1. Associations among Lead Dose Biomarkers, Uric Acid, and Renal Function in Korean Lead Workers
Virginia M. Weaver, 2005
Chorong Shin
Mar. 31, 2015
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2. Contents 1. Introduction 2. Materials and Methods 3. Results
4. Discussion
5. Conclusion
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3. Introduction Lead poisoning 시 흔히 발병하는 ‘Gout’
: 체내에 uric acid 가 분해되거나 소변을 통해 배출되지 않고, 축적되면서 발생하는 질병
Uric acid
Comes from the breakdown of substances called purines.
= 핵산 등에 포함된 푸린염기의 최종분해산물 중 하나가 ‘uric acid’.
요산 일나트륨(Monosodium urate)
Uric acid crystal
(사진 출처 : David C. Dugdale, 2013)
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4. Introduction The possibility that increased uric acid is one mechanism
연구의 목적
lead dose 와 serum uric acid level 간에는 연관성이 있음. (Ehrlich et al. 1998; Wang et al. 2002)
Uric acid accelerates renal dysfunction from other cause. (Kang et al. 2002; Mazzali et al. 2001b)
Also lead exposure increases the risk for adverse renal outcomes. (Weaver et al. 2003)
=저자의 선행연구
Lead cause nephrotoxicity by several mechanisms.
Uric acid is also a nephrotoxicant, and increasing evidence suggests that this toxicity occurs at lower levels than previously recognized (Johnson et al. 2003)
The possibility that increased uric acid is one mechanism
by which lead causes nephrotoxicity
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5. Introduction
연구의 목적
저자의 선행연구 (2003)
- lead exposure/dose 와 adverse renal function 사이의 연관성을 확인함
- But 총 803명의 workers 중 ‘the oldest tertile of workers (> 46 years of age)’ 에서만 연관성을 확인할 수 있었음
따라서 본 연구(2005) 에서는
1. the entire population of lead workers에 대한 data를 모두 분석
2. the oldest tertile of workers를 대상으로 별도의 분석을 실시
→ whether relations between lead biomarkers and renal outcomes were altered after adjustment for uric acid
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6. Introduction
연구의 목적
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7. current and former lead workers
Materials & Methods
Study population
they produced lead batteries, lead oxide, lead crystal, or radiators or were secondary lead smelters
→ they handled or is handling lead & occupationally exposed to lead
enrolled in a longitudinal study for lead effects
Not exposed to other (known) renal toxicants
current and former lead workers
(n=803)
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8. Materials & Methods Questionnaires : medical/occupational history
Data collection
Questionnaires : medical/occupational history
Blood pressure measurements
Height and weight measurement
Blood specimen(sample) : for blood lead, BUN(혈중 요소질소), serum creatinine, uric acid
Spot urine sample : for NAG, RBP(레티놀 결합단백질), urinary creatinine
Tibia lead conc.
4-hr urine collection after oral administration of 10 mg/kg DMSA : for DMSA chelatable lead, creatinine clearance
* BUN (Blood Urea Nitrogen) : 체내 단백질 대사의 최종산물
* 요 중 NAG (N-acetyl-beta-D-glucosaminidase) : 신세뇨관 간질 손상의 지표로 생각됨. (Yoon et al. 2008)
* DMSA 착화(chelatable) 후 urine lead 측정 : 납 작업자들의 체중당 10 mg의 DMSA를 경구 투여한 후 4시간 동안의 소변을 받아 측정함. (Yoon et al. 2006)
* Chelate 기 : 금속과 결합하는 성질을 가짐.
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9. Materials & Methods Fig. 1 Renal function outcomes blood pressure
1) Measured creatinine clearance (unit : mL/min)
[Urinary creatinine (mg/dL) * urine volume (mL)] / serum creatinine (mg/dL)
2) Calculated creatinine clearance
(unit : mL/min)
[(140-age)*weight (kg)*(0.85 for females]) / [serum creatinine (mg/dL) * 72]
blood pressure
Fig. 1
Lead biomarkers
-Blood lead
-Tibia lead
-Urine lead
(DMSA-chelatable lead)
Renal function outcomes
-Serum creatinine
-Urine creatinine
-BUN
-Creatinine clearnace
(Measured / Calculated)
-NAG
-RBP
uric acid
(in spot urine sample)
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10. Materials & Methods Table 4 Table 5 Table 6 (older tertile)
Adjustment for age, sex, BMI,
job duration, (+alcohol drinking, tobacco use, diabetes, hypertension)
Statistical analysis : linear regression modeling
Table 4
Table 5
Table 6 (older tertile) Y X
Renal function
-BUN
-Serum creatinine
-Measured creatinine
-Calculated creatinine
-NAG
-RBP
Uric acid Y X
Uric acid
Lead -blood/tibia lead
Systolic Blood pressure
Renal function
-serum creatinine Y X
Renal function
-BUN
-Serum creatinine
-Measured creatinine
-Calculated creatinine
-NAG
Lead
-blood/tibia lead
Uric acid
Lead + Uric acid
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11. Results 2019-08-27 hEX-Tox paper review
Table 1. Selected demographic, exposure, and health outcome measures (categorical variables of 803 current and former lead workers in South Korea.
