Email this article Lead nephropathy: revisiting an overlooked cause of kidney disease
Datonye Dennis Alasia
Nephrology Unit, Department of Internal Medicine, University of Port Harcourt, Port Harcourt, Nigeria
Correspondence: Datonye Dennis Alasia, Nephrology Unit, Department of Internal Medicine, University of Port Harcourt teaching hospital, PMB 6173, Port Harcourt, Rivers State, Nigeria. E-mail: datonye@ddalasia.com or datonyedennis@gmail.com
Key words: lead exposure; kidney disease.
Received for publication: 30 January 2010.
Revision received: 10 May 2010.
Accepted for publication: 11 May 2010.
©Copyright D.D. Alasia., 2010
Licensee PAGEPress, Italy
Nephrology Reviews 2010; 2:e8
doi:10.4081/nr.2010.e8
Share |
AbstractDespite the recognition of lead nephropathy as a consequence of environmental and occupational lead exposure, lead nephropathy still appears to be underrecognized by physicians as a cause and promoter of chronic kidney disease (CKD), especially in people with more apparent causative factors such as diabetes and hypertension. This review focuses on the clinical, pathophysiological and epidemiological perspectives of lead nephropathy with the objective of promoting the awareness of this important but overlooked cause of CKD among physicians. Literature was reviewed using available medical journals and online literature search through Google, Pubmed, Medline, Medscape and HINARI databases. The key words employed were: Lead Nephropathy, Environmental and Occupational lead exposure and chronic kidney disease. Lead nephropathy which is a tubulointerstitial nephritis, may present acutely or chronically in association with hypertension. The clinical diagnosis of lead nephropathy is complex, because the symptoms are varied and non-specific especially with subclinical nephrotoxicity. The recognition of lead nephropathy can be enhanced if physicians have a high index of suspicion in the assessment of patients with renal disease. It is recommended that the evaluation of environmental and occupational nephrotoxins like lead be incorporated into programs for the prevention of CKD, especially in developing countries where lead exposure and toxicity still remain largely unchecked and the prevalence and burden of CKD is increasing. |
Introduction
The renal effect of lead toxicity has been documented since 1863 when Lancereux published a report of lead induced nephrotoxicity,1,2,3,4 characterized by substantial atrophy of the renal cortex and tubular fibrosis, in the kidney of a painter who habitually held his paint brushes in the mouth.1,2 In the late 1920s an epidemic of chronic nephritis which resulted from childhood lead poisoning was noticed in Queensland, Australia.2,5 In the United states of America between 1920 to 1930, cases of lead nephropathy were reported among people who consumed illegally made alcohol (moonshine) stored in containers with high lead content.2,6 Since that time lead nephropathy7,8,9 has become a well recognized clinical entity and a known cause of acute and chronic kidney disease with the predominant involvement of the renal interstitium.1,2,3
Despite the recognition of lead nephropathy as a consequence of environmental and occupational lead exposure.2,7,9 lead nephropathy still appears to be underrecognized by clinicians as a cause and promoter of CKD, especially in people with more apparent or easily identifiable causative factors such as diabetes and hypertension.4,9,10 This assertion is supported by reports4,11 of patients in whom the identification and treatment of lead toxicity resulted in improved renal function. These patients were earlier thought to have CKD from more obvious risk factors.
This scenario thus makes it evident that lead nephropathy can only be recognized if clinicians have a high index of suspicion and take action to estimate lead exposure and toxicity in patients with CKD. This review focuses on the clinical, pathophysiological and epidemiological perspectives of lead nephropathy with the objective of promoting the awareness of this important but overlooked cause of CKD among physicians, especially in developing countries where lead exposure is largely uncontrolled.2,7,8,9
Clinical presentation of lead nephropathy
The three clinical manifestations of lead nephropathy1,3,4 are acute lead nephropathy, chronic lead nephropathy and lead induced systemic hypertension.
Acute lead nephropathy results from short-term massive exposure to lead1,3,4 and occurs most commonly in children below the age of six years, who are exposed to a high-dose oral intake of lead,1,3,12, and occasionally in adults with recent severe inhalation of lead. The features of acute lead nephropathy become noticeable at blood lead levels above 80-100 ug/dL1,3,12 and include the classic extra renal symptoms such as abdominal colics and the renal effect which manifests as azotemia and the Fanconi syndrome which is characterized by aminoaciduria, glycosuria, phosphaturia, hypercalciuria and hyperuricemia all resulting from lead induced isolated proximal tubular defects.3,12,13 Acute renal failure resulting from acute tubular necrosis may also occur as a consequence of selective cellular accumulation and direct cytotoxic damage in the proximal tubules,1,3,12,13 while vitamin D-resistant rickets may possibly occur in children.3,12,13 Consequently incomplete recovery and a protracted low-grade exposure may maintain a chronic tubulointerstitial nephritis which may progress to chronic renal disease.1,3,4,5,14
Chronic lead nephropathy which1,2,7,11,15 results from long-term lead exposure, is a slowly progressive interstitial nephritis which is frequently associated with hypertension and hyperuricemia.3,4,15 Chronic lead nephropathy is usually identified after blood lead levels have exceeded 40-60 ug/dL;3,4,12 however, it has been shown that at blood lead levels less than 25 ug/dL the inhibition of the metabolic activation of vitamin D takes place in the kidneys, as a result of lead accumulation.2,3,7,12 With continuous lead exposure and blood lead levels of 40-80 ug/dL, acid fast intranuclear inclusion bodies consisting of lead-protein complexes are formed and deposited in the tubules.2,3,7 These changes result in defective tubular function manifesting as hyperuricemia which is a common feature of lead nephropathy.16,17,18,19,20 As a result, the combination of hyperuricemia and renal failure in the absence of renal intratubular uric acid deposition or stone formation should increase the suspicion of lead nephropathy. Chronic lead nephropathy then progresses to chronic kidney failure due to the progressive destruction of tubular cells and their replacement by fibrosis,1,2,3,11 leading to significant nephron loss. This late stage of lead nephropathy is characterized by interstitial fibrosis with atrophy and dilatation of tubules and relative sparing of glomeruli; at this stage the tubular intranuclear inclusion bodies are uncommon.2,3
Lead induced systemic hypertension has been shown to occur in the absence of symptomatic lead intoxication and before the onset of clinically apparent renal failure.2,4,7 Several epidemiological studies21,22,23,24,25,26,27 have shown that a relatively low level of lead exposure is associated with a significant increase in blood pressure and chronic kidney disease. The epidemiological association of lead nephropathy and hypertension has been shown7,23,24 to contribute to the disease burden attributable to lead exposure, as a result of lead induced blood pressure increase and its associated cardiovascular risk.7,23,24 The role of lead in the induction of hypertension in persons with and without renal disease is supported by a study25 which analyzed the bone lead levels from transilliac bone biopsies of patients with end-stage renal disease. This study25 showed that 5% of the European dialysis population had significantly elevated bone lead levels signifying a contributory or causal role for lead in hypertension and renal disease in the study subjects. This association is also supported by other studies26,27 using the EDTA-lead mobilization test which demonstrated significant elevation of chetable lead in the subjects studied. The findings of elevated lead burden was remarkably found in persons without a history of overt lead exposure,26,27 with about 15% of the subjects diagnosed as 'essential' hypertensives.27 In the absence of these assessments, the subjects would have been labeled as people with essential hypertension.26,27
The analysis of results from the Second National Health and Nutrition Examination Survey (NHANES II) in the USA shows that blood lead levels where significantly higher in groups with diastolic blood pressure above
90 mmHg.28 Blood lead increase from 0.68 to 1.45 umol/L (14-30 ug/dL) resulted in an increase of 7 mmHg in mean systolic blood pressure and 3 mmHg in mean diastolic blood pressure.29 The NHANES III survey30 also showed that lead level remains significantly and positively related to elevated BP and hypertension among blacks, who had higher blood lead concentrations compared with whites. The positive correlation between increasing blood lead levels and hypertension is also demonstrated with another analysis of the NHANES II survey,31 and other studies in Taiwan32 and Korea.33 Though there are contrasting results34,35,36,37,38,39,40 from other smaller epidemiological surveys34,35,36,39 and analyses of large scale studies,37,38,40 which indicate a negative or weak association on the relationship between blood lead levels and hypertension. However the seemingly small elevation of blood pressure induced by increased blood lead level remains significant.41,42,43 This is due to the strong association between blood pressure and cardiovascular morbidity and mortality. There is, therefore, a growing consensus that lead contributes to hypertension in the general population.
