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Role of Cadmium and Lead in Nephrotoxicity

Hafiza Samar Fatima

Avaliable from January, 2018


Nephrotoxicity stands amongst the most widely recognized kidney issues and happens when human body is presented to a medication or toxins that give harm to kidneys. At the point when kidney harm happens, patient cannot free his assortment of abundance urine, and squanders. It can be acute and chronic. Lead and cadmium are the two most commonly known nephrotoxic metals. People who work or live in such environmental settings which made them exposed to these toxins are at risk. Prolonged exposure to these metals leads to their accumulation in tissues especially kidneys. Proximal tubular dysfunction, hypertension, hyperuricemia and decreased glomerular filtration rate are the common effects of cadmium and lead nephrotoxicity respectively. Proper medication can reduce these dysfunctional ties but best treatment is to reduce exposure so one can avoid the accumulation of these toxins in kidneys and other tissues.


The kidney is a fundamental organ required by the body to play out a few imperative capacities including the support of homeostasis, direction of the extracellular environment, for example, detoxification, and discharge of dangerous metabolites and medications (Ferguson et al., 2008). The kidneys are a couple of bean molded organs situated in the back of the abdomen area. Every kidney is around 4 or 5 inches long - about the extent of a clench hand (WebMD, 2014).The bean-molded kidneys have an external arched side and an internal curved side called the renal hilus .A thin connective tissue called the renal capsule encompasses and keeps up the kidneys shape and ensures the inward tissues. Inside the renal capsule is the external layer called the renal cortex, deep to this layer is the renal medulla. Each pinnacle of the renal pyramid is associated with a minor calyx, an empty gathering tube for urine (New Health Adviser, 2014). 

In people, the kidneys are found high in the stomach pit, one on every side of the spine, and lie in a retroperitoneal position at a marginally diagonal point (Boron, 2004). An ordinary human kidney contains 800,000 to 1.5 million nephrons (Guyton and Hall, 2006). The kidney is habitually an objective organ for metal harmfulness since it concentrates huge numbers of these components amid discharge and has countless procedures which are exceedingly touchy to metal-actuated irritation (SpingerLink, 2002).

Nephron is the essential auxiliary and utilitarian unit of the kidney. Its central capacity is to manage the centralization of water and solvent substances like sodium salts by sifting the blood, reabsorbing what is required and discharging the rest as urine. A nephron takes out squanders from the body, directs blood volume and pulse, controls levels of electrolytes and metabolites, and manages blood pH (Maton et al., 1993). 

Nephrotoxicity is a kidney-particular toxicity in which discharge does not go easily inferable from dangerous chemicals or medications (Finn and Porter, 2003). Chemotherapy or anticancer drug has been of constrained use because of nephrotoxicity (Kohli et al., 2000). The normal ecological contaminations lead and cadmium are each known to instigate ceaseless renal sickness and the atomic components of such poisonous occasions are being illuminated. Nephrotoxicity of these metals is because of the way that urinary disposal is a primary course of discharge, and the proximal tubules are particularly delicate because of their high reabsorptive action. Renal obsessive impacts of these metals shift with the substance type of the metal, the dosage, and whether the introduction is intense or unending in nature. The few separated investigations of consolidated metal exposures show that these neurotic impacts might be changed because of obscure co-operations of these metals inside the kidney (Madden and Fowler, 2000).

The mammalian kidney is a fundamentally and practically complex organ that assumes a vital part in control and direction of homeostasis with different reabsorptive, secretory, metabolic and endocrine capacities. Inability to play out these capacities is showed in reabsorptive and secretory imperfections along the nephron, which in instances of restricted glitches result in a little molecular weight proteinuria, in more extreme cases display additionally polyuria, glucosuria, aminoaciduria, phosphaturia, and expanded discharge of electrolytes, and also a lifted blood urea nitrogen and creatinine, while in most serious structures, a summed up harm to the kidney capacities shows as the Fanconi disorder ( Bergeron et al., 2000).


