AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Lead has been recognized as a poison for more than 2000 years. In 200 BCE, the Greek poet and philosopher Nikander was the first to note the clinical syndrome of lead poisoning. The high lead concentration in Roman wine was postulated to be the basis for some of the problems that contributed to the downfall of the Roman Empire. The English aristocracy of the 17th and 18th centuries experienced widespread lead poisoning from the consumption of Portuguese wine transported with submerged lead bars to enhance taste and to prevent spoilage. The industrial revolution in the 19th century fostered the use of lead and consequently caused a surge in the incidence of lead poisoning. With the induction of high standards of industrial hygiene, symptomatic lead intoxication in the present day has become extremely rare.

The first report of nephrotoxicity attributable to lead was published in 1863 by Lancereaux. He noted substantial atrophy of the kidney cortex and tubular fibrosis in the kidney of an artist who habitually held paintbrushes in his mouth. In the late 1920s, an epidemic of chronic nephritis in Queensland, Australia, due to childhood lead poisoning brought to light the full spectrum of lead-induced nephropathy. Subsequently, reports of lead nephropathy appeared among "moonshiners" (ie, distillers of illegal corn whiskey) in the southeastern United States and in industrial lead workers.

Three forms of lead nephropathy currently are recognized. First is acute lead poisoning resulting from acute massive exposure to lead, which causes classic symptoms, including colic, encephalopathy, anemia, neuropathy, and Fanconi syndrome. Second is chronic lead nephropathy, which is a slowly progressive interstitial nephritis resulting from excessive cumulative exposure to lead and is frequently associated with hypertension and gout. Third is lead-induced hypertension. Lead has been associated epidemiologically with the development of hypertension.

Furthermore, lead exposure, at much lower levels than those causing lead nephropathy, acts as a cofactor with more established renal risk factors to increase the risk of chronic kidney disease and the rate of progression. Adverse renal effects have been reported at mean blood lead levels of less than 5 mcg/dL. Cumulative lead dose has also been associated with worse renal function.

Pathophysiology

Routes of lead absorption

Lead may be absorbed through the skin, gastrointestinal tract, or lungs. Lead absorption from the gastrointestinal tract depends on several factors, including particle size, gastrointestinal transit time, nutritional status, and age. The smaller the particle size, the better the absorption. Thus, exposure to lead dust results in higher absorption than exposure to the equivalent amount of lead from chips of lead paint. Nutritional status also affects the absorption of lead. Iron deficiency, calcium deficiency, low-energy (calorie) intake, and high-fat intake have been associated with enhanced lead absorption. Children absorb lead more readily than adults.

Lead is also readily absorbed after inhalation of dust or fumes. While inorganic lead is not absorbed through the skin, lead in organic matrices may be absorbed.

Persons who survive gunshot wounds and have retained bullets or pellets may eventually develop poisoning. Bullets located in areas bathed by fluids are more likely to dissolve, while those embedded in soft tissues are likely to be walled off by inflammation.

Metabolism of lead

Lead entering the intravascular space binds quickly to red blood cells. Lead has a half-life of approximately 30 days in the blood, from where it diffuses into the soft tissues, including the kidneys, brain, liver, and bone marrow. Lead then diffuses into bone and is stored there for a period that corresponds to a half-life of several decades. Increased bone turnover with pregnancy, menopause, lactation, or immobilization can increase blood lead levels. Estimations of blood lead levels are more useful for diagnosing acute lead poisoning, while the extent of past lead exposure can be estimated by determining the body burden of lead based on results from the edetate (EDTA) calcium disodium (CaNa₂EDTA) lead mobilization test. The kidney excretes lead by glomerular filtration and tubular secretion. Lead has bidirectional transport across the tubular epithelium. The clearance of lead ranges from 1-3 mL/min and is relatively independent of kidney function.

Toxicokinetics

Nephrotoxicity results because the kidney is the main route of elimination of lead. Lead is absorbed by the proximal tubular cells of the renal tubules, where it binds to specific lead-binding proteins. With acute lead nephrotoxicity, these lead-protein complexes are observed as typical intracellular inclusions. Individual differences in susceptibility to lead poisoning may lie in genetic variability of the lead-binding proteins.

Lead accumulates in the mitochondria and causes both structural and functional alterations. The effects include mitochondrial swelling and the inhibition of respiratory function and energy (adenosine triphosphate) production. Consequently, energy-dependent processes, including tubular transport, are impaired. Mitochondrial enzymes, such as aminolevulinic acid synthase and ferrochelatase, are also inhibited by lead. Lead affects a heme-containing hydroxylase enzyme, which converts 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D. The lead-binding proteins are postulated to facilitate the movement of lead across the mitochondrial membranes. Removal of lead using chelation therapy reverses the proximal reabsorptive defect and removes the intranuclear inclusion bodies of acute lead nephropathy.

Chronic lead nephropathy is frequently associated with gout and hypertension. In a 1993 study by Cardenas et al of workers exposed to a lead pollutant in a battery factory, the renal excretion of 6-keto-prostaglandin factor 1-alpha (a vasodilator) was reduced in patients who had been exposed to lead. In addition, they had enhanced excretion of thromboxane (a vasoconstrictor). The postulation was that the decrease in the synthesis of ecosanoids may contribute to the pathophysiology of hypertension and may make the kidney more vulnerable to the effects of drugs that reduce the synthesis of locally produced vasodilators, such as nonsteroidal anti-inflammatory drugs.

Lead may have direct effects on arterial smooth muscle through its interference with calcium metabolism. Abnormalities in the renin-angiotensin axis are also described with lead poisoning. Finally, some observations indicate that lead stimulates the sodium-lithium countertransport system in the same direction as observed in essential hypertension.

