Associations of blood lead with estimated glomerular filtration rate using MDRD, CKD-EPI and serum cystatin C-based equations

Article (PDF Available)inNephrology Dialysis Transplantation 26(9):2786-92 · September 2011with46 Reads
DOI: 10.1093/ndt/gfq773 · Source: PubMed
Abstract
Low-level lead exposure is widespread and has been implicated as a chronic kidney disease (CKD) risk factor. However, studies evaluating associations of lead dose with newer, potentially more accurate, estimates of kidney function, in participants with a wide range of glomerular filtration rates (GFRs), are scarce. We compared associations of blood lead and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and cystatin C single variable, multivariable and combined creatinine/cystatin C equations in 3941 adults who participated in the 1999-2002 National Health and Nutrition Examination Survey cystatin C subsample. Geometric mean blood lead was 1.7 μg/dL. After multivariable adjustment, differences [95% confidence interval (CI)] in mean eGFR for a doubling of blood lead were -1.9 (-3.2, -0.7), -1.7 (-3.0, -0.5) and -1.4 (-2.3, -0.5) mL/min/1.73 m(2), using the cystatin C single variable, multivariable and combined creatinine/cystatin C equations, respectively, reflecting lower eGFR with increased blood lead. The corresponding differences (95% CI) were -0.9 (-1.9, 0.02) and -0.9 (-1.8, 0.01) using the creatinine-based MDRD and CKD-EPI equations, respectively. In participants aged ≥60 years, differences in mean eGFR ranged from -3.0 to -4.5 mL/min/1.73 m(2), and odds of reduced eGFR (<60 mL/min/1.73 m(2)) were increased for all estimates of GFR. These results support the inclusion of cystatin C-based eGFR in future lead research and provide additional evidence for environmental lead exposure as a CKD risk factor.

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Nephrol Dial Transplant (2011) 26: 2786–2792
doi: 10.1093/ndt/gfq773
Advance Access publication 19 January 2011
Associations of blood lead with estimated glomerular filtration rate
using MDRD, CKD-EPI and serum cystatin C-based equations
June T. Spector
1,2
, Ana Navas-Acien
1,3,4
, Jeffrey Fadrowski
4,5
, Eliseo Guallar
3,4,6,7
, Bernard Jaar
3,4,6
and
Virginia M. Weaver
1,4,6
1
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD,
2
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA,
3
Department of
Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD,
4
Welch Center for Prevention,
Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD,
5
Department of Pediatrics, Johns Hopkins
School of Medicine, Baltimore, MD,
6
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD and
7
Department
of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Research, Madrid, Spain
Correspondence and offprint requests to: Virginia M. Weaver; E-mail: vweaver@jhsph.edu
Abstract
Background. Low-level lead exposure is widespread and
has been implicated as a chronic kidney disease (CKD) risk
factor. However, studies evaluating associations of lead
dose with newer, potentially more accurate, estimates of
kidney function, in participants with a wide range of glo-
merular filtration rates (GFRs), are scarce.
Methods. We compared associations of blood lead and
estimated glomerular filtration rate (eGFR) using the Mod-
ification of Diet in Renal Disease (MDRD), Chronic Kid-
ney Disease Epidemiology Collaboration (CKD-EPI) and
cystatin C single variable, multivariable and combined cre-
atinine/cystatin C equations in 3941 adults who partici-
pated in the 1999–2002 National Health and Nutrition
Examination Survey cystatin C subsample.
Results. Geometric mean blood lead was 1.7 lg/dL. After
multivariable adjustment, differences [95% confidence
interval (CI)] in mean eGFR for a doubling of blood lead
were 1.9 (3.2, 0.7), 1.7 (3.0, 0.5) and 1.4 (2.3,
0.5) mL/min/1.73 m
2
, using the cystatin C single variable,
multivariable and combined creatinine/cystatin C equations,
respectively, reflecting lower eGFR with increased blood
lead. The corresponding differences (95% CI) were 0.9
(1.9, 0.02) and 0.9 (1.8, 0.01) using the creatinine-
based MDRD and CKD-EPI equations, respectively. In par-
ticipants aged 60 years, differences in mean eGFR ranged
from 3.0 to 4.5 mL/min/1.73 m
2
, and odds of reduced
eGFR (<60 mL/min/1.73 m
2
) were increased for all
estimates of GFR.
Conclusions. These results support the inclusion of cysta-
tin C-based eGFR in future lead research and provide addi-
tional evidence for environmental lead exposure as a CKD
risk factor.
Keywords: blood lead; kidney function; lead exposure; NHANES
Introduction
Recent research suggests that environmental lead exposure
increases risk for chronic kidney disease (CKD), even at
the lower levels currently observed in the USA and other
developed countries [1–8]. The association between lead
exposure and CKD has been observed in prospective
studies, in a variety of populations, and is consistent with
experimental and mechanistic evidence [2, 3, 5, 9–14].
Environmental lead exposure remains widespread globally
[6, 7, 15]. Moreover, lead accumulated in bone from past
exposure remains a source of current endogenous exposure
[16]. The increasing prevalence of CKD [17] and the fact
that lead exposure is preventable and treatable with chela-
tion in selected settings [18] highlight the need to fully
characterize kidney risk from lead exposure. In such re-
search, accurate assessment of kidney function is essential
to avoid kidney disease misclassification resulting in under-
estimation of risk. Equations to estimate glomerular filtra-
tion rate (GFR) are the most common method for assessing
kidney function clinically and in large epidemiologic stud-
ies, where GFR assessment with an exogenous filtration
marker is not possible. Ongoing efforts to improve the
accuracy of these approaches have resulted in new serum
creatinine-based equations and equations incorporating se-
rum cystatin C. However, publications utilizing these
newer techniques in research on the impact of lead on the
kidney are scarce.
