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Environmental Lead Exposure and Progressive Renal Insufficiency
Ja-Liang Lin, MD;
Dan-Tzu Tan, RN;
Kuan-Huang Hsu, PhD;
Chun-Chen Yu, MD
Arch Intern Med. 2001;161:264-271.
ABSTRACT
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Background Several recent studies show that serum creatinine level or creatinine
clearance is inversely associated with blood lead levels. However, the studies
did not allow direct inferences about causality.
Objective To evaluate the relation between body lead burden (BLB) and progressive
renal insufficiency in patients without previous heavy lead exposure.
Design A prospective, longitudinal study with a controlled clinical trial.
Patients One hundred ten patients with chronic renal insufficiency (serum creatinine
level, 133-354 µmol/L [1.5-4.0 mg/dL]) and normal BLB (EDTA mobilization
tests, <600 µg per 72-hour urine collection) and without a history
of previous heavy lead exposure were divided into 2 groups according to BLB:
the high-normal BLB group (BLB  80 µg and <600 µg) and the
low BLB group (BLB <80 µg). Patients were prospectively followed
up for 2 years.
Main Outcome Measures The primary outcome was a 1.5 times increase in the initial creatinine
level. The secondary outcome was a change over time in the value of creatinine
clearance. At the end of follow-up, a 3-month clinical trial with chelation
therapy for patients with high-normal BLB was performed to clarify the role
of environmental lead exposure in progressive renal insufficiency.
Results Fifteen patients (14 in the high-normal BLB group and 1 in the low BLB
group) reached the primary outcome within 24 months. Renal outcome was significantly
better in the low BLB group (P<.001). From month
12 to month 24, renal function of high-normal BLB patients had a greater rate
of progressive renal insufficiency than that of low BLB patients. In the Cox
multivariate regression analysis, BLB was the most important risk factor for
determining the progression of renal insufficiency. After chelation therapy,
significant improvement in renal function was noted. In addition, the effect
of improving renal function lasted for more than 12 months in these patients.
Conclusions Long-term low-level environmental lead exposure may subtly affect progressive
renal insufficiency in the general population. Progressive renal insufficiency
may be improved for at least 1 year after lead chelating therapy. Further
investigations are needed to clarify this observation.
INTRODUCTION
LEAD IS STILL one of the major environmental pollutants in the world.
It is well known to induce nephropathy in persons with heavy or occupational
lead exposure,1, 2, 3, 4
but few studies have attempted to evaluate the renal effects of environmental
low-level lead exposure. Several recent epidemiological studies5, 6
showed that serum creatinine level or creatinine clearance was inversely associated
with blood lead levels. The studies do not allow direct inferences about causality
because they are only cross sectional. A longitudinal retrospective study7 demonstrated an acceleration of age-related impairment
of renal function in association with blood lead levels. However, the study
was retrospective and, like previous cross-sectional epidemiological studies,
did not control for many factors affecting the progression of renal insufficiency,
such as daily protein intake, daily urinary protein level, and use of converting
enzyme inhibitors. In addition, blood lead level reflects levels of exposure
to lead during the recent weeks and months only and does not indicate body
lead burden (BLB). The most reliable measurements of BLB are attained using
bone radiograph fluorescence and EDTA mobilization tests.8
In previous works,9, 10, 11, 12, 13
investigators used the EDTA mobilization test to assess the BLB of patients
with chronic renal disease without previous lead exposure. They demonstrated
that long-term low-level environmental lead exposure (1) may be associated
with impaired renal function9, 10
in a small group of patients, (2) can subtly affect urate excretion in patients
with chronic renal disease,11 and (3) is associated
with renal tubular and glomerular damage in a general population.12, 13 However, whether long-term low-level
environmental lead exposure is associated with the progression of renal insufficiency
remains unknown. In addition, although lead chelation therapy has been successfully
introduced to treat chronic lead-related nephropathy2, 3
in persons with occupational exposure to lead and rats with long-term low-level
lead exposure,14 the efficacy of this therapy
for patients with low-level environmental lead exposure is unknown.
To determine whether long-term low-level environmental lead exposure
plays a role in the progression of renal insufficiency in patients with chronic
renal insufficiency (CRI), we performed a prospective, longitudinal study
with a controlled clinical trial.
