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Nephrology 19 (2014) 56–59
Brief Communication
Is lead chelation therapy effective for chronic kidney disease? A meta-analysis SHI-KUN YANG,* LI XIAO,* PAN-AI SONG, XIAO-XUAN XU, FU-YOU LIU and LIN SUN Department of Nephrology, The Second Xiangya Hospital, Kidney Institute of Central South University, Changsha, Hunan Province, China
KEY WORDS: calcium disodium EDTA, chelation, chronic kidney disease, lead. Correspondence: Dr Lin Sun, Department of Nephrology, The Second Xiangya Hospital, Kidney Institute of Central South University, Changsha, Hunan Province 410011, China. Email: [email protected] doi:10.1111/nep.12162 *These authors contributed equally to this work. None of the authors have any conflicts of interest.
ABSTRACT: The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure and the presence of chronic kidney injury. Some studies have suggested that chelation therapy with calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) might help decrease the progression of chronic kidney disease among patients with measurable body lead burdens. However, calcium disodium EDTA chelation in lead exposure is controversial due to the potential for adverse effects such as acute tubular necrosis. Therefore, we investigated the available randomized controlled trials assessing the renoprotective effects of calcium disodium EDTA chelation therapy. Our meta-analysis shows that calcium disodium EDTA chelation therapy can effectively delay the progression of chronic kidney disease in patients with measurable body lead burdens reflected by increasing the levels of estimated glomerular filtration rate (eGFR) and creatinine clearance rate (Ccr). There appears to be no conclusive evidence that calcium disodium EDTA can decrease proteinuria.
The kidney is the target of numerous xenobiotic toxicants, including environmental chemicals. The anatomical, physiological, and biochemical features of the kidney make it particularly sensitive to many environmental compounds.1 The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure to this metal and the presence of chronic kidney injury, even at levels of exposure considered to be ‘normal or tolerable’.2,3 Some small studies have suggested that calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) chelation therapy might help decrease chronic kidney disease progression in patients with measurable body lead burdens. We conducted a meta-analysis of trials to assess the renoprotective effects of calcium disodium EDTA. We performed a literature search on Medline, EMBASE, Cochrane Central Register of Controlled Trials (CCRCT) (all to May 2013) using the keywords: chelator, EDTA, calcium disodium EDTA, chelation therapy, lead, heavy metal nephropathy and kidney disease. The inclusion criteria were: (i) study design (randomized controlled trials); (ii) intervention (trials of calcium disodium EDTA chelation therapy versus placebo); (iii) target population (chronic kidney disease patients with abnormal body lead burdens). Two of the 56
authors (SKY and PAS) independently examined the titles and abstracts of all studies, and excluded all studies that did not clearly meet the inclusion criteria. The full-text articles were retrieved for a comprehensive review and were independently rescreened. When disagreement on study inclusion existed, exclusion or data extraction between the reviews occurred, differences were resolved by consensus with the senior authors (LX and LS). The studies’ quality was assessed using the Jadad composite scale by two authors (SKY and XXX) independently (Table 1). The studies were categorized as low-quality if the score was 2 or less, and high-quality if the score was at least 3.10,11 For each study, data regarding the level of estimated glomerular filtration rate (eGFR), creatinine clearance (Ccr) and proteinuria in both the calcium disodium EDTA and control groups were used respectively to generate the standardized mean differences (SMD) and the 95% confidence intervals (CI). The statistical heterogeneity of effect sizes among individual studies was assessed using the χ2 test (P < 0.1 indicating significant) and the I2 statistic (I2 value > 50% means significant heterogeneity).12 Where no significant statistical heterogeneity was identified, the fixed-effects estimate was used preferentially. All statistical analyses were performed using Review Manager version 5.1. © 2013 Asian Pacific Society of Nephrology
Chelation therapy for CKD
Table 1 Characteristic of included studies Study
Study design
No. patients
Chen 20124
Randomized single-blind
Lin 20065
Randomized single-blind
Lin 20016
Randomized single-blind
Lin 20037
Randomized single-blind
Lin JL 20068
Randomized single-blind
Lin-Tan 20079
Randomized single-blind
T: 25 C: 25 T: 16 C: 16 T: 20 C: 10 T: 32 C: 32 T: 15 C: 15 T: 58† C: 58‡
Mean age (years)
Gender (M/F)
Scr (mg/dL)
Study duration (month)
Chelator does and regimen
Jadad Score
T: 60.1 ± 12.8 C: 56.1 ± 7.8 T: 58.6 ± 10.9 C: 54.8 ± 13.1 T: 53.4 ± 11.9 C: 54.3 ± 10.4 T: 57.9 ± 10.7 C: 57.6 ± 12.8 T: 59.5 ± 12.6 C: 57.9 ± 7.1 T: 57.8 ± 10.9 C: 57.3 ± 13.2
T: 19/6 C: 21/4 T: 14/2 C: 13/3 T: 16/4 C: 7/3 T: 26/6 C: 25/7 T: 11/4 C: 13/2 T: 47/11 C: 42/16
T: 2.8 ± 0.7 C: 2.9 ± 0.6 T: 2.1 ± 0.7 C: 2.0 ± 0.5 NR
27
3
T: 2.7 ± 0.9 C: 2.6 ± 0.5 T: 3.0 ± 0.5 C: 2.7 ± 0.5 T: 2.4 ± 0.8 C: 2.4 ± 0.7
27
1 g calcium disodium EDTA/week until body lead burden was
Nephrology 19 (2014) 56–59
Brief Communication
Is lead chelation therapy effective for chronic kidney disease? A meta-analysis SHI-KUN YANG,* LI XIAO,* PAN-AI SONG, XIAO-XUAN XU, FU-YOU LIU and LIN SUN Department of Nephrology, The Second Xiangya Hospital, Kidney Institute of Central South University, Changsha, Hunan Province, China
KEY WORDS: calcium disodium EDTA, chelation, chronic kidney disease, lead. Correspondence: Dr Lin Sun, Department of Nephrology, The Second Xiangya Hospital, Kidney Institute of Central South University, Changsha, Hunan Province 410011, China. Email: [email protected] doi:10.1111/nep.12162 *These authors contributed equally to this work. None of the authors have any conflicts of interest.
