Heavy metals include both non-toxic and toxic elements. Iron (Fe), Cobalt (Co) Copper (Cu) Manganese (Mn) Molybdenum (Mo) and Zinc (Zc) Magnesium(Mg) are the trace elements and are required in a very minute amount, whereas other metals are non-essential, toxic to animals and even fatal when accumulated these metals includes; Mercury (Hg), Arsenic (As), Lead (Pb) Plutonium (Pu), Vanadium (v), Tungsten (w) and Cadmium (Cd), (Deevikaet al., 2012). 

  Heavy metals with established toxic action to humans include cadmium (Morrow, 2010 and Hayes, 2007) lead (Eric, 2013 and Patrick, 2006 and mercury (Bojorklund, 1995).Each of these has been studied in isolation for toxicity (Morrow, 2010; Patrick,2006 and Clarkson, and Magoss. 2006). But in the ecosystem, be it air, (atmosphere, land and water) where they occur they do not exist in isolation. They occur in close association with other metal and non-metallic elemental pollutants. Among the metallic pollutant could be calcium, copper, zinc, magnesium, manganese, iron and others. Metals are known to interact with one another. Interaction can bring about two element together include proximately and could cause out right displacement with one another. When ingested in food and water they can antagonize each other. When it comes to intestinal hand and pulmonary absorption it is there   conceivable that the presence of other element can affect the toxic potential of each of the heavy metal that has been study in isolation.

Egborge (1994) reported that Warri River had and unacceptability high cadmium level, 0.3mg/l of H2O, was 60-fold above the maximal allowable level of 0.005mg/l. This report prompted our early studies on the hepato-, nephro-  and  goladal toxicity  of cadmium in rat expose to this high close via water and diet. The diet was formulated with fish expose to 0.3mgCd/water in the ambient water, as protein source and the toxic effects investigated and reported. (Asagba and Obi, 2000; Asagba and Obi, 2001; Obi and Ilori, 2002; Asagba and Obi, 2004a; Asagba and Obi, 2004b; Asagba and Obi, 2005). The  studies focus on cadmium without taken into consideration the fact that other metal were also present the river water and as such were co-consumed by the communities using the river water for cooking  drinking and other domestic purposes. Hence it is desirable to know if the presence of other metal would enhance or diminish the toxic potential of cadmium or indeed that of any other metal such as lead that was mention above. Therefore the aim of this present studies was to re-examine the toxic potential of cadmium in the presence of other metals such as magnesium.  The objective set out to achieve were:

⦁ Re-examination of the kidney toxicity of cadmium using established toxicity index for kidney such as Creatinine, Blood urea nitrogen and Alkaline phosphatase.

⦁ Re-examine the status of the parameters in the absence of cadmium but in the presence of magnesium.

⦁ Re-examine this parameterin the presence of cadmium and magnesium.



Cadmium (Cd) in its purest form is a soft silver-white metal that is found naturally in the earth’s crust. It melts at 3210c and boils at 7670c. The divalent element has an atomic number of 48, a relative atomic mass of 112.41 and belongs to group 12, period 5 and block – d of the periodic table. It is insoluble in water, although its chloride and sulphate salt are freely soluble. The most common forms of cadmium found in the environment exist in combination with other elements. For example, cadmium oxide (CdO),(a mixture of cadmium and oxygen),cadmium chloride (CdCl) (combination of cadmium and chlorine), and cadmium sulphide(CdS) (a mixture of cadmium and sulphur) are commonly found in the environment.   HISTORY

 Cadmium is typically a metal of the 20th century, even though large amount of this by- product of zinc production have been emitted by non ferrous smelters during the19th century. Currently, cadmium is mainly used in rechargeable batteries and for the production of special alloys although emission in the environment have markedly declined in most industrialized countries, cadmium remains a source of concern for industrial workers and for populations living in polluted areas,especially in less developed countries (Sethi and Khandelwal,2006). In the industries, cadmium is hazardous both by inhalation and ingestion and can cause acute and chronic intoxications. Cadmium dispersed in the environment can persist in soils and sediments for decades. When taken up by plants, cadmium concentrates along the food chain and ultimately accumulates in the body of people eating contaminated foods. Cadmium is also present in tobacco smoke, further contributing to human exposure. By far, the most salient toxicological property of cadmium is its exceptionally long-life in the human body. Once absorbed, cadmium irreversibly accumulates in the human body, particularly in the kidneys and other vital organs such as the lungs or the liver. In addition to its extraordinary cumulative properties, cadmium is also a high toxic metal that can disrupt a number of biological systems, usually at those that are much lower than those toxic metals (Norsbergget al., 2007; Bernard, 2004). USE OF CADMIUM

