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• W1965450284 abstract "Related Article, p. 530Given the increasing incidence and prevalence of chronic kidney disease (CKD),1Levey A.S. Atkins R. Coresh J. et al.Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes.Kidney Int. 2007; 72: 247-259Google Scholar, 2Coresh J. Selvin E. Stevens L.A. et al.Prevalence of chronic kidney disease in the United States.JAMA. 2007; 298: 2038-2047Google Scholar approaches to slow disease progression are essential. For more than a decade, Ja-Liang Lin and colleagues have published randomized placebo-controlled clinical trials reporting that treatment with calcium disodium EDTA slows CKD progression. Lead chelation has been implicated as the mechanism, and benefits in diabetic and nondiabetic patients with CKD with mean blood lead levels as low as 2.6 μg/dL have been reported (Table 1). Similar study designs have been used across publications. Initially, patients are observed to compare CKD progression prior to chelation. Then, patients whose chelatable lead levels are within certain ranges (generally 60-600 μg excreted in a 72-hour urine collection after intravenous administration of 1 g of calcium disodium EDTA and thus lower than the level commonly considered for chelation in lead poisoning) are randomly assigned. The treatment group receives weekly calcium disodium EDTA until lead levels decrease to a defined target. The control group receives placebo infusions. In the follow-up period, chelation is repeated for defined indications, such as increased serum creatinine level or chelatable lead levels higher than specified cutoffs. The results of their latest trial,3Chen K.H. Lin J.L. Lin-Tan D.T. et al.Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.Am J Kidney Dis. 2012; 60: 530-538Abstract Full Text Full Text PDF Scopus (26) Google Scholar which is focused on patients with type 2 diabetes with nephropathy, are reported in this issue of the American Journal of Kidney Diseases and are consistent with earlier trials in observing a benefit of calcium disodium EDTA in slowing CKD progression. The present study builds on a 2006 study4Lin J.L. Lin-Tan D.T. Yu C.C. Li Y.J. Huang Y.Y. Li K.L. Environmental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes.Kidney Int. 2006; 69: 2049-2056Google Scholar of patients with diabetes by including a larger sample size and doubling the follow-up time. The chelation data reported by these authors to date are summarized in Table 1.Table 1Chelation Data Reported by Lin and ColleaguesStudyaReference number and year published.CKD CauseTreatment/Follow-up (mo)GroupNo.LeadKidney FunctionbKidney function is estimated glomerular filtration rate (in mL/min/1.73 m2) except where indicated.Blood Level (μg/dL)cLead dose and kidney function data are those just prior to onset of chelation unless only baseline data at the beginning of observation period are provided.Chelatable (μg/72 h)cLead dose and kidney function data are those just prior to onset of chelation unless only baseline data at the beginning of observation period are provided.PretreatmentcLead dose and kidney function data are those just prior to onset of chelation unless only baseline data at the beginning of observation period are provided.Annual ChangeLin et al9Lin J.L. Ho H.H. Yu C.C. Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency A randomized, controlled trial.Ann Intern Med. 1999; 130: 7-13Google Scholar (1999)Non-DM14CaEDTA15NR254.9 ± 118.10.0043 ± 0.0016d1/serum creatinine (L/μmol).+0.00034d1/serum creatinine (L/μmol).Control16NR279.7 ± 149.20.0042 ± 0.0013d1/serum creatinine (L/μmol).−0.00051d1/serum creatinine (L/μmol).Lin et al11Lin J.L. Tan D.T. Hsu K.H. Yu C.C. Environmental lead exposure and progressive renal insufficiency.Arch Intern Med. 2001; 161: 264-271Google Scholar (2001)Non-DM14CaEDTA245.2 ± 2.5198.0 ± 83.937.8 ± 15.6eCreatinine clearance (mL/min).+2.6eCreatinine clearance (mL/min).Control125.4 ± 2.7212.0 ± 132.034.8 ± 12.0eCreatinine clearance (mL/min).