The clinical complications which are associated with both acute and chronic lead nephropathy are not limited to the kidneys 2,3,12 and include malignant renal disease, cardiovascular related morbidity, the consequences of lead induced renal function impairment,2,7,23,44,45 as well the extra renal manifestations of lead exposure. An increased incidence of renal adenocarcinoma has been reported among lead workers.2,44,45 The higher incidence of renal malignancy in lead workers has also been shown to contribute to the overall mortality among people with significant occupational lead exposure,23 though a casual relationship has not been established. In addition anemia is usually observed in both acute and chronic lead nephropathy.2,3,46
Pathophysiology of lead nephropathy
The role of lead storage and excretion
Lead nephropathy results primarily because the kidney is a major route for the elimination of lead via glomerular filtration and tubular secretion in addition to the kidney also being a minor storage site for absorbed lead following prolonged excessive absorption.3,7,12 The tubulointerstitial structures of the kidney are particularly vulnerable to the toxic effects of lead due to the high reabsorptive activity of the tubules which results in high concentration of lead in the already poorly perfused medulla.1,2,3 Following its uptake, lead is absorbed by the proximal tubular cells where it binds to specific lead binding proteins forming lead-protein complexes. The lead binding proteins which are postulated to facilitate the movement of lead across the mitochondrial membranes of renal tubular cells possess genetic variability in their expression which is thought to determine or modulate the individual differences in the susceptibly to lead nephropathy.3,47
Renal mitochondrial structural and
functional alterations
Following its movement into the mitochondria of renal tubular cells, lead accumulates in the mitochondria resulting in both structural and functional alterations.1,2,3,7,12 The structural alterations result in mitochondrial swelling and inhibition of respiratory function and energy (adenosine triphosphate [ATP]) production. This disruption of energy production impairs energy dependent processes including tubular transport leading to proximal tubular reabsorptive defects which lead to the features of Fanconi syndrome3,13 and hyperuricemia.3,15,17 The impairment of mitochondrial enzyme function is another important pathogenetic process of lead toxicity,2,3,7,12 as the activity of mitochondrial enzymes such as aminolevulinic acid synthase, ferrochelatase and vitamin D hydroxylase are inhibited.
Autoimmune basis of lead and heavy metal kidney disease
Exposure to toxic metals like mercury, cadmium, lead, nickel and silica have been associated with the induction of autoantibodies and autoimmune diseases, though no precise mechanisms have been elucidated.
The activation of ‘metal-specific’ T cells with a preferential T-helper cell type 2 responses, following the presentation of metal induced cryptic self peptides and polyclonal T- and B-cell activation have been suggested.48 The manner in which Pb affects the immune cells is not well understood as both immunosuppression in vivo and enhanced lymphocyte proliferation in vitro have been reported in addition to the various immunomodulatory actions of lead on both cellular and humoral components of the immune system involving B cells, T cells, natural killer (NK) cells, and mediators like cytokines, chemokines, and nitric oxide (NO).49 Razani-boroujerdi et al. demonstrated that, depending on the concentration of Pb, in vitro proliferation of splenic lymphocytes is either stimulated or inhibited in the presence of Pb,50 while Mishra et al. reported significantly lower CD4 and CD45RA+ isoforms in lead exposed subjects compared to controls and a correlation between higher blood lead level (BLL) and lower CD4 cell percentage.51 It is thus probable that the adverse effects of lead on the immune system may affect the kidneys especially in subjects with chronic exposure.
Hyperuricemia resulting from impaired tubular function5,16,17,18 and altered purine metabolism through the inhibition of guanine aminohydrolase dependent hydrolytic deamination of guanine to xanthine52 has been identified as a significant promoter of lead nephropathy. Hyperuricemia can mediate both hypertension and kidney injury53 as elevated uric acid levels have been shown to worsen endothelial dysfunction through the stimulation of vascular smooth muscle proliferation resulting in thickening of the afferent arteriole of the glomerulus. Hyperuricemia is also shown53 to inhibit the release of nitric oxide within the vasculature of the kidneys which worsens renal blood flow and impairs glomerular filtration. All these mechanisms explain the role of hyperuricemia in the pathogenesis of lead nephropathy and the frequent association of chronic lead nephropathy with gout.
Eicosanoid pathway abnormalities
Other abnormalities which have been suggested as pathogenetic pathways in lead nephropathy include the reduced renal excretion of the vasodilator 6-keto-prostaglandin factor-1-alpha; found to be reduced in patients who have been significantly exposed to lead.1,54 The enhanced renal excretion of the vasoconstrictor thromboxane and a decrease in the synthesis of ecosanoids,54 have also been demonstrated. The effects of lead on eicosanoid synthesis and excretion may thus contribute to the pathophysiology of lead nephropathy and hypertension; by making the kidney more vulnerable to the effects of drugs like non-steroidal anti-inflammatory drugs (NSAIDs) that reduce the synthesis of locally produced vasodilators, in addition to promoting injury to the glomerulus and renal medulla.
Lead and hypertension
Lead induces nephropathy and hypertension through its effects as a direct tubular toxin resulting in alteration in tubular function and indirectly through alterations on cation transport55,56,57,58,59 and other neurohumoral mechanisms59,60,61,62,63,64 which affect vascular reactivity.