The objective of this study was to evaluate these recently
developed GFR-estimating approaches in lead research.
Therefore, we compared associations of blood lead level
with estimated glomerular filtration rate (eGFR) calculated
with recently developed equations to associations using the
Modification of Diet in Renal Disease (MDRD) equation
[20, 21], a serum creatinine-based equation routinely used
in clinical practice and research. We used four new
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approaches: the creatinine-based Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation [22], de-
veloped to be more accurate than the MDRD equation at
higher GFRs, and three serum cystatin C-based equations:
(i) cystatin C only; (ii) cystatin C, age, sex and race and (iii)
cystatin C, age, sex, race and serum creatinine [23]. We
used data from US adults who participated in the cystatin C
subsample of the 1999–2002 National Health and Nutrition
Examination Survey (NHANES). To our knowledge, this is
the first study to evaluate associations of lead dose with
these potentially more accurate eGFR approaches.
Materials and methods
Study population
NHANES 1999–2002 was conducted using a complex multistage sam-
pling design to obtain a representative sample of the noninstitutionalized,
civilian US population [24]. The study protocols were approved by the
National Center for Health Statistics Institutional Review Board. All par-
ticipants provided oral and written consent.
In 2006, cystatin C was assayed on stored serum samples from all
NHANES 1999–2002 participants aged 60 years as well as on a 25%
random sample of those aged 12–59 years [25, 26]. The younger group
was supplemented with all individuals with a serum creatinine >1.2 mg/
dL (SI conversion: multiply by 88.4 for micromoles per liter) in males and
>1.0 mg/dL in females [25, 26]. Of 4563 adults aged 20 years with
cystatin C measures available, we excluded pregnant women and those
missing blood lead levels and other variables of interest, leaving 3941
participants with complete data.
Blood lead measurement
Blood lead was measured at the Centers for Disease Control and Preven-
tion’s National Center for Environmental Health [24]. Lead was measured
in whole blood together with cadmium using a Perkin-Elmer Model SI-
MAA 6000 simultaneous multielement atomic absorption spectrometer
with Zeeman background correction. Strict quality control procedures
were followed including confirmation that collection and storage materials
were not contaminated. The limit of detection was 0.3 lg/dL [27]; results
were below the limit of detection in 0.5% of participants in our study
population. For these values, a level equal to the limit of detection divided
by the squared root of two was imputed [28, 29]. National Institute of
Standards and Technology whole-blood standard reference materials were
used for external calibration. The interassay coefficients of variation
ranged from 3.1 to 7.0% for concentrations ranging from 2.1 to 29.3 lg/
dL [30, 31].
Estimates of GFR
Serum creatinine was measured using a kinetic rate Jaffe´ method with a
Hitachi Model 704 multichannel analyzer (Boehringer Mannheim Diag-
nostics, Indianapolis, IN) [24]. Serum creatinine concentrations were cali-
brated to standard creatinine [32]. The interassay coefficients of variation
were 2.7 and 2.2% at mean creatinine concentrations of 1.67 and 6.51 mg/
dL, respectively, for 1999–2000 [33] and 4.4 and 1.5% at mean creatinine
concentrations of 0.68 and 7.0 mg/dL, respectively, for 2001–2002 [34].
Serum cystatin C was measured using an automated particle-enhanced
nephelometric assay (Dade Behring N Latex Cystatin C run on a Dade
Behring Nephelometer II; Siemens Healthcare Diagnostics, Deerfield, IL)
[24]. The assay range was 0.23–7.25 mg/L. The interassay coefficients of
variation were 5.05 and 4.87% at mean cystatin C concentrations of 0.97
and 1.90 mg/L, respectively [35]. The following equations were used to
estimate GFR:
MDRD eGFR ¼ 175 3 (serum creatinine)
1.154
3 age
0.203
3 1.212
(if black) 3 0.742 (if female) [20]
CKD-EPI eGFR ¼ 141 3 min(Scr/j,1)
a
3 max(Scr/j,1)
1.209
3
0.993
Age
3 1.159 (if black) 3 1.018 (if female), where Scr is serum
creatinine, j is 0.7 for females and 0.9 for males, a is 0.329 for
females and 0.411 for males, min indicates the minimum of Scr/j
or 1 and max indicates the maximum of Scr/j or 1 [22]
Cystatin C single variable eGFR ¼ 76.7 3 serum cystatin C
1.19
[23]
Cystatin C multivariable eGFR ¼ 127.7 3 (serum cystatin C)
1.17
3
age
0.13
3 1.06 (if black) 3 0.91 (if female) [23]
Combined cystatin C/creatinine eGFR ¼ 177.6 3 serum creatinine
0.65
3 serum cystatin C
0.57
3 age
0.20
3 (0.82 if female) 3 (1.11 if black)
[23]
Other variables
Information on age, sex, race/ethnicity, education, smoking, income and
alcohol consumption was based on self-report [24]. Body mass index was
calculated by dividing measured weight in kilograms by measured height
in meters squared. Serum cotinine was measured by an isotope-dilution
high-performance liquid chromatography/atmospheric pressure chemical
ionization tandem mass spectrometric method. Hypertension was defined
as a mean systolic blood pressure 140 mmHg or mean diastolic blood
pressure 90 mmHg, based on three blood pressure measurements ob-
tained during the medical examination, or a self-reported physician diag-
nosis. Diabetes mellitus was defined as a fasting glucose 126 mg/dL, a
non-fasting glucose 200 mg/dL or a self-reported physician diagnosis.