−5.1eCreatinine clearance (mL/min).Lin et al8Lin 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: 277-286Google Scholar (2003)Non-DM27CaEDTA326.1 ± 2.5150.9 ± 62.432.0 ± 12.1+1.1Control325.9 ± 3.0144.5 ± 87.931.5 ± 9.0−2.7Lin et al4Lin J.L. Lin-Tan D.T. Yu C.C. Li Y.J. Huang Y.Y. Li K.L. Environmental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes.Kidney Int. 2006; 69: 2049-2056Google Scholar (2006)T2DM15CaEDTA157.5 ± 4.6148.0 ± 88.622.4 ± 4.4−3.5Control155.9 ± 2.2131.4 ± 77.426.3 ± 6.2−10.6Lin et al5Lin J.L. Lin-Tan D.T. Li Y.J. Chen K.H. Huang Y.L. Low-level environmental exposure to lead and progressive chronic kidney diseases.Am J Med. 2006; 119 (e701-e709): 707Google Scholar (2006)Non-DMfGroup with lowest lead exposure.27CaEDTA162.6 ± 1.043.1 ± 13.741.2 ± 11.2+3.0Control163.0 ± 1.147.1 ± 15.842.6 ± 9.7−2.0Lin-Tan et al12Lin-Tan D.T. Lin J.L. Yen T.H. Chen K.H. Huang Y.L. Long-term outcome of repeated lead chelation therapy in progressive non-diabetic chronic kidney diseases.Nephrol Dial Transplant. 2007; 22: 2924-2931Google Scholar (2007)Non-DM51CaEDTA585.0 ± 2.2164.1 ± 111.136.8 ± 12.7−0.3Control585.1 ± 2.6151.5 ± 92.636.0 ± 11.2−2.9Chen et al3Chen K.H. Lin J.L. Lin-Tan D.T. et al.Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.Am J Kidney Dis. 2012; 60: 530-538Abstract Full Text Full Text PDF Scopus (26) Google Scholar (2012)T2DM27CaEDTA257.1 ± 4.1142.1 ± 39.227.6 ± 4.7−4.6Control256.3 ± 2.4151.3 ± 93.629.5 ± 6.2−8.8Abbreviations: CaEDTA, calcium disodium EDTA; CKD, chronic kidney disease; DM, diabetes mellitus; NR, not reported; T2DM, type 2 diabetes mellitus.a Reference number and year published.b Kidney function is estimated glomerular filtration rate (in mL/min/1.73 m2) except where indicated.c Lead dose and kidney function data are those just prior to onset of chelation unless only baseline data at the beginning of observation period are provided.d 1/serum creatinine (L/μmol).e Creatinine clearance (mL/min).f Group with lowest lead exposure. Open table in a new tab Strengths of this body of research include prospective study design with longitudinal statistical analyses, randomization, assessment of bioavailable lead dose, and controlling for multiple risk factors for CKD progression. However, a number of limitations also have been raised. First, the results are at best single blinded. The researchers are not blinded and the treatment protocol, which includes additional calcium disodium EDTA infusions as needed based on lead levels during follow-up, may differ from the placebo protocol; therefore, patients may be able to discern their treatment group. Second, the generalizability of these findings to other populations is commonly questioned, in particular, whether lead exposure in Taiwanese patients is higher compared with other countries, such as the United States. However, the mean blood lead level in participants in the lowest lead-exposed study5Lin J.L. Lin-Tan D.T. Li Y.J. Chen K.H. Huang Y.L. Low-level environmental exposure to lead and progressive chronic kidney diseases.Am J Med. 2006; 119 (e701-e709): 707Google Scholar was lower than that observed in a recent large general population study of 50- to 70-year-olds in Baltimore, MD.6Martin D. Glass T.A. Bandeen-Roche K. Todd A.C. Shi W. Schwartz B.S. Association of blood lead and tibia lead with blood pressure and hypertension in a community sample of older adults.Am J Epidemiol. 2006; 163: 467-478Google Scholar Last, sample sizes are small, raising concerns that despite randomization, differences between groups, such as the cause of CKD (in studies of nondiabetic CKD) or socioeconomic status, may be explanatory factors.Despite these limitations, the body of research raises an important question: should practitioners consider the use of chelation therapy in their patients with CKD with lead levels that are not typical of “lead poisoning”? As we have stated previously,7Weaver V, Jaar B. Lead nephropathy and lead-related nephrotoxicity. In: Basow D, ed. UpToDate. Waltham, MA: UpToDate.Google Scholar such therapy cannot be recommended without additional double-blind randomized studies in larger and diverse populations at other centers. However, such research is clearly indicated based on the Taiwanese work to date. If a benefit of therapy with calcium disodium EDTA (or preferably with an oral chelating agent such as dimercaptosuccinic acid [DMSA]) is proved without an adverse impact on other organs (eg, the central nervous system, through lead mobilization or from chelation itself), the potential public health impact would be very significant.Whether such research will ever be conducted is uncertain. An editorial that accompanied the 2003 chelation publication of Lin et al8Lin 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: 277-286Google Scholar referred to an earlier study,9Lin J.L. Ho H.H. Yu C.C. Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency A randomized, controlled trial.Ann Intern Med. 1999; 130: 7-13Google Scholar noting: Inexplicably, even though that study was a well-designed prospective trial, it has had a limited effect on the nephrology community. Very few clinics that treat progressive renal failure assess the body lead burden, even in patients with possible ‘saturnine gout.' Critics argued that this small study was neither blinded nor placebo-controlled. Clinicians may not have identified with the unique nature of the population under study (in Taiwan) or may have been dissuaded by historical caveats about EDTA toxicity.10Marsden P.A. Increased body lead burden—cause or consequence of chronic renal insufficiency?.N Engl J Med. 2003; 348: 345-347Google Scholar(p346)Despite continued publications by Lin and colleagues in high-impact journals, these statements remain as true in 2012 as they were in 2003. This may be because this body of research deals with 2 controversial areas: (1) whether low-level lead exposure causes nephrotoxicity, and (2) the settings in which lead chelation is beneficial.The vast majority of nephrologists have never received formal training for heavy metal toxicity. High-level lead exposure is known to cause lead nephropathy; however, fortunately, this is increasingly rare. Lead-related nephrotoxicity at lower exposure levels, as a cofactor with diabetes, hypertension, or other traditional CKD risk factors, is not commonly considered. Thus, Lin's research may have limited resonance in the nephrology community. However, the impact of chelation therapy on CKD progression is not necessarily related to the nephrotoxicity of environmental lead exposure. If such therapy is beneficial, the mechanism may be due to removing lead from the body, but chelation also might directly benefit kidney function regardless of lead exposure. Antioxidant effects of calcium disodium EDTA have been reported.13Jacobsen C. Hartvigsen K. Thomsen M.K. et al.Lipid oxidation in fish oil enriched mayonnaise: calcium disodium ethylenediaminetetraacetate, but not gallic acid, strongly inhibited oxidative deterioration.J Agric Food Chem. 2001; 49: 1009-1019Google Scholar, 14Saxena G. Flora S.J. Lead-induced oxidative stress and hematological alterations and their response to combined administration of calcium disodium EDTA with a thiol chelator in rats.J Biochem Mol Toxicol. 2004; 18: 221-233Google Scholar Calcium disodium EDTA administration has been shown to reduce kidney damage in a rat model of acute kidney injury induced by ischemia.15Foglieni C. Fulgenzi A. Ticozzi P. et al.Protective effect of EDTA preadministration on renal ischemia.BMC Nephrol. 2006; 7: 5Google Scholar Similarly, in a non–lead-exposed rat model, giving DMSA during nephrosclerosis induction is reported to prevent kidney damage.16Gonick H.C. Cohen A.H. Ren Q. et al.Effect of 2,3-dimercaptosuccinic acid on nephrosclerosis in the Dahl rat I. Role of reactive oxygen species.Kidney Int. 1996; 50: 1572-1581Google Scholar In rodent models of lead-related nephrotoxicity,17Sanchez-Fructuoso A.I. Blanco J. Cano M. et al.Experimental lead nephropathy: treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Google Scholar, 18Sanchez-Fructuoso A.I. Cano M. Arroyo M. Fernandez C. Prats D. Barrientos A. Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Google Scholar, 19Khalil-Manesh F. Gonick H.C. 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: 35-54Google Scholar the benefits of chelation do not appear to accrue as a result of undoing structural damage,19Khalil-Manesh F. Gonick H.C. 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: 35-54Google Scholar again suggesting that the underlying mechanism may involve improving hemodynamics by reducing reactive oxidant species through lower lead levels and/or by direct action of the chelating agent.16Gonick H.C. Cohen A.H. Ren Q. et al.Effect of 2,3-dimercaptosuccinic acid on nephrosclerosis in the Dahl rat I. Role of reactive oxygen species.Kidney Int. 1996; 50: 1572-1581Google ScholarIn regard to the second controversy, indications for chelation in lead poisoning continue to be debated in the occupational medicine and clinical toxicology communities. Chelation with DMSA did not improve cognitive function in lead-poisoned children,20Rogan W.J. Dietrich K.N. Ware J.H. et al.The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead.N Engl J Med. 2001; 344: 1421-1426Google Scholar, 21Dietrich K.N. Ware J.H. Salganik M. et al.Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry.Pediatrics. 2004; 114: 19-26Google Scholar although the dose used may not have achieved adequate reduction of brain lead levels.22Stangle D.E. Strawderman M.S. Smith D. Kuypers M. Strupp B.J. Reductions in blood lead overestimate reductions in brain lead following repeated succimer regimens in a rodent model of childhood lead exposure.Environ Health Perspect. 2004; 112: 302-308Google Scholar Side effects of chelation also are considerations. At much higher equivalent doses than the calcium disodium EDTA protocol used by Lin and colleagues, DMSA is known to impair cognitive function in rats without lead exposure.23Stangle D.E. Smith D.R. Beaudin S.A. Strawderman M.S. Levitsky D.A. Strupp B.J. Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure.Environ Health Perspect. 2007; 115: 201-209Google Scholar Acute kidney injury has been reported with early use of calcium disodium EDTA at high doses.24Wedeen R.P. Batuman V. Landy E. The safety of the EDTA lead-mobilization test.Environ Res. 1983; 30: 58-62Google Scholar Alternative medicine practitioners have used EDTA without calcium for autism and coronary artery disease, a practice that has caused deaths from hypocalcemia.25Baxter A.J. Krenzelok E.P. Pediatric fatality secondary to EDTA chelation.Clin Toxicol (Phila). 2008; 46: 1083-1084Google Scholar The ongoing National Institutes of Health–sponsored Trial to Assess Chelation Therapy (TACT) for cardiac disease (http://nccam.nih.gov/health/chelation/), which, importantly, used EDTA without calcium, has proved controversial due in part to concerns regarding safety.26Jackson G. Chelation therapy is TACT-less.Int J Clin Pract. 2008; 62: 1821-1822Google Scholar Thus, chelation may be viewed cautiously or with frank skepticism by many in the medical community. However, although it is important to monitor chelation side effects, it is important to note that the Taiwanese group uses EDTA at a dose that is much lower than those associated with side effects in the literature described above and in a form that contains calcium.In order to circumvent these controversies in an effort to move this research line forward, the question can be reframed to ask: Does treatment with calcium disodium EDTA (or an oral agent such as DMSA) slow progression of CKD? The study of agents that may modulate inflammation and oxidative stress in order to slow CKD progression is not novel. Recently, bardoxolone methyl, an oral antioxidant inflammation modulator, has shown promise in the treatment of advanced diabetic nephropathy.27Pergola P.E. Raskin P. Toto R.D. et al.Bardoxolone methyl and kidney function in CKD with type 2 diabetes.N Engl J Med. 2011; 365: 327-336Google Scholar Pentoxifylline, with diverse anti-inflammatory, antiproliferative, and antifibrotic properties, has been examined in multiple studies of animals and humans and currently is being examined in the PREDIAN (Pentoxifylline for Renoprotection in Diabetic Nephropathy) trial to determine its efficacy in slowing CKD progression in patients with diabetic nephropathy.28Navarro-Gonzalez J.F. Muros M. Mora-Fernandez C. Herrera H. Meneses B. Garcia J. Pentoxifylline for renoprotection in diabetic nephropathy: the PREDIAN Study Rationale and basal results.J Diabetes Complications. 2011; 25: 314-319Google Scholar Statins, which are known to have “lipid-independent actions” involving oxidative stress modulation, have been examined repeatedly for benefit in slowing CKD progression and decreasing cardiovascular morbidity and mortality in patients with CKD.29Cachofeiro V. Goicochea M. de Vinuesa S.G. Oubina P. Lahera V. Luno J. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease.Kidney Int Suppl. 2008; 111: S4-S9Google Scholar Multiple other agents, such as uric acid–lowering drugs, angiotensin-converting enzyme inhibitors, vitamin D, omega-3 fatty acids, and N-acetylcysteine, have been examined in acute and chronic kidney injury, with direct or indirect effects on oxidative stress and inflammation implicated in the mechanism of potential benefit. In the context of therapy to slow CKD progression, potentially through an antioxidant mechanism, calcium disodium EDTA may be more relevant to the broader nephrology community and considered worthy of further study.In the interim, how should the existing research by Lin and colleagues affect the clinical care of patients with CKD? An occupational and environmental history is essential; a