With lead nephropathy, uric acid excretion is disproportionally lower than expected for the patients' glomerular filtration rate (GFR). Studies have suggested enhanced reabsorption and reduced secretion of uric acid, explaining the high prevalence of gout. Altered purine metabolism or increased nucleoprotein metabolism is also implicated.

Frequency

United States

Toxic nephropathies are estimated to cause less than 1% of all end-stage kidney disease. The exact incidence and prevalence of lead nephropathy is not known, although 3 million workers in the United States are at risk for toxic lead exposure. Data from the Third National Health and Nutrition Assessment Survey (NHANES III), Phase 2, on the epidemiology of childhood lead poisoning indicate that the geometric mean blood lead level in children aged 1-5 years is 2 mcg/dL. An estimated 7.6% of children in the United States have blood lead levels equal to or greater than 10 mcg/dL.

Low socioeconomic status is also a risk factor for lead exposure. Blood lead levels are higher in developing countries because of continued use or later phaseout of leaded gasoline and paint. Occupational exposure in these countries is higher as well.

• Occupational lead exposure: In 1987, Pinto de Almeida et al compared the kidney function of 52 primary lead smelter workers (mean blood lead level, 64.1 mcg/dL) with that of 44 control workers (mean blood lead level, 25.5 mcg/dL). Seventeen (32.7%) lead workers had a serum creatinine value higher than 1.5 mg/dL, compared with only 1 of the control workers. Also in 1987, Verschoor et al compared the kidney function of 155 lead workers and 125 control patients and found several markers of tubular function to be affected by lead. Less severe occupational exposure (blood lead levels, <60 mcg/dL) is rarely associated with nephrotoxicity, as was demonstrated by Chia et al in 1995, among others.
• Environmental lead exposure: Environmental lead exposure, with blood lead levels of less than 10 mcg/dL, has also been correlated with kidney function abnormalities. A study of 965 men and 106 women from Belgium found that a 10-fold increase in blood lead levels was associated with a 10- to 13-mL/min reduction in creatinine clearance (CrCl). A cross-sectional analysis of the relationship of CrCl and blood lead levels in the Normative Aging Study also found that an increase of 10 mcg/dL in blood lead levels was associated with a 9% reduction in CrCl. A longitudinal analysis of the Normative Aging Study found that a 10-fold increase in blood lead levels predicted a 0.08 mg/dL increase in serum creatinine levels. Payton et al in 1994 and Kim et al in 1996 concluded that low-level lead exposure is associated with impairment of kidney function.

Mortality/Morbidity

• Acute lead nephropathy is usually completely reversible with chelation therapy.
• Deaths may result from the elevated intracranial tension associated with lead encephalopathy.
• Patients with chronic lead nephropathy may have a progressive decline in kidney function and eventually require renal replacement therapy.

Race

• The NHANES III data have shown higher lead levels among non-Hispanic blacks and Mexican Americans. Whether this translates into a higher incidence of lead nephropathy among these persons is not known.

Sex

• Because of occupational exposures, men have higher lead levels than women.
• The prevalence or incidence of lead nephrotoxicity in different sexes is not known.
• No sex difference in incidence is reported in children.

Age

• Acute lead poisoning and consequent nephropathy is usually observed in children aged 3 months to 6 years. Risk factors for children include mouthing behavior, pica, living in the inner city, living in older housing, and poor nutrition. Lead toxicity in adults is often the consequence of occupational lead exposure, although many cases result from exposures secondary to hobbies and related activities. Acute massive exposure in adults commonly occurs from inhalation of lead fumes.
• Chronic lead nephropathy is usually a result of years of repetitive or continuous lead exposure and, thus, manifests in adulthood. Older adults have greater risk of potential exposure to lead throughout their lives. Lead is stored in the bones. In elderly individuals, bone resorption from processes such as osteoporosis may release the stored lead and cause nephrotoxicity, hypertension, and cognitive decline. Similarly, lactation, pregnancy, hyperparathyroidism, and prolonged immobilization may mobilize bone lead.
• Childhood lead exposure leading to subsequent chronic nephropathy has been reported from Queensland, Australia. In 1954, Henderson reported on 401 individuals diagnosed with lead poisoning from 1915-1934. Of these, 165 had died, 108 from hypertension or nephritis. However, studies from the United States have failed to show any kidney impairment as long as 35 years after childhood poisoning; but, nonetheless, a correlation between childhood lead poisoning and subsequent hypertension and tubular defects has been reported.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Acute lead nephropathy
• • Children aged 3 months to 6 years usually develop acute lead poisoning because of pica.
  • Adults may develop acute poisoning from high-dose respiratory exposure.
  • Manifestations may be highly varied, with multisystem involvement common.
    • Gastrointestinal - Colic, anorexia, nausea, vomiting, and constipation
    • Neurological - Headache, tremor, dizziness, malaise, extensor paralysis, mononeuritis, mental impairment, convulsions, and coma
    • Kidney - Fanconi syndrome, azotemia, isolated proximal tubular defects, rickets, or osteomalacia (Delayed nephrotoxicity [ie, chronic tubulointerstitial nephritis] may develop in some patients.)
    • Hematological - Anemia
    • Miscellaneous - Muscle weakness
• Chronic lead nephropathy
• • Kidney failure develops from years of continuous or intermittent lead exposure. Occasionally, chronic lead nephropathy may manifest in survivors of childhood lead poisoning. The diagnosis of chronic lead nephropathy is one of exclusion of other diseases.
  • More than 50% of the patients with lead nephropathy manifest saturnine gout. Even though hyperuricemia is universal with renal insufficiency, gout is rare unless the patient has underlying lead nephropathy. In fact, tests for estimating lead burden should be considered in every patient with the combination of chronic kidney disease and gout.
  • Hypertension, of relatively new onset, is present in most patients.
• Lead and hypertension
• • Epidemiological evidence has linked hypertension and lead poisoning. Lead workers have been shown to have higher systolic and diastolic blood pressures in several studies. Mortality data show that death from hypertensive cardiovascular disease is more frequent among lead workers than the general population.
  • Exposure to lower concentrations of lead, such as via environmental sources, has also been linked to hypertension. The NHANES III data showed an association between blood lead levels and systolic and diastolic blood pressure regardless of the subject's race or sex. An increase in blood lead levels from 14 mcg/dL to 30 mcg/dL resulted in an increase of 7 mm Hg in mean systolic blood pressure and 3 mm Hg in mean diastolic blood pressure. Similar conclusions were reached by a British study of 7371 middle-aged men and a number of smaller studies performed throughout the world. A meta-analysis of 15 epidemiological studies from 1985-1993 by Schwartz indicated a consistent effect of lead on blood pressure; an average decease of blood lead levels from 10 mcg/dL to 5 mcg/dL was associated with a decrease in blood pressure of 1.25 mm Hg.
  • The Normative Aging Study found no association between blood lead levels and hypertension. However, bone lead levels were correlated positively with hypertension. The correlation of hypertension with bone lead suggests that the hypertensive effect of lead may depend on the cumulative lifetime dose of lead.
  • Lead may also contribute to the disproportionate representation of African American men with hypertensive nephrosclerosis and diabetic nephropathy in end-stage renal disease programs in the United States.