Table 2. Selected demographic, exposure, and health outcome measures
(continuous variables) of 803 current and former lead workers in South Korea.
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12. (after adjustment for age, sex, BMI and alcohol use)
Results
Lead measure associations with uric acid levels
In linear regression modeling of uric acid levels in all 803 lead workers,
(after adjustment for age, sex, BMI and alcohol use)
None of the lead measures was associated with uric acid levels. (p > 0.05)
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13. Results Y=uric acid Lead measure associations with uric acid levels
*Adjusted for age, sex, BMI,
and alcohol use.
Lead measure associations with uric acid levels
Y=uric acid
Method 1 :
Age modified
& No adjustment for
Blood pressure, Renal function
Method 2 :
Additional Adjustment for Blood pressure
Method 3 :
Additional Adjustment
for Renal function
Age(years) : oldest (oldest age tertile is the reference category.)
Age category 2 : median
Age category 1 : youngest
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14. Results Y=uric acid Lead measure associations with uric acid levels
Method 1 : age modified relations between the lead biomarkers and uric acid levels (no adjustment for blood pressure, renal function) → Result : Blood/Tibia lead were associated with uric acid in the oldest age tertile.
In other age tertiles : β-coefficient <0.
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15. Results Y=uric acid Lead measure associations with uric acid levels
Systolic blood pressure, serum creatinine의 additional adjustment 후 (method 1→ 2→ 3) : Blood / Tibia lead (X) 와 uric acid level (Y) 간의 association이 점점 감소하는 경향을 보임 (β-coefficient 값 증가, p-Value 감소).
However, blood lead remained associated with uric acid (β = , p = 0.01) when these associations were modeled in the 133 oldest workers who had serum creatinine greater than the median value (0.86 mg/dL).
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16. Results Associations between uric acid levels and renal outcomes
*Adjusted for age, sex, BMI, current/former worker status, and hypertension.
(+ systolic blood pressure, alcohol ingestion and diabetes for NAG, RBP models)
Associations between uric acid levels and renal outcomes
Y= adverse renal outcomes
Uric acid levels were associated in all renal outcome models(p<0.05) except NAG.
Higher uric acid was associated with worse renal function but, conversely, with lower RBP.
일반적으로 요세관 장해가 발생(=worse renal function)되면 요중 RBP가 증가(=higher RBP) (Yoon et al. 2006)하지만, 본 연구의 결과는 반대로 나타남
These associations remained significant after the lead biomarkers were added into the models.
Blood pressure is controlled with other covariates.
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17. Results
Effect of uric acid adjustment on lead measure associations in renal function models.
Adjustment uric acid
266 oldest workers
The median age : 51.1 years
(Range : 46.0 – 64.8 years)
In 1st Result (Table 4), there is associations of lead biomarkers (Blood / Tibia lead) with uric acid in the oldest tertile (n= 266).
And the associations between higher lead dose and worse renal function were also primarily in the oldest tertile.
So that associations between the lead biomarkers and the renal outcomes (after adjustment for uric acid) were modeled in only this group.
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18. Results
*Adjusted for age, sex, BMI, current/former worker status, and hypertension.
(+ systolic blood pressure, alcohol ingestion and diabetes for NAG, RBP models)
Effect of uric acid adjustment on lead measure associations in renal function models.
Y= adverse renal outcomes
Only models in which p ≤ 0.05 for the lead variable without uric acid adjustment are shown.
(exception of the measured creatinine clearance model)
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19. Results
*Adjusted for age, sex, BMI, current/former worker status, and hypertension.
(+ systolic blood pressure, alcohol ingestion and diabetes for NAG, RBP models)
Effect of uric acid adjustment on lead measure associations in renal function models.
Y= adverse renal outcomes
Blood pressure is controlled with other covariates.