 Cadmium metals havea specific property that makes it suitable for a wide variety of industrial applications. These include excellent corrosion resistance, low melting temperature, high ductility, high thermal and electrical conductivity (National resources Canada, 2007). It is used and traded globally as a metal and as a component in 6 classes of products, where it impacts distinct performance averages. According to the US geological survey, the principal use of cadmium where: nickel-cadmium (Ni-Cd) batteries, 83%, pigments 8%; coating and platting 7%; stabilizer for plastics, 1.2%; and others (including non ferrous alloys, semi conductors and photovoltaic devices). 0.8% (USGS, 2008).Cadmium is also present as an impurity in the non ferrous metals (Zinc, Lead and copper), iron and steel, fossil fuels (coal, oil, gas, peat and wood), cement and phosphate fertilizers. In these products the presence of cadmium generally does not affect performance; rather, it is regarded as an environmental concern (international cadmium association, 2011). Cadmium is also produced from recycled materials (such as Ni-Cd batteries and manufacturing scrap) and some residues (e.g. cadmium containing dusts from electrical and furnaces) or intermediate products. Recycling accounts for approximately 10- 15% 0f the production of cadmium in developed countries (National Resources Canada, 2007).

The primary use of cadmium in the form of cadmium hydroxide is the electrode Ni-Cd batteries because of their performance characteristics (e.g. higher cycle lives, excellent low- and high – temperature performance), Ni-Cd batteries are used extensively in the rail-roads and air craft industries(for starting an emergency power), and in consumer products (e.g. cordless power tools telephones, portable computer, camcorders, portable household appliances and toys) (ATSDR, 2008; USG, 2008). Cadmium sulphide compounds (e.g. cadmium sulphide, cadmium sulphoselenide and cadmium lithopone) are used as pigments in a wide variety of applications, including engineering plastics, glass,glazes, ceramics, rubber, enamels, artists colours and fireworks. Ranging in colour from yellow to deep-red maroon, cadmium pigments have good covering power, and are highly resistant to a wide range of atmospheric and environmental conditions (e.g. the presence of hydrogen sulphide orsulphur dioxide. Light, high temperature and pressure) (Herron, 2001; ATSDR,2008; International Cadmium Association, 2011).

Cadmium and cadmium alloys are used as engineeredor electroplated coatings on iron, steel, aluminum, and other non-ferrous metals. They are particularly suitable for industrial applications requiring, a high degree of safety or durability (e.g. aerospace industry, industrial fastenerselectrical parts automotive systems military equipment, and marine /offshore installations) because they demonstrate good corrosion resistance in alkaline or salt solutions, have a low coefficient of friction and good conductive properties, and are readily solderable (UNEP, 2008; International Cadmium Association, 2011).Cadmium salts of organic acid (generally Cadmium Laurate or Cadmium Stearate, used in combination with barium sulphate) were widely used in the past as heat and light stabilizers for flexible polyvinyl chloride and other plastics (Herron, 2001; UNEP, 2008). Small quantities of cadmium are used in various alloys to improve their thermal and electrical conductivity, to increase the mechanical properties of the base alloy (e.g. strength, durability, extrudability, hardness, wear resistance, tensile and fatigue strength), or to lower the melting point. The metals most commonly alloyed with cadmium include copper, zinc, and lead, tin, silver and other precious metals. Other minor use of cadmium includes telluride and cadmium sulphidein solar cells. And other semi-conducting cadmium compounds in a Varity of electronic applications (Morrow, 2011; UNEP, 2008; International Association, 2011). ROLE OF CADMIUM IN OXIDATIVE STRESS INDUCTION