Statistical analysis
Data were obtained from the NHANES Web site [24] and merged and
analyzed using STATA 10 (StataCorp, College Station, TX). Statistical
analyses were performed using the survey commands in STATA 10 with
specific weights for the cystatin C subsample to account for the complex
sampling design.
Distribution of blood lead was right skewed and log-transformed for the
analyses. Tertile cut-points were based on weighted distributions in the whole
study population. In separate linear regression models for each equation,
differences in mean eGFR were estimated comparing each of the two higher
tertiles of blood lead to the lowest tertile and for doubling of lead levels.
These linear regression models were conducted in all participants and in
those <60 and 60 years of age. In separate logistic regression models
for each equation, odds ratios for reduced eGFR (<60 mL/min/1.73 m
2
)
were estimated only in participants 60 years because few participants
<60 years of age had reduced eGFRs (103 participants with the MDRD
equation and 53–60 participants with the other equations). Model adjustment
was based on biological plausibility and known lead and kidney confound-
ers. Adjustment for cadmium was performed since this is another proximal
tubule nephrotoxicant for which exposure is common environmentally.
P-values for linear trend in logistic and linear regression models were ob-
tained by including blood lead tertiles coded as ordinal variables; results
obtained by entering blood lead as tertile medians were similar. To assess
the dose–response relationship in a flexible manner, we also estimated odds
ratios for reduced eGFR by modeling blood lead levels with restricted quad-
ratic splines with knots at the 5th, 50th and 95th percentiles. Spline models
were conducted only in participants 60 years due to the small number of
participants <60 years of age with eGFR <60 mL/min/1.73 m
2
.
Results
The geometric mean blood lead was 1.7 lg/dL for all par-
ticipants, 2.2 lg/dL for participants aged 60 years and
1.6 lg/dL for participants aged <60 years. Corresponding
values for blood cadmium were 0.45, 0.50 and 0.44 lg/L,
respectively. Median eGFR levels were lowest using the
MDRD equation (Table 1). The weighted prevalence of
reduced eGFR (<60 mL/min/1.73 m
2
) was 8.4% for the
MDRD equation, 6.5% for the CKD-EPI equation and
6.6%, 8.6% and 6.4% for the three cystatin C equations,
respectively, consistent with previous prevalence estimates
[17]. Geometric mean [95% confidence interval (CI)] blood
lead levels for participants with cystatin C multivariable
eGFR <60 and 60 mL/min/1.73 m
2
were 2.3 (2.1, 2.5)
and 1.7 (1.6, 1.7) lg/dL, respectively. Mean blood lead
levels were also significantly higher in participants with
reduced kidney function using the other equations
Associations of blood lead with GFR estimates 2787
(data not shown). All eGFR measures were highly
correlated, particularly for eGFR levels calculated with
the same serum measure: correlations between eGFR cal-
culated using the MDRD equation and eGFR using CKD-
EPI, cystatin C single variable, cystatin C multivariable and
cystatin C/creatinine equations were 0.95, 0.71, 0.72 and
0.93, respectively (Appendices 1–3).
In the overall sample, multivariable adjusted differences
(95% CI) in mean eGFR for a doubling of blood lead
were 1.9 (3.2, 0.7), 1.7 (3.0, 0.5) and 1.4
(2.3, 0.5) mL/min/1.73 m
2
for the cystatin C single
variable, cystatin C multivariable and cystatin C/creatinine
equations, respectively (Table 2). The corresponding dif-
ferences (95% CI) were 0.9 (1.9, 0.02) and 0.9 (1.8,
0.01) using the creatinine-based MDRD and CKD-EPI
equations, respectively. For comparison with studies that
used serum creatinine and cystatin C as kidney outcomes
without incorporating them into estimating equations, fully
adjusted mean differences (95% CI) for a doubling of blood
lead for serum creatinine and cystatin C were 0.05 (0.02,
0.07) mg/dL and 0.04 (0.02, 0.07) mg/L, respectively. The
difference in mean level (95% CI) for a doubling of blood
lead using the traditional Cockcroft–Gault equation for cre-
atinine clearance [36] was 2.2 (3.5, 0.8); however,
median creatinine clearance was 107.7 mL/min indicating
a substantial overestimation of GFR. After correction for
body surface area, an approach reported to be more accu-
rate [37] and providing a more comparable result, the dif-
ference in mean level (95% CI) was 1.4 (2.4, 0.3)
although the median (98.3 mL/min/1.73 m
2
) remained
higher than those using the eGFR equations.
In participants aged 60 years, differences in mean
eGFR for a doubling of blood lead ranged from 3.0 to
4.5 mL/min/1.73 m
2
across equations (Table 2). In
younger participants, the differences were smaller (range
0.2 to 2.2 mL/min/1.73 m
2
) and, although not statisti-
cally significant, were larger for the cystatin C single and
multivariable estimates.