PATIENTS, MATERIALS, AND METHODS
We conducted a 3-year, prospective, longitudinal study. The protocol
was approved by the Clinical Research Committee of Chang Gung Memorial Hospital,
Taipei, Taiwan, and all the patients gave informed consent.
STUDY PATIENTS
Men and women aged 18 to 70 years who had CRI caused by various diseases
were eligible for the study if they met the following criteria: (1) a serum
creatinine concentration of 133 to 354 µmol/L (1.5-4.0 mg/dL) and follow-up
for at least 6 months in the outpatient department of Chang Gung Memorial
Hospital to determine whether renal function was stable and blood pressure
(<140/90 mm Hg), hyperlipidemia (cholesterol level, <6.21 mmol/L [<240
mg/dL]), and daily protein intake (<1 g/kg body weight) were well controlled;
(2) without a known history of previous lead exposure, BLB had to be normal
(<600 µg) as measured by calcium disodium EDTA mobilization tests
and 72-hour urine collections; and (3) stable renal function (changes in creatinine
clearance less than 0.08 mL/s [<5 mL/min] during the 6-month period) and
a serum creatinine level of at least 133 µmol/L (1.5 mg/dL) for 6 months
preceding study entry. Renal diseases were diagnosed based on the findings
of history taking, laboratory evaluations, renal echogram, and radiological
and renal histological examinations.
To avoid the possibility that changes in the rate of progression of
renal insufficiency might be related to the intrinsic diseases rather than
the BLBs, we excluded patients with (1) potential reversible renal insufficiency,
such as malignant hypertension, urinary tract infection, hypercalcemia, and
drug-induced nephrotoxicity; (2) systemic diseases, such as connective tissue
diseases or diabetes mellitus, and receiving drugs that might alter the natural
history of renal disease, such as nonsteroidal anti-inflammatory drugs, corticosteroids,
or immunosuppressive agents; (3) rapid progressive glomerulonephritis or severe
daily urinary protein intake (>10 g/d); (4) previous heavy lead exposure,
including histories of lead poisoning or occupational lead exposure; and (5)
a drug allergy history or no informed consent.
Blood pressure was controlled with the use of diuretics and converting
enzyme inhibitors given with or without calcium blocking agent therapy. These
drugs were not changed but were dose adjusted during the study period. Patients
without hypertension did not use any converting enzyme inhibitors. Because
renal function deteriorated more quickly in patients with hypertension, hypercholesterolemia,
and high protein intake, we were careful to ensure that blood pressure, cholesterol
level, and protein intake were well controlled in all patients. Phosphate
levels were controlled by administration of calcium carbonate. No patient
received vitamin D3 (calcitriol) therapy or erythropoietin treatment.
Patients received dietary consultation and were advised to follow a normal
protein diet. The diet required a daily intake of 0.8 to 1.0 g of protein
per kilogram provided by foods containing most or all essential amino acids,
such as meat, fish, chicken, and eggs. A nutritionist reviewed the dietary
intake of each patient every 3 to 6 months. The 24-hour urine urea excretion
was measured every 3 months to assess nitrogen balance and dietary compliance.15 To assess whether there were any differences in the
rate of progression of renal insufficiency, serum creatinine, cholesterol,
urinary protein, and urea levels were checked every 3 months.
MEASUREMENTS OF BLOOD LEAD LEVEL AND BLB
Body lead burden was determined using the protocol of EDTA mobilization
tests developed by Emmerson and modified by Batuman et al.16
Every patient received an intravenous infusion of 1 g of calcium disodium
EDTA mixed with 200 mL of normal saline solution over 2 hours. They collected
24-hour urine samples in 2-L bottles on 3 consecutive days to assess BLBs.
Urine samples were collected by spontaneous voiding. All patients were hydrated
orally with water sufficient to provide a steady urine flow of at least 1
mL/min. Patients who did not have an accurate urine collection (>1 lost urine
collection) or who had inadequate urine flow collected another urine sample
after the next weekly EDTA therapy. Blood lead and urine lead excretion were
quantified using an electrothermal atomic absorption spectrometer (model 5100PC;
Perkin-Elmer, Norwalk, Conn) with Zeeman background correction and an L'vov
platform (Behringer method). All urinary lead determinations were performed
at least in duplicate. The hospital laboratory participated in the external
quality control program for lead measurement held by the College of American
Pathologists for 5 years and obtained the excellent degree every year.