Method 1 : Adjustment for (only) lead measure
Method 2 : Adjustment for (only) uric acid
Method 3 : Lead measure,
uric acid 함께 adjustment
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20. Results
Effect of uric acid adjustment on lead measure associations in renal function models.
Y= adverse renal outcomes
Associations between the lead measures and NAG were unchanged after adjustment for uric acid.
However, fewer associations between lead biomarkers and clinical renal outcomes remained significant (p ≤ 0.05) after adjustment for uric acid.
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21. Discussion
Individuals who have been heavily exposed to lead are at increased risk for both gout and renal disease. (Batuman 1993; Shadick et al. 2000)
& High-level lead exposure → decreased glomerular filtration → great decreased urate clearance(제거) (Emmerson and Ravenscroft 1975)
Associations between lead measures and uric acid have been examined in populations encompassing a wide range of lead does (Table 7).
Uric acid
Relations between lead dose and gout / uric acid have also been studied in various patient populations.
Increased EDTA-chelatable lead burden have been reported in patients who have both gout and renal disease compared with patients with gout alone or with renal disease of known non-lead-related etiology (Batuman 1993; Miranda-Carus et al. 1997; Sanchez-Fructuoso et al. 1996)
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22. Mean blood lead levels were similar
Discussion
Lin et al (2001) study
1) measurement of blood lead and EDTA-chelatable lead in 67 patients with chronic renal insufficiency and gout & 34 patients with chronic renal insufficiency only.
Mean blood lead levels were similar
in the two groups,
but mean EDTA-chelatable lead levels were significantly different (p < 0.01).
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23. All four uric acid measures were associated with EDTA-chelatable lead
Discussion
Lin et al (2001) study
1) measurement of blood lead and EDTA-chelatable lead in 67 patients with chronic renal insufficiency and gout & 34 patients with chronic renal insufficiency only.
All four uric acid measures were associated with EDTA-chelatable lead
after adjustment for age, sex, BMI, daily protein intake and creatinine clearance.
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24. Discussion Lin et al (2001) study A treatment group receiving 1 g EDTA
per week for 4 weeks
Lin et al (2001) study
2) 30 participants with chronic renal insufficiency, gout and EDTA-chelatable lead levels (range from 80.2 to 361 ug/ 72hr) 의 Daily protein intake, Creatinine clearance, Serum urate, Daily urate excretion, Urate clearance, Fractional urate excretion 을 측정
In the study group, after treatment,
EDTA-chelatable lead : declined
( → 41 ug/72hr)
serum urate : decreased
(10.2 → 8.6 mg/dL)
urate clearance : increased
(2.7 → 4.2 mL/min)
creatinine clearance : increased
(50.8 → 54.2 mL/min)
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25. Discussion
Lower lead levels are associated with increases in uric acid
The data (discussed above and presented in Table 7) are generally consistent with the premise that in young (and relatively healthy) workers, a higher lead dose is required before associations with uric acid are present
→ However, in studies that include participants with other risk factors for elevated uric acid (ex. older age), lower lead levels are associated with increases in uric acid.
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26. Discussion ① Lead & Hypertension & Uric acid & Renal dysfunction
Rodent model of hyperuricemia (고요산혈증)
→ A range of adverse renal and vascular outcomes, similar to those noted in humans with primary hypertension (Mazzali et al. 2002) and/or renal dysfunction (Nakagawa et al. 2003), was observed in these rats.
In humans, uric acid was found to be associated with reduced renal blood flow & increased renal vascular resistance in patients with primary hypertension (Messerli et al. 1980).
Afferent renal arterial(구심성 신동맥) thickening has also been observed in hyperuricemic rats.
(Mazzali et al. 2002) ①
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27. Discussion Lead & Hypertension & Uric acid & Renal dysfunction
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28. Discussion ② Lead & Hypertension & Uric acid & Renal dysfunction
Sanchez-Fructuoso et al. (2002) Study
- hypertrophy(비대증) of the medium & small renal arteries(동맥) and arterioles(정맥) in rats whose blood lead levels ranged from 52.9 to 33.2 ug/dL at day 90.
→ However, these vascular abnormalities were not observed in rat whose lead exposures, over a 12-month period, were either lower blood lead levels (20~30 ug/dL) or much higher blood lead levels of 45.5~125.4 ug/dL. (Khalil-Manesh et al. 1993) ②
Table 2.
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29. Discussion ③ Lead & Hypertension & Uric acid & Renal dysfunction
Uric acid was not measured in these rodent studies.