The adjusted odds ratios (95% CI) for reduced eGFR
(<60 mL/min/1.73 m
2
) for increasing blood lead levels in
Table 1. Median (interquartile range) levels of blood lead and eGFR by participant characteristics using different estimating equations (BMI, body mass
index)
a
Characteristic
n
(weighted %)
Blood lead
level (lg/dL)
a
MDRD CKD-EPI
Cystatin C
single variable
Cystatin C
multivariable
Cystatin C/
creatinine
Overall 3941 (100.0) 1.7 (1.1, 2.5) 85.0 (73.1, 99.6) 94.5 (80.0, 108.6) 95.7 (80.5, 109.8) 93.4 (77.1, 108.4) 93.8 (80.2, 108.3)
Age <60 years 1332 (77.3) 1.6 (1.0, 2.3) 89.3 (77.4, 103.4) 100.8 (87.1, 112.6) 100.0 (86.9, 113.4) 98.7 (85.8, 113.5) 99.5 (87.4, 112.6)
Age 60 years 2609 (22.7) 2.2 (1.6, 3.1) 70.5 (59.0, 82.5) 73.4 (60.3, 85.0) 76.7 (63.0, 89.3) 70.7 (57.7, 82.0) 73.2 (60.9, 84.2)
Male 2010 (49.2) 2.1 (1.4, 3.0) 86.2 (74.1, 99.8) 94.4 (81.0, 107.5) 93.1 (79.5, 104.7) 96.2 (79.7, 110.9) 95.0 (82.0, 108.0)
Female 1931 (50.8) 1.4 (0.9, 2.1) 83.5 (71.3, 99.6) 94.5 (78.6, 109.5) 97.1 (81.5, 113.4) 91.5 (74.2, 106.1) 92.7 (78.3, 108.5)
White 2113 (72.8) 1.7 (1.1, 2.4) 82.2 (70.9, 93.5) 91.4 (77.6, 104.2) 93.1 (78.6, 106.3) 90.8 (75.0, 103.3) 90.7 (78.0, 102.8)
Black 705 (10.2) 1.7 (1.2, 2.8) 97.7 (79.7, 111.1) 104.7 (84.5, 121.1) 103.1 (84.7, 117.3) 106.9 (86.1, 123.2) 104.4 (87.5, 120.2)
Mexican
American
861 (6.9) 1.7 (1.1, 2.8) 102.0 (86.8, 117.9) 111.8 (97.1, 121.8) 108.0 (93.1, 121.4) 109.4 (93.0, 122.9) 112.4 (96.3, 125.9)
Other race/
ethnicity
262 (10.0) 1.9 (1.0, 2.7) 92.9 (77.6, 109.9) 102.7 (86.2, 115.2) 100.0 (84.7, 115.3) 98.0 (83.1, 116.1) 103.5 (85.5, 117.9)
<High school 1482 (21.5) 1.9 (1.3, 3.1) 91.3 (74.6, 105.8) 99.0 (80.2, 115.0) 93.1 (75.8, 108.0) 90.3 (71.3, 109.6) 94.9 (78.1, 113.2)
High school
graduation
934 (27.5) 1.9 (1.2, 2.8) 85.4 (72.4, 100.3) 95.7 (79.2, 109.4) 93.1 (79.5, 106.3) 91.4 (75.6, 104.5) 92.2 (78.8, 108.6)
>High school 1525 (51.0) 1.5 (1.0, 2.2) 83.0 (72.9, 95.3) 93.2 (80.1, 105.2) 98.6 (82.6, 111.5) 96.2 (80.6, 110.7) 93.8 (81.1, 106.7)
BMI <25 kg/m
2
1209 (36.2) 1.7 (1.1, 2.7) 86.1 (73.8, 100.4) 96.1 (81.8, 110.5) 100.0 (85.8, 115.3) 98.1 (82.9, 114.5) 98.1 (84.2, 110.8)
BMI 25–29 kg/m
2
1504 (34.1) 1.8 (1.1, 2.6) 83.2 (72.0, 97.9) 92.7 (77.9, 106.7) 94.4 (79.5, 108.0) 93.3 (77.5, 107.0) 92.0 (78.6, 107.3)
BMI 30 kg/m
2
1228 (29.7) 1.6 (1.0, 2.3) 85.5 (73.1, 101.2) 94.0 (80.0, 108.1) 89.3 (74.9, 103.1) 86.8 (71.0, 101.8) 90.2 (77.8, 105.6)
Never smoker 1921 (49.1) 1.4 (0.9, 2.1) 83.9 (72.1, 98.9) 94.4 (78.7, 108.8) 98.6 (81.5, 113.4) 96.1 (78.2, 111.8) 94.6 (80.2, 110.4)
Former smoker 1330 (26.4) 1.8 (1.3, 2.7) 80.7 (70.5, 91.4) 89.1 (76.5, 101.4) 94.4 (79.5, 108.0) 91.2 (75.2, 103.7) 90.7 (77.1, 102.2)
Current smoker 690 (24.5) 2.1 (1.5, 3.2) 91.1 (77.9, 104.5) 102.1 (88.0, 115.8) 91.8 (79.5, 103.1) 91.7 (77.5, 105.7) 97.6 (83.7, 110.7)
Cotinine <0.3
ng/mL
a
2717 (60.6) 1.5 (1.0, 2.3) 82.6 (70.9, 95.9) 91.4 (77.3, 104.9) 97.1 (81.5, 111.5) 94.5 (76.7, 108.8) 92.4 (78.6, 106.8)
Cotinine 0.3–2.9
ng/mL
a
333 (9.3) 1.4 (1.0, 2.3) 88.3 (72.6, 99.2) 100.0 (81.7, 111.8) 95.7 (80.5, 109.8) 96.2 (80.1, 113.5) 98.6 (81.0, 110.3)
Cotinine 3.0–99.0
ng/mL
a
275 (8.4) 2.0 (1.2, 2.7) 90.5 (76.4, 105.0) 102.1 (84.9, 116.7) 100.0 (79.5, 113.4) 98.6 (79.9, 116.9) 98.2 (83.5, 117.0)
Cotinine 100
ng/mL
a
616 (21.6) 2.2 (1.6, 3.4) 90.4 (76.7, 103.7) 100.8 (85.0, 112.9) 89.3 (79.5, 100.0) 90.7 (77.4, 103.2) 94.7 (82.5, 108.0)
Never alcohol
drinker
1383 (28.5) 1.4 (1.0, 2.1) 83.7 (70.0, 98.9) 93.2 (76.0, 106.5) 89.3 (73.2, 106.3) 85.7 (68.5, 105.2) 89.5 (73.9, 107.5)
Former alcohol
drinker
501 (7.9) 1.9 (1.3, 2.7) 84.1 (71.1, 99.5) 88.6 (75.0, 102.2) 89.3 (74.0, 104.7) 86.3 (67.9, 103.7) 88.7 (72.9, 104.9)