Epidemiology
General incidence and prevalence
The exact incidence and prevalence of lead nephropathy is unknown;1,9 however, the incidence and prevalence of toxic nephropathies may be indicative of the burden of lead nephropathy.1,4 In the USA, toxic nephropathies are estimated to cause less than 1% of all end-stage renal disease,1,4 with three million workers in the US at risk for toxic lead exposure; approximating 1.02% of the US population.1
Correspondingly, a study in Nigeria65 carried out at the Lagos University Teaching Hospital (LUTH), Lagos, estimated that toxic nephropathies were responsible for 0.7% of all cases of end-stage renal disease in Lagos, Nigeria.
Sources and pathways of lead exposure: the majority of lead pollution, however, derives from human activity to extract and exploit the metal.2 Lead is used in the production of lead acid batteries, solder, alloys, cable sheathing, pigments, rust inhibitors, ammunition, glazes, and plastic stabilizers.
It is also used in the production of tetraethyl and tetramethyl lead which have been used extensively as antiknock compounds in petrol.2,7 Workers are also exposed to lead in many occupations such as2,7,12 motor vehicle assembly, panel beating, battery manufacture and recovery, soldering, lead mining and smelting, lead alloy production, and in the glass, plastics and printing industries. Other occupations include ceramic and paint workers, automobile radiator repairers, petrol attendants and petroleum refining workers as well as welding, pottery and ceramic ware production and the production of jewellery. Water is another important source of lead exposure as the previous almost universal use of lead compounds in plumbing fittings and as solder in water-distribution systems resulted in significant lead exposure from drinking water.2,7,12 Lead is also used in cosmetics and traditional remedies, paint, can and ceramic glazing.2,7 These various uses of lead have contributed significantly to the environmental levels of lead making it a common pollutant. Sources of lead in the environment can be categorized7 into distal sources which include water, paint, leaded gasoline, high vehicular traffic emission, cottage and major industrial activities, cosmetics and traditional remedies, cans and lead-glazed ceramics. These distal sources dispense lead to the proximal sources which are water, air, dust and food, thus providing two routes for uptake: inhalation and ingestion. Factors which increase the risk for lead exposure in children include mouthing behavior such as pica, exposure to lead from flaking paint in old housing and poor nutritional status which promotes the gastrointestinal absorption of lead.7,8,66,67
Genetic predisposition
Susceptibility to lead toxicity has been shown to be influenced by genetic variability. The polymorphic genes which potentially modulate the toxicity of lead are the genes coding for δ-aminolevulinic acid dehydratase (ALAD) on chromosome 9q34 an enzyme of heme biosynthesis, which exists in two polymorphic forms of codominant alleles ALAD 1 and 2; the vitamin D receptor (VDR) gene and hemochromatosis gene coding for the HFE protein.68
The variability in the expression of ALAD and vitamin D receptor genes has been shown to influence the susceptibility to lead toxicity and outcome in various organs.47,68 The ALAD-1 is the more predominant allele.47,68,69,70,71 while the rarer ALAD-2 allele has been associated with high blood lead levels and has been thought to increase the risk of lead toxicity by generating a protein that binds lead more tightly than the ALAD-1 protein.48,68 Most of the studies evaluating the association of genetic variability and outcome of lead exposure have been in occupationally exposed subjects. Shaik and Jamil,69 in a study of lead workers in India, did not find any significant difference in blood lead level for ALAD 1-1 and 1-2 genotypes compared with ALAD 2-2 genotypes. However, subjects with ALAD1-2/2-2 genotype group showed higher blood lead level than subjects from the ALAD1-1 genotype group. Chia et al.70 in a study of Vietnamese and Singaporean lead workers, showed that workers with the ALAD2 allele appeared more susceptible to the toxic effects of lead on renal function, especially at higher lead levels. Another study71 among Koreans subjects did not find any association between ALAD genotype with blood pressure, but reported that subjects with the VDR B gene allele in hetero and homozygous combination had higher systolic and diastolic blood pressure as well as higher prevalence of hypertension. In spite of the above mentioned association of the varied genetic variability in lead toxicity, more research is needed to justify the assessment of these genetic polymorphisms in lead exposure screening and evaluation.
Racial predisposition
There is no conclusive evidence of racial predisposition to lead nephropathy,9 although the reports of some surveys have suggested racial differences in blood lead level and lead exposure related outcomes. The results of the NHANES III survey41 in the USA showed higher lead levels among non-Hispanic blacks and Mexican Americans; with mean blood lead levels being significantly higher for black men and women compared with white men and women.
The NHANES III survey41 also indicated a significant association between high blood lead levels and higher systolic blood pressure among black men and women, in contrast to a negative association of high blood lead level with high blood pressure among white men and women.
Though these findings may suggest a higher incidence of lead induced hypertension among blacks than in whites, it is not certain whether these associations translate into higher incidence of lead nephropathy among blacks, especially considering previous geographical influence and the present socioeconomic index of the affected groups.
Geographical predisposition
There is no report of geographical predisposition for lead nephropathy as the difference in the incidence of lead nephropathy in various parts of the world is unknown;1,2,7,8,9 however, due to the significantly higher level of environmental lead exposure in developing countries resulting largely from high leaded gasoline use,2,7,8,9 it could, therefore, be extrapolated that there may be a higher risk of lead nephropathy amongst people living in the developing world. Furthermore, the risk for lead nephropathy may be most significant in developing countries where risk factors for CKD such as obesity, hypertension and diabetes mellitus and infection are increasing on a background of relative lead overexposure.8,9 The increased geographical risk for lead nephropathy is not limited to developing countries as certain population groups in developed countries continue to experience higher levels of lead exposure and an extrapolated risk of nephropathy, in spite of the overall decline of lead exposure in these countries.72,73,74 These populations include inner city children, refugee or migrant children, adults of lower socioeconomic status, and children of parents with poor income and lower socio-economic status.8,9,75,76,77
The role of environmental lead exposure
Environmental lead exposure is a risk factor for lead nephropathy,2,8,9 as shown in cross sectional analysis78 and longitudinal data79 which suggest an acceleration of age-related impairment of renal function in association with long-term low-level lead exposure. Low-level environmental lead exposure has been shown to contribute to lead nephropathy even at blood lead levels below 5 ug/dL,2,8 especially in susceptible populations9 like hypertensives and diabetics. Therefore, populations with higher environmental lead exposure are at higher risk for lead nephropathy.
The role of occupational lead exposure
Occupational lead exposure is an important pathway for lead exposure and a significant risk for the development of lead nephropathy,2,7,8,9 as various studies80,81,82,83,84,85 have shown a significant association of renal impairment among lead workers compared to controls.