Nephrotoxicity can be analyzed through a straightforward blood test. Assessment of nephrotoxicity through blood tests incorporates the estimations of blood urea nitrogen (BUN), grouping of serum creatinine, glomerular filtration rate and creatinine freedom. In any case, these appraisals of nephrotoxicity are just conceivable when a lions share of kidney capacity is harmed (Kirtane et al.,2005).

Biomarkers assign the biomolecules demonstrating the relationship between exogenous dangerous substances and maladies. For the most part, biomarkers empower us to decide early harm to wellbeing created by introduction to exogenous lethal substances, and give an understanding into the component of the onset of these toxicants to antagonistically influence certain gatherings or people (Finn and Porter, 2003). The ID of biomarkers that can be resolved from blood or urine came about because of introduction to a nephrotoxicant is a promising methodology (Shao et al., 2011). Particularly, urine is viewed as appealing and proficient example since it is non-intrusive and simple to be gotten in impressive sums (Wu et al., 2010).


Various components, for example, dietary status, associative introduction to a few follow components, nearness of high-fondness metal-restricting proteins, or other intracellular terminals for metal sequestration and cell sort are altogether known to assume real parts in deciding both the nature and degree of metal-or metalloid-instigated nephrotoxicity (Sabolic, 2006). 


Cadmium and lead are two of the most common and two of the most nephrotoxic metals known to man (Gonick, 2008). These are known to be thought by the kidney and to deliver a range of organelle/biochemical wounds to the nephron by various components (Fowler et al., 2002).


Exposure Sources And Absorption: Nephrotoxicity brought about by cadmium has been depicted in settings of modern presentation and ecological contamination. Cadmium, a metal customarily got as a by-result of zinc refining, is utilized modernly in plating of steel, colors, plastics, compounds, and nickel-cadmium batteries, and in atomic and electronic building (Friberg, 1984). Since the biologic half-existence of cadmium is long (more than 30 year), delayed low-level introduction prompts to extreme collection in specific tissues, particularly the kidney (Gonick ,1978). Absorption of lead relies upon the physical and substance condition of the metal, and is impacted by age, physiological status, healthful status and hereditary elements (WHO, 1995). Natural cadmium introduction happens in occupants living in vicinity to modern contamination (EFSA, 2010). Furthermore in overwhelming smokers (FAO 2011), as tobacco smoke yields high cadmium focuses (IPCS, 2007).

Cadmium Induced Nephrotoxicity Mechanism

In circulating blood, it binds to albumin and is transported to the liver, where it binds to glutathione (GSH) and metallothionein-1 (MT-1). The Cd-MT-1 complex is secreted in bile and subsequently reabsorbed into the blood by means of enterohepatic circulation. Cd-MT-1 is a low molecular weight complex (< 7kDa) which is easily filtered by the glomerulus and is entirely reabsorbed in the S1 segment of the PCT (proximal convulated tubule) by endocytosis in a process mediated by the proteins megalin and cubilin (Klassen etal., 2004). The ZIP-8 transporter is also located in PCT cells, and it is able to transport Cd and other divalent metals through the apical membrane of these cells; however, the role it plays in Cd toxicity is unknown (Edward and Prozialeck, 2009). Inside the intracellular medium of PCT cells, the Cd-MT-1 complex is put away and separated by lysosomes. Free Cd is then transported to the cytoplasm by lysosomal DMT-1(divalent metal transporter) (Liu et al., 2001). Activation of protein kinase C builds articulation of DMT-1, in this manner expanding tubular danger by Cd (Olivi, 2001). Free Cd amasses in mitochondria, obstructing the respiratory chain at complex III. This outcomes in mitochondrial brokenness and the development of free radicals, which initiates caspase proteins and the apoptosis procedure. Free Cd likewise ties to protein sulfhydryl gatherings and influences the structure and capacity of the proteins. It has been shown that Cd meddles with enzymatic exercises of the calcium-calmodulin complex, hinders Na+-K+-ATPase action, and animates movement by MAP (mitogen activated protein) kinases. In paracellular tight intersections, it influences the dispersion of paracellular tight intersection proteins and abatements transepithelial resistance (Hirano et al., 2005). Just 10% of sifted Cd is reabsorbed into distal finishes of the nephron, and it is conceivable that the Cd s hypercalciuric impact is the aftereffect of hindrance of calcium direct action in the distal tubule. (Barbier et al., 2004). Another nephrotoxicity instrument is the one interceded by the development of against MT antibodies; introduction to Cd builds MT generation in the liver and kidneys, which constitutes a defensive reaction to farthest point its lethality. In any case, once the MTs ability for Cd stockpiling has been surpassed, free Cd can initiate the arrangement of antibodies against MT, which are likewise lethal to PCT cells (Klaassen et al., 2009).