patient-administered questionnaire that can be used for this purpose is available online.7Weaver V, Jaar B. Lead nephropathy and lead-related nephrotoxicity. In: Basow D, ed. UpToDate. Waltham, MA: UpToDate.Google Scholar If work or hobbies involving nephrotoxicants are identified, patients can be counseled to reduce or stop exposure. Occupational physicians can be consulted to assist with workplace accommodations as needed.Given the global public health burden of CKD, strategies to prevent CKD and delay its progression remain a priority. Skepticism concerning the nephrotoxicity of low-level lead exposure may persist after reading the most recent study3Chen K.H. Lin J.L. Lin-Tan D.T. et al.Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.Am J Kidney Dis. 2012; 60: 530-538Abstract Full Text Full Text PDF Scopus (26) Google Scholar by Lin's group, and as with any research study, there is a risk that future trials to replicate the results, if attempted by others, may not show the same benefits. However, the slowing of CKD progression with calcium disodium EDTA has been consistent across multiple studies from this group and remains intriguing. Because a minority of the strategies studied to date to slow CKD progression have consistently been successful, this body of research makes a compelling case for further well-designed, preferably multicenter, studies. Related Article, p. 530 Related Article, p. 530 Related Article, p. 530 Given the increasing incidence and prevalence of chronic kidney disease (CKD),1Levey A.S. Atkins R. Coresh J. et al.Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes.Kidney Int. 2007; 72: 247-259Google Scholar, 2Coresh J. Selvin E. Stevens L.A. et al.Prevalence of chronic kidney disease in the United States.JAMA. 2007; 298: 2038-2047Google Scholar approaches to slow disease progression are essential. For more than a decade, Ja-Liang Lin and colleagues have published randomized placebo-controlled clinical trials reporting that treatment with calcium disodium EDTA slows CKD progression. Lead chelation has been implicated as the mechanism, and benefits in diabetic and nondiabetic patients with CKD with mean blood lead levels as low as 2.6 μg/dL have been reported (Table 1). Similar study designs have been used across publications. Initially, patients are observed to compare CKD progression prior to chelation. Then, patients whose chelatable lead levels are within certain ranges (generally 60-600 μg excreted in a 72-hour urine collection after intravenous administration of 1 g of calcium disodium EDTA and thus lower than the level commonly considered for chelation in lead poisoning) are randomly assigned. The treatment group receives weekly calcium disodium EDTA until lead levels decrease to a defined target. The control group receives placebo infusions. In the follow-up period, chelation is repeated for defined indications, such as increased serum creatinine level or chelatable lead levels higher than specified cutoffs. The results of their latest trial,3Chen K.H. Lin J.L. Lin-Tan D.T. et al.Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.Am J Kidney Dis. 2012; 60: 530-538Abstract Full Text Full Text PDF Scopus (26) Google Scholar which is focused on patients with type 2 diabetes with nephropathy, are reported in this issue of the American Journal of Kidney Diseases and are consistent with earlier trials in observing a benefit of calcium disodium EDTA in slowing CKD progression. The present study builds on a 2006 study4Lin J.L. Lin-Tan D.T. Yu C.C. Li Y.J. Huang Y.Y. Li K.L. Environmental exposure to lead and progressive diabetic nephropathy in patients with type II diabetes.Kidney Int. 2006; 69: 2049-2056Google Scholar of patients with diabetes by including a larger sample size and doubling the follow-up time. The chelation data reported by these authors to date are summarized in Table 1. Abbreviations: CaEDTA, calcium disodium EDTA; CKD, chronic kidney disease; DM, diabetes mellitus; NR, not reported; T2DM, type 2 diabetes mellitus. Strengths of this body of research include prospective study design with longitudinal statistical analyses, randomization, assessment of bioavailable lead dose, and controlling for multiple risk factors for CKD progression. However, a number of limitations also have been raised. First, the results are at best single blinded. The researchers are not blinded and the treatment protocol, which includes additional calcium disodium EDTA infusions as needed