The first evidence of increased lipid peroxidation (LPO) in mice hepatocytes co-cultured with Cd was given by Muller in 1987. The author described Cd-induced production of reactive oxygen species (ROS) through interaction with critical subcellular sites such as mitochondria, peroxisomes and microsomes that resulted in the generation of free radicals and LPO in subcellular membranous structures. Production of ROS has been reported later in a variety of cell culture systems, as well as in intact animals via all routes of exposure (Hartet al., 1999; Amaraet al., 2008). They  also found early signs of oxidative stress in the liver of mice exposed to a single oral Cd dose (20 mg kg-1 b. w. in the form of CdCl2) through increased LPO level, expressed as malondialdehyde (MDA) after 6 h, 12 h, and 24 h (Djukić-Ćosićet al., 2008). Since Cd has no redox activity, it may enhance ROS production by suppressing free-radical scavengers suchas glutathione (GSH) and by inhibiting detoxifying enzymes such as superoxide dismutase, catalase, and GSH peroxidase, and/or through other indirect mechanisms (Valko et al., 2005). The ways in which Cd can induce the formation of reactive species are summarised in Figure 1. Available data confirm that the formation of free radicals such as superoxide ion, hydrogen peroxide, and hydroxyl radicals involves depletion of GSH and changes in the activity of antioxidant enzymes (Liuet al.,2009). Our recent findings (Djukić-Ćosićet al., 2007) showed that an acute oral Cd dose (20 mg Cd kg-1 b. w.) significantly decreased the glutathione (GSH) content in mice liver 4 h, 6 h, and 12 h after Cd administration and increased GSH in the kidney after 12 h, 24 h, and 48 h, but did not cause significant GSH changes in the testis. A twoweeks oral Cd exposure (at dose of 10 mg kg-1 b. w. of Cd given as aqueous solution of CdCl2) lowered renallevels and increased liver and testicular levels of GSH.These results, together with related findings of otherauthors, show that the effect of Cd on GSH tissue levelsvaries with animal species, dose, route, and durationof exposure. In general, acute exposure to metalsdecreases GSH levels due to the formation of metal-GSH complexes and/or consumption by the GSHperoxidaseunder oxidative stress induced by metals.

Figure 1 Pathways of Cd-induced generation of reactive oxygen species (adapted from ref. (Valko et al., 2005).By DanijelaĐukić-Ćosić).

Cadmium impairs enzyme activity of antioxidativedefence system (superoxide dismutase, SOD; catalase, CAT; glutathione

peroxidase, GSH-Px; glutathione-S-transferase, GST; gluathionereductase, GR) and of the non-enzymatic component glutathione, GSSG and GSH

Cadmium also elevates the levels of Fenton metals (Fe + 3+ Cu 2+), which can break down hydrogen peroxide, H202 to a reactive hydroxyl radical, OH.

(Casalinoet al., 1997) have proposed yet anothermechanism of Cd-induced ROS production via ironCadmium may displace Fe from variouscytoplasmic and membrane proteins and consequently,increased concentration of ionic Fe stimulates ROSproduction in tissue. This is in agreement with the recent findings, which clearly show that acute andsubacute Cd exposures change Fe content in the liverof mice (Djukić-Ćosićet al., 2008). The results of this study also indicatethat Cd affects MDA levels in a time-dependentmanner. The observed MDA levels positivelycorrelated with Fe in the liver. Oral exposure to a singledose of Cd (20 mg kg-1 b. w.) significantly increasedLPO in the liver at 6 h, 12 h, and 24 h, and liver Feafter 4 h and 6 h up to 110 % of control level. However,in mice orally exposed to Cd for two weeks (10 mgkg-1 b. w. in form of CdCl2 in aqueous solution), wefound liver Fe reduced by 80 % and MDA by 74 %.There are several other proposed mechanisms ofCd-induced oxidative stress. One of these is Cdinduced inflammation in the liver. Kupffer cells are reactivated in response to Cd overload and produce inflammatory mediators such as IL-1β, TNF-α, IL-6,and IL-8, which in turn stimulate generation of freeradicals in the liver (Yamanoet al., 2000). It has also been suggestedthat mitochondria are an important target of Cdtoxicity (Belyaevaet al., 2008).When it comes to ROS production, the results oflong-term exposure to low levels of Cd depend onexperimental conditions such as dose, time intervalsof oxidative stress evaluation, and animal speciesstudied. It seems that ROS production has an importantrole in chronic Cd nephrotoxicity (Shaikh et al., 1999), immunotoxicity(Ramirez and Gimenez, 2003).and carcinogenesis (Waisberget al., 2003). On the other hand,chronic exposure to Cd often elevates tissue GSH,without elevating tissue LPO levels (Amaraet al.,2008;Shaikh et al., 1999). This isconfirmed by our own results (Djukić-Ćosićet al., 2008), which showedinitial increase in liver LPO and Fe levels 24 h aftera single oral dose, which dropped after repeated Cddosing. Prolonged Cd exposure through drinking wateralso caused a two-phase ROS response. At the beginning, ROS production rose, only to drop back tonormal after eight weeks of exposure (Thijssenet al., 2007). It has beenshown that ROS production does not play an essentialrole in chronic Cd-induced malignant transformationin rat liver cells (Diwan et al.,2005). EXPOSURE AND METABOLISM