Current alcohol
drinker
2057 (63.5) 1.8 (1.2, 2.6) 85.6 (73.8, 100.0) 95.8 (82.0, 110.3) 97.1 (84.7, 111.5) 96.9 (82.0, 110.7) 95.6 (83.3, 109.2)
Diabetes 547 (6.8) 2.0 (1.2, 2.8) 81.2 (63.8, 104.4) 86.2 (67.0, 104.9) 82.6 (65.6, 104.7) 75.9 (62.7, 103.0) 83.5 (65.2, 103.0)
No diabetes 3394 (93.2) 1.7 (1.1, 2.5) 85.1 (73.4, 99.5) 94.8 (80.4, 108.7) 95.7 (81.5, 109.7) 94.5 (78.4, 109.1) 94.1 (81.0, 108.4)
Hypertension 2210 (35.3) 1.9 (1.3, 2.7) 78.3 (65.5, 91.1) 84.5 (69.0, 98.8) 85.8 (71.6, 100.0) 81.6 (65.7, 97.4) 84.4 (69.8, 98.0)
No hypertension 1731 (64.7) 1.6 (1.0, 2.4) 88.6 (76.4, 102.0) 99.8 (85.6, 111.8) 100.0 (85.8, 113.4) 98.5 (84.5, 113.5) 99.3 (86.1, 112.1)
a
Conversion factors for units: to convert lead to micromoles per liter, multiply by 0.0483; to convert cotinine to nanomoles per liter, multiply by 5.68.
Kidney outcomes in mL/min/1.73 m
2
.
2788 J.T. Spector et al.
participants 60 years of age were similar for all equations
(Table 3 and Figure 1). In models adjusted for all covariates
except cadmium, differences in mean kidney outcome and
odds ratios for reduced kidney function were consistent with
fully adjusted models but were generally stronger.
Discussion
In this large representative sample of US adults, higher
blood lead levels were associated with lower eGFR levels
and reduced eGFR (<60 mL/min/1.73 m
2
) with all equa-
tions examined. Mean differences in eGFR by blood lead
levels were larger with cystatin C compared to creatinine
equations in analyses in all participants reflecting results in
those <60 years of age. For all equations, differences in
eGFR levels with increasing blood lead levels were larger
for participants 60 years of age. In this age group, mean
eGFR differences for a doubling in blood lead levels
ranged from 3.0 mL/min/1.73 m
2
with the CKD-EPI
equation to 4.5 mL/min/1.73 m
2
with the cystatin C
single variable equation. Odds of reduced eGFR for a
doubling of blood lead level, examined in participants
60 years, were consistently increased with all equations.
Lead is a widespread environmental toxicant [15, 38]. In
the human body, lead accumulates in bone and the biological
half-life is on the order of decades [16]. Thus, although
exposure to lead has decreased in developed countries after
the institution of public health measures banning lead in
gasoline, paint and solder, the body burden of lead resulting
from past exposures remains an important source of endog-
enous exposure [16, 18]. Moreover, exogenous exposure
continues to occur through folk remedies, glazed pottery,
industrial sources, lead paint, active smoking and exposure
to secondhand smoke [6, 39, 40]. Certain populations are
disproportionately exposed to lead, especially workers in
occupations such as construction and residents in low socio-
economic status communities [6]. Globally, exposure re-
mains higher in developing countries [41–43]. Given the
magnitude of exposure, the impact of lead dose on kidney
function is a substantial public health concern.
Our results are consistent with publications in other
NHANES analyses using the MDRD equation to estimate
GFR [7, 8]. The CKD-EPI equation was recently published
[22], and to our knowledge, there are no publications ex-
amining associations between blood lead and GFR esti-
mated with this equation. A few studies have examined
associations between blood lead and kidney function us-
ing serum cystatin C or single variable cystatin C-based
eGFR equations [1, 4, 44, 45]. In a cross-sectional study
of Swedish women, higher blood lead levels were associ-
ated with lower serum cystatin C-based eGFR [4, 46].