based on lead levels during follow-up, may differ from the placebo protocol; therefore, patients may be able to discern their treatment group. Second, the generalizability of these findings to other populations is commonly questioned, in particular, whether lead exposure in Taiwanese patients is higher compared with other countries, such as the United States. However, the mean blood lead level in participants in the lowest lead-exposed study5Lin J.L. Lin-Tan D.T. Li Y.J. Chen K.H. Huang Y.L. Low-level environmental exposure to lead and progressive chronic kidney diseases.Am J Med. 2006; 119 (e701-e709): 707Google Scholar was lower than that observed in a recent large general population study of 50- to 70-year-olds in Baltimore, MD.6Martin D. Glass T.A. Bandeen-Roche K. Todd A.C. Shi W. Schwartz B.S. Association of blood lead and tibia lead with blood pressure and hypertension in a community sample of older adults.Am J Epidemiol. 2006; 163: 467-478Google Scholar Last, sample sizes are small, raising concerns that despite randomization, differences between groups, such as the cause of CKD (in studies of nondiabetic CKD) or socioeconomic status, may be explanatory factors. Despite these limitations, the body of research raises an important question: should practitioners consider the use of chelation therapy in their patients with CKD with lead levels that are not typical of “lead poisoning”? As we have stated previously,7Weaver V, Jaar B. Lead nephropathy and lead-related nephrotoxicity. In: Basow D, ed. UpToDate. Waltham, MA: UpToDate.Google Scholar such therapy cannot be recommended without additional double-blind randomized studies in larger and diverse populations at other centers. However, such research is clearly indicated based on the Taiwanese work to date. If a benefit of therapy with calcium disodium EDTA (or preferably with an oral chelating agent such as dimercaptosuccinic acid [DMSA]) is proved without an adverse impact on other organs (eg, the central nervous system, through lead mobilization or from chelation itself), the potential public health impact would be very significant. Whether such research will ever be conducted is uncertain. An editorial that accompanied the 2003 chelation publication of Lin et al8Lin 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: 277-286Google Scholar referred to an earlier study,9Lin J.L. Ho H.H. Yu C.C. Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency A randomized, controlled trial.Ann Intern Med. 1999; 130: 7-13Google Scholar noting: Inexplicably, even though that study was a well-designed prospective trial, it has had a limited effect on the nephrology community. Very few clinics that treat progressive renal failure assess the body lead burden, even in patients with possible ‘saturnine gout.' Critics argued that this small study was neither blinded nor placebo-controlled. Clinicians may not have identified with the unique nature of the population under study (in Taiwan) or may have been dissuaded by historical caveats about EDTA toxicity.10Marsden P.A. Increased body lead burden—cause or consequence of chronic renal insufficiency?.N Engl J Med. 2003; 348: 345-347Google Scholar(p346) Despite continued publications by Lin and colleagues in high-impact journals, these statements remain as true in 2012 as they were in 2003. This may be because this body of research deals with 2 controversial areas: (1) whether low-level lead exposure causes nephrotoxicity, and (2) the settings in which lead chelation is beneficial. The vast majority of nephrologists have never received formal training for heavy metal toxicity. High-level lead exposure is known to cause lead nephropathy; however, fortunately, this is increasingly rare. Lead-related nephrotoxicity at lower exposure levels, as a cofactor with diabetes, hypertension, or other traditional CKD risk factors, is not commonly considered. Thus, Lin's research may have limited resonance in the nephrology community. However, the impact of chelation therapy on CKD progression is not necessarily related to the nephrotoxicity of environmental lead exposure. If such therapy is beneficial, the mechanism may be due to removing lead from the body, but chelation also might directly benefit kidney function regardless of lead exposure. Antioxidant effects of calcium disodium EDTA have been reported.13Jacobsen C. Hartvigsen K. Thomsen M.K. et al.Lipid oxidation in fish oil enriched mayonnaise: calcium disodium ethylenediaminetetraacetate, but not gallic acid, strongly inhibited oxidative deterioration.J Agric Food Chem. 2001; 49: 1009-1019Google Scholar, 14Saxena G. Flora S.J. Lead-induced oxidative stress and hematological alterations and their response to combined administration of calcium disodium EDTA with a thiol chelator in rats.J Biochem Mol Toxicol. 