Lead, renal disease and hypertension

Abstract

Related articles, pp. 43, 51, and 59The simultaneous publication by the Spanish group of three articles related to lead intoxication (“Erythrocyte Aminolevulinate Dehydratase Activity as a Lead Marker in Patients With Chronic Renal Failure,” “Experimental Lead Nephropathy: Treatment With Calcium Disodium Ethylenediaminetetraacetate,” and “Lead Mobilization During Calcium Disodium Ethylenediaminetetraacetate Chelation Therapy in the Treatment of Chronic Lead Poisoning”)1Fontanellas A Navarro S Moran-Jiménez M-J et al.Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.Am J Kidney Dis. 2002; 40: 43-50Google Scholar, 2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar is noteworthy in several respects, chiefly with regard to the diagnosis of chronic lead exposure and to the relationship of lead exposure to renal disease, gout, and hypertension. The potential contribution of lead exposure to these three entities has intrigued investigators for several decades,4Wedeen RP Malik DK Batuman V Detection and treatment of occupational lead nephropathy.Arch Intern Med. 1979; 139: 53-57Google Scholar, 5Batuman V Maesaka JK Haddad B Tepper E Landy E Wedeen RP The role of lead in gout nephropathy.N Engl J Med. 1981; 304: 520-523Google Scholar, 6Batuman V Landy E Maesaka JI Wedeen RP Contribution of lead to hypertension with renal impairment.N Engl J Med. 1983; 309: 17-21Google Scholar but establishing the incidence of lead-related disease has been hampered by the problem of diagnosing chronic, as contrasted to acute, lead “intoxication.” Blood lead levels, reflecting recent or continuous exposure, are adequate to define the latter condition but not the former, where blood levels are commonly normal. To circumvent this problem, investigators have had to resort to measurements such as the calcium disodium ethylenediaminetetraacetate (CaEDTA) lead mobilization test,7Emmerson BT Chronic lead nephropathy: The diagnostic use of calcium EDTA and the association with gout.Aust NZ J Med. 1963; 12: 310-324Google Scholar bone biopsies for lead content,8Van de Vyver FL D'Haese PC Visser WJ et al.Bone lead in dialysis patients.Kidney Int. 1988; 33: 601-607Google Scholar or the indirect measure of bone lead through x-ray fluorescence,9Wedeen RP Ty A Udasin I Favata EA Jones KW Clinical application of in vivo tibial K-XRF for monitoring lead stores.Arch Environ Health. 1995; 50: 355-361Google Scholar as bone is the long-term repository for lead. Now, with the advent of the clinical paper by Fontanellas et al,1Fontanellas A Navarro S Moran-Jiménez M-J et al.Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.Am J Kidney Dis. 2002; 40: 43-50Google Scholar we have an alternative, simpler measure, namely the ratio of erythrocyte aminolevulinate dehydratase (ALAD) activity to “restored” ALAD activity. It is well appreciated that erythrocyte ALAD is exquisitely sensitive to inhibition by lead, but not as well appreciated that erythrocyte ALAD levels can be restored by replacing the lead with zinc and by the -sulfhydryl (-SH) donor, dithiothreitol. Indeed, restored ALAD can be shown to be increased following exposure to lead, presumably as a compensatory effect.10Fujita H Sato K Sano S Increase in the amount of erythrocyte delta-aminolevulinic acid dehydratase in workers with moderate lead exposure.Int Arch Occup Environ Health. 1982; 50: 287-297Google Scholar As erythrocyte ALAD has also been shown to be inhibited by a nonspecific uremic inhibitor(s), it was important to “restore” the ALAD level to normal and to express ALAD activity as a ratio between lead-affected and restored levels. Utilizing this approach, the investigators were able to separate cleanly uremic lead-exposed from uremic non-lead-exposed individuals, as determined by the results of the CaEDTA lead mobilization test. Now the challenge will be to apply this test to a large number of uremic patients, both predialysis and during dialysis, to hypertensive patients, with and without uremia, and to gouty patients, with and without uremia. As Batuman et al5Batuman V Maesaka JK Haddad B Tepper E Landy E Wedeen RP The role of lead in gout nephropathy.N Engl J Med. 1981; 304: 520-523Google Scholar, 6Batuman V Landy E Maesaka JI Wedeen RP Contribution of lead to hypertension with renal impairment.N Engl J Med. 1983; 309: 17-21Google Scholar have implied, it is the gouty or hypertensive patient with mild nephropathy who is most likely to have chronic lead intoxication, and thus we are left to wonder whether it is the lead exposure, or the increase in reactive oxygen species secondary to lead, that is responsible for the renal impairment. As indicated by Fontanellas et al,1Fontanellas A Navarro S Moran-Jiménez M-J et al.Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.Am J Kidney Dis. 2002; 40: 43-50Google Scholar there are a number of recent articles attesting to the predilection of lead exposure to cause accumulation of reactive oxygen species, coincident with an increase in blood pressure, as well as to the ability of scavengers to reduce both the reactive oxygen species and blood pressure.11Gonick HC Ding Y Bondy SC Ni Z Vaziri ND Lead-induced hypertension: Interplay of nitric oxide and reactive oxygen species.Hypertension. 1997; 30: 1487-1492Google Scholar, 12Ding Y Vaziri ND Gonick HC Lead-induced hypertension. II. Response to sequential infusions of L-arginine, superoxide dismutase, and nitroprusside.Environ Res. 1998; 76: 107-113Google Scholar, 13Vaziri ND Ding Y Ni Z Gonick HC Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: Effect of lazaroid therapy.Kidney Int. 1997; 52: 1042-1046Google ScholarThe second and third papers by Sánchez-Fructuoso et al2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar employ a rat model of chronic lead intoxication to explore the effects of CaEDTA chelation. Lead-exposed animals receive 500 ppm lead acetate in their drinking water for 90 days and are then either removed from exposure or removed from exposure and treated with CaEDTA intermittently for an additional 49 days. An important codicil to the experimental design was that the dosage of lead was sufficient to produce blood lead levels (52.9 ± 3.8 g/dL) that in humans would be diagnostic of moderate lead toxicity, and the dose of CaEDTA was geared to the dosage commonly used in humans. These facts are of importance in interpreting the variability of earlier results where, for instance, there was internal redistribution of lead following CaEDTA therapy from bone and kidney to brain and liver,14Cory-Slechta D Weiss B Cox CH Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy.J Pharmacol Exp Ther. 1987; 243: 804-813Google Scholar giving concern that the increased brain levels may prove to be deleterious. According to Sánchez-Fructuoso et al,2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar however, the reduction in brain, liver, and kidney lead after CaEDTA was continuous. In these papers, there are several important findings of note. First is the appearance of hypertrophy of the muscle layer of small and medium caliber arteries, indistinguishable from changes in humans characteristic of nephroangiosclerosis, that was partially reversible by treatment with CaEDTA. Yet, the effect of CaEDTA treatment on mean blood pressure was not significant and the effect of lead exposure on blood pressure, although statistically significant, was not impressive (123.4 ± 1.2 mm Hg versus 132.0 ± 1.1 mm Hg). The dosage of lead employed by the authors was at the point shown in several reviews to separate “low lead” exposure, where hypertension is invariable, from “high lead” exposure, where the advent of hypertension was not seen.15Sharp DS Becker CE Smith AH Chronic low-level lead exposure. Its role in the pathogenesis of hypertension.Med Toxicol. 1987; 2: 210-232Google Scholar The observation by Sánchez-Fructuoso et al2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar calls into question the commonly accepted notion that vascular changes within the kidney are a result of blood pressure elevation and suggests instead that either lead or reactive oxygen species more directly affect vascular morphology. The failure of CaEDTA chelation treatment to affect blood pressure also stands in contrast to the findings of Khalil-Manesh et al,16Khalil-Manesh F Gonick HC Weiler EW et al.Effect of chelation treatment with dimercaptosuccinic acid (DMSA) on lead-related blood pressure changes.Environ Res. 1994; 65: 86-99Google Scholar Ding et al,12Ding Y Vaziri ND Gonick HC Lead-induced hypertension. II. Response to sequential infusions of L-arginine, superoxide dismutase, and nitroprusside.Environ Res. 1998; 76: 107-113Google Scholar and Vaziri et al13Vaziri ND Ding Y Ni Z Gonick HC Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: Effect of lazaroid therapy.Kidney Int. 1997; 52: 1042-1046Google Scholar, 17Vaziri ND Ding Y Ni Z Compensatory up-regulation of nitric-oxide synthase isoforms in lead-induced hypertension; reversal by a superoxide dismutase-mimetic drug.J Pharmacol Exp Ther. 2001; 298: 679-685Google Scholar that treatment of lead-exposed animals with the lead chelator, 2,3 dimercaptosuccinic acid (which is also a scavenger of reactive oxygen species), or with Lazaroids (a nonchelating scavenger) or Tempol (a superoxide dismutase mimetic) significantly reduces hypertension in such animals. In the paper on lead mobilization an important observation was that bone lead content remained constant after lead intoxication, whether CaEDTA or simple removal was used as treatment. Yet, CaEDTA persisted in causing increased urinary lead, raising the issue of whether, in these animals, the mobilizable lead originated from bone (as has been assumed in all previous studies) or from soft tissue. In humans, in contrast, CaEDTA chelation treatment has been demonstrated to reduce bone lead using both iliac crest bone biopsy and x-ray fluorescence to measure the lead content.18Batuman V Wedeen RP Bogden JD Balestra DJ Jones K Schidlovsky G Reducing bone lead content by chelation treatment in chronic lead poisoning: An in vivo X-ray fluorescence and bone biopsy study.Environ Res. 1989; 48: 70-75Google ScholarThese are three important studies, raising questions for the future as well as providing some answers. Some day we will hopefully have sufficient knowledge to place in perspective the contribution of lead to renal impairment, hypertension, and gout and to gear the therapy of these conditions appropriately. The current appreciation of the role played by reactive oxygen species in lead-induced disease and the reversal by scavengers of lead-related hypertension suggests that one such therapeutic approach would involve the use of suitable reactive oxygen species scavengers. Related articles, pp. 43, 51, and 59 The simultaneous publication by the Spanish group of three articles related to lead intoxication (“Erythrocyte Aminolevulinate Dehydratase Activity as a Lead Marker in Patients With Chronic Renal Failure,” “Experimental Lead Nephropathy: Treatment With Calcium Disodium Ethylenediaminetetraacetate,” and “Lead Mobilization During Calcium Disodium Ethylenediaminetetraacetate Chelation Therapy in the Treatment of Chronic Lead Poisoning”)1Fontanellas A Navarro S Moran-Jiménez M-J et al.Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.Am J Kidney Dis. 2002; 40: 43-50Google Scholar, 2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar is noteworthy in several respects, chiefly with regard to the diagnosis of chronic lead exposure and to the relationship of lead exposure to renal disease, gout, and hypertension. The potential contribution of lead exposure to these three entities has intrigued investigators for several decades,4Wedeen RP Malik DK Batuman V Detection and treatment of occupational lead nephropathy.Arch Intern Med. 1979; 139: 53-57Google Scholar, 5Batuman V Maesaka JK Haddad B Tepper E Landy E Wedeen RP The role of lead in gout nephropathy.N Engl J Med. 1981; 304: 520-523Google Scholar, 6Batuman V Landy E Maesaka JI Wedeen RP Contribution of lead to hypertension with renal impairment.N Engl J Med. 1983; 309: 17-21Google Scholar but establishing the incidence of lead-related disease has been hampered by the problem of diagnosing chronic, as contrasted to acute, lead “intoxication.” Blood lead levels, reflecting recent or continuous exposure, are adequate to define the latter condition but not the former, where blood levels are commonly normal. To circumvent this problem, investigators have had to resort to measurements such as the calcium disodium ethylenediaminetetraacetate (CaEDTA) lead mobilization test,7Emmerson BT Chronic lead nephropathy: The diagnostic use of calcium EDTA and the association with gout.Aust NZ J Med. 1963; 12: 310-324Google Scholar bone biopsies for lead content,8Van de Vyver FL D'Haese PC Visser WJ et al.Bone lead in dialysis patients.Kidney Int. 1988; 33: 601-607Google Scholar or the indirect measure of bone lead through x-ray fluorescence,9Wedeen RP Ty A Udasin I Favata EA Jones KW Clinical application of in vivo tibial K-XRF for monitoring lead stores.Arch Environ Health. 