Table 2. Differences (95% confidence interval) in mean eGFR (mL/min/1.73 m
2
) by blood lead levels
a
Blood lead, lg/dL
b
Mean eGFR in
all participants All participants
a
Age <60
a
Age 60
a
MDRD
Tertile 1 (1.3)
c
91.4 0.00 (reference) 0.00 (reference) 0.00 (reference)
Tertile 2 (>1.3–2.2)
c
84.5 1.7 (3.7, 0.2) 1.1 (3.5, 1.3) 3.8 (5.8, 1.9)
Tertile 3 (>2.2)
c
83.2 2.4 (4.5, 0.3) 0.8 (3.4, 1.7) 7.1 (9.5, 4.8)
P trend 0.03 0.5 <0.001
Doubling of lead level 0.9 (1.9, 0.02) 0.2 (1.2, 0.9) 3.3 (4.8, 1.9)
CKD-EPI
Tertile 1 (1.3)
c
99.8 0.00 (reference) 0.00 (reference) 0.00 (reference)
Tertile 2 (>1.3–2.2)
c
91.2 1.3 (2.9, 0.3) 0.9 (2.8, 1.0) 3.1 (5.0, 1.2)
Tertile 3 (>2.2)
c
88.4 1.8 (3.7, 0.1) 0.3 (2.7, 2.0) 6.1 (8.3, 3.9)
P trend 0.07 0.7 <0.001
Doubling of lead level 0.9 (1.8, 0.01) 0.2 (1.2, 0.8) 3.0 (4.2, 1.8)
Cystatin C single variable
Tertile 1 (1.3)
c
100.6 0.00 (reference) 0.00 (reference) 0.00 (reference)
Tertile 2 (>1.3–2.2)
c
93.7 1.6 (4.2, 1.0) 1.2 (4.3, 2.0) 4.5 (6.7, 2.3)
Tertile 3 (>2.2)
c
88.2 3.3 (5.3, 1.4) 2.2 (4.9, 0.4) 7.8 (10.3, 5.2)
P trend 0.001 0.09 <0.001
Doubling of lead level 1.9 (3.2, 0.7) 1.3 (2.8, 0.3) 4.5 (5.6, 3.3)
Cystatin C multivariable
Tertile 1 (1.3)
c
98.8 0.00 (reference) 0.00 (reference) 0.00 (reference)
Tertile 2 (>1.3–2.2)
c
91.4 1.2 (3.6, 1.2) 1.0 (3.9, 2.0) 3.7 (5.7, 1.8)
Tertile 3 (>2.2)
c
86.9 2.9 (4.7, 1.1) 1.9 (4.5, 0.6) 6.8 (9.0, 4.6)
P trend 0.003 0.1 <0.001
Doubling of lead level 1.7 (3.0, 0.5) 1.1 (2.7, 0.4) 4.0 (5.0, 2.9)
Cystatin C/creatinine
Tertile 1 (1.3)
c
100.6 0.00 (reference) 0.00 (reference) 0.00 (reference)
Tertile 2 (>1.3–2.2)
c
91.8 1.7 (3.6, 0.3) 1.2 (3.6, 1.2) 4.2 (6.0, 2.4)
Tertile 3 (>2.2)
c
88.7 2.8 (4.3, 1.2) 1.3 (3.3, 0.7) 7.6 (9.8, 5.4)
P trend 0.001 0.2 <0.001
Doubling of lead level 1.4 (2.3, 0.5) 0.7 (1.7, 0.4) 3.9 (5.2, 2.7)
a
Models adjusted for survey year, age (years modeled as restricted cubic spline with five knots), sex, race/ethnicity, body mass index (kg/m
2
), education
(<high school, high school, >high school), smoking status (never, former, current), cotinine category, alcohol intake (never, former, current), hyper-
tension (yes, no), diabetes mellitus (yes, no) and blood cadmium (ln lg/L).
b
Blood lead levels (ug/dL). Conversion factors for units: to convert lead to micromoles per liter, multiply by 0.0483.
c
Blood lead levels (lg/dL).
Associations of blood lead with GFR estimates 2789
Associations were comparable to estimates using creatinine
clearance as the kidney outcome [4]. An association between
blood lead level and serum cystatin C was observed in Bel-
gian adolescents [1]. In US adolescents, blood lead levels
were associated with decreased cystatin C-based eGFR [47]
levels; the association with creatinine-based eGFR was not
statistically significant [44]. In a cross-sectional study of
European children, on the other hand, higher blood lead
levels were associated with lower serum cystatin C and
creatinine levels and these paradoxical associations were
attributed to hyperfiltration [45].
Strengths of our study include those related to
NHANES data: a relatively large sample size; representa-
tion of the US noninstitutionalized civilian population;
high-quality, standardized laboratory procedures and ex-
tensive quality control. This is also one of the few data sets
to date that includes serum creatinine and cystatin C and
blood lead. Limitations include lack of GFR measurement
using an exogenous filtration marker. The GFR-estimating
equations used in this study have important limitations
and differences. The MDRD equation systematically
underestimates GFR at higher levels; the CKD-EPI equa-
tion was developed to be more accurate in this range [22].
Both equations use serum creatinine, which is generated
from muscle metabolism and overestimates GFR in indi-
viduals with low muscle mass such as the elderly [19].
Cystatin C is a 120-amino acid cysteine protease inhibitor
that is freely filtered at the glomerulus and reabsorbed and
catabolized in the proximal tubules [19]. It is produced
and secreted by all nucleated cells [19]; the resulting lack
of muscle mass confounding may increase its accuracy as
a kidney filtration marker [48,49].Researchtoassess
accuracy of cystatin C-based eGFR is ongoing [50, 51].
Associations between cystatin C and age, sex, race, nu-
tritional factors, body composition and inflammatory
markers, that persisted after adjustment for GFR, have
recently been reported [35, 52]. Thus, the use of multi-
variable equations that incorporate age, sex and race as
well as equations that use both creatinine and cystatin C
may provide more accurate estimations of GFR [23, 51].