To view Figure 1, Click below
Figure 1: Physiopathological mechanisms of cadmium-induced kidney injury DM T-1: divalent metal transporter 1; M T: metallothionein.

Individuals with beginning renal harm are more helpless to the nephrotoxic impacts of Cd (Hotz et al., 1999). In patients with diabetic nephropathy, urinary discharge of CD is straightforwardly identified with expanded urinary discharge of beta-2-microglobulin and albuminuria (Nordberg et al., 2006). Determining Cd levels in the bloodstream is used to diagnose acute exposure, whilst urinary excretion of Cd is used to assess Cd body burden and is useful for evaluating chronic exposure (Bernard, 2008). Cadmium .because of its long half life, initiates the amalgamation of a protein called metallothionein by the liver, which goes about as cadmium scavenger. Low metallothionein levels, press lack, more established age, female sexual orientation, smoking history, and place of living arrangement (vicinity to mechanical cadmium sources) are hazard components for creep mium toxicity (Klassen et al ., 2004). Clinically, cadmium nephro-poisonous quality presents with elements of proximal tubular brokenness, for example, glucosuria, ami-noaciduria, and low atomic weight professional proteinuria. These indications of poisonous quality may happen at much lower levels of urinary cadmium focuses than those recog-nized as poisonous by the World Health Organization. Other renal signs incorporate hypercalciuria and renal stones (Olivi et al., 2001).


Treatment for chronic or acute cadmium nephrotoxicity ought to be preventive. Once there is obvious renal ailment, the individual ought to be expelled from all further presentation to cadmium. British against lewisite (BAL) ought not be controlled in light of the fact that there is confirmation that the cadmium-BAL complex is more poisonous to the kidney than cadmium alone (Blanusa et al., 2000). At present there is constrained involvement with the utilization of chelating specialists, for example, calcium disodium ethylenediaminetetraacetic acid (calcium EDTA), in treating acute or perpetual cadmium harming in people (Waters et al., 2005).


Exposure Sources And Absorption

The primary courses of systemic introduction are transcendently by means of ingestion or inward breath. Presentation to inorganic lead happens basically through ingestion of sustenance and drinking water, despite the fact that introduction by means of soil and tidy, air, and chippe leaded paint essentially adds to the general presentation (WHO, 1995). Modern parts that vigorously add to the arrival of lead incorporate metal mining, coal mining and electrical offices Non-modern sources are air-borne lead from leaded fuel vapor and toxic paints (EFSA, 2010). Soil and family tidy are essential wellsprings of lead introduction for babies and youthful youngsters, because of hand to mouth exercises (WHO, 2011). Word related presentation to lead and inorganic lead mixes may happen in an assortment of occupations, including lead purifying and refining, steel welding or cutting operations, battery assembling or reusing, radiator repair shops, development and different occupations including fire binding of lead solder. The US National Institute for Occupational Safety and Health (NIOSH) recognized more than 100 occupations in which laborers might be presented to inorganic lead mixes (ATSDR, 2007). Absorption of lead relies on upon the physical and substance condition of the metal, and is affected by age, physiological status, nutritious status and hereditary components (WHO, 1995). Lead in entire blood has a short half-life (35 days).Thus the utilization of blood lead estimations are confined to observing simultaneous lead presentation. For appraisal of more remote lead introduction, different techniques must be utilized (Abudhaise, 1995).