Workers are mainly exposed to cadmium via fume or dust inhalation in the workplace through the respiratory route. Cadmium can also be orally introduced by consuming contaminated food or water through the gastrointestinal track (GLT). About 50-80% of absorbed cadmium accumulates in the liver and kidneys, where the accumulation ratio depends on the administration route; non oral (such as inhalation, subcutaneous, intra-peritoneal or intravenous) exposure to cadmium initially results in liver accumulation, followed by a subsequent decrease and shift to the kidneys, whereas oral exposure to cadmium results in accumulation in the kidneys as well as the liver (Ohtaand Cherian,1991; Ohtaet al., 2000).                                                                                    

The highest concentration of cadmium (10-100ppm) are found in internal organs of mammals, mainly in the kidneys and liver as well as in some species of fish, muscles and oysters; especially when caught  in polluted seas. Tobacco smoking is an important additional source of exposure to cadmium. Absorption by oral route varies around 5%, but can be increased up to 15% in subjects with low iron stores. When exposure is by inhalation, it is estimated that between 10% and 50% of cadmium is absorbed, depending on the particle size and the solubility of cadmium compounds. In the case of cadmium in tobacco smoke (mainly in the form of CdO), an average of 10% of Cd is absorbed. Absorption of cadmium through the skin is negligible (Nordberg et al., 2007; Bernard and Lauwerys,1986).Regardless the route of exposure, cadmium is efficiently retained in the organism and remains accumulated throughout life. The cadmium body burden, negligible at birth, increases continuously during life until approximately the age of about 60-70 years from which cadmium body burden levels-off and can even decrease cadmium concentrates in the liver and even more in the kidneys; which can contain up to  50% of the total body burden of cadmium in subjects with low environmental exposure. Accumulation of cadmium in kidney is due to the ability of this tissue to synthesize matallothionein (a cadmium-inducible protein that protect the cell by tightly binding the toxic Cd2+ ion). The stimulation of metallothionein by zinc probably explains the protection effect of this essential element towards cadmium toxicity. Because of its small size, metallothionein is rapidly cleared from plasma by glomerular filtration before being taken up by the proximal tubular cells. This glomerular filtration pathwayis at the origin of the selective accumulation ofcadmium in proximal tubular cells and thus in the renal cortex where this segment of the nephron is located. Cadmium does not easily cross the placental or haemato- encephalic barriers, explaining its very low toxicity to the foetus and the central nervous system as compared with other heavy metals. Cadmium is mainly eliminated via the urine. The amount of cadmium excreted daily in urine is however very low, representing somewhat 0.005-0.01% 0f the total body burden. RENAL EFFECTS.

There is now a consensus among scientists to say that in chronic cadmium poisoning, the kidney (which is the main storage organ of cadmium) is the critical target i.e. the first organ to display signs of toxicity (Nordberget al., 2007; Bernard and lauwerys, 1986; Bernardet al., 1992). Cadmium nephropathy has been described in industrial workers exposure mainly by inhalation, and in the general population exposed through contaminated foods. The various studies conducted on human populations and experimental animals have demonstrated that cadmium exerts its renal toxicity in a strictly dose- dependent manner, the adverse effects occurring only when the cadmium concentration in the renal cortex reaches a critical threshold. The total concentration of cadmium in the renal cortex from which renal effects are likely to occur has been estimated at 150-200ppm (μg/g wet weight of renal cortex), both in human subjects and in experimental animals (Bernard and Lauwerys, 1986; Bernard et al., 1992). As most renalcadmium is bound to metallothionein, the form of cadmium responsible for renal damage is the highly toxic Cd2+ion that avidly reacts with cellular components.The critical 

