copper is an antioxidant ; its concentration is highest in the liver , kidney , heart , and brain . it is involved in the processes of skeletal development , phospholipid synthesis , electron transport , connective tissue , and blood cells formation among others . the cases of copper excess are rare , but liver disorders , including cirrhosis , may occur . bird and thomas were the first to point out the inhibitory effect of copper on the mineralization process of rachitic rats cartilage . komleh et al . reported that , contrary to zinc excretion , the copper and manganese urinary levels were lower in stone formers than in normal subjects . meyer and angino noticed the inhibitory activity of copper against growth of calcium phosphate crystals but not on oxalate . magnesium is the one of the most important minerals ; it is needed by every cell of the human body and is involved in more than 300 biochemical reactions . only 1% of total magnesium is found in blood , the rest is present in combination with calcium and phosphorus . magnesium is considered as a one of the most important inhibitors of lithogenesis in urinary tract , but its real role in this process has never been fully explained . studies showed decreased calcium oxalate in vitro crystallization and growth in the presence of supraphysiologic concentration of mg . several studies demonstrate that a low level of magnesium in urine is a risk factor for lithogenesis [ 22 , 25 , 28 ] . some early studies showed that dietary mg deficiency causes experimental urolithiasis , and high levels of this element in urine reduce the concentration of oxalate available for calcium oxalate precipitation . on the other hand , some data show that urinary mg excretion is not significantly different in stone patients and healthy controls [ 32 , 33 ] . schmiedl and schwille found no difference in urinary magnesium level in recurrent stone disease when compared to control group ; whereas atakan et al . found urinary mg level to be higher in healthy controls and no differences in serum levels [ 8 , 34 ] . this may support the thesis about its role as a potential inhibitor of lithogenesis . it is known as an element deficiency , of which is the most common in the world , causing anemia . this element is responsible for muscle and cognitive functioning , carrying oxygen via hemoglobin and myoglobin . its excess may cause many disorders like liver damage , diabetes mellitus and skin pigmentation . the fe ions have the ability to establish stable chemical interactions with oxalate ions on the surface of calcium oxalate crystals , thus disturbing their development [ 17 , 27 ] . it is interesting that ferric ions are probably unable to act as a powerful inhibitor in the presence of physiological concentrations of citrate , due to the formation of highly stable complexes in solution without inhibitory activity . some authors reported that fe does not affect the formation and growth of calcium oxalate crystals . its deficiency may cause a reduction in an immunological response , steroidogenesis , co2 transportation , reproduction , and many other crucial processes . it has been shown that zinc supplementation is effective in reducing morbidity and mortality from diarrhea , malaria , hiv - infections , and gastrointestinal disorders by protecting the immune system response . the data concerning the role of zn in lithogenesis are divergent ( see below ) [ 18 , 20 ] . cadmium is a widely disseminated metal that can be imported and accumulated in living cells thereby drastically interfering with their biological mechanisms . molecular aspects of cd - dependent regulation of gene expression and signal transduction pathways in different model system are well documented . the long - term exposure to cadmium leads to renal damage due to massive low - weight tubular proteinuria [ 38 , 39 ] . on the other hand , a study of almost 2,700 renal cadaver samples showed that subjects who had died of renal disease had lower cd concentrations . . only few studies can be found in medical literature with respect to cd in lithogenesis . boron is an ultra - trace element , and is poorly studied with respect to its biological role in human . it can be found in the bone and in the brain taking part in cell membrane functioning , calcium , phosphorus and fluoride metabolism . reported low calcium oxalate urine excretion in postmenopausal women as a metabolic response to dietary boron supplementation during low magnesium intake . the toxicity of lead is well documented and some authors reported its higher amount in calcium - containing stones than in organic phases . it is also suggested that the reduction of pb concentration observed when compared to historical data is a result of changes in pollution e.g. , replacement of lead water pipes by those made of polyvinyl . its role in lithogenesis is unknown , but some authors have found a correlation between lead in stones and urine , which may lead to the conclusion that it may play some role in the process of crystallization in the urinary tract . indicate that vanadate and other vanadium compounds increase glucose transport activity and improve glucose metabolism . in general , the toxicity of vanadium compounds is low and most of its toxic effects result from local irritation of the eyes and upper respiratory tract rather than systemic toxicity . the author found in own study a positive correlation between v level and the content of magnesium phosphates and phosphate salts . this suggests that this element may promote or support the crystallization of phosphate - containing crystals in the human urinary tract . the results of the same study demonstrated the group of three elements that showed positive two - element correlations in pattern ( v  v , pb  v , pb  pb , and al  pb ) . in the study of stones done by abboud , vanadium was not detected , but the stones were collected from a poorly industrialized area of jordan . selenium acts similarly to vitamin e as an antioxidant ( glutathione peroxidase ) and anti - inflammatory agent in the form of selenoproteins . it plays important role in protein biosynthesis , supports liver , testicular , heart function , and