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Prospective and longitudinal human studies of lead and cadmium exposure and the kidney
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cadmium and lead accumulate in humans and can have toxic effects. Exposure to cadmium is well known to cause kidney damage. Cadmium binds to metallothioneins, proteins that play a role in cadmium transport. Lead exposure’s main effect is on the central nervous system, but associations with kidney disease have also been found, although it is unknown if the latter is a causal association. The main source of both metals within the non-smoking population is from the diet.

This thesis aims to 1) compare the biomarkers lead and cadmium concentration in whole-blood, plasma and urine with regard to their ability to discriminate between individuals with different mean concentrations, and to describe the effect of urinary dilution, 2) estimate the association between end-stage renal disease and blood concentrations of cadmium, lead and mercury, using prospectively collected samples for exposure evaluation, 3) use longitudinal data on kidney function makers to evaluate kidney recovery after a substantial decrease in cadmium exposure, and 4) assess the influence of metallothionein polymorphisms (MT1A rs11076161, MT2A rs10636 and MT2A rs28366003) on cadmium-associated kidney toxicity and recovery due to a reduction in Cd exposure.

Repeated sampling of whole-blood, plasma and urine was conducted on 48 occupationally lead-exposed men and 20 individuals under normal environmental lead exposure, for estimation of the day-to-day and between individual-variation. Prospective samples were obtained for 118 cases that later in life developed end-stage renal disease, and 378 matched controls. Erythrocyte cadmium, lead, and mercury concentrations were determined and the risk of developing end-stage renal disease associated with metal concentrations was estimated. For evaluation of kidney recovery after a reduction in cadmium exposure and to test for gene-environment interactions, follow-up data on N-acetyl-β‑d-glucosaminidase, β2‑microglobulin, albumin, and gene polymorphisms were obtained for 412 individuals within the Chinese population and the relation to blood and urinary cadmium was assessed.

The concentration of lead in blood was found to be the biomarker with the largest fraction of the total variance attributable to between-individual variation, and was therefore the biomarker with the best ability to discriminate between individuals with different mean concentrations, both for individuals under occupational and normal environmental exposure (91 and 95%, respectively). Adjusting for urinary dilution had a great effect on the fraction of the total variance attributable to between-individual variation among individuals with normal lead exposure but only a minor effect among those who were occupationally exposed. Variance analysis showed that blood concentrations were also the best discriminating biomarker for cadmium.

Erythrocyte lead was, in a univariate model, associated with an increased risk of developing end-stage renal disease [odds ratio (OR) = 1.54 for an interquartile range increase, with a 95% confidence interval (CI) = 1.18-2.00], while erythrocyte mercury was negatively associated (OR = 0.75 for an interquartile range increase, with a 95% CI = 0.56-0.99). For erythrocyte cadmium, the OR was 1.15 with a 95% CI of 0.99-1.34. Associations with lead and cadmium were only seen among men. In the study on kidney recovery, the proportion of individuals with albumin level above the 95th percentile decreased between baseline and follow up, but no decrease was found for the tubular markers N-acetyl-β‑d-glucosaminidase and β2-microglobulin. Metallothionein polymorphisms modified cadmium-associated effects on N-acetyl-β‑d-glucosaminidase and β2-microglobulin levels but did not modify cadmium-associated change in any of the kidney function markers between baseline and follow up after a substantial decrease in exposure.

Blood concentrations of lead and cadmium are the biomarkers with the best ability to discriminate between individuals with different mean concentrations. Adjustment for urinary dilution has great influence on the fraction of the total variance attributed to between individual variation among urine samples with low lead concentrations, but only a small influence on samples with high lead concentrations. This suggests a difference in excretion. The association between end-stage renal disease and low-level lead exposure, as assessed through prospective erythrocyte samples, gives reason for concern, although further studies are needed to determine causality. A cadmium-associated increase in albumin is reversible after a substantial reduction in exposure, but this is not the case for the observed tubular effects. The tubular kidney effects of cadmium might be modified by the MT1A rs11076161 polymorphism.