2004; 18: 221-233Google Scholar Calcium disodium EDTA administration has been shown to reduce kidney damage in a rat model of acute kidney injury induced by ischemia.15Foglieni C. Fulgenzi A. Ticozzi P. et al.Protective effect of EDTA preadministration on renal ischemia.BMC Nephrol. 2006; 7: 5Google Scholar Similarly, in a non–lead-exposed rat model, giving DMSA during nephrosclerosis induction is reported to prevent kidney damage.16Gonick H.C. Cohen A.H. Ren Q. et al.Effect of 2,3-dimercaptosuccinic acid on nephrosclerosis in the Dahl rat I. Role of reactive oxygen species.Kidney Int. 1996; 50: 1572-1581Google Scholar In rodent models of lead-related nephrotoxicity,17Sanchez-Fructuoso A.I. Blanco J. Cano M. et al.Experimental lead nephropathy: treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Google Scholar, 18Sanchez-Fructuoso A.I. Cano M. Arroyo M. Fernandez C. Prats D. Barrientos A. Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Google Scholar, 19Khalil-Manesh F. Gonick H.C. 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: 35-54Google Scholar the benefits of chelation do not appear to accrue as a result of undoing structural damage,19Khalil-Manesh F. Gonick H.C. 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: 35-54Google Scholar again suggesting that the underlying mechanism may involve improving hemodynamics by reducing reactive oxidant species through lower lead levels and/or by direct action of the chelating agent.16Gonick H.C. Cohen A.H. Ren Q. et al.Effect of 2,3-dimercaptosuccinic acid on nephrosclerosis in the Dahl rat I. Role of reactive oxygen species.Kidney Int. 1996; 50: 1572-1581Google Scholar In regard to the second controversy, indications for chelation in lead poisoning continue to be debated in the occupational medicine and clinical toxicology communities. Chelation with DMSA did not improve cognitive function in lead-poisoned children,20Rogan W.J. Dietrich K.N. Ware J.H. et al.The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead.N Engl J Med. 2001; 344: 1421-1426Google Scholar, 21Dietrich K.N. Ware J.H. Salganik M. et al.Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry.Pediatrics. 2004; 114: 19-26Google Scholar although the dose used may not have achieved adequate reduction of brain lead levels.22Stangle D.E. Strawderman M.S. Smith D. Kuypers M. Strupp B.J. Reductions in blood lead overestimate reductions in brain lead following repeated succimer regimens in a rodent model of childhood lead exposure.Environ Health Perspect. 2004; 112: 302-308Google Scholar Side effects of chelation also are considerations. At much higher equivalent doses than the calcium disodium EDTA protocol used by Lin and colleagues, DMSA is known to impair cognitive function in rats without lead exposure.23Stangle D.E. Smith D.R. Beaudin S.A. Strawderman M.S. Levitsky D.A. Strupp B.J. Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure.Environ Health Perspect. 2007; 115: 201-209Google Scholar Acute kidney injury has been reported with early use of calcium disodium EDTA at high doses.24Wedeen R.P. Batuman V. Landy E. The safety of the EDTA lead-mobilization test.Environ Res. 1983; 30: 58-62Google Scholar Alternative medicine practitioners have used EDTA without calcium for autism and coronary artery disease, a practice that has caused deaths from hypocalcemia.25Baxter A.J. Krenzelok E.P. Pediatric fatality secondary to EDTA chelation.Clin Toxicol (Phila). 2008; 46: 1083-1084Google Scholar The ongoing National Institutes of Health–sponsored Trial to Assess Chelation Therapy (TACT) for cardiac disease (http://nccam.nih.gov/health/chelation/), which, importantly, used EDTA without calcium, has proved controversial due in part to concerns regarding safety.26Jackson G. Chelation therapy is TACT-less.Int J Clin Pract. 