Challenges for environmental epidemiology research: are biomarker concentrations altered by kidney function or urine concentration adjustment?
Biomonitoring has become a standard approach for exposure assessment in occupational and environmental epidemiology. The use of biological effect markers to identify early adverse changes in target organs has also become widely adopted. However, the potential for kidney function to affect biomarker levels in the body and the optimal approach to adjustment of biomarker concentrations in spot urine samples for hydration status are two important but underappreciated challenges associated with biomarker use. Several unexpected findings, such as positive associations between urine nephrotoxicant levels and estimated glomerular filtration rate (eGFR), have been reported recently in research using biomarkers. These and other findings, discussed herein, suggest an impact of kidney glomerular filtration or tubule processing on biomarker levels. This is more commonly raised in the context of decreased kidney filtration, traditionally referred to as reverse causality; however, recent data suggest that populations with normal kidney filtration may be affected as well. Misclassification bias would result if biomarkers reflect kidney function as well as either exposures or early biological effect outcomes. Furthermore, urine biomarker associations with eGFR that differ markedly by approach used to adjust for urine concentration have been reported. Associations between urine measures commonly used for this adjustment, such as urine creatinine, and specific research outcomes could alter observed biomarker associations with outcomes. Research recommendations to address the potential impact of kidney function and hydration status adjustment on biomarkers are provided, including a range of approaches to study design, exposure and outcome assessment, and adjustment for urine concentration.
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.|Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Virginia M
VM
Weaver
National Center for Environmental Assessment, United States Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
Dennis J
DJ
Kotchmar
Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.|Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Jeffrey J
JJ
Fadrowski
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
Ellen K
EK
Silbergeld
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism* / Q000652:urine*; D002104:Cadmium / Q000378:metabolism* / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000378:metabolism* / Q000652:urine*; D004784:Environmental Monitoring / Q000379:methods; D016021:Epidemiologic Studies; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007223:Infant; D007671:Kidney Concentrating Ability; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure / Q000032:analysis; D055815:Young Adult
D015415:Biomarkers; D002104:Cadmium; D003404:Creatinine