Abstract [sv]

För att bedöma exponering för kadmium och bly mäts ofta deras koncentrationer i blod eller urin. Dessa studerades i longitudinella data för 48 blyarbetare och 20 individer med normal miljömässig exponering. Blod- och urinprover togs var annan till var tredje månad. Kadmium- och blykoncentrationer mättes sedan i helblod, plasma och urin. Koncentrationer av bly i blod var den biomarkör som hade den största andelen av den totala variationen som kunde förklaras av skillnader mellan individer, och var därför den biomarkör med den bästa förmågan att särskilja på individer med olika medelkoncentration, både för individer med yrkesexponering och normal miljömässig exponering (91 respektive 95% av variansen berodde på vilken individ blodprovet kom ifrån). Justering för urinens utspädning av bly i urin förbättrar oftast urins användbarhet som biomarkör. För bly stämde detta bara hos dem som inte var blyarbetare. Blodkoncentrationer var också den biomarkör med störst andel av den totala variation som kunde förklaras med skillnader mellan individer för kadmium.

Kadmium och bly ackumuleras i njure respektive ben och kan ha toxikologiska effekter. Det är välkänt att höga exponeringsnivåer av kadmium orsakar njurskada och även vid lägre exponeringsnivåer har studier funnit samband med markörer för njurfunktion. Exponering för bly påverkar i första hand det centrala nervsystemet. Studier har dock funnit samband mellan koncentrationer av bly i blod och njurens glomerulära filtrationshastighet. Det är oklart både om dessa associationer, vid låga exponeringsnivåer, är viktiga för hälsan och om de verkligen beror på att kadmium och bly orsakar njurskada. För att studera end-stage renal disease användes prospektiva kohorter där personer lämnat blodprov för forskning: Västerbottens interventionsprogram med prover som tagits vid Västerbottens hälsoundersökningar, MONICA-undersökningar i Norr- och Västerbotten, mammografiundersökningarna i Västerbotten och Malmö kost cancer. Sammanlagt ingick över ett hundra tusen individer i dessa kohorter. Med hjälp av det Svenska njurregistret identifierades sedan 118 personer som senare i livet fått end-stage renal disease. Dessa jämfördes med 378 kontroller. För dessa 496 personer tinades blodprovet (närmare bestämt röda blodkroppar) upp och analyserades för kadmium och bly. För att undersöka njurens förmåga till återhämtning studerades tre områden i Kina varav ett tidigare varit kraftigt kadmiumexponerat. Erytrocytkoncentrationer av bly var, utan att ta hänsyn till några andra variabler, associerat med en ökad risk för att utveckla end-stage renal disease (med oddskvoten 1.54 för en interquartile range ökning av erytrocytbly, med ett 95% konfidensintervall 1.18-2.00). Sambanden kvarstod också efter att ha tagit hänsyn till övriga variabler. För erytrocytkadmium var oddskvoten 1.15 med 95% konfidensintervall 0.99-1.34, och sambandet försvagades när hänsyn togs till andra variabler. Associationerna sågs bland män men inte bland kvinnor.

Eftersom kadmium vid höga nivåer orsakar njurskada är det också av intresse att studera om påverkan på njuren går över om exponeringen minskas. Totalt följdes 412 individer upp med mätningar av markörer för njurfunktion och kadmiumkoncentrationer i blod och urin. Första undersökningen gjordes 1998, då man just hade slutat äta kadmiumförorenat ris. En andra undersökning gjordes 2006. Andelen individer med avvikande albuminvärde i urin var lägre vid uppföljningen jämfört med vid baslinjen, men ingen minskning sågs för markörer för tubulär förmåga att återta proteiner.

Åttioprocent av kadmium i celler är bundet till proteinet metallotheonin, vilket skyddar mot cellskada, men har också en roll i transporten av kadmium från levern till njurarna. En tidigare studie har visat att njurens känslighet för kadmiumexponering var associerad med genetiska skillnader i detta protein. För att studera genetiska associationer studerades de 412 personerna i den kinesiska studien [då också individernas genotyper av metallotheonin-polymorfierna MT1A rs11076161 (G/A), MT2A rs10636 (G/C) och MT2A rs28366003 (A/G) bestämdes]. Genetiken spelade roll för sambandet mellan förmåga att återta proteiner och kadmium men påverkade inte förändring av njurfunktion efter att man slutat äta kadmiumförorenat ris.