ABSTRACT: The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure and the presence of chronic kidney injury. Some studies have suggested that chelation therapy with calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) might help decrease the progression of chronic kidney disease among patients with measurable body lead burdens. However, calcium disodium EDTA chelation in lead exposure is controversial due to the potential for adverse effects such as acute tubular necrosis. Therefore, we investigated the available randomized controlled trials assessing the renoprotective effects of calcium disodium EDTA chelation therapy. Our meta-analysis shows that calcium disodium EDTA chelation therapy can effectively delay the progression of chronic kidney disease in patients with measurable body lead burdens reflected by increasing the levels of estimated glomerular filtration rate (eGFR) and creatinine clearance rate (Ccr). There appears to be no conclusive evidence that calcium disodium EDTA can decrease proteinuria.
The kidney is the target of numerous xenobiotic toxicants, including environmental chemicals. The anatomical, physiological, and biochemical features of the kidney make it particularly sensitive to many environmental compounds.1 The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure to this metal and the presence of chronic kidney injury, even at levels of exposure considered to be ‘normal or tolerable’.2,3 Some small studies have suggested that calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) chelation therapy might help decrease chronic kidney disease progression in patients with measurable body lead burdens. We conducted a meta-analysis of trials to assess the renoprotective effects of calcium disodium EDTA. We performed a literature search on Medline, EMBASE, Cochrane Central Register of Controlled Trials (CCRCT) (all to May 2013) using the keywords: chelator, EDTA, calcium disodium EDTA, chelation therapy, lead, heavy metal nephropathy and kidney disease. The inclusion criteria were: (i) study design (randomized controlled trials); (ii) intervention (trials of calcium disodium EDTA chelation therapy versus placebo); (iii) target population (chronic kidney disease patients with abnormal body lead burdens). Two of the 56
authors (SKY and PAS) independently examined the titles and abstracts of all studies, and excluded all studies that did not clearly meet the inclusion criteria. The full-text articles were retrieved for a comprehensive review and were independently rescreened. When disagreement on study inclusion existed, exclusion or data extraction between the reviews occurred, differences were resolved by consensus with the senior authors (LX and LS). The studies’ quality was assessed using the Jadad composite scale by two authors (SKY and XXX) independently (Table 1). The studies were categorized as low-quality if the score was 2 or less, and high-quality if the score was at least 3.10,11 For each study, data regarding the level of estimated glomerular filtration rate (eGFR), creatinine clearance (Ccr) and proteinuria in both the calcium disodium EDTA and control groups were used respectively to generate the standardized mean differences (SMD) and the 95% confidence intervals (CI). The statistical heterogeneity of effect sizes among individual studies was assessed using the χ2 test (P < 0.1 indicating significant) and the I2 statistic (I2 value > 50% means significant heterogeneity).12 Where no significant statistical heterogeneity was identified, the fixed-effects estimate was used preferentially. All statistical analyses were performed using Review Manager version 5.1. © 2013 Asian Pacific Society of Nephrology
Chelation therapy for CKD
Table 1 Characteristic of included studies Study
Study design
No. patients
Chen 20124
Randomized single-blind
Lin 20065
Randomized single-blind
Lin 20016
Randomized single-blind
Lin 20037
Randomized single-blind
Lin JL 20068
Randomized single-blind
Lin-Tan 20079
Randomized single-blind
T: 25 C: 25 T: 16 C: 16 T: 20 C: 10 T: 32 C: 32 T: 15 C: 15 T: 58† C: 58‡
Mean age (years)
Gender (M/F)
Scr (mg/dL)
Study duration (month)
Chelator does and regimen
Jadad Score
T: 60.1 ± 12.8 C: 56.1 ± 7.8 T: 58.6 ± 10.9 C: 54.8 ± 13.1 T: 53.4 ± 11.9 C: 54.3 ± 10.4 T: 57.9 ± 10.7 C: 57.6 ± 12.8 T: 59.5 ± 12.6 C: 57.9 ± 7.1 T: 57.8 ± 10.9 C: 57.3 ± 13.2
T: 19/6 C: 21/4 T: 14/2 C: 13/3 T: 16/4 C: 7/3 T: 26/6 C: 25/7 T: 11/4 C: 13/2 T: 47/11 C: 42/16
T: 2.8 ± 0.7 C: 2.9 ± 0.6 T: 2.1 ± 0.7 C: 2.0 ± 0.5 NR
27
3
T: 2.7 ± 0.9 C: 2.6 ± 0.5 T: 3.0 ± 0.5 C: 2.7 ± 0.5 T: 2.4 ± 0.8 C: 2.4 ± 0.7
27
1 g calcium disodium EDTA/week until body lead burden was
