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Chronic kidney disease of unknown etiology (CKDu) is a tubulointerstitial disease that disproportionately affects young, primarily male, agricultural workers in Mesoamerica and South Asia who lack traditional risk factors for kidney disease. Extensive research in adult populations suggests the etiology is multifactorial and indicates that early childhood exposures could have an integral role. Evaluating subclinical kidney disease in children is important both for identification of prevention strategies and to understand relevant exposures.
A systematic literature search was conducted in six databases for studies that report on kidney health outcomes of pediatric populations living in proximity to CKDu-affected areas with no limitations on geography or study design. Studies were independently screened for inclusion and underwent quality assessment using the Appraisal Tool for Cross-Sectional Studies (AXIS) or the JBI Critical Appraisal Tool for Cohort Studies based on the study design by at least two authors. Data are compared narratively and graphically.
We included 19 peer-reviewed publications and two meeting abstracts from eight different countries including 13 from Mesoamerica, 5 from Sri Lanka, and one each from India, Brazil, and Egypt.
The most common study design involved cross-sectional analysis of biological specimens from children in an established CKDu endemic area. None of the 3 cohort studies took biologic samples longer than 3 years. Overall, 37% of studies were appraised as high quality, 47% medium, and 16% low. Marked decreases in estimated glomerular filtration rate were generally not identified and albuminuria differed widely between countries with only populations in Mexico showing a high prevalence of albuminuria. Novel urinary biomarkers frequently demonstrated subclinical kidney damage and higher levels were sometimes associated with areas of high CKDu endemicity in adults, although the specific biomarker(s) varied between studies. Epidemiologic factors associated with evidence of subclinical kidney damage in children included proximity to agriculture or agrichemicals. Despite heterogenous study outcomes, all studies concluded that there were signs of kidney damage in children living in CKDu endemic areas or with a CKDu-relevant environmental exposure.
All included studies showed evidence of kidney damage in a pediatric population suggesting that the pathophysiologic process leading to CKDu may begin prior to adulthood. This challenges the assumption that children are not exposed to the etiologic agents of CKDu. It is known that CKDu is a multifactorial disease, and the studies included in this review strongly suggest that at least some of these factors occur prior to adulthood and possibly even in utero. We recommend longitudinal studies of children, continued investigations into noninvasive urinary biomarkers, early-life animal model studies, and concurrent biologic and environmental sampling. Future research aimed at elucidating the multifaceted factors and exposures impacting entire communities, including children, is imperative for disease prevention strategies.