Lead Nephropathy
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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 patients exposed to lead. In addition, they had enhanced excretion of thromboxane (a vasoconstrictor). 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 3 million workers in the United States are at risk for toxic lead exposure, whether occupational or environmental.
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 μg/dL) with that of 44 control workers (mean blood lead level, 25.5 μg/dL) and found that 17 (32.7%) of the 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 μg/dL) is rarely associated with nephrotoxicity, as was demonstrated by Chia et al, among others.
Environmental lead exposure
Environmental lead exposure, with blood lead levels lower than 10 μg/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 relation between 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 recent study from Taiwan found a higher rate of progression in diabetics with high normal body lead burden. [1]
Payton et al in 1994 and Kim et al in 1996 concluded that low-level lead exposure is associated with impairment of kidney function.
Acute lead poisoning and consequent nephropathy are usually observed in children aged 3 months to 6 years. [2] 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.
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 to 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; however, a correlation between childhood lead poisoning and subsequent hypertension and tubular defects has been reported.
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:
Gastrointestinal (GI) –Colic, anorexia, nausea, vomiting, and constipation
Neurologic – Headache, tremor, dizziness, malaise, extensor paralysis, mononeuritis, mental impairment, convulsions, and coma
Renal – Fanconi syndrome, azotemia, isolated proximal tubular defects, rickets, or osteomalacia (Delayed nephrotoxicity [ie, chronic tubulointerstitial nephritis] may develop in some patients.)
Hematologic – 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 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 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.
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 epidemiologic studies from 1985-1993 by Schwartz indicated a consistent effect of lead on blood pressure; an average decrease in blood lead levels from 10 μg/dL to 5 μg/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.
Most patients with acute lead nephropathy present with neurologic manifestations; kidney involvement is detected incidentally. Neurologic findings include the following:
Irritability
Impairment of memory
Poor attention span
Tremors
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 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:
Features of long-standing, slowly progressive chronic kidney disease
Moderate-to-considerable contraction of both kidneys
Definitive evidence of excessive past lead exposure
Exclusion of alternative causes for chronic kidney disease
The differential diagnosis of lead nephropathy includes the following conditions:
Light Chain-Associated Renal Disorders
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. [3]
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.
In a 2002 study, Fontanellas et al found that patients with a history of chronic lead exposure and those with renal failure and positive ethylenediaminetetraacetic acid (EDTA) chelation test results showed marked reductions 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 (ratios, 0.5 and 0.47) had higher ratios.
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 [4] 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.
More than 90% of the total burden of lead is in bone, with 70% in dense bone. Therefore, 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 × 10-6 and transiliac lead-to-calcium ratios exceeding 140 × 10-6 are consistent with the diagnosis of lead nephropathy. However, data from Belgium have demonstrated that the chelation test provides as accurate an estimate of body lead burden as transiliac biopsy does results. Thus, bone biopsies are not indicated for the diagnosis of lead poisoning.
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.
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:
Lead-induced nuclear inclusion bodies
Clumped granular chromatin
Pseudoinclusions 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 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. [5]
Huang WH, Lin JL, Lin-Tan DT, Hsu CW, Chen KH, Yen TH. Environmental lead exposure accelerates progressive diabetic nephropathy in type II diabetic patients. Biomed Res Int. 2013. 2013:742545. [Medline]. [Full Text].
Mitra AK, Haque A, Islam M, Bashar SA. Lead poisoning: an alarming public health problem in Bangladesh. Int J Environ Res Public Health. 2009 Jan. 6(1):84-95. [Medline]. [Full Text].
Pollack AZ, Mumford SL, Mendola P, Perkins NJ, Rotman Y, Wactawski-Wende J, et al. Kidney biomarkers associated with blood lead, mercury, and cadmium in premenopausal women: a prospective cohort study. J Toxicol Environ Health A. 2015. 78(2):119-31. [Medline]. [Full Text].
Navas-Acien A, Tellez-Plaza M, Guallar E, Muntner P, Silbergeld E, Jaar B, et al. Blood cadmium and lead and chronic kidney disease in US adults: a joint analysis. Am J Epidemiol. 2009 Nov 1. 170(9):1156-64. [Medline]. [Full Text].
Yang SK, Xiao L, Song PA, Xu XX, Liu FY, Sun L. Is lead chelation therapy effective for chronic kidney disease? A meta-analysis. Nephrology (Carlton). 2014 Jan. 19(1):56-9. [Medline].
Adult blood lead epidemiology and surveillance–United States, 2005-2007. MMWR Morb Mortal Wkly Rep. 2009 Apr 17. 58(14):365-9. [Medline]. [Full Text].
Evans M, Fored CM, Nise G, Bellocco R, Nyrén O, Elinder CG. Occupational lead exposure and severe CKD: a population-based case-control and prospective observational cohort study in Sweden. Am J Kidney Dis. 2010 Mar. 55(3):497-506. [Medline].
Pranay Kathuria, MD, FACP, FASN, FNKF Professor of Medicine, Director, Division of Nephrology and Hypertension, Program Director of Nephrology Fellowship, University of Oklahoma School of Community Medicine
Pranay Kathuria, MD, FACP, FASN, FNKF is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Heart Association, American Society of Hypertension, American Society of Nephrology, National Kidney Foundation
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital
Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, Phi Beta Kappa
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc<br/>Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology for asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contract payment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor; Received contract payment from Healthcare Quality Strategies, Inc for independent cont.
Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.
James W Lohr, MD Professor, Department of Internal Medicine, Division of Nephrology, Fellowship Program Director, University of Buffalo State University of New York School of Medicine and Biomedical Sciences
James W Lohr, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Nephrology, Central Society for Clinical and Translational Research
Disclosure: Received research grant from: GSK<br/>Partner received salary from Alexion for employment.
Lead Nephropathy
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