STUDY PROTOCOL
Sample Collection Period (Months 0-3)
Blood lead levels, hemoglobin levels, BLBs, and biochemical data were
checked in all eligible patients. Based on the findings of a previous work13 that the mean BLB of healthy persons is 76.6 µg
and of patients with CRI is 84.5 µg, we divided our patients into 2
groups: those with low BLB (<80 µg) and those with high-normal BLB
(80 µg and <600 µg).
Clinical Observation Period (Months 4-27)
Serum creatinine, cholesterol, and daily urinary urea levels were measured
at the beginning and end and every 3 months during the 24-month clinical observation
period with an autoanalyzer system (model 736; Hitachi, Tokyo, Japan). Two
consecutive 24-hour urine collection samples and laboratory data were obtained
from each patient, and the means of the 2 measurements were recorded. Patients
who did not have an accurate urine collection (>1 lost urine collection) or
who had inadequate urine flow (<1 mL/min) collected another urine sample.
At the end of this period, we compared the changes in renal function between
the 2 groups and assessed the relation between BLB and the progression of
renal insufficiency.
The primary outcome measure was a 1.5 times increase in the initial
serum creatinine level, confirmed 1 month later, or the need for hemodialysis.
The secondary outcome measures were changes over time in the values of creatinine
clearance, urine protein excretion, daily protein intake, mean arterial pressure,
serum cholesterol, and body mass index.
Chelation Clinical Trial (Months 28-30) and Follow-up (Months 31-42)
The high-normal BLB group assessed their BLB again at the beginning
of the period. Thirty-six patients with serum creatinine levels less than
371 µmol/L (<4.2 mg/dL) were randomly assigned to either the control
or the study group (1:2). The randomization was performed according to the
random digital method in which digital numbers came from a computer. This
study is a single-blind experiment. The control group received a weekly intravenous
infusion of 1 vial (20 mL) of 50% glucose, as a placebo, mixed with 200 mL
of normal saline solution over 2 hours. The study group received a weekly
intravenous infusion of 1 vial (1 g) of calcium disodium EDTA mixed with 200
mL of normal saline solution over 2 hours. Because these drugs were prepared
at the pharmacy, patients did not know which drugs they received. Patients
collected 24-hour urine samples in 2-L bottles for 3 consecutive days to assess
BLB every 2 weeks, and the treatment would be held if the EDTA mobilization
test was less than 80 µg per 72-hour urine collection. At the end of
this period, we compared the changes of renal function before and after the
clinical trial. The same laboratory measurements were taken every 3 months
for 12 months after chelation therapy to compare the changes in renal function.
STUDY COMPLIANCE
Patients were withdrawn from this study if they (1) did not complete
the study or regularly check biochemical data; (2) had poor control of their
hypertension (>160/95 mm Hg), hyperlipidemia (cholesterol level, >6.21 mmol/L
[>240 mg/dL]), or protein intake greater than 1.5 g/kg per day for more than
6 months; and (3) had acute deterioration of renal function secondary to drug
therapy or other etiologies, eg, trauma and hyperthermia, during the study
periods.
STATISTICAL ANALYSIS
The primary outcome measure was analyzed with the log-rank test, with
the status of renal function determined as of the last day of the third year
of treatment. For all patients who did not complete the 2-year study, data
were censored after the last visit. Cox proportional hazards regression was
used to determine the significance of the variables in predicting primary
renal outcome. Progressive renal insufficiency of the 2 study groups was compared.
The  2 test, t test, and Mann-Whitney U test were used to measure the differences between groups.
The Mann-Whitney U test was used for data not distributed
in a normal fashion. To protect against a type I error due to the one planned
interim analysis, the significant level for outcome measures was set at P<.01; P = .05 to .01 was considered
possible significance. All P values were 2-tailed.
All results are presented as mean ± SD.
An intent-to-treat analysis was performed. In addition, we conducted
a sensitivity analysis that assigned the mean value of renal function in the
study group to patients lost to follow-up in the control group and the mean
value of renal function in the control group to patients lost to follow-up
in the study group.
