μg/g creatinine in the urine and between 10.7 and 46.7 μg/L in the blood [129], while its concentration in the medulla and cortex of the kidney reached 41.6 and 27.8 μg/g w.w., respectively (data presented as GM) [128]. “Itai-Itai” disease first manifested in kidney failure, accompanied by anemia, bone weakening, spinal and leg pains, and deformities, as well as idiopathic bone fractures. Kidney failure, which was a consequence of tubular dysfunction (epithelial cell damage) and glomerular dysfunction, was one of the most dangerous outcomes. This disease resulted in multiple deaths due to kidney failure. The concentration of β2-MG in the urine of “Itai-Itai” disease patients exceeded 1000 μg/g creatinine [129], indicating irreversible kidney damage. The histopathological examination of the renal tissues showed atrophy of the tubular epithelium, accompanied by dilatation of the lumen, the disappearance of renal tubules, and hyalinization and sclerosis in the glomeruli [130].
As in “Itai-Itai” disease patients, analogical changes characterized by damage to the tubules and glomeruli, including irreversible nephropathy, have been found worldwide in the kidneys of individuals chronically exposed to Cd in the workplace [84,121]. Workers employed in a nickel–cadmium battery factory presented Cd concentrations in the blood and urine reaching 10.21 ± 2.671 µg/L (mean ± standard deviation (SD)) and 5.16 µg/g creatinine (median; range: 1.93–8.76 µg/g creatinine), respectively, resulting in damage to the tubules and glomeruli [121]. More recent data show that the present occupational exposure to Cd poses a risk of developing pathological changes in the structure and function of the kidney, such as tubulointerstitial injury, the degeneration of the tubular epithelial cells in the cortex, and microproteinuria [23,89,90,94]. The NOAEL and LOAEL of the Cd concentration in the blood for kidney damage in people occupationally exposed to this heavy metal for 30 years were estimated (based on the concentration of β2-MG in the urine) to be 2.2 and 2.7 µg/L, respectively, while in the case of 40-year exposure, these values reached 1.7 and 2.0 µg/L, respectively [23].
High environmental exposure to Cd (10 µg Cd/L in the blood and higher) resulting in the development of serious kidney damage, as in “Itai-Itai” disease patients, is not found nowadays. However, as mentioned above, epidemiological studies over the years have indicated a risk of kidney injury as an outcome of even low-level exposure [2,54,99,102,131]. The influence of low to moderate exposure to this xenobiotic on renal tissue is described and discussed in detail later in this review.
The revelation of Cd’s damaging impact on the kidneys of “Itai-Itai” disease patients and workers occupationally exposed to this xenobiotic prompted experimental studies using animal models or kidney cell cultures to unveil the mechanisms behind this effect and establish the threshold concentration of Cd in the kidneys, blood, and urine for nephrotoxicity. The toxic effect of this heavy metal in rodent renal tissue manifests in numerous defects analogical to those observed in the human kidney, with an identical destruction process, advancing from tubular damage to glomerular disruption. The main histopathological changes in the kidneys of rodents due to Cd exposure are the hypertrophy of epithelial cells, the desquamation of tubular epithelial cells, the dilatation of tubules, and the enlargement of renal glomeruli [132,133,134]. Although multiple studies have been conducted regarding the toxic effect of this xenobiotic on the renal tissue of laboratory animals, experiments using models that closely reflect the current lifetime human environmental exposure levels are lacking. Studies on the nephrotoxicity of Cd have mainly been conducted in animal models exposed to moderate, high, and even very high doses of this xenobiotic; furthermore, the exposure routes often do not correspond to those affecting humans (Tables S3 and S4). These studies provided important data on the impact of Cd on the kidney and the possible mechanisms underlying its nephrotoxicity; however, they did not explain the effects of Cd under low-level long-term exposure.
The critical concentration of Cd in the renal cortex, endangering 10% of the population, is currently considered to be 50 µg/g w.w. and above [9,24,135]. The results of epidemiological studies suggest that damage to the kidney may occur at lower concentrations of this metal; however, evaluating the threshold level is difficult because epidemiological data on the concentration of this element in renal tissues are lacking. It is important to underline that the risk of damage to the kidney depends on not only the level of exposure to Cd, but also factors such as the exposure duration and chemical form of the xenobiotic, as well as the characteristics of the exposed person (mainly age, sex, diet, and health status), which are recognized as important determinants [2,14,47,63,67,68,126,136].

This entry is adapted from the peer-reviewed paper 10.3390/ijms24098413

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