Physical

• Acute lead nephropathy
• • Most patients present with neurological manifestations; kidney involvement is detected incidentally. Neurological findings include irritability, impairment of memory, poor attention span, tremors, and signs of increased intracranial pressure. Peripheral neuropathy, especially motor axonopathies, may develop, causing wrist drop or foot drop.
  • A gingival lead line may be observed, especially in adults.
  • Patients may have transient hypertension.
  • Findings of anemia, including pallor, may be noted.
• Chronic lead nephropathy
• • This disease has no characteristic findings.
  • Most patients are hypertensive at diagnosis.
  • Anemia is common.
  • Acute gouty arthritis may be present.
  • Eventually, with progression of kidney disease, uremic manifestations may develop.

Causes

Exposures to lead can occur from a multitude of sources, including occupational and environmental exposure, hobbies, and a variety of miscellaneous causes. The most significant exposure in adults usually occurs at the workplace, while for children, environmental exposure is most important. Although lead toxicity can occur after a single event, it is usually a result of chronic exposure.

• Occupational lead exposure
• • Sites and occupations associated with lead exposure include pipe cutting, lead mining and ore crushing, lead and copper smelting, welding operations, construction, the rubber industry, the plastic industry, radiator repair, battery manufacturing, soldering of lead products, the printing industry, glass manufacture, organic lead production, solid waste combustion, frit manufacture, and paint and pigment manufacture.
  • Lead workers may expose family members to lead by transporting lead dust from the workplace to their homes.
• Environmental lead exposure
• • Exposure from lead-based paint was significant among children in the past. Although banned from use in residential paint, lead continues to be used in nonresidential settings, and, due to its past use, lead paint can still be found in many older homes.
  • Leaded gasoline contaminates the atmosphere. Although lead has been removed from gasoline in Western countries, leaded gasoline continues to be used in the developing world.
  • Water remains an important source of lead poisoning because lead from the atmosphere contaminates bodies of water. The nature of plumbing also may be important in this regard. Although use of lead pipes (largely replaced by copper or polyvinyl pipes) has declined considerably since the 1950s, old public water systems continue to have networks of lead pipe plumbing. Because the use of lead-based soldering of copper pipes was permitted until 1986, homes with copper plumbing may have substantial lead in the water.
  • Soil contamination with lead, as occurs in soil surrounding lead smelters and in homes from deterioration of exterior surfaces, can be an important source of exposure.
  • Food has been an important source of lead exposure. Surface contamination of homegrown vegetables, storage cans with lead solder seams (banned in 1991), and kitchenware are sources of lead contamination in food. 
• Hobbies and related activities: Hobbies, such as glazed pottery making, target shooting at firing ranges, lead soldering, painting, and home remodeling, may result in lead exposure.
• Miscellaneous
• • Lead is found in several folk remedies and health foods.
  • Topical agents that contain lead, such as kohl and surma, may be ingested accidentally.
  • Moonshine ethanol (ie, illegally distilled corn whiskey) made in lead-containing vessels, such as discarded automobile radiators, has been associated with lead poisoning and even local epidemics.
  • Huffing (ie, deeply inhaling fumes to achieve a "high") of leaded gasoline could also cause poisoning.
  • Retained lead bullets and pellets may gradually release lead into body fluids.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The diagnosis of lead nephropathy requires a high index of suspicion. Most important is obtaining a detailed history that includes occupational or environmental lead exposure, followed by the measurement of total body burden of lead. In 1973, Emmerson suggested the following diagnostic criteria for chronic lead nephropathy: (1) features of long-standing, slowly progressive chronic kidney disease; (2) moderate-to-considerable contraction of both kidneys; (3) definitive evidence of excessive past lead exposure; and (4) exclusion of alternative causes for chronic kidney disease.
• CBC count
• • A CBC count may serve to identify lead suppression of hematopoiesis and anemia of chronic kidney disease.
  • Peripheral blood smear analysis may show a hypochromic microcytic anemia and basophilic stippling in red blood cells.
• Chemistries
• • Acute lead nephrotoxicity is associated with hypophosphatemia and non–gap metabolic acidosis secondary to Fanconi syndrome and occasionally even hypocalcemia.
  • Chronic lead nephrotoxicity causes loss of kidney function and consequent elevated blood urea nitrogen and creatinine levels. Hyperuricemia is common.
• Heme enzymes
• • Erythrocyte aminolevulinic acid dehydratase (ALAD) activity is strongly inhibited by lead because lead oxidizes ALAD's sulfhydryl group and removes zinc from its active site. Consequently, ALAD activity levels are decreased in persons with lead poisoning. Iron deficiency can increase ALAD activity and may mask the lead-induced inhibition of ALAD activity at least in the initial stages; thus, determining iron reserves before examining ALAD activity levels is important.
    