Second, reverse causation, specifically increased blood
lead levels as a result of reduced kidney excretion, cannot
be excluded due to the cross-sectional study design. How-
ever, the temporal relation between lead exposure and CKD
onset and/or progression is a critical factor in determining
causality. Longitudinal data in both CKD patient and gen-
eral populations have reported lead dose to be a predictor of
kidney function decline for follow-up periods as long as
4to>6 years, respectively [2, 3, 5, 9–11]. Further, reverse
causality should be most prominent in populations with
CKD. However, analyses to address this in the Normative
Aging Study population found that blood lead was posi-
tively associated with serum creatinine even over the nor-
mal range where a substantial decrease in lead excretion is
unlikely [3, 5]. In addition, the impact of lead chelation on
kidney function in CKD patients provides evidence against
reverse causality [10]. Third, cumulative lead dose could
not be analyzed. Blood lead reflects current exogenous ex-
posure as well as endogenous exposure from accumulated
body burden. Bone lead is a better marker of cumulative
Table 3. Odds ratios (95% confidence interval) for reduced eGFR (<60
mL/min/1.73 m
2
) by blood lead levels for participants 60 years of age
a
Cases/
noncases
(weighted %) Odds ratios
MDRD
1.3
b
78/358 (20.6) 1.00 (reference)
>1.3–2.2
b
179/655 (23.8) 1.29 (0.87, 1.93)
>2.2
b
391/948 (31.2) 1.90 (1.26, 2.87)
P trend 0.002
Doubling of lead level 1.38 (1.17, 1.63)
CKD-EPI
1.3
b
76/360 (19.6) 1.00 (reference)
>1.3–2.2
b
164/670 (21.1) 1.14 (0.76, 1.71)
>2.2
b
382/957 (29.2) 1.78 (1.18, 2.69)
P trend 0.003
Doubling of lead level 1.37 (1.15, 1.62)
Cystatin C single variable
1.3
b
68/368 (15.8) 1.00 (reference)
>1.3–2.2
b
146/688 (19.2) 1.25 (0.86, 1.82)
>2.2
b
332/1007 (24.4) 1.57 (1.01, 2.46)
P trend 0.040
Doubling of lead level 1.41 (1.17, 1.70)
Cystatin C multivariable
1.3
b
97/339 (22.4) 1.00 (reference)
>1.3–2.2
b
214/620 (27.3) 1.48 (1.04, 2.12)
>2.2
b
423/916 (33.0) 2.02 (1.28, 3.17)
P trend 0.004
Doubling of lead level 1.53 (1.31, 1.80)
Cystatin C/creatinine
1.3
b
70/366 (17.4) 1.00 (reference)
>1.3–2.2
b
163/671 (20.6) 1.33 (0.95, 1.86)
>2.2
b
354/985 (27.2) 2.00 (1.29, 3.08)
P trend 0.003
Doubling of lead level 1.46 (1.21, 1.75)
a
Models adjusted for survey year, age (years modeled as restricted cubic
spline with five knots), sex, race/ethnicity, body mass index (kg/m
2
),
education (<high school, high school, >high school), smoking status
(never, former, current), cotinine category, alcohol intake (never, former,
current), hypertension (yes, no), diabetes mellitus (yes, no) and blood
cadmium (ln lg/L).
b
Blood lead levels (lg/dL). Conversion factors for units: to convert lead to
micromoles per liter, multiply by 0.0483.
Fig. 1. Odds ratios for reduced eGFR with blood lead levels modeled with
restricted quadratic splines with knots at the 5th, 50th and 95th percentiles.
MDRD: thick solid line; CKD-EPI: thin solid line; cystatin C single var-
iable: dashed and dotted line; cystatin C multivariable: dashed line; cys-
tatin C/creatinine combined: dotted line.
2790 J.T. Spector et al.
lead exposure [16] but has never been measured in
NHANES. Fourth, our study may be subject to survival
bias, due to increased mortality of CKD patients, and to
other selection biases which could underestimate the effect
of lead on kidney function, such as exclusion of institution-
alized participants and need for mobility to attend the ex-
amination portion of the NHANES evaluation. The specific
criteria used to derive the cystatin C subsample could also
result in selection bias. Finally, residual confounding by
recently reported factors, including nutritional factors and
inflammatory markers, whose associations with cystatin C
persist after adjustment for GFR, may also affect our study
[35, 52].
In conclusion, in this large representative sample of US
adults, higher blood lead levels were associated with
lower eGFR and increased odds of reduced eGFR, irrespec-
tive of the endogenous marker of GFR and estimating
equation used. In all participants, larger differences in mean
eGFR for a doubling of blood lead were observed with
the cystatin C equations. In participants aged 60 years,
the association between lead and reduced eGFR was ob-
served throughout the range of blood lead levels with no
apparent threshold. Given the global burden of CKD, it is
essential to conduct research on potential risk factors that are
common and preventable, including lead exposure. These
results support the inclusion of cystatin C-based eGFR in
future lead research and provide additional evidence for
environmental lead exposure as a CKD risk factor.
Acknowledgements. This work was supported by the National Institutes
of Health National Institute of Environmental Health Sciences (grants 2
and 3 ES007198) and the National Institute for Occupational Safety and
Health (grant T42 OH008428 from the Education and Research Center for
Occupational Safety and Health at the Johns Hopkins Bloomberg School
of Public Health). Support for J.T.S. was provided by the Occupational
Physicians Scholarship Fund and is currently provided by the National
Institute of Environmental Health Sciences (grant 5T32ES015459-02).
The results presented in this paper have not been published previously in
whole or part, except in abstract form. Aspects of this work were accepted
as an abstract at the American Society of Nephrology Annual Conference,
in San Diego, CA, in October/November 2009. The abstract can be
accessed online at http://www.asn-online.org/education_and_meetings/
renal_week/archives/RW09Abstracts.pdf. SA-PO2758, 742A.
Conflict of interest statement. None declared.