RESULTS
One hundred ninety-six patients with a serum creatinine level of 133
to 354 µmol/L (1.5-4.0 mg/dL) were screened for the study. One hundred
ten patients with CRI were enrolled, and 96 completed the 24 months of observation.
Fifty-five patients with high-normal BLB (80 µg and <600 µg,
estimated by EDTA mobilization tests) and 55 with low BLB (<80 µg)
eligible for the study were assigned to 2 study groups according to their
BLB. Six participants (3 were noncompliant and 3 dropped out for unknown reasons)
in the high-normal BLB group and 8 (4 were noncompliant, 1 died, and 3 dropped
out for unknown reasons) in the low BLB group were excluded from this study.
CLINICAL OBSERVATION PERIOD
Table 1 summarizes demographic
data (age, sex, and body mass index), baseline chronic disease condition (serum
creatinine level, prevalence of hypertension, hyperlipidemia, and underlying
disease distribution), use of converting enzyme inhibitors in hypertensive
patients, daily urinary urea and protein levels, and BLBs for participants
in each group. No significant differences in these baseline values between
the 2 groups were noted. Similarly, mean arterial pressure, serum cholesterol,
body mass index, and daily urinary protein excretion and protein intake did
not differ significantly between the 2 groups during the observation period
(Table 2). Table 3 compares the progression of renal insufficiency in the high-normal
BLB and low BLB groups during the observation period. Creatinine clearance
in the low BLB group was greater than that in the high-normal BLB group in
months 18 to 24 of observation. Similar results were also noted in the sensitivity
test (Table 4).
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Table 1. Baseline Characteristics of 110 Patients With an Elevated
Lead Burden at Study Entry*
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Table 2. Intent-to-Treat Analysis of Body Mass Index, Mean Arterial
Pressure (MAP), Serum Cholesterol Level, Daily Urine Protein Level, and Daily
Protein Intake in Study Patients During the 24-Month Observation Period*
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Table 3. Intent-to-Treat Analysis of Renal Function During 24 Months
of Observation*
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Table 4. Sensitivity Analysis of Renal Function During Months 12 to
24 of the Observation Period*
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Fifteen patients (14 in the high-normal BLB group and 1 in the low BLB
group) reached the primary outcome within 24 months; all had a serum creatinine
level 1.5 times the initial level, and none needed hemodialysis. Renal outcome
was better in the low BLB group (P<.001 by log-rank
test) (Figure 1). In the Cox regression
analysis, high-normal BLB was the most important risk factor for progressive
renal insufficiency, even after adjusting for age, sex, smoking, hypertension,
hyperlipidemia, daily urinary protein level, daily protein intake, body mass
index, and underlying diseases (Table 5). In addition, age and body mass index also significantly predict
progressive renal insufficiency. Similarly, if we entered BLB in the Cox multivariate
regression analysis as a continuous measurement rather than as an arbitrary
categorical variable, BLB remained the important risk factor (risk ratio,
1.006; 95% confidence interval, 1.002-1.010; P =
.004) after adjusting for other relating factors.
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Kaplan-Meier estimates of primary renal outcome in patients with
chronic renal insufficiency who had high-normal (80 µg and <600
µg) and low (<80 µg) body lead burdens (BLBs) (P<.001
by log-rank test).
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Table 5. Cox Regression Analysis of Overall Risk of Progressive Renal
Insufficiency in All Patients According to Baseline Prognostic Factors and
Primary Outcome*
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CHELATION CLINICAL TRIAL AND FOLLOW-UP
Thirty-six patients with high-normal BLB participated in the clinical
trial, including 24 study group patients and 12 control group patients. The
basic characteristics of both groups were similar (Table 6). Following 3 months of lead chelation therapy, the BLB
of the study group decreased to 39.2 ± 29.4 µg (range, 0.0-73.6
µg). The average therapeutic dose of EDTA was 5 g (range, 3-13 g). The
improvement in renal function in the study group was greater than that of
the control group after chelation therapy. In addition, during follow-up after
chelation therapy, the effect of improving renal function in the study group
persisted for at least 12 months (Table
7). Two study group patients and 1 control group patient were lost
to follow-up for unknown reasons during the 12-month study. The sensitivity
analysis shows similar results (Table 8).