    
    • Uremic patients, besides those with lead exposure, may also have lower ALAD activity. The ratio of ALAD to restored ALAD has been suggested as a superior marker of chronic lead exposure.
    • Erythrocyte ALAD levels can be restored by replacing the lead with zinc and by the negative sulfhydryl donor, dithiothreitol. Restored ALAD is increased following exposure to lead, presumably as a compensatory effect. In a 2002 study, Fontanellas et al found that patients with a history of chronic lead exposure and those with renal failure and positive EDTA chelation test results showed a marked reduction in the ratio of ALAD to restored ALAD (0.16 and 0.19, respectively). In contrast, normal controls and patients with chronic kidney disease and normal lead excretion (ratio 0.5 and 0.47) had higher ratios.
    • Inhibition of ALAD results in an increase in blood and urinary concentrations of aminolevulinic acid. The urinary excretion of aminolevulinic acid has also been widely used as a measure of the biologic effect of lead in workers who are occupationally exposed.
  • Similarly, heme enzymes, such as zinc-protoporphyrin and free erythrocyte protoporphyrin, are known to be altered by lead and have been used in the past for lead detection. Results from these tests reflect lead exposure in the previous 3 months (approximate life of a red blood cell) and cannot be used to assess the body burden of lead. Furthermore, erythrocyte protoporphyrin levels are elevated in persons with iron deficiency anemia.
• Urinary markers
• • Chronic lead nephropathy occurs as a progressive interstitial nephropathy, which is difficult to diagnose at an early stage. Urinary analysis shows mild-to-moderate proteinuria. Blood urea nitrogen levels, serum creatinine values, and the GFR are abnormal only in late stages of nephropathy, when the changes are already irreversible.
  • A number of potential markers of early kidney changes have been studied in individuals exposed to lead. Of the early markers of nephrotoxicity, urinary N-acetyl-beta-D-glucosaminidase excretion has been shown to increase in early lead nephropathy. However, more recent studies have questioned its usefulness as a marker of chronic lead nephropathy, reporting that the elevation in urinary N-acetyl-beta-D-glucosaminidase activity may be an overly sensitive indicator and the rise could be secondary to concomitant cadmium exposure and even may be secondary to a sharp increase in lead burden, rather than cumulative exposure of lead.
  • The renal excretion of 6-keto-prostaglandin factor 1-alpha is reduced in patients exposed to lead, and excretion of thromboxane is enhanced.
• Blood lead level
• • In the United States, the average blood lead level in unexposed individuals is 3 mcg/dL. Medical surveillance is needed for children when their blood level exceeds 10 mcg/dL.
  • Acute lead poisoning is recognized when classic symptoms of acute intoxication are present and the blood lead level is elevated (>40 mcg/dL). When the blood lead level exceeds 150 mcg/dL, encephalopathy is common and may be accompanied by fatal seizures. However, blood lead levels correlate best with recent exposure, and a normal value does not exclude remote exposure with an increased body burden of lead. Thus, blood lead levels are not useful for investigating chronic lead nephropathy.
  • The best measure for assessing the total accumulation of lead in the body is CaNa₂EDTA lead mobilization test.
• CaNa₂EDTA lead mobilization test
• • The test is performed by administering 2 g of CaNa₂EDTA intramuscularly in 2 divided doses 12 hours apart or 1 g intravenously and collecting urine for 24 hours. Patients with kidney disease should collect urine over 3-6 days. EDTA is a chelation agent for lead sequestered in 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 mcg of lead over the collection period. 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 8 hours. A positive mobilization test result is a ratio of the dose of EDTA administered (in mg) to the quantity of lead excreted (in mcg) of greater than 0.6.

Imaging Studies

• Kidney ultrasound: Kidneys are contracted with chronic lead nephropathy.
• X-ray fluorescence
• • X-ray fluorescence (XRF) is a safe, noninvasive, and reliable technique to measure lead in the skeleton. XRF works by emitting x-rays at bone to activate electrons in different electron shells. Lead atoms respond to x-ray excitation by fluorescing, with greater fluorescence associated with higher concentrations of lead. The photons are collected in a detector and counted, yielding an estimate of bone lead.
  • Two types of XRF are used. L-line XRF stimulates electrons in the L electron shell, whereas K-line XRF acts only on electrons in the K shell. The L-line XRF uses weakly penetrating radiation, and measurements reflect lead in the subperiosteal bone, which is a mobilizable compartment of lead. Accurate calibration is somewhat difficult with this technique. The latter technique permits detection of lead molecules from the full thickness of bone and allows accurate assessment of the lead-to-calcium ratio. The exposure to radiation in this technique is much less compared with that of a conventional x-ray film.
  • The XRF technique to determine skeletal lead stores has been proposed as an epidemiological tool to help screen large populations because the CaNa₂EDTA mobilization test is too cumbersome, invasive, and expensive to be used in the general population.

Procedures

• Bone lead measurements
• • More than 90% of the total burden of lead is in bone, with 70% in dense bone. Therefore, a direct measurement of dense bone lead content can be an accurate diagnostic test.
  • In 1988, Wedeen et al suggested that iliac crest bone lead-to-calcium ratios exceeding 100 X 10^-6 and transiliac lead-to-calcium ratios exceeding 140 X 10^-6 are consistent with the diagnosis of lead nephropathy. However, data from Antwerp, Belgium, have demonstrated that the chelation test provides as accurate an estimate of body lead burden when compared with transiliac biopsy results. Thus, bone biopsies are not indicated for the diagnosis of lead poisoning.
• Kidney biopsy: Kidney biopsy is not needed for diagnosis. Results may show nonspecific changes of a chronic tubulointerstitial nephritis.

