Correspondence
Environmental Lead Exposure and Chronic Renal Disease
N Engl J Med 2003; 348:1810-1812May 1, 2003
- Article
To the Editor:
Lin et al. (Jan. 23 issue)1 implicate lead exposure in the progression of renal disease on the basis of the effect of EDTA chelation. However, there are compelling experimental data implicating iron (mobilized from endogenous sources and participating in free-radical reactions) in a wide variety of immune and nonimmune glomerular diseases,2 as well as models of progressive kidney diseases.3 This evidence includes an increase in catalytic iron and the beneficial effect of iron chelators, an iron-deficient diet, or both.2,3 The affinity constants of complexes of EDTA with Fe2+, Fe3+, Pb2+ are 14.3, 25.1, and 18.0 (log K, which denotes the stability constants of the normal EDTA complexes with metals), respectively.4 Given these affinity constants, as well as the higher tissue content of iron and the demonstrated efficacy of EDTA in enhancing excretion of urinary iron,5 is not the beneficial effect of EDTA more likely to be explained by its chelation of iron rather than lead?
5 ReferencesAli K. Owda, M.D.
Muhammad G. Alam, M.D., M.P.H.
Sudhir V. Shah, M.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205
shahsudhirv@uams.edu 1
Lin J-L ,Lin-Tan D-T ,Hsu K-H ,Yu C-C . Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med 2003;348:277-286
Full Text | Web of Science | Medline2
Shah SV . The role of reactive oxygen metabolites in glomerular disease. Annu Rev Physiol 1995;57:245-262
CrossRef | Web of Science | Medline3
Shah SV . Role of iron in progressive renal disease. Am J Kidney Dis 2001;37:Suppl 2:S30-S33
CrossRef | Web of Science | Medline4
Flaschka HA. EDTA titrations: an introduction to theory and practice. 2nd ed. New York: Pergamon Press, 1964.
5
Cantilena LR Jr ,Klaassen CD . The effect of chelating agents on the excretion of endogenous metals. Toxicol Appl Pharmacol 1982;63:344-350
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To the Editor:
Lin et al. present evidence that a high–normal body lead burden accelerates the progression of nondiabetic chronic renal failure. Moreover, lead-chelation therapy reduced the progression of chronic renal failure. Given the biologic plausibility, these results from Taiwan are probably generalizable to other populations. In the United States, low-income populations and blacks are at particularly high risk for end-stage renal disease.1-3 These groups also have the highest blood lead levels.4 For each age category, the blood lead level is higher for blacks than for whites. Similarly, the age-specific incidence of nondiabetic and diabetic end-stage renal disease is higher for blacks (Table 1Table 1
Incidence Rate and Excess Risk of Nondiabetic and Diabetic End-Stage Renal Disease (ESRD) among Blacks and Whites in the United States, 1997–2000.). The reasons for the excess risk of end-stage renal disease among blacks remain unclear.1 We noted, however, that in the trial by Lin et al., the mean base-line blood lead level (approximately 6 μg per deciliter) was similar to the blood lead level in blacks in several age groups in the United States.4 These findings are consistent with the hypothesis that interventions to reduce the body lead burden may narrow the sociodemographic gap in the incidence of end-stage renal disease in the United States. Since diabetes is the main cause of end-stage renal disease,1,3 studies are needed to assess whether lead-chelation therapy also reduces the progression of diabetic nephropathy.4 ReferencesAntonio A. Lopes, M.D., Ph.D.
Universidade Federal da Bahia, Salvador, BA 40110-100, Brazil
aaslopes@ufba.br Friedrich K. Port, M.D.
University Renal Research and Education Association, Ann Arbor, MI 481031
Lopes AA ,Port FK ,James SA ,Agodoa L . The excess risk of treated end-stage renal disease in blacks in the United States. J Am Soc Nephrol 1993;3:1961-1971
Web of Science | Medline2
Young EW ,Mauger EA ,Jiang KH ,Port FK ,Wolfe RA . Socioeconomic status and end-stage renal disease in the United States. Kidney Int 1994;45:907-911
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Renal Data System. USRDS 2002 annual data report: atlas of end-stage renal disease in the United States. Bethesda, Md.: National Institute of Diabetes and Digestive and Kidney Diseases, 2002.
4
Brody DJ ,Pirkle JL ,Kramer RA , et al. Blood lead levels in the US population: phase 1 of the Third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1991). JAMA 1994;272:277-283[Erratum, JAMA 1995;274:130.]
CrossRef | Web of Science | Medline
To the Editor:
The patients in the study by Lin et al. had blood lead levels that were similar to those in the general populations of Europe and the United States. Also, in occupational health studies, workers exposed to lead who have blood, urine, and bone lead concentrations that are 3 to 10 times as high as those in unexposed controls have not had appreciable renal effects.1,2 The reported association between the body lead burden and the rate of decline in renal function could be explained by confounding. Blood lead in nonexposed persons is well correlated with alcohol consumption, which in turn may influence drug intake (e.g., analgesics). EDTA treatment might be beneficial for the kidneys for other reasons than lead chelation. Cadmium is known to be nephrotoxic and is mobilized by EDTA. Indeed, recent data show that relatively low environmental exposure to cadmium (but not lead) affects renal function3 and suggest that it increases the risk that end-stage renal disease will develop.4
4 ReferencesCarl-Gustaf Elinder, M.D., Ph.D.
Anders Alvestrand, M.D., Ph.D.