 Lead Induced Nephrotoxicity Mechanism

Pb attached low atomic weight proteins (<1% of the aggregate) is sifted unreservedly at the glomerulus and is reabsorbed by PCT cells by endocytosis. Inside the cell, Pb causes mitochondrial harm, development of free radicals, intracellular consumption of GSH and apoptosis (Wang et al., 2009). Pb likewise influences enzymatic responses in which calcium assumes a part, and the calcium-detecting receptor can likewise be initiated by Pb, which proposes that there might be different instruments for lead nephrotoxicity (Handlogten et al., 2000)

 Pb prompts initiation of translation atomic element kappa B, enactment of the intrarenal renin-angiotensin framework and fascination of macrophages, which creates a fiery procedure in the renal interstitium that might be included in the improvement of tubulointerstitial harm and high blood pressure (Bravo et al., 2007 ). In endothelial cells, it has been demonstrated that expanded development of free radicals instigated by Pb diminishes nitric oxide generation and the declaration of the protein guanylate cyclase. These impacts clarify how hypertension can create accordingly movement of NADP(H) oxidase by expanding generation of hydrogen superoxide and hydrogen peroxide, in this way influencing oxidative anxiety and the intracellular redox potential (Bannon et al., 2003). 

Nephrotoxicity connected with lead may have acute and chronic indications. Intense lethality causes coordinate proximal tubular damage, likely coming about because of intranuclear, cytoplasmic, and mitochondrial consideration bodies made out of a lead–protein complex (Moreno et al., 2009). Intense poisonous quality most normally shows with a Fanconi sort syndrome, including glucosuria, aminoaciduria, and phosphate squandering, conceivably created by mitochondrial brokenness. Incessant lead introduction may bring about hypertension, gout, and interstitial nephritis and fibrosis. The incessant nephrotoxicity of lead traditionally shows as diminished assessed glomerular filtration rate (eGFR), with insignificant proteinuria and insipid urine residue. Drawn out exposures, regardless of the possibility that low level, may bring about CKD (chronic cadmium disease) by creating interstitial nephritis, hypertension and hyperuricemia (Lai et al., 2008).

Physiopathological mechanisms of lead-induced kidney injury cGM P:
Figure 2: Physiopathological mechanisms of lead-induced kidney injury cGM P: cyclic guanosine monophosphate; NF-κβ: nuclear factor kappa B.


Intense lead inebriation without renal inclusion or lead nephropathy customarily is treated with EDTA chelation. Inspite of the fact that sodium EDTA has been demonstrated to have dangerous inclinations as a result of its calcium chelation properties, calcium EDTA in suitable measurements is helpful and generally innocuous. Progressed renal ailment identified with lead inebriation (GFR under half of ordinary) must be dealt with warily, on the grounds that EDTA is sifted by the glomerulus, much as inulin may be. In such occasions, the measurement and implantation rate of EDTA ought to be diminished in extent to the serum creatinine height. Lead nephropathy ought to be dealt with vivaciously, be that as it may, in light of the fact that treatment may balance out or enhance renal capacity (Gonick, 2008).


Kidneys are the consequential organs present in our body whose basic function is to filter waste from blood. Nephrotoxicity by various exogenous substances specially metals like cadmium and lead are well known because of their common prevalence in surrounding environment. Both cadmium and lead are the most common nephrotoxic metals which alter the normal kidney functions and make kidney susceptible to various abnormalities which can be chronic and acute. Common outcomes of nephrotoxicity are hypertension, hyperuricemia and decreased glomerular filtration rate. Their abundant availability in the surrounding environment enhances the chance of exposure to these metals and accumulation in body tissues. Chelation therapy is playing role in its treatment but most effective of all the treatments to avoid or limit exposure to lead and cadmium.


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*Corresponding author:

Hafiza Samar Fatima, College of Earth and Environmental Science, Punjab University, Lahore, Pakistan Email:


Fatima HS. Role of Cadmium and Lead in Nephrotoxicity (2018) Edelweiss Appli Sci Tech 2: 74-78


Nephrotoxicity, kidneys, cadmium, lead