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Table 6. Baseline Characteristics of 36 Patients With High-Normal Body
Lead Burden (80 µg and <600 µg) at Study Entry*
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Table 7. Intent-to-Treat Analysis of Increments of Renal Function After
Chelation Therapy and During 12-Month Follow-up Compared With Renal Function
Before Chelation Therapy*
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Table 8. Sensitivity Analysis of Increments of Renal Function After
Chelation Therapy and During 12-Month Follow-up Compared With Renal Function
Before Chelation Therapy*
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COMMENT
In this prospectively longitudinal study, we first demonstrated that
patients with a high-normal BLB had more rapidly progressive renal insufficiency
during 2-year follow-up; even the ranges of their BLBs and blood lead levels
were within reference limits. The mean blood lead level of our patients was
only 0.26 µmol/L (5.4 µg/dL), which is far less than the upper
limit of the reference range (0.97 µmol/L [20 µg/dL])7 and between those of European (0.55 µmol/L [11.4
µg/dL])5 and American (0.13 µmol/L
[2.7 µg/dL]) general populations.17 The
mean BLB of our patients was only 106.1 µg, which is far less than toxic
(>1000 µg)2 and subtle poisoning (>600
µg) levels.16 Hence, environmental lead
exposure might not be innocent in the progression of renal insufficiency in
the general population.
Although the pathogenesis of progressive renal insufficiency is unknown,
results of experimental studies in animals and some studies in humans18, 19, 20 have suggested that
progression of different types of renal disease might largely be due to hemodynamic
and metabolic factors rather than to the activity of underlying diseases.
On the basis of the observations of clinical studies,21, 22, 23
blood pressure control, a restricted daily protein diet, control of hyperlipidemia,
and reduction of daily urinary protein excretion are effective in retarding
the development and progression of renal insufficiency. In the Cox multivariate
regression analysis, we also first demonstrated that a BLB greater than or
equal to 80 µg and less than 600 µg is the most important risk
factor for determining the progression of renal insufficiency, even after
adjusting for possible factors affecting progression of renal insufficiency.
In addition, renal function of patients with CRI and high-normal BLB (80
µg and <600 µg) significantly improved after their BLBs were
reduced to less than 80 µg by chelation therapy. The effects lasted
for at least 12 months. At the end of 12-month follow-up, increments of renal
function up to 10.2% in the study group and decrements of renal function up
to 11.1% in the control group were noted. Results of the clinical trial further
confirm the initial findings of the 2-year follow-up and imply that environmental
lead exposure might play an important role in the progression of CRI. Based
on the findings of the present study and previous epidemiological studies5, 6, 7, 9, 10, 11, 12, 13
of the relations between environmental low-level lead exposure and renal function,
we suggest that long-term low-level environmental lead exposures might subtly
affect progressive renal insufficiency in the general population.
After EDTA chelation therapy, the amount of BLB in the study group decreased
from 198.0 µg to 39.2 µg, and their renal function increased 8%.
Three months later, renal function increased to 12.8%. Twelve months later,
the increments of renal function remained at 10.2%. The effect of improving
renal function lasted for at least 1 year after chelation therapy. The findings
are similar to those of previous short-term studies in chelation therapy of
lead workers2, 3 and rats with
long-term low-level lead exposure.14 In addition,
the results are also in agreement with those of a previous study9
in a small group of patients with CRI. Hence, it seems reasonable to conclude
that long-term low-level environmental lead exposure might play a role in
progressive renal insufficiency. The EDTA chelating agent is safe in treating
patients with CRI with a smaller dose and a longer interval.3, 9, 12, 24
Wedeen et al25 extensively used EDTA as test
doses in large numbers of patients and as therapy in a smaller number, yet
they never encountered any evidence of nephrotoxicity. The same findings were
also noted in previous studies.2, 3, 4, 9, 10, 11, 12, 13, 16
Hence, the EDTA chelation therapy might be a better alternative to treat patients
with progressive renal insufficiency. The results of the present study shed
further light on the treatment of CRI. Further investigation is needed to
confirm our observations.