Morbidity and mortality
Low level lead exposure is associated with chronic kidney disease in the general population86 and populations with hypertension.87 In addition, longitudinal data88,89,90 suggest an acceleration of CKD progression in non-diabetic populations with low-level environmental lead exposure. Lead toxicity is associated with renal impairment and an increase in the all cause circulatory and cardiovascular mortality in the USA as shown in the Second National Health and Nutrition Assessment Survey (NHANES II).31 Evidence from other studies have also established an association between lead exposure, hypertension and hyperuricemia which lead to increased cardiovascular risk as well as an increase in all cause mortality.2,31,90 It has also been shown that persons with occupational exposure to lead have significantly higher mortality from chronic non-malignant renal disease, hypertension related conditions and renal malignancies.23,44,45
Diagnosis and treatment
The clinical diagnosis of lead nephropathy is complex because the symptoms of lead intoxication are variable and non-specific;1,2,3 therefore a high index of suspicion is required in the assessment of patients with renal disease in order to obtain a detailed history of occupational or environmental lead exposure. The assessment of lead exposure can be made using a lead exposure risk assessment questionnaire such as the modified lead assessment questionnaire of Knosset with a reported sensitivity of 89.2% and a negative predictive value of 96.4%,91 and the CDC questionnaire,92 largely used in children, which can be modified for the specific population and setting as shown by Stefanak et al.93 who modified its use in a pregnant population and reported a sensitivity of 75.7% and a negative predictive value of 93.1%.
These questionnaire tools can be used to evaluate environmental and occupational lead exposure risk through the assessment of demographics, housing conditions, smoking status, alcohol use, occupational and work duration history, dietary history, water source, lead exposure risk, the use of protective wear as well as safe behavioral practice and previous blood exposure monitoring and action.
A diagnostic criteria for chronic lead nephropathy has been suggested by Emmerson.3,4 The criteria are: i) features of long-standing, slowly progressive chronic renal disease; ii) moderate-to-considerable contraction of both kidneys; iii) definitive evidence of excessive past lead exposure; iv) exclusion of alternative causes for chronic renal disease. Other important features include the presence of gout and hypertension which are major clinical manifestations of lead nephropathy.3,4,18
Assessing the lead burden
The blood lead level in lead nephropathy is expected to be above 40 ug/dL1,3,4,12 with the risk of renal failure at blood lead levels above 60 ug/dL.1,3,4,12 The blood lead levels in acute lead nephropathy are usually above 100 ug/dL and when values exceed 150 ug/dL features of encephalopathy begin to manifest.1,3,4,12
Heme enzymes such as zinc-protoporphyrin and free erythrocyte protoporphyrin are altered by lead and can be used as indirect means of assessing lead exposure.12,46,94,95 The levels of these enzymes are elevated in lead toxicity with erythrocyte protoporphyrin levels above 35 ug/dL and 50 ug/dL correlating with blood lead level above 25 ug/dL and 40 ug/dL, respectively.7,12,46
The best measure for assessing the total accumulation of lead in the body is CaNa2 EDTA lead mobilization test.3,4,96 The test is performed by administering CaNa2EDTA 2 gr intramuscularly in 2 divided doses 12 hours apart or 1 gr intravenously, and by collecting urine for 24 hours. Patients with renal insufficiency should collect urine over 3-6 days. EDTA chelates lead sequestered in the body storage sites and mobilizes it for renal excretion in the form of lead-EDTA chelate.
Individuals without any unusual prior exposure to lead would excrete less than 650 ug of lead over the collection period, a cumulative excretion greater than this level is indicative of excessive lead burden. In children, a dose of 30-50 mg/kg of CaNa2EDTA is administered intramuscularly or intravenously, and urine is collected over eight hours. A positive mobilization test is a ratio of the dose of EDTA administered (in mg) to the quantity of lead excreted (in mcg) greater than 0.6.
The dimercaptosuccinic acid (DMSA) chelation test is another method of assessing body lead burden,97 it involves the measurement of urine lead, and urinary delta-aminolevulinic acid levels after oral administration of 10 mg/kg DMSA).97 The DMSA lead mobilization test (LMT) is believed to be a good predictor of lead exposure related symptoms and DMSA appears to have several major advantages over CaNa2EDTA98,99,100 as it can be administered orally, is less acutely toxic with a large therapeutic index, and it does not appear to redistribute lead to the brain or to induce significant elimination of essential trace elements. In addition to its role in the treatment of metal intoxication, DMSA offers considerable diagnostic potential for safe and convenient LMT.97,100 However, experience on its use is still limited and standard protocols which are needed to define what constitutes significant chelation induced lead diuresis after DMSA test are only now being developed.
The other methods of measuring body lead burden are methods which assess bone lead.101,102 These methods include X-ray fluorescence (XRF) which has been shown to be a safe, non-invasive, and reliable technique to measure lead in the skeleton.102 It measures subperiosteal and full thickness of bone lead as well as direct measurement of dense bone lead content. Illiac crest bone lead-to-calcium ratios exceeding 100×10–6 and transiliac lead-to-calcium ratios exceeding 140×10–6 are thus consistent with lead exposure levels capable of causing lead nephropathy. The body lead burden can also be measured through trans-iliac bone biopsy;99,101 however there is no indication for performing bone biopsies to diagnose lead poisoning.
Assessing renal function
The assessment of renal function in lead nephropathy involves the evaluation of global renal function and assessment of tubular and glomerular parameters.103,104
The assessment of tubular function is important in the evaluation of lead nephropathy as chronic lead nephropathy can be missed in its early stages because changes induced by chronic low-level lead exposure are subtle and not reflected by changes in routine renal function tests.104 In addition routine urinary analysis is usually unremarkable and may show only mild-to-moderate proteinuria.3,4,96
Lead-induced renal dysfunction can be detected in its early stages through the measurement of proteins and enzymes from the tubules and glomeruli excreted in urine, which reflect the functional integrity of these portions of the kidney.103,105 Various markers of proximal tubular integrity, such as α1-microglobulin, β2-microglobulin, retinol binding protein and enzymes such as lyzozyme, ribonuclease, N-acetyl-β-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), alkaline phosphates (AP) and γ-glutamyltransferase (GGT) and distal tubular markers like tamm-Horsfall glycoprotein, the enzyme kallikrein have been used and tried. Glomerular urinary markers are the high molecular weight proteins, transferrin, immunoglobulin G (IgG) and albumin. The urinary levels of these markers are usually not significantly altered in lead nephropathy as observed in various studies.84,104,106
The tubular urinary markers have been the subject of various studies attempting to identify sensitive and specific markers of lead nephropathy, useful in early diagnosis. Urinary NAG has been reported as a consistent and sensitive marker of early tubular impairment in association with lead biomarkers by various studies.54,80,81,82,104,105,106,107,108 In addition to urinary NAG, Pergande at al.104 also found increased excretion of urinary α-1-microglobulin, ribonuclease, and Tamm-Horsfall protein and suggest that the combined determination of NAG and α-1-microglobulin in urine could be helpful in the early detection of lead-induced changes in the kidney. The report of good correlation between urine α-1-microglobulin and lead dose biomarkers is also supported by Chia et al.95 who found a significant association between urinary α-1-microglobulin and time-integrated blood lead indices in lead exposed workers, with a good dose response and dose effect relationship.