Histologic Findings

The potential effects of lead extend from reversible proximal tubular changes to interstitial nephritis and chronic kidney disease.

Acute lead nephropathy

The characteristic histological finding is the presence of acid-fast nuclear inclusion bodies in the proximal tubular cells, which are lead-protein complexes. Three types of characteristic changes in the nuclei are described: (1) lead-induced nuclear inclusion bodies, (2) clumped granular chromatin, and (3) pseudo inclusions or nuclear invagination of cytoplasmic contents.

Other ultrastructural changes include swollen mitochondria in the tubular lining cells, with distorted cristae. Endoplasmic reticula are swollen and increased in number. Lysosomes are often numerous, some of which may have a laminated appearance and may contain dense bodies of varying sizes. Brush border structures are distorted, with a reduced number of microvilli or with swollen microvilli. Most of these histopathologic changes are reversible with treatment.

Chronic lead nephropathy

Changes in chronic lead nephropathy are nonspecific. Macroscopically, kidneys appear contracted and have a granular surface. The cut surface shows general loss of cortical tissue, corticomedullary demarcation, and vascular markings. The pyramids are small but intact.

Upon histopathologic analysis, the tissue shows varying degrees of relatively acellular interstitial nephritis. Areas of dilated tubules alternate with atrophic tubules, rendering a granular appearance to the kidney surface. A large proportion of glomeruli are lost without leaving a trace, which is a characteristic feature. The remaining glomeruli are irregularly distributed, some with periglomerular fibrosis.

Glomerular cells have nonspecific abnormalities, such as occasional swelling and distortion of organelles in the cytoplasm, but have normal basement membranes. The glomeruli also show adhesive glomerulitis, with damage varying from single adhesions to complete obliteration of the capsular space. The inclusion bodies described in acute lead nephropathy are usually absent. The vessels show arteriolar nephrosclerotic changes. Immunofluorescence reveals a variety of immunoglobulin deposits in glomerular capillaries and tubular basement membranes, suggesting a role for immune mechanisms.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

The most important step in treatment is to prevent further exposure to lead. Accurate assessment of environmental and occupational exposure is essential. Modifying children's behavior to decrease hand-to-mouth activity is beneficial.

The US Occupational Safety and Health Administration has recommendations for occupational lead exposure. Under these guidelines, the permissible exposure limit is 50 mcg/m³ for an 8-hour, time-weighted average. Workers with blood lead levels greater than or equal to 60 mcg/dL must be removed from the work place. Additionally, employees should be removed from the work place if the average of their last 3 blood lead levels is 50 mcg/dL or greater. Individuals with blood lead levels greater than or equal to 40 mcg/dL must undergo medical evaluation.

Community-wide preventive actions are recommended when children are found to have blood lead levels greater than or equal to 10 mcg/dL. With blood lead levels from 15-19 mcg/dL, nutritional and educational interventions are recommended. With blood lead levels greater than or equal to 20 mcg/dL, medical evaluations and environmental interventions are recommended.

• Acute lead poisoning and nephropathy
• • With acute lead poisoning, obtain a plain radiograph of the abdomen. If suggestive radiopacities are observed, gastric lavage, cathartics, or whole bowel irrigation may be used to limit absorption.
  • The indications for chelation therapy are well defined with acute lead poisoning.
  • Institute chelation therapy in children with lead levels greater than or equal to 45 mcg/dL. Treat children with levels greater than or equal to 70 mcg/dL as medical emergencies.
  • • Succimer and penicillamine are oral chelation agents. Penicillamine may be used when blood lead levels are 25-40 mcg/dL, especially with a negative CaNa₂EDTA mobilization test result. Succimer may be an alternative; its main indication is in persons with blood lead levels greater than or equal to 45 mcg/dL.
    • Intravenous therapy is preferable with blood lead levels greater than or equal to 70 mcg/dL. Use the combination of British antilewisite (BAL) and CaNa₂EDTA with blood lead levels greater than or equal to 70 mcg/dL and in the presence of lead encephalopathy.
    • The CaNa₂EDTA lead mobilization test is useful for identifying patients in whom therapy will be successful.
  • In adults, consider chelation therapy for patients with blood lead levels greater than or equal to 70 mcg/dL. Also consider chelation therapy in symptomatic adults with blood lead levels exceeding 50 mcg/dL.
  • • Available chelation agents for adults are BAL and CaNa₂EDTA.
    • Penicillamine and succimer do not have US Food and Drug Administration approval for treatment, although they are effective treatments.
  • Chelation therapy reverses Fanconi syndrome, transient hypertension, and tubular structural changes observed on histopathology findings.
• Chronic lead nephropathy
• • Patients with chronic lead nephropathy, in the absence of marked interstitial fibrosis and with only minimal impairment in kidney function, may respond to chelation therapy.
  • Extremely limited data are available regarding the benefits of chelation therapy with documented lead nephropathy. In 1979, Wedeen et al treated patients with occupational lead nephropathy and found a 20% improvement in the GFR in 4 of 8 patients administered EDTA 3 times a week for 6-50 months. The reported improvements in kidney function could be from reversal of acute on chronic lead nephropathy.
  • Lin and coworkers from Taiwan performed 3 well-designed studies addressing populations of patients with high-normal lead levels and chronic kidney disease.
  • • The first of these studies included 32 subjects with chronic kidney disease (serum creatinine level of 1.5-4 mg/dL) and mildly elevated lead burden (lead excretion value of 150-600 mcg with the 3-d CaNa₂EDTA lead mobilization test). Subjects were randomized to receive EDTA chelation therapy or placebo weekly for 2 months and were followed for an additional 12 months. The reciprocal of serum creatinine (1/Cr) versus time data suggested that using chelation may slow the progression of renal disease.
    • The same group published results of chelation therapy in 36 subjects (24 study group subjects and 12 controls) with serum creatinine values of 1.5-4 mg/dL and high-normal bone lead burden. This time, chelation therapy with CaNa₂EDTA was administered weekly for 3 months. The treated group had an improvement in CrCl of as much as 10.2%, while kidney function declined by as much as 11% in the control group at 1 year.
    • The third study by Lin et al was published in 2003 and included 202 subjects who were followed for 2 years. Sixty-four with a high-normal body lead burden (urinary lead excretion >80 mcg and <600 mcg after 1 g of CaNa₂EDTA infusion) and serum creatinine levels of less than 4.2 mg/dL were randomized to chelation or placebo. In the initial 3 months, the chelation group received 1 g of CaNa₂EDTA every week and the controls received placebo. In the ensuing 24 months, repeated chelation therapy was administered weekly to patients with high-normal lead unless upon repeated testing the body lead burden fell below 60 mcg. The GFR increased by 11.9% (3.4 mL/min) versus a 3.6% (-1 mL/min) decline in the control group (P<.001) at the end of the initial 3 months. Thereafter, no further improvement in the GFR was observed in these patients.
    • At the end of 27 months, the mean change in GFR was +2.1 mL/min in the chelation group and -6 mL/min in the control group (P<.001) over the 27-month study.
  • These studies suggest that in patients with increased lead burden, chelation with small doses of CaNa₂EDTA at longer intervals might be safe for treating chronic kidney disease. However, repeated and chronic exposure to CaNa₂EDTA may create its own nephrotoxicity; therefore, use caution when deciding to institute chelation therapy. Exclude other causes of kidney disease, and define an endpoint of therapy, such as normalization of the CaNa₂EDTA test results and/or improvement in kidney function.