Karolinska Institutet, S-141 86 Stockholm, Sweden
anders.alvestrand@klinvet. ki. se 1
Gerhardsson L ,Chettle DR ,Englyst V , et al. Kidney effects in long term exposed lead smelter workers. Br J Ind Med 1992;49:186-192
Medline2
Roels H ,Lauwerys R ,Konings J , et al. Renal function and hyperfiltration capacity in lead smelter workers with high bone lead. Occup Environ Med 1994;51:505-512
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Alfven T ,Jarup L ,Elinder CG . Cadmium and lead in blood in relation to low bone mineral density and tubular proteinuria. Environ Health Perspect 2002;110:699-702[Erratum, Environ Health Perspect 2002;110:A505.]
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Hellstrom L ,Elinder CG ,Dahlberg B , et al. Cadmium exposure and end-stage renal disease. Am J Kidney Dis 2001;38:1001-1008
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Author/Editor Response
Although EDTA could chelate many metals, it is distributed mainly in the extracellular fluid and is rapidly excreted by glomerular filtration.1 Hence, EDTA is not a good iron chelator. In contrast, deferoxamine can effectively chelate iron and enter the intracellular space where iron is mainly deposited.1
There is much evidence that lead is associated with impaired renal function. However, impairment of renal function has not been observed in patients with hemochromatosis, such as iron workers.1 There is no definite evidence that iron exposure, as in patients receiving multiple transfusions, is related to progressive renal diseases in humans.1 On the contrary, deferoxamine chelation therapy causes acute renal failure in children with iron overload.2 Dimercaptosuccinic acid, a lead chelator without iron-chelating ability, is also effective in improving renal function in rats with lead exposure.3 All these findings did not support the speculation that EDTA chelation therapy slows the progression of renal disease through chelation of iron.
We agree that further studies are needed to clarify the effect of an elevated lead burden on renal function in specific groups of patients, such as patients with diabetes and black patients.
Although EDTA treatment increases cadmium excretion in rabbits with exposure to cadmium, severe renal tubular degeneration and necrosis develop. Similar damage occurs in rats and humans.1 Therefore, chelating agents are not recommended in patients with cadmium overload except in life-threatening situations. Hence, the slowed progression of renal insufficiency in our patients is unlikely to have been due to the removal of cadmium. The relation between environmental cadmium exposure and progressive renal disease is controversial. In the Cadmibel study, with a five-year follow-up of nearly 600 persons in Belgium with cadmium exposure, no evidence of progressive renal damage was observed.4 The absence of a history of toxic metal exposure or alcoholism in our patients precludes the significance of these confounding factors.
Many studies have documented an association between occupational exposure to lead and impairment of renal function. Loghman-Adham reviewed 20 studies of occupational lead exposure and concluded that such exposure results in abnormalities in renal function; only 3 studies showed no changes in renal function.5
5 ReferencesJa-Liang Lin, M.D.
Chun-Chen Yu, M.D.
Dan-Tzu Lin-Tan, R.N.
Chang Gung Memorial Hospital, Taipei 105, Taiwan
jllin99@hotmail.com 1
Friberg L, Nordberg GF, Vouk VB, eds. Handbook on the toxicology of metals. 2nd ed. Amsterdam: Elsevier Science, 1986.
2
Koren G ,Bentur Y ,Strong D , et al. Acute changes in renal function associated with deferoxamine therapy. Am J Dis Child 1989;143:1077-1080
Web of Science | Medline3
Khalil-Manesh F ,Gonick HC ,Cohen A ,Bergamaschi E ,Mutti A . Experimental model of lead nephropathy. II. Effect of removal from lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA). Environ Res 1992;58:35-54
CrossRef | Web of Science | Medline4
Hotz P ,Buchet JP ,Bernard A ,Lison D ,Lauwerys R . Renal effects of low-level environmental cadmium exposure: 5-year follow-up of a subcohort from the Cadmibel study. Lancet 1999;354:1508-1513
CrossRef | Web of Science | Medline5
Loghman-Adham M . Renal effects of environmental and occupational lead exposure. Environ Health Perspect 1997;105:928-939
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- Citing Articles (4)
Citing Articles
1
CHARLES RV TOMSON, ROBERT N FOLEY, QI LI, DAVID T GILBERTSON, JAY L XUE, ALLAN J COLLINS. (2008) Race and end-stage renal disease in the United States Medicare population: The disparity persists. Nephrology 13:7, 651-656
CrossRef2
Sundararaman Swaminathan, Sudhir V Shah. (2008) Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease. Current Opinion in Nephrology and Hypertension 17:2, 143-148
CrossRef3
Carolina García Carrasco, Fernando Muñoz Díaz, Antonio Manuel Arranz Carrero, Juan De Dios Arrebola García, Dolores Magro Ledesma. (2007) Saturnismo como causa de dolor abdominal. Gastroenterología y Hepatología 30:10, 618-619
CrossRef4
S SHAH. (2006) Oxidants and Iron in Progressive Kidney Disease. Journal of Renal Nutrition 16:3, 185-189
CrossRef