Similarly Jung et al.108 found both urine NAG and urine α-1-microglobulin useful indicators in early lead nephropathy and propose the use of urine α-1-microglobulin as an early and reliable indicator of lead nephropathy. Weaver et al.81 also reported a good association between lead biomarkers with RBP and NAG. The trend in these reports does suggest that urinary α-1-microglobulin and NAG are reliable markers which can be used in the early diagnosis of lead nephropathy.
Histological diagnosis
Renal biopsy is not obligatory for diagnosis of lead nephropathy as it shows non-specific changes of a chronic tubulo-interstitial nephritis.3,4
Radiological evaluation
Imaging studies such as kidney ultrasound will show bilaterally contracted kidneys with chronic lead nephropathy.1,3 A plain radiograph of the abdomen should be obtained in acute lead poisoning which may reveal abdominal radiopacities.1
Ancillary investigations
The assessment of lead related effects and complications are important components in the evaluation of lead nephropathy. A full blood count (FBC) test may serve to identify lead suppression of hematopoiesis and anemia of lead toxicity and chronic renal disease. Peripheral blood smear may show a hypochromic microcytic anemia and basophilic stippling in red blood cells.1,3
Treatment and medical care. The mainstay of treatment for acute and chronic lead nephropathy is chelation therapy.4,96,109 Chelation therapy involves the use of compounds containing sulfhydryl groups that bind lead resulting in the formation of a complex which is excreted either renally or hepatically.1,3 The oral chelation agents used in the treatment of lead nephropathy are penicillamine and DMSA, while dimercaprol and edetate calcium disodium are administered parenterally.1,3,4 The indications for chelation therapy in acute lead poisoning.1,3,4,96 include blood lead levels greater than or equal to 45 ug/dL in children who should be treated with oral chelation agents such as succimer and penicillamine. Penicillamine may be used when blood lead levels are in the range of
25-45 ug/dL especially with a negative CaNa2EDTA mobilization test; though succimer could be used as an alternative to penicillamine it is preferred when blood lead levels are greater than or equal to 45 ug/dL. Children with levels greater than or equal to 70 ug/dL should be treated as medical emergencies, preferably with intravenous therapy.
A combination of British anti-Lewisite (BAL) and CaNa2EDTA is advised1 when blood lead level is greater than or equal to 70 ug/dL, especially with the occurrence of lead encephalopathy.
In adults, chelation should be considered for patients with blood lead levels greater than or equal to 70 ug/dL;1,3,4 however, symptomatic adults with blood lead levels exceeding 50 ug/dL may also be candidates for chelation therapy. The preferable chelation agents for adults are BAL and CaNa2EDTA.1,3,4
Chelation therapy is useful in the management of acute lead nephropathy as it reverses Fanconi syndrome, transient hypertension, and tubular structural changes observed on histopathology.3,15 In chronic lead nephropathy, chelation therapy has been shown to slow the progression of chronic kidney disease with improvement in creatinine clearance and glomerular filtration rate.4,10,20,89,99 The changes observed in response to chelation therapy in chronic lead nephropathy most likely occur in the absence of marked interstitial fibrosis and with moderate impairment of renal function.3,4,15 Chelation therapy may be achieved through the use of either BAL, CaNa2EDTA or DMSA,1,3,100,110 with well defined endpoints of therapy such as normalization of the CaNa2EDTA test to normal levels and or improvement in renal function.
In acute lead nephropathy, the reduction of the amount of lead absorbed from the gastrointestinal tract is important adjunct in the management of acute lead poisoning;1 this is achieved through the use of gastric lavage, cathartics and whole bowel irrigation after suspect radiopacities are observed on plain abdominal radiograph.
Post treatment care. Following initial treatment, further chelation therapy, either oral or intravenous, may be continued on an outpatient basis if indicated.1,3,4 Renal and liver functions must be monitored during therapy in order to detect drug toxicity early.3,4,10 Dietary modification is an important adjunct to post treatment care with the aim of reducing lead absorption. It is advised that the diet should provide sufficient calories and be rich in calcium, zinc, and iron.21,66,67,111
Data from the Normative Aging Study21 has suggested that low dietary intake of vitamin D may increase accumulation of lead in bones, while low dietary intake of vitamin C and iron may increase blood lead levels in subjects who are middle-aged to elderly. Similarly low calcium levels and iron deficiency have also been found to increase the absorption of lead in children.66,67,111 Though no studies have specifically addressed treatment of lead exposure with calcium and iron supplementation, it does seem to be a logical step to limit lead absorption.
Patient education
Patients should be educated regarding the health risks of lead and sources that may cause lead poisoning. This is a very important step in preventing further exposure to lead and its adverse health effects.1,3 Secondary prevention measures which involve the early detection and treatment of lead poisoning should be instituted and involves the targeted screening of people with high risk of environmental and especially occupational lead exposure. This will enhance adequate medical surveillance as this is expected to promote early diagnosis and treatment of persons with lead nephropathy.
Conclusions
In spite of the recognition of environmental and occupational lead exposure as a risk factor for disease, the adverse health consequences of lead toxicity still contribute significantly to the overall disease burden in many countries.2,7,8,9 This situation is worse in developing countries where programs for the control, prevention and treatment of lead exposure and toxicity are none existent or poorly developed.2,7 Correspondingly, CKD and ESRD are issues of global public health concern with rising incidence worldwide.9,112 Though environmental and occupational nephrotoxins like lead, mercury and cadmium are established causes of kidney disease,2,7,9 the present efforts aimed at reducing the rising prevalence of CKD appear to focus largely on the more visible causative factors like diabetes and hypertension and infrequently consider other risk factors like environmental and occupational nephrotoxins, of which lead is a major contributor.8,9
Lead nephropathy which is primarily a tubulointerstitial nephritis may present acutely or chronically in association with hypertension.3,15 The clinical diagnosis of lead nephropathy is complex2,3,4,9 because the symptoms of lead intoxication are variable and non-specific as a result of subclinical nephrotoxicity from low level lead exposure.2,3,4,9 However, identification of lead nephropathy can be improved if physicians have a high index of suspicion in the assessment of patients with renal disease in order to identify features that may suggest lead nephropathy. These features3,4 are evidence and risk of excessive present or past lead exposure, slowly progressive chronic renal disease, moderate-to-considerable contraction of both kidneys, hyperuricemia without renal intratubular uric acid deposition or stone formation15,18,19 and hypertension,2,21,22 in addition to the assessment of tubular urinary parameters such as NAG and α-1-microglobulin. Finally, it is recommended that evaluation of environmental and occupational nephrotoxins like lead be incorporated into programs for the prevention of CKD, especially in developing countries where lead exposure and toxicity still remain largely unchecked2,7,8,9 and the prevalence and burden of CKD is increasing.9,112
References
1. Kathuria P, Jadav P. Lead Nephropathy.
eMedicine specialities: Nephrology: eMedicine Journal 2008 February. [December 2009];Vol 2:(12).