Consultations

• Toxicologist
• Nephrologist

Diet

The diet should be adequate in energy (caloric) intake and replete in calcium, zinc, and iron. Data from the Normative Aging Study suggest 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 lead levels in blood in subjects who range in age from middle-aged to elderly. Similar data associate calcium and iron deficiency with lead absorption in children. Although no studies have specifically addressed treatment of lead exposure with calcium and iron supplementation, it is a logical therapy to help limit the absorption of lead.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The mainstay of treatment is chelation therapy. Chelation agents contain sulfhydryl groups that bind lead, and the resulting complex is excreted either renally or hepatically. Oral chelation agents are succimer and penicillamine, while dimercaprol and CaNa₂EDTA are administered parenterally.

Drug Category: Chelation agents

Reduce blood levels and depot stores in lead poisoning.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Take care to prevent further lead exposure.
• Chelation therapy, either oral or intravenous, may be continued in an outpatient setting if indicated. Carefully monitor kidney and liver function during therapy.
• All occupational exposures must be reported to the US Occupational Safety and Health Administration, and childhood cases must be reported to local health authorities.

Transfer

• Transfer of patients may be indicated if appropriate facilities for treatment are not available.

Deterrence/Prevention

• Primary prevention of lead poisoning includes all methods to prevent lead exposure.
• • Environmental measures include abatement of lead paint usage, removal of lead from gasoline, and removal of lead solder from cans. Lead abatement in dwellings must be performed by skilled and experienced workers.
  • Occupational measures focus on engineering controls, such as isolation by containment and local exhaust systems, personal protective equipment (eg, respirators), and good work practices.
• The US Occupational Safety and Health Administration standards should be followed in the work place.
• • These standards for permissible exposure limit lead in the workplace to a maximum of 50 mcg/m³ of air averaged over an 8-hour period.
  • Medical surveillance is indicated when workers are exposed to lead levels exceeding 30 mcg/m³ for more than 30 days per year (regardless of respiratory protection).
  • Workers should be educated regarding the health risks of lead and sources that may cause poisoning.
• Efforts to prevent lead poisoning have focused primarily on secondary prevention because the cost of primary prevention in the form of environmental inspection and abatement of all homes and other sources of lead is prohibitive. This does not underscore the importance of primary prevention.
• Secondary prevention focuses on the early detection of lead poisoning.
• • The US Centers for Disease Control and Prevention (CDC) have devised a screening questionnaire to determine which children are at high risk for lead poisoning. The CDC recommends universal screening of blood lead levels for all children receiving Medicaid or the Supplemental Food Program for Women, Infants, and Children (WIC) in areas in which more than 27% of the houses were built before 1950 and in populations in which the 1- and 2-year-old children have elevated lead levels of greater than 12%. Targeted screening based on risk assessment is recommended for all other children.
  • Medical evaluation, treatment, and environmental and public health follow-up are essential in individuals with elevated blood lead levels.

Complications

• Central nervous system: Neuropsychiatric problems, impaired cognition, learning difficulties, and antisocial behavior are described in both children and adults.
• Peripheral nervous system: Lead selectively affects motor axons, causing segmental demyelination and axonal degeneration. The upper extremities are affected more often than the lower extremities, and extensors are affected more often than flexors. Hand drop and foot drop are common manifestations of axonopathy.
• Anemia: Inhibition of enzymes in the heme synthetic pathway, including aminolevulinic acid synthase, ALAD, and ferrochelatase, causes anemia. With kidney disease, erythropoietin production is impaired and, thus, causes anemia.
• Bone disease
• • Lead can interfere with bone development, leading to the formation of lead lines at bone metaphyses. These lines represent periods of growth arrest, not lead, per se.
  • Lead interferes with the conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D and causes rickets or osteomalacia. Patients with Fanconi syndrome may develop vitamin D–resistant rickets.
• Reproductive system: Lead is a known reproductive toxin. In males, it causes reductions in sperm count and fertility. In females, it increases the risk of spontaneous abortions, stillbirths, and preterm births. Offspring may experience lead poisoning in utero and may have developmental delay. Recent research has demonstrated that these reproductive effects occur at relatively low levels of exposure, even those that were previously considered safe. Skeletal lead may be mobilized during pregnancy and lactation and can be transported to the fetus or the neonate.
• Renal cancer: An increased prevalence of renal adenocarcinoma is reported among lead workers. Variability in individual susceptibility may be explained by differences in lead-binding proteins.