growth [ 29 , 47 ] . supplementation with se in many diseases appears worthwhile , but interestingly there are only a few studies available . it is believed that se may protect against some cancers , including urological ones . the select ( selenium and vitamin e cancer prevention trial ) study showed that selenium and vitamin e , alone or in combination at the doses and formulations used , did not prevent prostate cancer in this population of relatively healthy men . there are also studies suggesting that higher levels of selenium taken from supplements or received naturally were associated with an increased risk of diabetes . there are only single papers that suggest that it , similarly to other metal elements , may have some interactions with stone constituents or be captured in the structure of crystals incidentally [ 10 , 50 ] . manganese is a component of antioxidative enzymes and plays an important role in the metabolic pathway of carbohydrates , proteins , and lipids . male rats receiving varying doses of manganese were noted to have viscous , gritty urine in the urinary bladder and the high - dose groups had urinary bladder stones . mn concentration in the serum and urine of active stone patients is shown to be lower than healthy people [ 6 , 20 ] . turgut et al . reported that low level of manganese might interfere with the fragility of urinary stones in eswl ( extracorporeal shockwave lithotripsy ) therapy . hofbauer suggested that nickel , manganese , lithium , and cadmium could be of significance in the pathological mechanism of stone formation , not from mineralogical or crystallographic viewpoints but for the smooth flow of enzymatic reactions in biological systems . the first paper on trace elements in urinary stones was published in 1963 . nagy et al . reported the examination of ag , al , ba , bi , cd , cr , cu , fe , mn , mo , ni , pb , si , sr and zn in 85 kidney stones by spectro - analytical method . eusebio and elliot and sutor as a first studied the influence of some trace elements on the crystallization process of calcium oxalate [ 24 , 54 ] . they reported about inhibitory activity of co , ni , pb , sn , v and zn on this process . so far only one epidemiologic study on trace elements in urinary stones was done by levinson et al . in the usa . after evaluating 20 elements in 186 stones they found no statistical difference in the trace element assemblages of mineralogically identical stones from the three geographical areas . found significantly higher concentration of fe , sb , sr , and zn in stones made of calcium oxalate ; fe , as , and zn in stones made of phosphates ; and sb ( antimony ) and as in stones made of uric acid . this observation can be explained by the effect of heterogenic isomorphism , which is the insertion of a foreign element into a crystal lattice of a salt . the same phenomenon is observed in crystals of apatite , in which phosphorus can be replaced by arsenic ion . , after an analysis of the distribution of seven metals in 78 stones , showed a high proportion of zn and sr in phosphate stone and , contrary to results of joost et al . , a lower proportion of these elements in calcium oxalate stones [ 10 , 11 ] . in the author 's study , a positive correlation of zn and sr concentrations in stones with calcium phosphate content , but not with calcium oxalate content , was found . studying the distribution of five metals ( fe , cu , cd , zn , and mg ) in 47 stones and hair , found significant differences among the element levels in stones , patient hair , and control hair . early studies by bird and thomas and recent publications by atakan et al . showed that low zn level in the urine of stone formers suggests its potential inhibiting action [ 8 , 21 ] . other data , however , show increased excretion of zn and cu in stone formers or even no difference between stone formers and healthy populations [ 11 , 16 , 56 ] . turgut et al . reported that low concentrations of zn , mn , and mg in calcium oxalate monohydrate stones appear to make them resistant to eswl . observed the negative correlation between mg level and the content of calcium oxalate and uric acid . this finding supports the conclusions of some authors who treat mg as an inhibitor of calcium oxalate stones . scott et al . found a high concentration of mg and k in phosphate stones and a relatively low concentration of na in calcium oxalate stones . increased scientific interest in trace elements has led to a search for reliable methods of quantifying and monitoring their levels in human body tissues . it is believed that not single elements , but rather their relationships may play a role in the crystallization process . we do not know whether elemental imbalances may be responsible for the process of lithogenesis . the concentration of some heavy metals ( including pb , cd , ni , and al ) is found to be higher in the nuclei as compared with the crust . this finding may support the thesis that these heavy metals may take part in the initiation of stone crystallization for instance as a nucleus or nidus for the formation of the stone , or simply contaminate the stone structure . the process of crystallization in the urinary tract occurs when the equilibrium between promoting and inhibiting factors is broken . according to results of many studies trace elements may play some role in the mechanism of stone creation ; however , further investigations are needed .
the process of crystallization in the urinary tract occurs when the equilibrium between promoting and inhibiting factors is broken . 
 many theories have been published to explain the mechanism of urinary stones formation ; however , none of these theories has paid attention to trace elements . 
 their role in lithogenesis is still unclear and under debate . 
 the findings of some studies may support the thesis that some major and trace elements may take part in the initiation of stone crystallization for instance as a nucleus or nidus for the formation of the stone , or simply contaminate the stone structure . 
 this review presents a comprehensive account of the basic principles of the basic data and the role of major and trace elements in lithogenesis .