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Kidney and Heavy Metals - the Role of Environmental Exposure (Review)

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Kidney and Heavy Metals - the Role of Environmental Exposure (Review) MOLECULAR MEDICINE REPORTS 15: 3413-3419, 2017 Kidney and heavy metals - The role of environmental exposure (Review) PAOLO LENTINI1*, LUCA ZANOLI2*, ANTONIO GRANATA3, SALVATORE SANTO SIGNORELLI2, PIETRO CASTELLINO2 and ROBERTO DELL'AQUILA1 1Department of Nephrology and Dialysis, ‘St. Bassiano’ Hospital, I-36061 Bassano del Grappa; 2Department of Internal Medicine, University of Catania, I-95124 Catania; 3Department of Nephrology ‘St. Giovanni di Dio’ Hospital, I-92100 Agrigento, Italy Received January 2, 2017; Accepted February 24, 2017 DOI: 10.3892/mmr.2017.6389 Abstract. Heavy metals are extensively used in agriculture 2. Mechanism of heavy metal toxicity and industrial applications such as production of pesticides, 3. Symptoms of exposure and toxicity batteries, alloys, and textile dyes. Prolonged, intensive or exces- 4. Laboratory testing sive exposure can induce related systemic disorders. Kidney is 5. Ultrasound examination a target organ in heavy metal toxicity for its capacity to filter, 6. Treatment reabsorb and concentrate divalent ions. The extent and the 7. Lithium expression of renal damage depends on the species of metals, 8. Cisplatin the dose, and the time of exposure. Almost always acute kidney 9. Cadmium impairment differs from chronic renal failure in its mechanism 10. Arsenic and in the magnitude of the outcomes. As a result, clinical 11. Mecrcury features and treatment algorithm are also different. Heavy 12. Lead metals in plasma exist in an ionized form, that is toxic and leads 13. Other heavy metals to acute toxicity and a bound, inert form when metal is conju- 14. Conclusion gated with metallothionein and are then delivered to the liver and possible causing the kidney chronic damage. Treatment regimens include chelation therapy, supportive care, decon- 1. Introduction tamination procedures and renal replacement therapies. This review adds specific considerations to kidney impairment due Heavy metals are chemical elements with a specific gravity, to the most common heavy metal exposures and its treatment. a measure of density compared to an equal amount of water, 5 times higher than the specific gravity of water (1-4C˚). Contents Availability of heavy metals is determined by physical factors (phase association, temperature, adsorption), chemical factors 1. Introduction (lipid solubility, kinetics) and biochemical factors (human trophism) (1). Therapeutic, accidental or occupational exposure to several metals may cause renal toxicity. The most common metals Correspondence to: Dr Paolo Lentini, Department of Nephro logy implicated in kidney toxicity are arsenic, barium, cadmium, and Dialysis, ‘St. Bassiano’ Hospital, I-36061 Bassano del Grappa, cobalt, copper, lead, lithium, mercury and platinum. Small Italy amounts of these trace elements are necessary for good health E-mail: [email protected] because they are important factors and cofactors in many biochemical cellular pathways, including nucleic acids and *Contributed equally proteins synthesis, and enzymatic reactions. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney A large amount of heavy metals results from agriculture disease; RRTs, renal replacement therapies; HD, hemodialysis; PD, and industrial activities such as production of pesticides, peritoneal dialysis; CRRTs, continuous renal replacement therapies; batteries, alloys, and textile dyes but natural phenomena such CVVH, continuous venous-venous hemofiltration; CVVHDF, as earthquakes, volcanic eruptions have also been reported to continuous venous-venous hemodiafiltration; HMP, hemoperfusion; significantly contribute to environmental pollution (2). TPE, therapeutic plasma exchange 2. Mechanism of heavy metals toxicity Key words: arsenic, cadmium, kidney, iron, lead, mercury, pollution, toxicity Heavy metals may enter chronically into the human body through food, water, air or skin whereas acute poisoning is 3414 LENTINI et al: KIDNEY AND HEAVY METALS the result from inhalation or skin contact of vapors, fumes, novel biomarkers is neutrophil gelatinase-associated lipo- dust in workplace, or an inappropriate use of some therapeutic calin (NGAL) (5). Urinary NGAL has also been shown to measures. Accidental ingestion is the most common route of predict kidney injury and dialysis requirement in welding exposure in children. Heavy metal toxicity results in damage workers (6). Pennemans et al (7) showed that urinary kidney of the central nervous system, blood, lungs, kidneys, liver injury molecule-1 levels are positively correlated with urinary and other organs; diagnostic medical devices, such as the cadmium concentration. Biomarkers and nephrotoxicity (e.g., use of barium or