concentration of free cadmium has been estimated at about 2ppm (Bernardet al., 1987).The earliest manifestation of cadmium –induced renal damage considered as critical consists in an increased urinary excretion of micro proteins (molecular weight <40 KD). Among the proteins, β2-microglobulin, retinol-binding proteins and α 1- microglobulin have been the most validated for the routine screening of tubular proteinuria. The increased loss of these proteins in urine is a reflection of the decreased tubular reabsorption capacity. In health, these proteins are almost completely reabsorbed by the proximal tubular cells meaning that a minute decrease of their fractional reabsorption drastically increases their urinary excretion. A modest increase in the urinary excretion of these proteins, as found at the early stage of cadmium nephropathy (in the range of 300-1000 μg/g creatinine for retinol-binding protein), is unlikely to compromise the renal function (Bernard, 2004). Such as small increase might even be reversible after removal from cadmium exposure.By contrast, when theurinary excretionof these proteins is increased by more than one orderof magnitude. Tubular dysfunction caused by cadmium become irreversible and may be associated with a lower glomerular filteration rate(GFR) and an accelerated decline of the GFR with ageing (Bernard,2004). Other solutes excreted in greater amount in the urine of subjects with cadmium nephropathy include total protein, albumin, amino acids, enzymes (e.g. N-acetyl-β–D glucosaminidase), tubular antigens,glucose calcium and phosphate. The disturbances of calcium may lead to bone demineration the formation of kidney stones and bone fractures. AND DISORDERS CAUSED BY CADMIUM EXPOSURE

Long-term exposure to cadmium leads to kidney damage and renal tubular dysfunction as assessed by increased urinary excretion of low molecular weight (MW) proteins such as α 1- microglolin and β- microgloblin (Kjellstron et al.,1977; Nogawa et al., 1984). Individual expose to high levels of cadmium develop severe renal dysfunction and bone damage characterized by osteoporosis. Osteomalacia bone mineral loss (Goyer et al., 1994; Zhu et al., 2004) and anaemia (Horiguchi et al., 1996). One mechanism of bone damage is depletion of the bone calcium pooldue to disrupted vitamin D metabolism in the kidneys, resulting from renal tubular dysfunction caused by cadmium and the continuous urinary excretion of cadmium and phosphorus (Akibaet al., 1980; Nogawa et al., 1987). Cellular cadmium uptake is thought to be mediated by calcium channel c (Lopezet al., 1989). Thus cadmium competition for cellular calcium uptake also explains the calcium deficiency in individuals exposed to cadmium olfactory toxicity (Gobba, 2006), male infertility (Queirozet al., 2006). Hypertension and cardiovascular diseases (Glauseret al., 1976) are alsoassociated with cadmium poisoning.

Carcinogenesis caused by cadmium exposure represents another concern. Many experimental and epidemiological studies have examined cancers of various organs such as the liver, kidneys, lung, prostate, breast, brain and nervous system, testis and hematopoietic system (Glauseret al., 1976). However, many human epidemiological surveillance investigations have not identified a relationship between cadmium exposure and cancer risk, although experiment animal studies have clearly demonstrated an association. Therefore, although the International Agency for research on cancer (IARC) has classified cadmium as carcinogenic in 1993, debate about this association has continued (Arisawaet al., 2007). 

Metallothionein is the most important factor regulating the biological effects of cadmium. Treating mice with low doses of heavy metals (such as cadmium or zinc), induces metallothionein and obviously reduces the toxicity of subsequently administered lethal doses of cadmium (Wobb, 1979). Transgenic mice that constantly over-express metallothionein genes are also cadmium tolerant (Palmiteret al., 1993). In contrast, knockout mice with defective metallothionein genes are more sensitive to cadmium toxicity than wild type mice (Liuet al., 2000). The findings of many similar studies support the notion that metallothionein is the main cellular determinants of the sensitivity of mammals and cultured mammalian cells of cadmium. DIAGNOSIS, TREATMENT AND PREVENTION OF CADMIUM POISONING