Kadmium- och blykoncentrationer i blod är de biomarkörer, av koncentrationer i blod, plasma och urin, med den bästa förmågan att skilja på individer med olika medelkoncentrationer. Justering för urinutspädning påverkade andelen av den totala variationen som kunde förklaras av skillnader mellan individer i stor utsträckning för individer med normal miljömässig exponering men inte bland yrkesexponerade, vilket tyder på en skillnad i hur utsöndringen går till. Associationen mellan end-stage renal disease och låg exponering för bly, uppmätta i prospektiva erytrocytprover, ger orsak till oro, men ytterligare studier behövs för att kunna utvärdera om detta är ett kausalt samband. En kadmiumrelaterad skada av den glomerulära filtrationen är reversibel efter en kraftig reducering i exponering, men detta är inte fallet för tubulär skada. De tubulära njureffekterna av kadmiumexponering kan påverkas av metallotheonin-polymorfier.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1561
Keyword [en]
Cadmium, end-stage renal disease, kidney, lead, longitudinal, matched case-control, mixed effects, prospective
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Occupational and Environmental Medicine
Identifiers
URN: urn:nbn:se:umu:diva-67832ISBN: 978-91-7459-583-3 (print)OAI: oai:DiVA.org:umu-67832DiVA: diva2:614173
Public defence
2013-05-02, Tripel, Samverkanhuset, Universitetstorget 4, Umeå, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-10 Created: 2013-04-03 Last updated: 2013-06-19Bibliographically approved
List of papers
1. Investigation of lead concentrations in whole blood, plasma and urine as biomarkers for biological monitoring of lead exposure
Open this publication in new window or tab >>Investigation of lead concentrations in whole blood, plasma and urine as biomarkers for biological monitoring of lead exposure
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2014 (English)In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, Vol. 24, no 1, 51-57 p.Article in journal (Refereed) Published
Abstract [en]

Lead in blood is a major concept in biomonitoring of exposure but investigations of its alternatives are scarce. The aim of the study was to describe different lead biomarkers' variances, day-to-day and between individuals, estimating their fraction of the total variance. Repeated sampling of whole blood, plasma and urine were conducted for 48 lead-exposed men and 20 individuals under normal environmental lead exposure, in total 603 measurements. For lead workers, the fraction of the total variance attributed to differences between individuals was 91% for whole-blood lead (geometric mean 227 μg/l; geometric standard deviation (GSD): 1.55 μg/l); plasma 78% (0.57 μg/l; GSD: 1.84 μg/l); density-adjusted urine 82%; and unadjusted urine 75% (23.7 μg/l; GSD: 2.48 μg/l). For the individuals under normal lead exposure, the corresponding fractions were 95% of the total variance for whole blood (20.7 μg/l; GSD: 8.6 μg/l), 15% for plasma (0.09 μg/l; GSD: 0.04 μg/l), 87% for creatinine-adjusted urine and 34% for unadjusted (10.8 μg/l; GSD: 6.7 μg/l). Lead concentration in whole blood is the biomarker with the best ability to discriminate between individuals with different mean concentration. Urinary and plasma lead also performed acceptably in lead workers, but at low exposures plasma lead was too imprecise. Urinary adjustments appear not to increase the between-individual fraction of the total variance among lead workers but among those with normal lead exposure.Journal of Exposure Science and Environmental Epidemiology advance online publication, 27 February 2013; doi:10.1038/jes.2013.4.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keyword
biomarker, environmental exposure, lead, occupational exposure, random effect, variance between individuals
National Category
Environmental Health and Occupational Health
Identifiers
urn:nbn:se:umu:diva-66944 (URN)10.1038/jes.2013.4 (DOI)000328604900008 ()23443239 (PubMedID)
Available from: 2013-03-08 Created: 2013-03-08 Last updated: 2017-12-06Bibliographically approved
2. End-stage renal disease and low level exposure to lead, cadmium and mercury: a population-based, prospective nested case-referent study in Sweden
Open this publication in new window or tab >>End-stage renal disease and low level exposure to lead, cadmium and mercury: a population-based, prospective nested case-referent study in Sweden
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2013 (English)In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 12, no 9Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Cadmium (Cd), lead (Pb), and mercury (Hg) cause toxicological renal effects, but the clinical relevance at low-level exposures in general populations is unclear. The objective of this study is to assess the risk of developing end-stage renal disease in relation to Cd, Pb, and Hg exposure.

METHODS: A total of 118 cases who later in life developed end-stage renal disease, and 378 matched (sex, age, area, and time of blood sampling) referents were identified among participants in two population-based prospective cohorts (130,000 individuals). Cd, Pb, and Hg concentrations were determined in prospectively collected samples.

