eMedicine Specialties > Nephrology > Drug- and Nephrotoxin-Associated Kidney Disorders

Lead Nephropathy

Author: Pranay Kathuria, MD, MBBS, FACP, FASN, Chief, Section of Nephrology, Associate Professor, Department of Internal Medicine, University of Oklahoma College of Medicine at Tulsa
Coauthor(s): Paresh Jadav, MD, Fellow, Department of Medicine, Division of Nephrology and Hypertension, University of Washington School of Medicine
Contributor Information and Disclosures

Updated: Feb 5, 2008

Introduction

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 (CaNa₂ EDTA) 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

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.

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