Diagnosis of chronic cadmium poisoning basically relies on the screening of proximal tubular dysfunction and the assessment of the cumulative exposure to cadmium using environment or biological indicators. The earliest manifestations of cadmium nephropathy consist in an increased urinary excretion of micro proteins (tubular proteinuria). The most commonly micro protein are β2-microgloblin, retinol-binding protein and α – microgloblin. These proteins  are usually measured in untimed urine samples and the β2- microgloblin test presents the drawback that β2-microgloblin is unstable in urine samples with a PH above 5.6, which necessitates to collect a new urine sample in above 20-30% of the cases. α-globlin is very stable in urine but because of its larger size, it is less specific of tubular damage and slightly less sensitive than the two other micro proteins. Retinol-bindind presents advantage of being stable, specific and as sensitive as β2- microglobin .when tubular dysfunction is at an early stage, there is a possibility of some reversal at least when the cadmium body burden is not too high (e.g cadmium in urine below 20 μg/g creatinine). 

Otherwise, cadmium-induce micro proteinuiria is irreversible and predictive of a faster decline of the GFR with ageing. Thereare no efficient treatments for chronic cadmium poisoning. Even after cessation of exposure, renal dysfunction and pulmonary impairment may progress. The only possible intervention is removal from the emphasis must be placed on primary prevention in order to maintain the levels of cadmium in the environment or in the food chain as low as possible (Bernard, 2008). MAGNESIUM

Magnesium (Mg) is the main intracellular earth metal cation with a free  concentration in the cytosol around 0.5 mmol/ l (Shilset al., 1994; Quamme,  1997;  Grubbs and Maguire,1987;  Williams, 1970;Flatman, 1991 ).  It is evident that Mg, whose gradient over the plasma membrane is slight, and whose free extracellular concentration (ionized Mg) is about 0.7 mmol/ l, at most can play the complementary role of a more long-term regulatory element (Shilset al., 1994;   Grubbs and Maguire,  1987; Williams, 1970 ). Nevertheless, with the recentdevelopments in analytical methods and instrumentation for measuring both ionized and cytosolic free Mg concentrations it has been possible to gain a better insight into the physiology of Mg. AND BIOCHEMISTRY OF MAGNESIUM

In order to understand the behaviour of Mg, it is useful to recall some basic facts about it.  Mg is a smaller ion that attracts water molecules more avidly. Thus in practice, the ion is quite large (Williams, 1970; Jungand Brierley, 1994). Its six coordination bonds also have more rigid coordination distances and directions than the moreflexible Ca with its six to eight coordination bonds (Williams, 1970). In contrast to Ca, Mg binds to neutral nitrogen groups such as amino-groups and imidazol in addition to oxygen especially in acidic groups, while calcium binds to oxygen in multidentate anions (Williams, 1970). As a result, magnesium binding to protein and other molecules generally is weaker than that of calcium, and it is more difficult for it to reach and adapt to more deeply-situated binding sites in proteins (Carafoli, 1987).and to pass through narrow channels in biological membranes. This may also be the reason for the difficulty in finding probes that are highly Mg-specific. Mg is a cofactor in hundreds of enzymatic reactions (Grubbsand Maguire, 1987; Wackerand  Parisi, 1968;  Romani and Scarpa, 1992).And is especially important for those enzymes that use nucleotides as cofactors or substrates. This is because, as a rule, it is not the free nucleotide but its Mg complex that is the actual cofactor or substrate. This is true for phosphotransferases and –hydrolases such as ATPases which are of central importance in the biochemistry of the cell, particularly in energy metabolism. In addition, Mg is required for protein and nucleic acid synthesis.There is alsoexperimental evidence for substitutive effects. Thus, Mg deficiency in the ratproduces an increase in the spermidine content of brain cortex ( Khawaja et al., 1984 ). of Mg

It has long been known that Mg is important for normal neurological andmuscular function,hypomagnesemia leads to hyperexcitability due mainly tocellular Ca transport and signalling (Shilset al., 1994; Grubbs and Maguire,1987; Wacker and Parisi, 1968). The adult body contains approximately21–28 g (about 1 mole) of Mg, muscle and soft tissues accounting foralmost half of this and bone for slightly more than half (Shilset al., 1994). Only about 1% ofMg is present in the blood plasma and red cells.


