Lead is the most notable and best studied environmental nephrotoxicant. Environmental levels of lead have increased as a result of human activities, including the Industrial Revolution, leaded gasoline, lead-based paint, mining operations, plumbing, and other industrial applications.
Acute lead poisoning (blood lead levels > 80–100 μg/dL) disrupts both proximal tubular structure and function. Clinically, acute lead poisoning is characterized by the development of glucosuria, aminoaciduria, phosphaturia, or Fanconi syndrome. The kidney manifestations of acute lead poisoning are usually reversible after cessation of lead exposure and, if indicated, chelation therapy.[1]
Chronic lead poisoning may also result in lead nephropathy, which is characterized by tubulointerstitial fibrosis, tubular atrophy, glomerular sclerosis, and ultimately diminished glomerular filtration rate (GFR). Chronic lead exposure has also been shown to cause hypertension.[1]
Epidemiological studies of the general population have reported associations between blood lead levels (BBLs) < 10 µg/dL increase the risk of chronic kidney disease (CKD), decreased estimated glomerular filtration rate (eGFR) and creatinine clearance. The associations are typically stronger in people with hypertension or diabetes. Individual with BBLs < 10 µg/dL during adulthood may have had higher BBLs earlier in life. It is unknown if blood or bone lead levels are more consistently associated with kidney effects.[2]
The association between lead exposure and GFR was evaluated in North American children with CKD in the Chronic Kidney Disease in Children (CKiD) study. Median blood lead level and measured GFR were 1.2 μg/dL and 44 mL/min/1.73 m2, respectively. The average percentage change in GFR for each 1 μg/dL increase in blood lead level was −2.1 (95% ocnfidence index [CI] −6.0 to 1.8). In analyses stratified by CKD diagnosis, the association between lead level and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1 μg/dL increase in lead level was associated with a −12.1 (95% CI −22.2 to −1.9) percentage change in GFR.[3]
Nephrotoxicity results from lead exposure because the kidney is the main route by which lead is eliminated. 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. The explanation for individual differences in susceptibility to lead poisoning may lie in the 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 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 study of exposure to a lead pollutant in a battery factory, renal excretion of 6-keto-prostaglandin factor 1-alpha (a vasodilator) was reduced in workers exposed to lead. In addition, they had enhanced excretion of thromboxane (a vasoconstrictor).[4] The hypothesis was that decreased synthesis of eicosanoids might contribute to hypertension and make the kidney more vulnerable to drugs that reduce the synthesis of locally produced vasodilators (eg, 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 is observed in essential hypertension.
With lead nephropathy, uric acid excretion is substantially lower than would be expected on the basis of the patient’s 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.
Toxic nephropathies are estimated to cause fewer than 1% of all cases of end-stage kidney disease. The exact incidence and prevalence of lead nephropathy are not known, although the US Occupational Safety and Health Administration (OSHA) estimates that approximately 804,000 workers in general industry and an additional 838,000 workers in construction are potentially exposed to lead.[5]
Environmental lead exposure, with blood lead levels lower than 10 μg/dL, has also been correlated with kidney function abnormalities.[2]
A cross-sectional analysis of the relation between creatinine clearance (CrCl) and blood lead levels in the Normative Aging Study also found that an increase of 10 μg/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. A study from Taiwan found a higher rate of progression in diabetics with high normal body lead burden.[6]
Acute lead poisoning and consequent nephropathy are usually observed in children aged 3 months to 6 years.[7] 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, though 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 the result of years of repetitive or continuous lead exposure and thus tends to manifest in adulthood. Older adults have a 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.
Lead nephropathy may be divided into 2 forms: acute and chronic.
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. The following manifestations have been noted:
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 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 the 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
Epidemiologic evidence has linked hypertension with 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 among the general population.
Exposure to lower concentrations of lead (eg, via environmental sources) has also been linked to hypertension. The National Health and Nutrition Examination Survey III (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 μg/dL to 30 μg/dL resulted in an increase of 7 mm Hg in mean systolic blood pressure and an increase of 3 mm Hg in mean diastolic blood pressure.
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.
Most patients with acute lead nephropathy present with neurologic manifestations; kidney involvement is detected incidentally. Neurologic findings include the following:
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 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.
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:
The differential diagnosis of lead nephropathy includes the following conditions:
A complete blood count (CBC) 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.
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. In a study of 250 healthy premenopausal women with low exposure levels, each twofold rise in lead measured in whole blood (median level 0.88 μg/dl) was associated with a decreased estimated glomerular filtration rate and increased creatinine levels.[8]
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, it is important to determine iron reserves before examining ALAD activity levels.