However, Goyer (1971) reported hyperuricemia that was not thought to be related to extent of renal insufficiency(dysfunction) in lead may be one of the exposures that does increase uric acid in rats despite the presence of the uricase enzyme
* uricase enzyme : 요산 산화 효소로, 이 효소와 반응을 거쳐 요산이 배설됨. ③
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30. Discussion ③ Lead & Hypertension & Uric acid & Renal dysfunction
Many mechanisms for the adverse effect of lead on the kidneys (either directly or through the vascular system) have been proposed .
(Nolan and Shaikh 1992; Sanchez-Fructuoso et al. 2002; Vaziri 2002)
One mechanism not commonly considered in low to moderate lead exposure is increased uric acid.
However, there are a number of similarities between the renal and vascular effects reported from low-level uric acid and those from lead exposure. ③
Support
- Tubulointerstitial fibrosis (간질성 섬유증), a classic finding in lead exposure, has been observed in the uric acid model in the absence of the urate crystals that are commonly seen in this pathology at higher levels of hyperuricemia. (Mazzali et al. 2001a)
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31. Discussion
Mazzali et al. (2001a) reported that increased systolic blood pressure was correlated with serum uric acid.
Increased systolic blood pressure was associated with lead dose in the same Korean lead worker population studied in this report (Lee et al. 2001)
; Similar associations have also been reported in other
populations (Sharp et al. 1987).
Increased juxtaglomerular renin staining was present in the uric acid mode (Mazzali et al. 2001a).
And data suggest that lead exposure also increases renin
Also renin was associated with hypertension.
Renin is increased with short-to-moderate term lead exposure in both animals and humans but is normal or decreased with prolonged exposure.
(Gonick and Behari 2002; Sharp et al. 1987; Vander 1988) ④
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32. Discussion ④ 예외
Increase urate → decrease NO (Neuronal nitric oxide) synthase expression
But Lead exposure → NO decreased → NO synthase expression(발현) up-regulated (increased)
The effects of lead and uric acid on the NO system are different. 따라서 casual pathway 성립하지 않는다.
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33. Conclusion Y=uric acid
The impact of adjustment for blood pressure and renal function suggests that the effect of lead on uric acid may be mediated through these pathways (Figure 2-A).
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34. Conclusion
133 oldest workers
At the moderate levels of lead exposure present in our population,
older workers comprise a susceptible population for increased uric acid.
blood lead remained associated with uric acid (β = , p = 0.01) after adjustment for renal function and blood pressure, when these associations were modeled in the 133 oldest workers who had serum creatinine greater than the median value (0.86 mg/dL).
Because of blood lead remained associated with uric acid in our most susceptible group (the older workers who had the greatest renal dysfunction), even after adjustment for renal function and blood pressure, mechanisms other than decreased glomerular filtration, such as decreased tubular secretion or even extra-renal mechanisms, may be involved at these exposure levels.
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35. Conclusion
1) Because our data suggest an effect of lead on uric acid beyond that due to renal dysfunction alone,
2) and Because uric acid was associated with adverse renal outcomes and resulted in reduced significance of lead biomarker associations in our population,
→ Uric acid may be one mechanism through which lead is nephrotoxic.
However, this is not the only mechanism for lead-related nephrotoxicity.
In our data, the association between blood lead and serum creatinine remained significant even after adjustment for uric acid (Table 6).
Also associations between lead dose and NAG were unchanged (Table 6).
And uric acid was inversely associated with RBP & the effects of lead and uric acid on the NO system are different.
→ Thus, other mechanisms must be involved.
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36. Conclusion Limitation
Conclusions regarding causality in this study must be limited because it is cross-sectional.
=일부 표본을 대상으로 분석한 결과를 바탕으로 하였기에, 전체 모집단에 대해 그 결과를 적용시킬 때 한계가 있음.
We weren’t able to adjust for the use of medications that influence uric acid because Koreans are not routinely provided with the names of their medications.
Our results do suggest that further evaluation of relations among the lead dose biomarkers, uric acid and renal function in our longitudinal data set would be of value.
These mechanistic relations may be clinically important.
EDTA chelation has been reported to improve both renal function and urate clearance in patients with renal insufficiency and gout, even when EDTA-chelatable lead body burdens were quite low (Lin et al. 2001).
If this work is replicated in other populations and low-level uric acid is found to be nephrotoxic, uric acid should also be monitored in patients who are in the early stages of diseases such as early chronic renal insufficiency and whose lead body burdens are amenable to chelation.
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