2008; 62: 1821-1822Google Scholar Thus, chelation may be viewed cautiously or with frank skepticism by many in the medical community. However, although it is important to monitor chelation side effects, it is important to note that the Taiwanese group uses EDTA at a dose that is much lower than those associated with side effects in the literature described above and in a form that contains calcium. In order to circumvent these controversies in an effort to move this research line forward, the question can be reframed to ask: Does treatment with calcium disodium EDTA (or an oral agent such as DMSA) slow progression of CKD? The study of agents that may modulate inflammation and oxidative stress in order to slow CKD progression is not novel. Recently, bardoxolone methyl, an oral antioxidant inflammation modulator, has shown promise in the treatment of advanced diabetic nephropathy.27Pergola P.E. Raskin P. Toto R.D. et al.Bardoxolone methyl and kidney function in CKD with type 2 diabetes.N Engl J Med. 2011; 365: 327-336Google Scholar Pentoxifylline, with diverse anti-inflammatory, antiproliferative, and antifibrotic properties, has been examined in multiple studies of animals and humans and currently is being examined in the PREDIAN (Pentoxifylline for Renoprotection in Diabetic Nephropathy) trial to determine its efficacy in slowing CKD progression in patients with diabetic nephropathy.28Navarro-Gonzalez J.F. Muros M. Mora-Fernandez C. Herrera H. Meneses B. Garcia J. Pentoxifylline for renoprotection in diabetic nephropathy: the PREDIAN Study Rationale and basal results.J Diabetes Complications. 2011; 25: 314-319Google Scholar Statins, which are known to have “lipid-independent actions” involving oxidative stress modulation, have been examined repeatedly for benefit in slowing CKD progression and decreasing cardiovascular morbidity and mortality in patients with CKD.29Cachofeiro V. Goicochea M. de Vinuesa S.G. Oubina P. Lahera V. Luno J. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease.Kidney Int Suppl. 2008; 111: S4-S9Google Scholar Multiple other agents, such as uric acid–lowering drugs, angiotensin-converting enzyme inhibitors, vitamin D, omega-3 fatty acids, and N-acetylcysteine, have been examined in acute and chronic kidney injury, with direct or indirect effects on oxidative stress and inflammation implicated in the mechanism of potential benefit. In the context of therapy to slow CKD progression, potentially through an antioxidant mechanism, calcium disodium EDTA may be more relevant to the broader nephrology community and considered worthy of further study. In the interim, how should the existing research by Lin and colleagues affect the clinical care of patients with CKD? An occupational and environmental history is essential; a patient-administered questionnaire that can be used for this purpose is available online.7Weaver V, Jaar B. Lead nephropathy and lead-related nephrotoxicity. In: Basow D, ed. UpToDate. Waltham, MA: UpToDate.Google Scholar If work or hobbies involving nephrotoxicants are identified, patients can be counseled to reduce or stop exposure. Occupational physicians can be consulted to assist with workplace accommodations as needed. Given the global public health burden of CKD, strategies to prevent CKD and delay its progression remain a priority. Skepticism concerning the nephrotoxicity of low-level lead exposure may persist after reading the most recent study3Chen K.H. Lin J.L. Lin-Tan D.T. et al.Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.Am J Kidney Dis. 2012; 60: 530-538Abstract Full Text Full Text PDF Scopus (26) Google Scholar by Lin's group, and as with any research study, there is a risk that future trials to replicate the results, if attempted by others, may not show the same benefits. However, the slowing of CKD progression with calcium disodium EDTA has been consistent across multiple studies from this group and remains intriguing. Because a minority of the strategies studied to date to slow CKD progression have consistently been successful, this body of research makes a compelling case for further well-designed, preferably multicenter, studies. Financial Disclosure: The authors declare that they have no relevant financial interests. Effect of Chelation Therapy on Progressive Diabetic Nephropathy in Patients With Type 2 Diabetes and High-Normal Body Lead BurdensAmerican Journal of Kidney DiseasesVol. 60Issue 4PreviewA previous study in type 2 diabetic patients with high-normal body lead burdens showed that EDTA chelation therapy for 3 months slows progressive diabetic nephropathy during a 12-month follow-up. The effect of a longer course of therapy on kidney function decrease over a longer follow-up is not known. Full-Text PDF" @default.
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