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 administering the negative sulfhydryl donor dithiothreitol. Restored ALAD is increased after exposure to lead, presumably as a compensatory effect.
Inhibition of ALAD results in an increase in blood and urinary concentrations of aminolevulinic acid. 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 (the approximate lifetime 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.
Chronic lead nephropathy occurs as a progressive interstitial nephropathy, which is difficult to diagnose at an early stage. Urinalysis shows mild-to-moderate proteinuria. Blood urea nitrogen (BUN) levels, serum creatinine values, and the glomerular filtration rate (GFR) are abnormal only in late stages of nephropathy, when the changes are already irreversible.
Several potential markers of early kidney changes have been studied in individuals exposed to lead. One early marker, urinary N-acetyl-beta-D-glucosaminidase excretion, has been shown to increase in early lead nephropathy. However, studies now question its usefulness as a marker, reporting that elevated urinary N-acetyl-beta-D-glucosaminidase activity may be an overly sensitive indicator and that the rise could be secondary to concomitant cadmium exposure[9] or even secondary to a sharp increase in lead burden rather than cumulative exposure to lead.
Renal excretion of 6-keto-prostaglandin factor 1-alpha is reduced in patients exposed to lead, and excretion of thromboxane is enhanced.
In the United States, the average blood lead level in unexposed individuals is 3 μg/dL. Medical surveillance is needed for children whose blood level exceeds 10 μg/dL.
Acute lead poisoning is recognized when classic symptoms of acute intoxication are present and the blood lead level is elevated (> 40 μg/dL). When the blood lead level exceeds 150 μg/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 the calcium disodium edetate (CaNa2 EDTA) lead mobilization test. This test is performed by administering 2 g of the agent intramuscularly (IM) in 2 divided doses 12 hours apart or 1 g intravenously (IV) and collecting urine for 24 hours. Patients with kidney disease should collect urine over 3-6 days.
Ethylenediaminetetraacetic acid (EDTA) is a chelation agent for lead sequestered in body storage sites, and it mobilizes lead for renal excretion in the form of lead-EDTA chelate. Individuals without any unusual previous exposure to lead would excrete less than 650 μg of lead over the collection period. Cumulative excretion that exceeds this amount is indicative of excessive lead burden.
In children, a dose of 30-50 mg/kg of CaNa2 EDTA is administered IM or IV, and urine is collected over 8 hours. A mobilization test result is considered to be positive when the ratio of the dose of EDTA administered (in mg) to the quantity of lead excreted (in μg) is greater than 0.6.
Radiographic fluoroscopy is a safe, noninvasive, and reliable technique for measuring lead in the skeleton. It 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 to obtain an estimate of bone lead.
Two types of radiographic fluoroscopy are used: L-line radiographic fluoroscopy stimulates electrons in the L electron shell, whereas K-line radiographic fluoroscopy acts only on electrons in the K shell.
The L-line technique 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 K-line 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 lower than that associated with conventional radiography.
The use of radiographic fluoroscopy to determine skeletal lead stores has been proposed as an epidemiologic tool for screening large populations, on the grounds that the calcium disodium edetate (CaNa2 EDTA) lead mobilization test is too cumbersome, invasive, and expensive to be used in the general population.
On kidney ultrasonography, kidneys are contracted in patients with chronic lead nephropathy.
Kidney biopsy is not needed for diagnosis. If it is performed, the results may show nonspecific changes characteristic of a chronic tubulointerstitial nephritis. See the image below.
 View Image | Kidney biopsy results from a patient with chronic lead nephropathy show nonspecific tubular atrophy and interstitial fibrosis. Note the absence of an .... |
The potential effects of lead extend from reversible proximal tubular changes to interstitial nephritis and chronic kidney disease.
The characteristic histologic finding of acute led nephropathy is the presence of acid-fast nuclear inclusion bodies in the proximal tubular cells, which are lead-protein complexes. There are 3 types of characteristic changes in the nuclei:
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 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.
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, giving the kidney surface a granular appearance. 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 exhibit 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.
Chelation therapy with calcium disodium ethylenediaminetetraacetic acid (EDTA) has been advocated as a means of decreasing the progression of chronic kidney disease in patients with measurable body lead burdens. This therapy is controversial, however, because of the potential for adverse effects (eg, acute tubular necrosis).
Yang and colleagues found, in a meta-analysis of randomized controlled studies assessing the renoprotective effects of calcium disodium EDTA chelation therapy, that this treatment can delay the progression of chronic kidney disease in patients with measurable body lead burdens by increasing levels of the estimated glomerular filtration rate and creatinine clearance rate.[10]
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.
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.
){kind=link}