2. Landrigan PJ. Current issues in the epidemiology and toxicology of occupational exposure to lead. Environ Health Perspect 1990;89:61-6.[PubMed]
3. Loghman-Adham M. Renal effects of environmental and occupational lead exposure: a review. Environ Health Perspect 1997;105:928-38.[FullText]
4. Bennett WM. Lead nephropathy: Nephrology forum. Kidney Int 1985;28:212-20. [FullText]
5. Inglis JA, Henderson DA, Emmerson BT. The pathology and pathogenesis of chronic lead nephropathy occurring in Queensland. J Pathol 1978;124:65-76. [PubMed]
6. Havelda CJ, Sohi GS, Richardson CE. Evaluation of lead, zinc, and copper excretion in chronic moonshine drinkers. South Med J 1980;73:710-5.[PubMed]
7. Fewtrell L, Kautmann R, Pruss-Ustun A. Lead: assessing the environmental burden of disease at national and local levels. WHO 2003 (WHO Environmental burden of disease series No 2).[FullText]
8. Tong S, Von Schirnding YE, Prapamontol T. Environmental lead exposure: a public health problem of global dimensions: Theme papers: Bulletin of the WHO 2000;78:1068-77.[FullText]
9. Ekong EB, Jaar BG, Weaver VM. Lead-related nephrotoxicity: a review of the epidemiologic evidence. Kidney Int 2006;70: 2074-84.[PubMed]
10. Prakash S, Hernandez GT, Dujaili I, Bhala V. Lead poisoning from an Ayurvedic herbal medicine in a patient with chronic kidney disease. Nat Rev Nephrol 2009;5:279-300.[PubMed]
11. Brewster UC, Perazella MA. A review of chronic lead intoxication: an unrecognized cause of chronic kidney disease. Am J Med Sci 2004:327:341-7.[PubMed]
12. Lead: Guidelines for drinking-water quality, 2nd ed. Vol 2. Health criteria and other supporting information. Geneva, World Health Organization (WHO);1996:254-75.[FullText]
13. Loghman-Adham M. Aminoaciduria and glycosuria following severe childhood lead poisoning. Pediatr Nephrol 1998;12:218-21.[PubMed]
14. Hu H. A 50-year follow-up of childhood plumbism: Hypertension, renal function and hemoglobin levels among survivors. Am J Dis Child 1991;145:681-7. [PubMed]
15. Perazella MA. Lead and the Kidney: nephropathy, hypertension and gout. Conn Med 1996;60:521-6.[PubMed]
16. Lin JL, Tan DT, Ho HH, Yu CC. Environmental lead exposure and urate excretion in the general population. Am J Med 2002;113:563-8.[PubMed]
17. Lin JL, Yu CC, Lin-Tan DT, Ho HH. Lead chelation therapy and urate excretion in patients with chronic renal diseases and gout. Kidney Int 2001;60:266-71.[PubMed]
18. Craswell PW, Price J, Boyle PD, et al. Chronic renal failure with gout: a marker of chronic lead poisoning. Kidney Int 1984;26:319-23.[PubMed]
19. Colleoni N, D'Amico G. Chronic lead accumulation as a possible cause of renal failure in gouty patients. Nephron 1986; 44:32-5.[PubMed]
20. Lin JL, Ho HH, Yu CC. Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency. Ann Intern Med 1999;130:7-13.[PubMed]
21. Cheng Y, Schwartz J, Sparrow D, et al. Bone lead and blood lead levels in relation to baseline blood pressure and the prospective development of hypertension: the Normative Aging Study. Am J Epidemiol 2001;153:164-71.[PubMed]
22. Hu H, Aro A, Payton M, et al. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA 1996;275:1171-6.[PubMed]
23. Selevan SG, Landrigan PJ, Stern FB, et al. Lead and Hypertension in a Mortality study of lead smelter workers. Environ Health Persp 1988;78:65-6.[PubMed]
24. Kopp SJ, Barron JT, Tow JP. Cardiovascular actions of lead and relationship to hypertension: a review. Environ Health Persp 1988;78:91-9.[Abstract]
25. Weedeen RP. Bone Lead, Hypertension and Lead nephropathy. Environ Health Perspect 1988;78:57-60.[PubMed]
26. Batuman V, Landy E, Maesaka JK, Weedeen RP. Contribution of lead to hypertension with renal impairment. N Engl J Med 1983;309:17-21.[PubMed]
27. Sanchez-Fructuoso AI, Torralbo A, Arroyo M, et al. Occult lead intoxication as a cause of hypertension and renal failure. Nephrol Dial Transplant 1996;11:1775-80.[PubMed]
28. Harlan WR. The relationship of blood lead levels to blood pressure in the US population. Environ Health Persp 1988;78:9-13.[PubMed]
29. Schwartz J. The relationship between blood lead and blood pressure in the NHANES II survey. Environ Health Persp 1998:78:15-22.[PubMed]
30. Vupputuri S, He J, Muntner P, et al. Blood Lead Level is associated with elevated Blood Pressure in Blacks. Hypertension 2003;41:463-8.[PubMed]
31. Pirkle JL, Schwartz J, Landis JR, Harlan WR. The relationship between blood lead levels and blood pressure and its cardiovascular risk implications. Am J Epidemiol 1985;121:246-58.[PubMed]
32. Chu NF, Liou SH, Wu TN, Chang PY. Reappraisal of the relation between blood lead concentration and blood pressure among the general population in Taiwan. Occup Environ Med 1999;56:30-3.[Abstract]
33. Nomiyama K, Nomiyama H, Liu SJ, et al. Lead induced increase of blood pressure in female lead workers. Occup Environ Med 2002;59:734-38.[PubMed]
34. Micciolo R, Canal L, Maranelli G, Apostoli P. Non-occupational lead exposure and hypertension in northern Italy. Int J Epidemiol 1994;23:312-20.[PubMed]