1995; 50: 355-361Google Scholar as bone is the long-term repository for lead. Now, with the advent of the clinical paper by Fontanellas et al,1Fontanellas A Navarro S Moran-Jiménez M-J et al.Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.Am J Kidney Dis. 2002; 40: 43-50Google Scholar we have an alternative, simpler measure, namely the ratio of erythrocyte aminolevulinate dehydratase (ALAD) activity to “restored” ALAD activity. It is well appreciated that erythrocyte ALAD is exquisitely sensitive to inhibition by lead, but not as well appreciated that erythrocyte ALAD levels can be restored by replacing the lead with zinc and by the -sulfhydryl (-SH) donor, dithiothreitol. Indeed, restored ALAD can be shown to be increased following exposure to lead, presumably as a compensatory effect.10Fujita H Sato K Sano S Increase in the amount of erythrocyte delta-aminolevulinic acid dehydratase in workers with moderate lead exposure.Int Arch Occup Environ Health. 1982; 50: 287-297Google Scholar As erythrocyte ALAD has also been shown to be inhibited by a nonspecific uremic inhibitor(s), it was important to “restore” the ALAD level to normal and to express ALAD activity as a ratio between lead-affected and restored levels. Utilizing this approach, the investigators were able to separate cleanly uremic lead-exposed from uremic non-lead-exposed individuals, as determined by the results of the CaEDTA lead mobilization test. Now the challenge will be to apply this test to a large number of uremic patients, both predialysis and during dialysis, to hypertensive patients, with and without uremia, and to gouty patients, with and without uremia. As Batuman et al5Batuman V Maesaka JK Haddad B Tepper E Landy E Wedeen RP The role of lead in gout nephropathy.N Engl J Med. 1981; 304: 520-523Google Scholar, 6Batuman V Landy E Maesaka JI Wedeen RP Contribution of lead to hypertension with renal impairment.N Engl J Med. 1983; 309: 17-21Google Scholar have implied, it is the gouty or hypertensive patient with mild nephropathy who is most likely to have chronic lead intoxication, and thus we are left to wonder whether it is the lead exposure, or the increase in reactive oxygen species secondary to lead, that is responsible for the renal impairment. As indicated by Fontanellas et al,1Fontanellas A Navarro S Moran-Jiménez M-J et al.Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.Am J Kidney Dis. 2002; 40: 43-50Google Scholar there are a number of recent articles attesting to the predilection of lead exposure to cause accumulation of reactive oxygen species, coincident with an increase in blood pressure, as well as to the ability of scavengers to reduce both the reactive oxygen species and blood pressure.11Gonick HC Ding Y Bondy SC Ni Z Vaziri ND Lead-induced hypertension: Interplay of nitric oxide and reactive oxygen species.Hypertension. 1997; 30: 1487-1492Google Scholar, 12Ding Y Vaziri ND Gonick HC Lead-induced hypertension. II. Response to sequential infusions of L-arginine, superoxide dismutase, and nitroprusside.Environ Res. 1998; 76: 107-113Google Scholar, 13Vaziri ND Ding Y Ni Z Gonick HC Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: Effect of lazaroid therapy.Kidney Int. 1997; 52: 1042-1046Google Scholar The second and third papers by Sánchez-Fructuoso et al2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar employ a rat model of chronic lead intoxication to explore the effects of CaEDTA chelation. Lead-exposed animals receive 500 ppm lead acetate in their drinking water for 90 days and are then either removed from exposure or removed from exposure and treated with CaEDTA intermittently for an additional 49 days. An important codicil to the experimental design was that the dosage of lead was sufficient to produce blood lead levels (52.9 ± 3.8 g/dL) that in humans would be diagnostic of moderate lead toxicity, and the dose of CaEDTA was geared to the dosage commonly used in humans. These facts are of importance in interpreting the variability of earlier results where, for instance, there was internal redistribution of lead following CaEDTA therapy from bone and kidney to brain and liver,14Cory-Slechta D Weiss B Cox CH Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy.J Pharmacol Exp Ther. 1987; 243: 804-813Google Scholar giving concern that the increased brain levels may prove to be deleterious. According to Sánchez-Fructuoso et al,2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar however, the reduction in brain, liver, and kidney lead after CaEDTA was continuous. In these papers, there are several important findings of note. First is the appearance of hypertrophy of the muscle layer of small and medium caliber arteries, indistinguishable from changes in humans characteristic of nephroangiosclerosis, that was partially reversible by treatment with CaEDTA. Yet, the effect of CaEDTA treatment on mean blood pressure was not significant and the effect of lead exposure on blood pressure, although statistically significant, was not impressive (123.4 ± 1.2 mm Hg versus 132.0 ± 1.1 mm Hg). The dosage of lead employed by the authors was at the point shown in several reviews to separate “low lead” exposure, where hypertension is invariable, from “high lead” exposure, where the advent of hypertension was not seen.15Sharp DS Becker CE Smith AH Chronic low-level lead exposure. Its role in the pathogenesis of hypertension.Med Toxicol. 1987; 2: 210-232Google Scholar The observation by Sánchez-Fructuoso et al2Sánchez-Fructuoso AI Blanco J Cano M et al.Experimental lead nephropathy: Treatment with calcium disodium ethylenediaminetetraacetate.Am J Kidney Dis. 2002; 40: 59-67Abstract Full Text Full Text PDF Scopus (29) Google Scholar, 3Sánchez-Fructuoso AI Cano M Arroyo M Fernández C Plats D Barrientos A Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in the treatment of chronic lead poisoning.Am J Kidney Dis. 2002; 40: 51-58Abstract Full Text Full Text PDF Scopus (13) Google Scholar calls into question the commonly accepted notion that vascular changes within the kidney are a result of blood pressure elevation and suggests instead that either lead or reactive oxygen species more directly affect vascular morphology. The failure of CaEDTA chelation treatment to affect blood pressure also stands in contrast to the findings of Khalil-Manesh et al,16Khalil-Manesh F Gonick HC Weiler EW et al.Effect of chelation treatment with dimercaptosuccinic acid (DMSA) on lead-related blood pressure changes.Environ Res. 1994; 65: 86-99Google Scholar Ding et al,12Ding Y Vaziri ND Gonick HC Lead-induced hypertension. II. Response to sequential infusions of L-arginine, superoxide dismutase, and nitroprusside.Environ Res. 1998; 76: 107-113Google Scholar and Vaziri et al13Vaziri ND Ding Y Ni Z Gonick HC Altered nitric oxide metabolism and increased oxygen free radical activity in lead-induced hypertension: Effect of lazaroid therapy.Kidney Int. 1997; 52: 1042-1046Google Scholar, 17Vaziri ND Ding Y Ni Z Compensatory up-regulation of nitric-oxide synthase isoforms in lead-induced hypertension; reversal by a superoxide dismutase-mimetic drug.J Pharmacol Exp Ther. 2001; 298: 679-685Google Scholar that treatment of lead-exposed animals with the lead chelator, 2,3 dimercaptosuccinic acid (which is also a scavenger of reactive oxygen species), or with Lazaroids (a nonchelating scavenger) or Tempol (a superoxide dismutase mimetic) significantly reduces hypertension in such animals. In the paper on lead mobilization an important observation was that bone lead content remained constant after lead intoxication, whether CaEDTA or simple removal was used as treatment. Yet, CaEDTA persisted in causing increased urinary lead, raising the issue of whether, in these animals, the mobilizable lead originated from bone (as has been assumed in all previous studies) or from soft tissue. In humans, in contrast, CaEDTA chelation treatment has been demonstrated to reduce bone lead using both iliac crest bone biopsy and x-ray fluorescence to measure the lead content.18Batuman V Wedeen RP Bogden JD Balestra DJ Jones K Schidlovsky G Reducing bone lead content by chelation treatment in chronic lead poisoning: An in vivo X-ray fluorescence and bone biopsy study.Environ Res. 1989; 48: 70-75Google Scholar These are three important studies, raising questions for the future as well as providing some answers. Some day we will hopefully have sufficient knowledge to place in perspective the contribution of lead to renal impairment, hypertension, and gout and to gear the therapy of these conditions appropriately. The current appreciation of the role played by reactive oxygen species in lead-induced disease and the reversal by scavengers of lead-related hypertension suggests that one such therapeutic approach would involve the use of suitable reactive oxygen species scavengers.