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Received for publication: 11.8.10; Accepted in revised form: 29.11.10
Appendix
Appendix 1. Correlation coefficients for eGFR by equation in all
participants (n ¼ 3941)
a
MDRD CKD-EPI
Cystatin C
single
variable
Cystatin C
multivariable
Cystatin C/
creatinine
CKD-EPI 0.95
Cystatin C
single variable
0.71 0.76
Cystatin C
multivariable
0.72 0.79 0.97
Cystatin C/
creatinine
0.93 0.94 0.90 0.92
a
P-value <0.001 for all correlations.
Appendix 2. Correlation coefficients for eGFRs by equation in
participants aged 60 years (n ¼ 2609)
a
MDRD CKD-EPI
Cystatin C
single
variable
Cystatin C
multivariable
Cystatin C/
creatinine
CKD-EPI 0.96
Cystatin C
single variable
0.72 0.76
Cystatin C
multivariable
0.73 0.76 0.98
Cystatin C/
creatinine
0.94 0.94 0.91 0.92
a
P-value <0.001 for all correlations.
Appendix 3. Correlation coefficients for eGFRs by equation in
participants aged <60 years (n ¼ 1332)
a
MDRD CKD-EPI
Cystatin C
single
variable
Cystatin C
multivariable
Cystatin C/
creatinine
CKD-EPI 0.94
Cystatin C
single variable
0.58 0.62
Cystatin C
multivariable
0.60 0.64 0.96
Cystatin C/
creatinine
0.92 0.91 0.84 0.86
a
P-value <0.001 for all correlations.
2792 J.T. Spector et al.
    • "However, data in children are scarce and less consistent than in adults (de Burbure et al. 2006; Fadrowski et al. 2010; Moel and Sachs 1992; Staessen et al. 2001). Furthermore, most studies of the association between lead and CKD evaluated glomerular filtration rate (GFR) using estimating equations based on serum creatinine or cystatin C (Spector et al. 2011). These equations have limited precision and accuracy compared with formal measurement of GFR (Fadrowski et al. 2011; Poggio et al. 2005; Rule et al. 2004; Schwartz et al. 2009; Staples et al. 2010; Stevens et al. 2007), and lack of formal measurement of GFR is commonly listed as a limitation in studies examining the impact of lead on the kidney. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The role of environmental exposure to lead as a risk factor for chronic kidney disease (CKD) and its progression remains controversial, and most studies have been limited by a lack of direct glomerular filtration rate (GFR) measurement. Objective: We evaluated the association between lead exposure and GFR in children with CKD. Methods: In this cross-sectional study, we examined the association between blood lead levels (BLLs) and GFR measured by the plasma disappearance of iohexol among 391 participants in the Chronic Kidney Disease in Children (CKiD) prospective cohort study. Results: Median BLL and GFR were 1.2 µg/dL and 44.4 mL/min per 1.73 m2, respectively. The average percent change in GFR for each 1-µg/dL increase in BLL was –2.1 (95% CI: –6.0, 1.8). In analyses stratified by CKD diagnosis, the association between BLL and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1-µg/dL increase in BLL was associated with a –12.1 (95% CI: –22.2, –1.9) percent change in GFR. In analyses stratified by anemia status, each 1-µg/dL increase in BLL among those with and without anemia was associated with a –0.3 (95% CI: –7.2, 6.6) and –4.6 (95% CI: –8.9, –0.3) percent change in GFR, respectively. Conclusions: There was no significant association between BLL and directly measured GFR in this relatively large cohort of children with CKD, although associations were observed in some subgroups. Longitudinal analyses are needed to examine the temporal relationship between lead and GFR decline, and to further examine the impact of underlying cause of CKD and anemia/hemoglobin status among patients with CKD.
    Full-text · Article · May 2013
    • "Reply Sir, We thank the authors for their interest in our manuscript [1] and for considering the impact of exposure to environmental toxicants on kidney function. Studies with prospective data in large populations, such as the PREVEND study, are uncommon in nephrotoxicant research but of great value. "
    Article · May 2012
    • "Very low levels were detected, and the reverse osmosis process would reduce even this small quantity [24]. The association of higher lead levels with lower GFR has been described previously [6, 25]. This could be in part due to decreased urinary excretion. "
    [Show abstract] [Hide abstract] ABSTRACT: After parents raised concerns about potential lead (Pb) contamination of calcium carbonate for treatment of hyperphosphatemia in chronic kidney disease (CKD), we measured blood Pb using high-resolution sector field inductively coupled mass spectrometry in a quality-assurance investigation of ten pediatric dialysis patients (nine on hemodialysis) and six patients before dialysis. We assessed the kidney function as cystatin C estimated glomerular filtration rate (eGFR), blood Pb levels, calcium carbonate dose, and standard laboratory parameters, as well as Pb levels in the dialysis feed water. Mean blood Pb concentration in the 16 pediatric CKD patients was 21.1 ± 15.8 µg/l with a maximum of 58 µg/l, which was significantly higher than that of 467 apparently healthy controls (median 6.35 µg/l, interquartile range 4.47, 8.71) and comparable to that of ten adult peritoneal dialysis (PD) patients. Lead levels correlated with red blood cell distribution width, eGFR, and calcium carbonate dose. Pb in dialysate feed water was always <0.00018 mg/l, which is below the accepted limit for water for dialysis of 0.005 mg/l. We found a high prevalence of elevated Pb levels in pediatric CKD patients that correlated with the calcium carbonate dose and GFR. Lead levels should be monitored in these patients.
    Full-text · Article · Apr 2012
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