Patient Education

• Workers should be educated regarding the health risks of lead and sources that may cause poisoning.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to report all occupational exposures to the US Occupational Safety and Health Administration
• Failure to report childhood cases to local health authorities

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Kidney biopsy results from a patient with chronic lead nephropathy show nonspecific tubular atrophy and interstitial fibrosis. Note the absence of an interstitial infiltrate. The one glomerulus included in the section is normal. Courtesy of Vecihi Batuman, MD, FACP.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• American Academy of Pediatrics Committee on Environmental Health. Screening for elevated blood lead levels. Pediatrics. Jun 1998;101(6):1072-8. [Medline].
• Batuman V. Lead nephropathy, gout, and hypertension. Am J Med Sci. Apr 1993;305(4):241-7. [Medline].
• Bennett WM. Lead nephropathy. Kidney Int. Aug 1985;28(2):212-20. [Medline].
• Brewster UC, Perazella MA. A review of chronic lead intoxication: an unrecognized cause of chronic kidney disease. Am J Med Sci. Jun 2004;327(6):341-7. [Medline].
• 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. Nov 1980;22(11):741-50. [Medline].
• 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. Jan 1993;50(1):28-36. [Medline].
• Centers for Disease Control and Prevention. Blood lead levels in young children--United States and selected states, 1996-1999. Morb Mortal Wkly Rep. Dec 22 2000;49(50):1133-7. [Medline].
• Centers for Disease Control and Prevention. Update: blood lead levels--United States, 1991-1994. Morb Mortal Wkly Rep. Feb 21 1997;46(7):141-6. [Medline].
• 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. Jan 15 2001;153(2):164-71. [Medline].
• Cheng Y, Willett WC, Schwartz J, et al. Relation of nutrition to bone lead and blood lead levels in middle-aged to elderly men. The Normative Aging Study. Am J Epidemiol. Jun 15 1998;147(12):1162-74. [Medline].
• 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. Jun 1995;27(6):883-95. [Medline].
• Chisolm JJ Jr. BAL, EDTA, DMSA and DMPS in the treatment of lead poisoning in children. J Toxicol Clin Toxicol. 1992;30(4):493-504. [Medline].
• Chisolm JJ Jr. The road to primary prevention of lead toxicity in children. Pediatrics. Mar 2001;107(3):581-3. [Medline].
• Chow KM, Liu ZC, Szeto CC. Lead nephropathy: early leads from descriptive studies. Intern Med J. Oct 2006;36(10):678-82.
• Clark CS, Thuppil V, Clark R, et al. Lead in paint and soil in Karnataka and Gujarat, India. J Occup Environ Hyg. Jan 2005;2(1):38-44.
• Craswell PW, Price J, Boyle PD, et al. Chronic lead nephropathy in Queensland: alternative methods of diagnosis. Aust N Z J Med. Feb 1986;16(1):11-9. [Medline].
• Ekong EB, Jaar BG, Weaver VM. Lead-related nephrotoxicity: a review of the epidemiologic evidence. Kidney Int. Dec 2006;70(12):2074-84.
• Emmerson BT. Chronic lead nephropathy. Kidney Int. Jul 1973;4(1):1-5. [Medline].
• Fels LM, Herbort C, Pergande M, et al. Nephron target sites in chronic exposure to lead. Nephrol Dial Transplant. 1994;9(12):1740-6. [Medline].
• Fontanellas A, Navarro S, Moran-Jimenez MJ, et al. Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure. Am J Kidney Dis. 40(1):43-50. [Medline].
• Gardella C. Lead exposure in pregnancy: a review of the literature and argument for routine prenatal screening. Obstet Gynecol Surv. Apr 2001;56(4):231-8. [Medline].
• Gerhardsson L, Chettle DR, Englyst V, et al. Kidney effects in long term exposed lead smelter workers. Br J Ind Med. Mar 1992;49(3):186-92. [Medline].
• Greenberg A, Parkinson DK, Fetterolf DE, et al. Effects of elevated lead and cadmium burdens on renal function and calcium metabolism. Arch Environ Health. Mar-Apr 1986;41(2):69-76. [Medline].
• Harlan WR. The relationship of blood lead levels to blood pressure in the U.S. population. Environ Health Perspect. Jun 1988;78:9-13. [Medline].
• Henderson DA. A follow-up of cases of plumbism in children. Australas Ann Med. Aug 1954;3(3):219-24. [Medline].
• Hu H. A 50-year follow-up of childhood plumbism. Hypertension, renal function, and hemoglobin levels among survivors. Am J Dis Child. Jun 1991;145(6):681-7. [Medline].
• Hu H, Aro A, Payton M, et al. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA. Apr 17 1996;275(15):1171-6. [Medline].
• Inglis JA, Henderson DA, Emmerson BT. The pathology and pathogenesis of chronic lead nephropathy occurring in Queensland. J Pathol. Feb 1978;124(2):65-76. [Medline].
• Khalil-Manesh F, Gonick HC, Cohen AH, et al. Experimental model of lead nephropathy. I. Continuous high-dose lead administration. Kidney Int. May 1992;41(5):1192-203. [Medline].