The mechanism by which chelation therapy improves renal function is
unknown. The effect of improving renal function after chelation therapy might
theoretically relate to removal of essential trace elements, such as zinc
and copper, which act as cofactors for enzymes that affect synthesis of vasoactive
hormones.18, 19 For example, zinc
is a cofactor for neutral metalloendopeptidase, a kidney enzyme of degrading
atrial natriuretic peptide,26 and for angiotensin-converting
enzyme.27 A depletion of zinc might cause an
elevation in atrial natriuretic peptide and a reduction in angiotensin II
formation together with a decline in blood pressure and an increase in renal
blood flow. However, the dimercaptosuccinic acid chelating agent, which also
improves renal function in rats with long-term low-level lead exposure, does
not alter the zinc and copper content of the kidney cortex.14
Hence, the hypotheses are against the results of an animal study14
of dimercaptosuccinic acid therapy. The other possible explanation might come
from the studies of cellular biology. Long-term low-level lead exposure, but
not long-term high-level lead exposure, might affect endothelium-derived relaxing
factor and endothelin 3.28, 29
The improvement in renal function in our patients after EDTA treatment could
therefore be a consequence of removal of excessive body lead. Further evaluation
is needed to clarify a definite mechanism.
We used serum creatinine and creatinine clearance to assess renal function
because these were the only quantitative measurements of renal function available
for prospective analysis in our patients. Furthermore, resource constraints
prohibited us from measuring inulin or isotopic clearance30
in this work. Our study is limited by using these methods to assess changes
in renal function because whether this method accurately reflects changes
in glomerular filtration has not been tested rigorously. Other limitations
of our study include the lack of a double-blind placebo design, the inability
to mask patients and providers, the relatively small sample size, and the
questionable generalizability of our findings to patients with multifactorial
etiologies of renal insufficiency.
In conclusion, long-term low-level environmental lead exposure may be
associated with chronic renal disease. Progressive renal insufficiency may
be improved after lead chelating therapy. Further investigation is needed
to confirm our observations and to clarify the mechanism by which long-term,
low-level lead exposure might affect renal function.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
This study was supported in part by grant NSC89-2314-B-182A-022 from
the National Science Council Foundation, Taipei, Taiwan, Republic of China.
From the Poison Center and the Division of Nephrology, Chang Gung Memorial
Hospital, Lin-Kou Medical Center, Medical College (Drs Lin and Yu and Ms Tan),
and the School of Public Health and Epidemiology (Dr Hsu), Chang Gung University,
Taipei, Taiwan, Republic of China.
Corresponding author and reprints: Ja-Liang Lin, MD, Poison Center
and Division of Nephrology, Chang Gung Memorial Hospital, 199, Tung Hwa North
Road, Taipei, Taiwan, Republic of China (e-mail: jllin99{at}hotmail.com).
REFERENCES
| |
1. Henderson DA. The etiology of chronic nephritis in Queensland. Med J Aust. 1958;1:377-386.
2. Wedeen RP, Maesaka JK, Weiner B, Mallick DK. Occupational lead nephropathy. Am J Med. 1975;59:630-641.
FULL TEXT
|
ISI
| PUBMED
3. Wedeen RP, Mallick DK, Batuman V. Detection and treatment of occupational lead nephropathy. Arch Intern Med. 1979;139:52-57.
4. Nuyts GD, Daelemans RA, Jorens PhG, Elseviers MM, Van de Vyver VD, De Broe ME. Does lead play a role in the development of chronic renal disease? Nephrol Dial Transplant. 1991;6:307-315.
5. Staessen JA, Lauwerys RR, Buchet JP, et al. Impairment of renal function with increasing blood lead concentrations
in the general population. N Engl J Med. 1992;327:151-156.
ABSTRACT
6. Payton M, Hu H, Sparrow D, Weiss ST. Low-level lead exposure and renal function in the Normative Aging Study. Am J Epidemiol. 1994;140:821-829.
FREE FULL TEXT
7. Kim R, Rotnitzky A, Sparrow D, Weiss ST, Wager C, Hu H. A longitudinal study of low-level lead exposure and impairment of renal
function: the Normative Aging Study. JAMA. 1996;275:1177-1181.