RESULTS: Erythrocyte lead was associated with an increased risk of developing end-stage renal disease (mean in cases 76 μg/L; odds ratio (OR) 1.54 for an interquartile range increase, 95% confidence interval (CI) 1.18-2.00), while erythrocyte mercury was negatively associated (2.4 μg/L; OR 0.75 for an interquartile range increase, CI 0.56-0.99). For erythrocyte cadmium, the OR of developing end-stage renal disease was 1.15 for an interquartile range increase (CI 0.99-1.34; mean Ery-Cd among cases: 1.3 μg/L). The associations for erythrocyte lead and erythrocyte mercury, but not for erythrocyte cadmium, remained after adjusting for the other two metals, smoking, BMI, diabetes, and hypertension. Gender-specific analyses showed that men carried almost all of the erythrocyte lead and erythrocyte cadmium associated risks.

CONCLUSIONS: Erythrocyte lead is associated with end-stage renal disease but further studies are needed to evaluate causality. Gender-specific analyses suggest potential differences in susceptibility or in exposure biomarker reliability.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keyword
Biobank; Cadmium, Case-referent, End-stage renal disease, Lead, Mercury
National Category
Environmental Health and Occupational Health
Identifiers
urn:nbn:se:umu:diva-66948 (URN)10.1186/1476-069X-12-9 (DOI)000314983200001 ()23343055 (PubMedID)
Available from: 2013-03-12 Created: 2013-03-08 Last updated: 2017-12-06Bibliographically approved
3. Renal function after reduction in cadmium exposure: an eight-year follow-up of residents in cadmium-polluted areas
Open this publication in new window or tab >>Renal function after reduction in cadmium exposure: an eight-year follow-up of residents in cadmium-polluted areas
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2012 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 120, no 2, 223-228 p.Article in journal (Refereed) Published
Abstract [en]

Background and objective: Long-term exposure to cadmium (Cd) causes renal dysfunction, but its change with exposure is unknown. We aimed at assessing the evolution of Cd-induced renal effects after a reduction in dietary exposure to Cd in rice.

Methods: 412 residents in previously Cd-polluted and non-polluted areas were examined twice: in 1998 and 2006. Changes in blood Cd, urinary Cd, and kidney function (N-acetyl-β-D-glucosaminidase = NAG, β2-microglobulin, and albumin in urine) were measured. Results: In the most polluted area, mean blood Cd was 8.9 μg/L in 1998 and 3.3 μg/L in 2006, and urinary Cd was 11.6 and 9.0 μg/g creatinine in 1998 and 2006, respectively. Urinary albumin in 1998 increased with urinary Cd but no such exposure-response appeared for 2006 albumin versus urinary Cd 1998, indicating recovery. Other biomarkers of kidney function were also elevated in 1998. Partial recovery was observed for NAG, among women, and suggested for β2-microglobulin, among young individuals. The probability of having a β2-microglobulin above the 95th percentile in 2006 was high in those with an elevated β2-microglobulin in 1998 (odds ratio: 24.8, 95% CI: 11.2-55.3), whereas corresponding estimates for albumin and NAG were 3.0 (1.2-7.5) and 2.6 (1.6-4.4), respectively.

Conclusions: Results suggest that a Cd-mediated increase in urinary albumin excretion is reversible upon substantial reduction of exposure. For the markers of tubular effects, a tendency towards improvement, but not complete recovery, was observed. Data from repeated observations suggests that β2-microglobulin may be more informative than NAG as an indicator for the individual's future tubular function.

Place, publisher, year, edition, pages
National Institute of Environmental Health Sciences, 2012
Keyword
albumin, β2-microglobulin, cadmium, environmental exposure, N-acetyl-β-D-glucosaminidase, renal function.
National Category
Environmental Health and Occupational Health
Identifiers
urn:nbn:se:umu:diva-50958 (URN)10.1289/ehp.1103699 (DOI)22027495 (PubMedID)
Available from: 2012-01-02 Created: 2012-01-02 Last updated: 2017-12-08Bibliographically approved
4. Genetic modification of cadmium-related kidney toxicity: a follow up study
Open this publication in new window or tab >>Genetic modification of cadmium-related kidney toxicity: a follow up study
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(English)Manuscript (preprint) (Other academic)
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-67831 (URN)
Available from: 2013-04-03 Created: 2013-04-03 Last updated: 2013-04-10Bibliographically approved

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