the direct injection of gallium during radio- renal tubular injury) will be an emerging concern in occupa- logical examination, are also unexpected forms of heavy metal tional health. toxicity. The kidney is a target organ in heavy metal toxicity for 5. Ultrasound examination its capability to reabsorb and concentrate divalent ions and metals. The magnitude of kidney impairment depends on the Despite not yet coded for kidney damage secondary to heavy nature, the dose, and the time of exposure. metal exposure, renal ultrasound examination may poten- Acute kidney injury (AKI) by heavy metals diverge from tially have a role in the differentiation of acute and chronic chronic kidney disease (CKD) for the mechanism of toxicity. damage (8,9). For this reason, clinical features and a therapeutic approach are also peculiar (3). 6. Treatment Heavy metals in plasma exist in two different patterns: protein bound (non-diffusible) and complex/ionized (diffus- Treatment regimens vary significantly and are tailored to each ible) forms. Metals are quickly cleared from the blood and are specific individual's medical condition and the circumstance sequestered in many tissues. of their exposure; a complete history of possible ingestion, The luminal fluid in the early proximal tubule can contain occupation, recreational activities and environment is critical both the bound form and the free form. In chronic intoxication in the diagnosis of heavy metal toxicity. the protein bound, inert form is conjugated with metallothio- Therapeutic approaches include supportive and decon- nein and glutathione, which are then released into the blood by tamination procedures (such as charcoal, cathartics, emesis, the liver and the kidney. These compounds are subsequently gastric lavage), supportive care (e.g., intravenous fluids, reabsorbed through an endocytotic process in segment S1 of cardiac stabilization, mechanical ventilation, exchange the proximal tubule and can lead to chronic inflammation, transfusion), chelation therapy, and renal replacement thera- fibrosis and renal failure (3,4). In acute intoxication, the main pies (RRTs); if hemodynamic instability occurs, continuous site of reabsorption is the apical membrane of the first zone renal replacement therapies (CCRTs), especially continuous of the proximal tubule, but also the loop of Henle and the venous-venous hemofiltration (CVVH) and continuous terminal segments can participate in reabsorption of heavy venous-venous hemodiafiltration (CVVHDF) are the selected metals. AKI is induced by the ionized form that produces extracorporeal regimens. Hemodialysis (HD) and peritoneal direct cellular toxicity, cellular membrane disruption and dialysis (PD) are often used, especially in acute intoxication uncoupling of the mitochondrial respiration pathway, with the without relevant hypotension, impaired mental status or release of numerous apoptosis signals such as cytokines and dyspnoea. The clinical and therapeutic algorithm should take reactive oxygen species (4). into account age, cardiovascular disease, liver and kidney disease that can reduce endogenous clearance; toxicological 3. Symptoms of exposure and toxicity parameters such as apparent distribution volume, protein binding, molecular weight, elimination half-life, toxic and Exposure to toxic heavy metals is generally classi- lethal dose (10). The kidney impairment and the therapeutic fied as acute (1-14 days), intermediate (15-354 days) and approaches to the most common toxic metals, previously chronic (≥365 days). Acute toxicity is abrupt or accidental analysed by our group (9), is reported in Table Ⅰ. contact or ingestion of high dose of heavy metals. Symptoms of acute toxicity are severe, rapid in onset and associated 7. Lithium with exposure or ingestion, headache, vomiting, dyspnoea, abdominal pain and sweating, whereas chronic intoxication is Lithium (Li) carbonate is a common medication prescribed for usually uneventful. Medical history and specific tests can help the treatment of bipolar manic-depressive disorder. Acute and to diagnose the specific agent. chronic maintenance therapy with lithium may lead to severe toxicity. 4. Laboratory testing Sources of exposure. Lithium ingestion can occur accidentally The diagnosis of heavy metal toxicity requires observation of or in suicide attempts. Anti-depressive therapy may also lead presenting symptoms, the history of potential exposure and the to excessive exposure. result of laboratory tests. Specific tests include blood count, liver and renal function, urinalysis, faecal tests, X-rays and Mechanism of kidney damage. Lithium is a small ion that fingernail analysis. Given the limitations of serum creatinine does not bind to proteins; however, lithium diffusion between as a marker of renal function, different urinary and serum intracellular and extracellular compartments
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