FREE FULL TEXT
8. Pollock CA, Ibels LS. Lead nephropathy: a preventable cause of renal failure. Int J Artif Organs. 1988;11:75-78.
ISI
| PUBMED
9. Lin JL, Ho HH, Yu C-C. Chelation therapy for paients with elevated body lead burden and progressive
renal insufficiency: a randomized, clinical trial. Ann Intern Med. 1999;130:7-13.
FREE FULL TEXT
10. Lin JL, Lim PS. Does lead play a role in the development of renal insufficiency in
some patients with essential hypertension? J Hum Hypertens. 1994;8:495-500.
ISI
| PUBMED
11. Lin JL, Huang PT. Body lead stores and urate excretion in men with chronic renal disease. J Rheumatol. 1994;21:705-709.
ISI
| PUBMED
12. Lin JL, Lim PS. Disappearance of immune deposits with EDTA chelation therapy in a case
of IgA nephropathy. Am J Nephrol. 1992;12:457-460.
ISI
| PUBMED
13. Lin JL, Yeh KH, Chen WY, Lai HH, Lin YC. Urinary N-acetyl-glucosaminidase excretion
and environmental lead exposure. Am J Nephrol. 1993;13:442-447.
ISI
| PUBMED
14. 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.
PUBMED
15. Isaksson B. Urinary nitrogen output as a validity test in dietary surveys. Am J Clin Nutr. 1980;33:4-5.
FREE FULL TEXT
16. Batuman V, Maesaka JK, Haddad B, Tepper E, Landy E, Weeden RP. The role of lead in gouty nephropathy. N Engl J Med. 1981;304:520-523.
ISI
| PUBMED
17. Pirkle JL, Brody DJ, Gunter EW, et al. The decline in blood lead levels in the United States: the National
Health and Nutrition Examination Surveys (NHANES). JAMA. 1994;272:184-191.
18. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potential adverse response to
renal ablation. Am J Physiol. 1981;241:F85-F93.
19. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease:
the role of hemodynamically mediated glomerular injury in the pathogenesis
of progressive glomerular sclerosis in aging, renal ablation, and intrinsic
renal disease. N Engl J Med. 1982;307:652-659.
ISI
| PUBMED
20. Obrador GT, Arora P, Kausz AT, Pereira BJ. Pre–end-stage renal disease care in the United States: a state
of disrepair. J Am Soc Nephrol. 1998;9:S44-S54.
21. Henrich WL. Approach to volume control, cardiac preservation, and blood pressure
control in the pre–end stage renal disease patients. J Am Soc Nephrol. 1998;9:S63-S65.
22. Mitch WE. Dietary protein restriction in patients with chronic renal failure. Kidney Int. 1991;40:326-341.
ISI
| PUBMED
23. Hunsicker LG, Adler S, Caggiula A, et al. Predictors of the progression of renal disease in the Modification
of Diet in Renal Disease Study. Kidney Int. 1997;51:1908-1919.
ISI
| PUBMED
24. Batuman V. Lead nephropathy, gout, and hypertension. Am J Med Sci. 1993;305:241-247.
ISI
| PUBMED
25. Wedeen RP, Batuman V, Landy E. Safety of EDTA lead mobilization test. Environ Res. 1983;30:58-62.
PUBMED
26. Carretero OA, Scicli AG. Zinc metallopeptidase inhibitors: an oral antihypertensive treatment. Hypertension. 1991;18:366-371.
FREE FULL TEXT
27. Maguire GA, Price CP. A continuous monitoring spectrophotometric method for measurement of
angiotensin-converting enzyme in human serum. Ann Clin Biochem. 1985;22:204-209.
28. Khalil-Manesh F, Gonick HC, Weiler EW, Prins B, Weber MA, Purdy RE. Lead-induced hypertension: possible role of endothelial factors. Am J Hypertens. 1993;6:723-729.
ISI
| PUBMED
29. Hermann M, Schulz E, Ruschitzka F, Muller GA. Preventive stategies in endothelin-induced renal failure. Kidney Int Suppl. 1998;67:S202-S204.
30. Levey AS, Perrone RD, Madias NE. Serum creatinine and renal function. Annu Rev Med. 1988;39:465-490.
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