Approximately 75% of the total plasma Mg is filtered through the glomerular membrane. In contrast to Na and Ca, only 15% of the filtered Mg is reabsorbedin the proximal tubules, most (50–60%) in the thick ascending loop of Henle (Shilset al., 1994;Quamme, 1997). Under normal conditions only 3–5% of the filtered Mg is excreted in theurine (Quamme, 1997).

As in the mucosa, both the paracellular pathway and epithelial transport areimportant in the tubular reabsorption of Mg which varies extensively with thefiltered load. Several drugs, particularly diuretics, thiazides, cisplatin, gentamycinand cyclosporin cause Mg loss into the urine by inhibiting the Mgreabsorption in the kidneys  (Shilset al., 1994; Quamme, 1997). The thiazide-sensitive Na –Clsymporter inthe distal convoluted tubule is implicated as being involved since in the rat itsamount correlates closely with dietary Mg intake, plasma ionized Mg andurinary excretion of Mg (Fanestilet al., 1999) In analogy with the mucosa, its function could be to provide Cl to a Mg –2Cl symporter.The mechanism of the paracellular transport of Mg has remained elusive butnow rapid progress is to be expected. A study of a rare genetic disease with Mgwasting — renal hypomagnesemia with hypercalciuria and nephrocalcinosis —has identified a mutated gene, paracellin-1, coding for a protein located in thetight junctions of the thick ascending limb of Henle. CLINICAL ASPECTS OF Mg

⦁ Mg deficiency as a risk factor

The important role of Mg in modulating transport functions and receptors,signal transduction, enzyme activities, energy metabolism, nucleic acid andprotein synthesis as well as protecting biological membranes makes Mgdeficiency a potential health hazard.The development of Mg deficiency is usually linked either to disturbances inthe intestinal Mg absorption and/or to an increased renal Mg excretion. Ingastrointestinal disorders like intestinal malabsorption, steatorrhea and chronicpancreatic insufficiency, non-absorbable magnesium-fatty acid soaps may beformed. Factors increasing renal Mg excretion are discussed earlier.Anorexia, nausea, vomiting, lethargy and weakness are typical early symptomsof Mg deficiency. If severe Mg deficiency develops, paresthesia, muscularcramps, irritability, decreased attention span and mental confusion often occur.The physical signs of Mg deficiency are largely due to the associatedhypocalcemia and hypokalemia.There is an accumulating body of evidence to suggest that dietary Mgdeficiency plays an important role in the pathogenesis of ischemic heart disease,congestive heart failure, sudden cardiac death, cardiac arrhythmias, vascularcomplications of diabetes mellitus, pre-eclampsia / eclampsia and hypertension(Arsenian, 1993). AND CADMIUM INTERACTION

Limited experimental data point to beneficial effects of Mg against Cd toxicity. (Boujelbenet al.,2006) showed that Mg supplementation could reduce both organ Cd accumulation and Cd-related LPO. The authors found that parental Mg supplementation (in form of sulphate) was associated with a dose dependent reduction in Cd levels in rat kidney, liver, and testis and lowered Cd-induced LPO in the liver and kidney. In the testis, the protective effect of Mg was present only during the early phase of Cd exposure. We investigated the effect of supplemental magnesium in mice exposed to Cd (Djukić-Ćosić et al., 2006). While acute oral Cd exposure (20 mg kg-1 b. w.) resulted in a significant renal Cd increase, pre- treatment with Mg (40 mg kg-1 b. w) efficiently lowered kidney Cd levels4 h and 6 h after Cd exposure. Similarly, the Cd content in the kidney was also elevated following two-week Cd exposure (10 mg kg-1 b. w. per os), and the effect was diminished by about 30 % in mice pre treated with Mg (20 mg kg-1 b. w. per day). These results provide evidence that Mg has the ability to protect the kidney from Cd accumulation and point to the beneficial effects of Mg supplementation against Cd-altered renal Cu and Zn levels (Djukić-Ćosić, et al., 2006). Further investigation showed that Mg pre treatment significantly lowered Cd content not only in the kidney (~30 %), but also in the lungs (50 %), spleen (~30 %), and testis (~30 %), following two week Cd exposure. Results of our investigation on rabbits exposed orally to Cd (as aqueous solution of CdCl2 at dose of 10 mg kg-1 b. w. per day) for four weeks also showed that concomitant Mg supplementation (40 mg kg-1 b. w. as an aqueous solution of Mg(CH2COO)2 per day given 1 h after Cd administration) had the beneficial effects against tissue accumulation of Cd. Excessive intake of Mg reduced blood, kidney, spleen, and bone Cd levels for about 30 % in respect to rabbits given only Cd. However, we did not observe any relevant changes in the lungs, heart, liver, pancreas, muscle, and brain. This suggests that Mg modifies Cdabsorption in the gastrointestinal system by affecting the intercellular leak of Cd from intestinal lumen to portal blood and thus reduces peripheral blood Cd. The effect of Mg supplementation on renal Cd retention could be explained by Cd-Mg competition during reabsorption. Furthermore, increased Mg in the lumen of the distal nephron could disable Cd uptake by intercellular transport and promote Cd elimination via urine. Biochemical parameter