35. Staessen JA, Roels H, Fagard R. Lead exposure and conventional and ambulatory blood pressure: a prospective population study. PheeCad Investigators. JAMA 1996;275:1563-70.[PubMed]
36. Wu TN, Shen CY, Ko KN, et al. Occupational lead exposure and blood pressure. Int J Epidemiol 1996;25:791-6. [PubMed]
37. Gartside PS. The relationship between blood lead and blood pressure in the NHANES II Survey: Additional calculations. Environ Heath Persp 1988;78:31-4.[Abstract]
38. Pocock SJ, Shaper AG, Ashby D, et al. The relationship between blood lead, blood pressure, stroke and heart attacks in Middle-Aged British men. Environ Health Perspect 1988;78:23-30.[PubMed]
39. Neri LC, Hewitt D, Orser B. Blood lead and Blood pressure: Analysis of cross sectional and longitudinal data from Canada. Environ Heath Perspect 1988;78:123-6.[PubMed]
40. Hond ED, Nawrot T, Staessen JA. Hypertension and low-Level lead exposure: a scientific issue or a matter of faith? Hypertension 2003;42:e9.[PubMed]
41. Vupputuri S, Batuman V, He J. Response: hypertension and low-level lead exposure in African Americans: a public health reality. Hypertension 2003;42:e9.[FullText]
42. Tyroler HA. Epidemiology of hypertension as a public health problem: An overview as background for evaluation of blood lead – blood pressure relationship. Environ Health Perspect 1988;78:3-7.[PubMed]
43. Landis JR, Flegal KM. A generalized mantel-haenszel analysis of the regression of blood pressure on blood lead using NHANES II Data. Environ Health Perspect 1988;78:35-41.[PubMed]
44. Cooper WC. Deaths from Chronic Renal Disease in US Battery and Lead production workers. Environ Health Perspect 1988;78:61-3.[Abstract]
45. Steenland K, Selevarn S, Landngan P. Mortality of lead smelter workers an update. Am J Pub Health 1992;82:1641-4.[PubMed]
46. Lead: Air quality guidelines, 2nd ed. Chapter 6.7. WHO Regional Office for Europe, Copenhagen, Denmark 2001:1-17.[FullText]
47. Kelada SN, Shelton E, Kaufmann RB, Khoury MJ. δ-Aminolevulinic acid dehydratase genotype and lead toxicity: a HuGE review. Am J Epidemiol 2001;154:1-13.[PubMed]
48. Greim P, Gleichmann E. Metal ion induced autoimmunity. Curr Opin Immunol 1995;7:831-8.[PubMed]
49. Singh VK, Mishra KP, Rani R, et al. Immunomodulation by Lead. Immunol Res 2003;28:151-66.[PubMed]
50. Razani-Boroujerdi S, Edwards B, Sopori ML. Lead stimulates lymphocyte proliferation through enhanced t cell-b cell interaction. J Pharmacol Exp Ther 1999;288:714-9.[PubMed]
51. Mishra KP, Rani R, Yadav VS, Naik S. Effect of lead exposure on lymphocyte subsets and activation markers. Immunopharmacol Immunotoxicol 2010 Jan 28. (Epub ahead of print). [PubMed]
52. Farkas WR, Stanawitz T. Effects of plumbous ion on guanine metabolism. J Inorg Biochem 1979;11:31-8. [PubMed]
53. Johnson RJ, Kang D, Feig D, et al. Is there a pathologic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-90.
54. Cardenas A, Roels H, Bernard AM, et al. Markers of early renal changes induced by industrial pollutants II: Application to workers exposed to lead. Br J Ind Med 1993;50:28-36.[PubMed]
55. Batuman V, Dreisbach A, Chun E, Naumoff M. Lead increases the red cell sodium–lithium countertransport. Am J Kidney Dis 1989:14:200-3.[PubMed]
56. Wedeen RP. Blood lead levels, dietary calcium, and hypertension. Ann Intern Med 1985;102:403-4.[PubMed]
57. Weiler E, Khalil-Manesh F, Gonick H. Effects of lead and natriuretic hormone on kinetics of sodium-potassium-activated adenosine triphosphatase: possible relevance to hypertension. Environ Health Perspect 1988;78:113-8.[PubMed]
58. Moreau T, Hannaert P, Orssaud G, et al. Influence of membrane sodium transport upon the relation between blood lead and blood pressure in a general male population. Environ Health Perspect 1988;78:47-51.[PubMed]
59. Khalil-Manesh F, Gonick HC, Weiler EW, et al. Lead induced Hypertension: Possible role of endothelial factors. Am J Hypertension 1993;6:723-9.[PubMed]
60. Gonick HC, Ding Y, Bondy SC, et al. Lead-induced hypertension: interplay of nitric oxide and reactive oxygen species. Hypertension 1997;30:1487-92.[PubMed]
61. Vaziri ND, Liang K, Ding Y. Increased nitric oxide inactivation by reactive oxygen species in lead-induced hypertension. Kidney Int 1999;56:1492-8.[PubMed]
62. Boscolo P, Carmignani M. Neurohumoral blood pressure regulation in lead exposure. Environ Health Perspect 1988;78:101-6.[Abstract]
63. Vander AJ. Chronic effects of lead on the renin-angiotensin system. Environ Health Perspect 1988;78:77-83.[PubMed]
64. Chai SS, Webb RC. Effects of lead on vascular reactivity. Environ Health Perspect 1988;78:85-9.[PubMed]
65. Menakaya NC, Adewunmi AJ, Braimoh RO, et al. End stage renal disease at the Lagos University Teaching Hospital, Nigeria: 10 year update review. Paper presented at the 17th Nigerian Association of Nephrology Conference 2005.
66. Alexander FW. The uptake of lead by children in differing environments. Environ Health Perspect 1974;7:155-9.[PubMed]