• 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. Apr 17 1996;275(15):1177-81. [Medline].
• Kumar BD, Krishnaswamy K. Detection of occupational lead nephropathy using early renal markers. J Toxicol Clin Toxicol. 1995;33(4):331-5. [Medline].
• Landrigan PJ, Todd AC. Lead poisoning. West J Med. Aug 1994;161(2):153-9. [Medline].
• Lane WG, Kemper AR. American College of Preventive Medicine Practice Policy Statement. Screening for elevated blood lead levels in children. Am J Prev Med. Jan 2001;20(1):78-82. [Medline].
• Lin JL, Ho HH, Yu CC. Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency. A randomized, controlled trial. Ann Intern Med. Jan 5 1999;130(1):7-13. [Medline].
• 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. Jan 23 2003;348(4):277-86. [Medline].
• Lin JL, Tan DT, Hsu KH, Yu CC. Environmental lead exposure and progressive renal insufficiency. Arch Intern Med. Jan 22 2001;161(2):264-71. [Medline].
• Loghman-Adham M. Renal effects of environmental and occupational lead exposure. Environ Health Perspect. Sep 1997;105(9):928-39. [Medline].
• Madden EF, Fowler BA. Mechanisms of nephrotoxicity from metal combinations: a review. Drug Chem Toxicol. Feb 2000;23(1):1-12. [Medline].
• 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. Sep 2 1982;307(10):573-9. [Medline].
• Markowitz M. Lead poisoning. Pediatr Rev. Oct 2000;21(10):327-35. [Medline].
• Moel DI, Sachs HK. Renal function 17 to 23 years after chelation therapy for childhood plumbism. Kidney Int. Nov 1992;42(5):1226-31. [Medline].
• Nye LJJ. An investigation of the extraordinary incidence of chronic nephritis in young people in Queensland. Med J Aust. 1929;2:145-59.
• Olivier AO. De l'albuminurie saturnine. Arch Gen Med. 1863;2:530.
• Omae K, Sakurai H, Higashi T, et al. No adverse effects of lead on renal function in lead-exposed workers. Ind Health. 1990;28(2):77-83. [Medline].
• Payton M, Hu H, Sparrow D, Weiss ST. Low-level lead exposure and renal function in the Normative Aging Study. Am J Epidemiol. Nov 1 1994;140(9):821-9. [Medline].
• Perazella MA. Lead and the kidney: nephropathy, hypertension, and gout. Conn Med. Sep 1996;60(9):521-6. [Medline].
• Philip AT, Gerson B. Lead poisoning--Part I. Incidence, etiology, and toxicokinetics. Clin Lab Med. Jun 1994;14(2):423-44. [Medline].
• Philip AT, Gerson B. Lead poisoning--Part II. Effects and assay. Clin Lab Med. Sep 1994;14(3):651-70. [Medline].
• Pinto de Almeida AR, Carvalho FM, Spinola AG, Rocha H. Renal dysfunction in Brazilian lead workers. Am J Nephrol. 1987;7(6):455-8. [Medline].
• 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. Feb 1985;121(2):246-58. [Medline].
• 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. Jun 1988;78:23-30. [Medline].
• Ritz E, Wiecek A, Stoeppler M. Lead Nephropathy. Contrib Nephrol. 1987;55:185-91. [Medline].
• Schwartz J. Lead, blood pressure, and cardiovascular disease in men. Arch Environ Health. Jan-Feb 1995;50(1):31-7. [Medline].
• Sokas RK, Besarab A, McDiarmid MA, et al. Sensitivity of in vivo X-ray fluorescence determination of skeletal lead stores. Arch Environ Health. Sep-Oct 1990;45(5):268-72. [Medline].
• Staessen J, Yeoman WB, Fletcher AE, et al. Blood lead concentration, renal function, and blood pressure in London civil servants. Br J Ind Med. Jul 1990;47(7):442-7. [Medline].
• Staudinger KC, Roth VS. Occupational lead poisoning. Am Fam Physician. Feb 15 1998;57(4):719-26, 731-2. [Medline].
• Tepper LB. Renal function subsequent to childhood plumbism. Arch Environ Health. Jul 1963;158:76-85. [Medline].
• Van de Vyver FL, D''Haese PC, Visser WJ, et al. Bone lead in dialysis patients. Kidney Int. Feb 1988;33(2):601-7. [Medline].
• Verschoor M, Wibowo A, Herber R, et al. Influence of occupational low-level lead exposure on renal parameters. Am J Ind Med. 1987;12(4):341-51. [Medline].
• Wedeen RP. Bone lead, hypertension, and lead nephropathy. Environ Health Perspect. Jun 1988;78:57-60. [Medline].
• Wedeen RP. Lead and hypertension: who cares?. Int J Occup Environ Health. Oct-Dec 2000;6(4):348-50. [Medline].
• Wedeen RP, D''Haese P, Van de Vyver FL, et al. Lead nephropathy. Am J Kidney Dis. Nov 1986;8(5):380-3. [Medline].
• Wedeen RP, Malik DK, Batuman V. Detection and treatment of occupational lead nephropathy. Arch Intern Med. Jan 1979;139(1):53-7. [Medline].
• Wedeen RP, Van de Vyver FL, D''Haese PC, et al. Bone lead and the diagnosis of lead nephropathy. Contrib Nephrol. 1988;64:102-8. [Medline].
• Weeden RP. Poison in the Pot: The Legacy of Lead. Carbondale, Ill: Illinois University Press; 1984.
• Yu TF. Lead nephropathy and gout. Am J Kidney Dis. Mar 1983;2(5):555-8. [Medline].

Article Last Updated: Feb 5, 2008