Creatinine is synthesized primarily in the liver from the methylation of glycocyamine (guanidino acetate, synthesized in the kidney from the amino acids arginine and glycine) by S-adenosyl methionine. It is then transported through blood to the other organs, muscle, and brain, where, through phosphorylation, it becomes the high-energy compound phosphocreatine.(Shemeshet al., 1985). During the reaction, creatine and phosphocreatine are catalyzed by creatine kinase, and a spontaneous conversion to creatinine may occur. (Grosset al., 2005)

Creatinine is removed from the blood chiefly by the kidneys, primarily by glomerular filtration, but also by proximal tubular secretion. Little or no tubular reabsorption of creatinine occurs. If the filtration in the kidney is deficient, creatinine blood levels rise. Therefore, creatinine levels in blood and urine may be used to calculate the creatinine clearance (CrCl), which correlates with the glomerular filtration rate (GFR). Blood creatinine levels may also be used alone to calculate the estimated GFR (eGFR).

Clinical significance

The GFR is clinically important because it is a measurement of renal function. However, in cases of severe renal dysfunction, the CrCl rate will overestimate the GFR because hypersecretion of creatinine by the proximal tubules will account for a larger fraction of the total creatinine cleared. (Harita, 2009)Ketoacids, cimetidine, and trimethoprim reduce creatinine tubular secretion and, therefore, increase the accuracy of the GFR estimate, in particular in severe renal dysfunction. The plasma level of creatinine is relative independent of protein ingestion, water intake rate of urine production and exercise.

Blood urea nitrogen

Blood urea nitrogen (BUN) is an indication of renal (kidney) health.The liver produces urea in the urea cycle as a waste product of the digestion of protein more than 90% of urea is excreted through the kidneys, with remaining loses through the gastro intestinal tract and the skin. Kidney disease is associated with urea retention in the blood. Urea clearance underestimates glomerular filtration rate (GFR) as it is reabsorbed. Measurement of urea can indicate kidney functional status and in special circumstances, measurement of urea in dialysis fluids is widely used in assessing the adequacy of renal replacement therapy. 

Urea was assayed based on the method described by Marcellin Berthelot in 1860. 

Clinical significance

   The main causes of an increase in BUN are: high protein diet, decrease in Glomerular Filtration Rate (GFR) (suggestive of renal failure) and in blood volume (hypovolemia), congestive heart failure, gastrointestinal hemorrhage, fever and increased catabolism.The main causes of a decrease in BUN are severe liver disease, anabolic state, and syndrome of inappropriate antidiuretic hormone.


Alkaline phosphatase (ALP) is an enzyme found in all body tissues. There are many different forms of ALP called isoenzymes. The structure of the enzyme depends on where in the body it is produced. This test is most often used to test ALP made in the tissues of the liver and bones. The ALP isoenzyme test is a lab test that measures the amounts of different types of ALP in the blood.

  Clinical significance 

When the serum alkaline phosphatase (ALP) test result is high  itis indicative of the  following diseases:

Bone disease, Hepatitis, Hyperparathyroidism, Leukemia, Liver disease, Lymphoma, Osteoblastic,s bone tumors, Osteomalacia, Paget's disease, Rickets, Sarcoidosis

Lower-than-normalserum levels of ALP isindicativeof the following disease:

Hypophosphatasia,Malnutrition,Protein deficiency, Wilson's disease.




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