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1. Introduction

According to the definition of chronic kidney disease (CKD), kidney damage or an estimated glomerular filtration rate (eGFR) of less than 60 ml/min per 1.73 square meters that lasts for three months or more is considered chronic. Kidney replacement therapy, such as dialysis or a kidney transplant, is required as kidney function gradually declines ^[1]. In patients with end-stage renal disease, various factors influence serum trace element concentrations, such as increased oral intake, impaired renal excretion, degree of renal impairment, medication use, dialysate contamination, quality of the water intake for dialysis, and metabolic changes associated with kidney failure ^[2]. Worldwide, environmental contamination is a leading source of illness, disability, and mortality. Examples include heavy metals, air pollutants, agricultural pesticides, and polluted food and water ^[3]. Heavy metal exposure may lead to a number of dangerous illnesses in individuals, including cancer, neurological conditions, and respiratory issues. Arsenic, chromium, cadmium, lead, and aluminum have been the most frequent heavy metals to cause poisoning in humans ^[4].

2. Heavy Metal Exposure

Depending on their dialysis indication, patients receiving hemodialysis three times a week are exposed to 300–600 L of water; according to their residual kidney function solute clearance, hemodialysis patients are also exposed to considerable volumes of dialysate water. Because heavy metal accumulation leads to several medical issues, including osteomalacia, low parathyroid hormone levels, anemia, increased erythropoietin needs, dialysis-induced encephalopathy, and increased mortality, it is therefore a serious concern for individuals receiving hemodialysis ^[5].

As heavy metals enter the body, they accumulate in the brain, parathyroid glands, bones, and other organs. Toxicological effects can result from heavy metal accumulation. Heavy metal toxicity often leads to accelerated cell death due to chronic disruption of cellular metabolism, and it can lead to interference with the glucose transphosphatase cycle, disruption of parathyroid hormone (PTH), bone metabolism, and alteration of essential serum elements such as calcium and phosphorus ^[6]. Heavy metal causes direct and indirect effects on the parathyroid glands, acting through different mechanisms. Accumulation of heavy metal in the parathyroid glands may increase or decrease the parathyroid response to hypocalcemia or hypercalcemia. In addition, it also interferes with the synthesis of PTH and inhibits the proliferation of parathyroid cells ^[7].

One harmful xenobiotic that causes a lot of major health issues is lead (Pb). Because of its many characteristics, such as its low melting point and resistance to corrosion, it has been used in a variety of items, despite being poisonous, such as paint, waterproofing tape, cosmetics, gasoline, etc. Consequently, reports of immunoregulatory, hematological, reproductive, and gastrointestinal issues have been made. Since the kidney is the primary organ for excretion from the body and is prone to renal damage from oxidative stress and lipid peroxidation, it is one of the sites of lead poisoning. Acute Pb poisoning has been linked to aminoaciduria, glycosuria, and phosphaturia as indicators of proximal tubule failure ^[8].

Human health is negatively impacted by cadmium, a hazardous heavy metal that comes from industrial and agricultural sources. It can cause cancerous tumors, bone disease, cardiovascular illness, infertility, and chronic kidney disease (CKD). The accumulation of cadmium in the kidneys, liver, and bones has an impact on health. The link between low-level environmental cadmium exposure and illnesses including renal disease, lung disease, hypertension, and dyslipidemia is becoming more and more clear. Environmental sources of cadmium include fuel burning, phosphate fertilizers, smoking, contaminated food or water, and inferior paints or cosmetics. In patients with end-stage renal disease (ESRD), including those receiving hemodialysis (HD) and peritoneal dialysis (PD), there is apparently a correlation between blood cadmium levels and mortality risk ^[9].

One 3d-transition element that occurs naturally is chromium (Cr; atomic number 24). With an average concentration of 125 mg/kg, chromium ranks as the sixth most prevalent metal in the Earth's crust ^[10][11]. The most stable forms of chromium are trivalent and hexavalent [Cr (III)], while it may exist in a range of oxidation states from -4 to +6. Furthermore, chromium metal, or Cr (0), is a form of chromium that is present in the environment. Compared to Cr (III), Cr (VI) is 100 times more poisonous and soluble in water. The unstable Cr (V), Cr (IV), and stable Cr (III) interact with proteins and DNA by a number of different mechanisms, resulting in DNA crosslinks and single- and double-stranded DNA breaks. The initial intracellular concentration of Cr (VI) determines the dose-dependent genetic alterations that occur ^[10][12]. Inducing cellular death, changing gene methylation, upsetting the control of histones and micro-RNA, creating microsatellite instability, and reducing the function of p16 and p53 tumor suppression are all possible effects of chromium intermediates and metabolites ^[10].

Naturally occurring metallic arsenic is found in large quantities in the Earth's crust and groundwater, as well as in trace levels in the air and food items, particularly seafood and shellfish. Arsenic is associated with many complications in the body's organ systems: skin, nervous, respiratory, cardiovascular, hematopoietic, immune, endocrine, liver, kidney, reproductive, and developmental ^[13]. In the general population, exposure to aluminum (Al) and other heavy metals through food (processed foods), beverages, and medications containing aluminums, aluminum cookware; or cosmetic products (e.g., antiperspirant, sunscreen, and toothpaste) ^[14]. The two major ways that heavy metals enter the human body are by ingestion (through food and drink) and inhalation; however, the skin can also absorb heavy metals. The primary metal refining process, downstream sectors that manufacture aluminum products (such as automobiles, airplanes, and metal goods), and aluminum welding present additional risks of inhalation exposure for workers in the aluminum sector. Additionally, cigarette smoke can raise the levels of heavy metals in the air ^[15]. Approximately 1.5 to 2% of inhaled aluminum and 0.01 to 5% of ingested aluminum are absorbed, and most of the absorbed aluminum is excreted in the urine. Heavy metal accumulation in the dialysis population may be due to environmental or dietary exposure or contaminated dialysate ^[15]. The back is most frequently afflicted by uremic pruritus, which can also affect the limbs, head, and abdomen. The painful sensation of uremic pruritus (UP) is widespread in people with end-stage renal disease (ESRD). It has an impact on hemodialysis (HD) patients' quality of life and is linked to a higher risk of death. The pathophysiology of UP is complex and poorly understood, despite its great occurrence. The main theories for UP include inflammation, central/peripheral nervous system dysfunction, endogenous opioid dysregulation, and loss of normal skin function. Iron deficiency anemia, hepatitis virus infection, xerosis, hyperparathyroidism hormones, precipitates containing calcium phosphate, and other illnesses are other variables that contribute to the pathophysiology of UP ^[14].

This study aimed to assess potential heavy metal toxicity levels in adults undergoing regular hemodialysis compared to a control group and to evaluate the effects of aluminum, lead, cadmium, chromium and arsenic on PTH and the disturbance in calcium, and phosphorus and other blood parameters. Additionally, it also aimed to investigate the relationship between uremic pruritus, anemia, and heavy metal levels in these individuals. To our knowledge, no similar studies have been performed in Saudi Arabia.