67. Mahaffey KR. Nutritional factors in lead poisoning. Nutrition Rev 1981;39:353.
68. Onalaja AO, Cluadio L. Genetic susceptibility to lead poisoning. Environ Health Perspect 2000;108:23-28.[PubMed]
69. Shaik AP, Jamil K. A study on the ALAD gene polymorphisms associated with lead exposure. Toxicol Ind Health 2008;24:501-6.[PubMed]
70. Chia S-E, Zhou HJ, Yap E, et al. Association of renal function and d-aminolevulinic acid dehydratase polymorphism among Vietnamese and Singapore workers exposed to inorganic lead. Occup Environ Med 2006;63:180-6.[Abstract]
71. Lee BK, Lee GS, Stewart WF, et al. Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and δ-aminolevulinic acid dehydratase genes. Environ Health Perspect 2001;109:383-9.[PubMed]
72. National Center for Environmental Health, Centers for Disease Control and Prevention. Blood lead levels – United States, 1999–2002. Morb Mort Wkly Rep 2005;54:513-6.[FullText]
73. Mahaffey KR, Annest JL, Roberts J, Murphy RS. National estimates of blood lead levels: United States, 1976-1980: association with selected demographic and socioeconomic factors. N Engl J Med 1982;307:573-9. [PubMed]
74. Muntner P, Menke A, DeSalvo KB, et al. Continued decline in blood lead levels among adults in the United States: The National Health and Nutrition Examination Surveys. Arch Intern Med 2005;165:2155-61.[PubMed]
75. Centers for Disease Control and Prevention (CDC). Elevated blood lead levels in refugee children. New Hampshire, 2003-2004. MMWR Morb Mort Wkly Rep 2005:54:42-6.[PubMed]
76. Centre for Disease Control and Prevention (CDC). Blood lead levels in young children in the United States and selected states, 1996-1999. MMWR Morb Mort Wkly Rep 2000;49:1133-7.[PubMed]
77. Inorganic lead. Geneva, World Health Organization, 1995 (Environmental Health Criteria, No. 165). [FullText]
78. Payton M, Hu H, Sparrow D, Weiss ST. Low-level lead exposure and renal function in the Normative Aging Study. Am J Epidemiol 1994;140:821-9.[PubMed]
79. Kim R, Rotnitsky A, Sparrow D, et al. A longitudinal study of low-level lead exposure and impairment of renal function. The Normative Aging Study. JAMA 1996;275:1177-81.[PubMed]
80. Ehrlich R, Robins T, Jordaan J, et al. Lead absorption and renal dysfunction in South African battery factory workers. Occup Environ Med 1998;55:453-60.[PubMed]
81. Weaver VM, Lee BK, Ahn KD, et al. Associations of lead biomarkers with renal function in Korean lead workers. Occup Environ Med 2003;60;551-82.[PubMed]
82. Verschoor M, Wibowo A, Herber R, et al. Influence of occupational low-level lead exposure on renal parameters. Am J Ind Med 1987;12:341-51.[PubMed]
83. Buchet JP, Roels H, Bernard A, Lauwerys R. Assessment of renal function of workers exposed to inorganic lead, calcium or mercury vapor. J Occup Med 1980;22:741-50.[PubMed]
84. dos Santos AC, Colacciopo S, Dal Bó CM, dos Santos NA. Occupational exposure to lead; kidney function tests, and blood pressure. Am J Ind Med 1994;26:635-43.[PubMed]
85. Weaver VM, Jarr BG, Schwartz BS, et al. Associations of lead dose biomarkers, uric Acid and Renal function in Korean lead workers. Environ Health Persp 2005; 113:36-42.[PubMed]
86. Muntner P, He J, Vupputuri S, et al. Blood lead and chronic kidney disease in the general United States population: results from the NHANES III survey. Kidney Int 2003;63:1044-50.[PubMed]
87. Yu CC, Lin JL, Tan DT. Environmental exposure to lead and progression of chronic renal diseases: a four-year prospective longitudinal study. J Am Soc Nephrol 2004;15:1016-22.[PubMed]
88. Lin JL, Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progressive renal insufficiency. Arch Intern Med 2001;161:264-71.[PubMed]
89. Lin JL, Lin-Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med 2003;348:277-86.[PubMed]
90. Staessen JA, Lauwerys RR, Buchet JP, et al. Impairment of renal function with increasing blood lead concentrations in the general population: the Cadmibel study group. N Engl J Med 1992;327:151-6.[PubMed]
91. Kosnett MJ, Becker CE, Osterloh JD, et al. Factors influencing bone lead concentration in a suburban community assessed by noninvasive K X-ray Fluorescence. JAMA 1994;271:197-203.[PubMed]
92. Schaffer SJ, Szilagyi PG, Weitzman M. Lead poisoning risk determination in an urban population through the use of a standardized questionnaire. Pediatrics 1994;93;159-63. [PubMed]
93. Stefanak MA, Bourguet CC, Benzies-Styka T. Use of the Centers for Disease control and prevention childhood lead poisoning risk questionnaire to predict blood lead elevations in pregnant women. Obstet Gynecol 1996;87:209-12.[PubMed]
94. Moore MR. Haematological effects of lead. Sci Total Environ 1988;71:419-31.[PubMed]
95. Chia KS, Jeyaratnam J, Lee J, et al. Lead induced nephropathy: relationship between various biological exposure indices and early markers of nephrotoxicity. Am J Ind Med 1995:27:883-95.[PubMed]
96. Hansen JP, Dossing M, Paulev PE. Chelatable lead body burden (by calcium-disodium EDTA) and blood lead concentration in man. J Occup Med 1981;23:39-43.[PubMed]
97. Hoet P, Buchet JP, Decerf L, et al. Clinical evaluation of a lead mobilization test using the chelating agent dimercaptosuccinic Acid. Clin Chem 2006;52:88-96.[PubMed]
98. Weeden RP, Batuman V, Landy E. The safety of the EDTA lead-mobilization test. Environ Res 1983:30:58-62.[PubMed]
99. Wedeen RP, Malik DK, Batuman V. Detection and treatment of occupational lead nephropathy. Arch Intern Med 1979; 139:53-7.[PubMed]
100. Lee BK, Schwartz BS, Stewart W, Ahn KD. Provocative chelation with DMSA and EDTA: evidence for differential access to lead storage sites. Occup Environ Med 1995;52:13-9.[PubMed]
101. Hu H, Rabinowitz M, Smith D. Bone lead as a biological marker in epidemiologic studies of chronic toxicity: conceptual paradigms. Environ Health Perspect 1998;106:1-8.[PubMed]
102. Todd AC, Chettle DR. In vivo X-ray fluorescence of lead in bone: review and current issues. Environ Health Perspect 1994;102: 172-7.[PubMed]
103. Fels LM, Herbort C, Pergande M, et al. Nephron target sites in chronic exposure to lead. Nephrol Dial Transplant 1994; 9:1740-9. [PubMed]
104. Pergande M, Jung K, Precht S, et al. Changed excretion of urinary proteins and enzymes by chronic exposure to lead. Nephrol Dial Transplant 1994;9:613-8.[PubMed]
105. Kumar BD, Krishnaswamy K. Detection of occupational lead nephropathy using early renal markers. J Toxicol Clin Toxicol 1995;33:331-5.[PubMed]
106. Gerhardsson L, Chettle DR, Englyst V, et al. Kidney effects in long term exposed lead smelter workers. Br J Ind Med 1992;49:186-92.[PubMed]
107. Endo G, Horiguchi S, Kiyota I. Urinary N-acetyl-D-glucosaminidase activity in lead exposed workers. J Appl Toxicol 1990;10:235-47.
108. Jung K-Y, Lee S-J, Kim J-Y, et al. Renal dysfunction indicators in lead exposed workers. J Occup Health 1998;40:103-9.[FullText]
109. Batuman V, Weeden RP, Bogden JD, et al. Reducing bone lead content by chelation treatment in chronic lead poisoning: an in vivo X-ray fluorescence and bone biopsy study. Environ Res 1989:48:70-5.[PubMed]
110. Graziano JH, Leong JK, Friedheim E. 2,3 Dimercaptosuccinic acid: a new agent for the treatment of lead poisoning. J Pharmacol Exp Ther 2006;206:696-700.[PubMed]
111. Blake KC, Barbezat GO, Mann M. Effect of dietary constituents on the gastrointestinal absorption of 203Pb in man. Environ Research 1983;30:182-7.[Abstract]
112. Nwankwo E, Bello AK, El Nahas AM. Chronic kidney disease: stemming the Global tide. Am J Kidney Dis 2005;45:201-8.[PubMed]
[TOP]
