Environmental fluoride exposure and implications on potential pediatric kidney health risks: an approach with urinary biomarkers.

BACKGROUND: Environmental fluoride exposure at elevated levels is potentially linked to kidney injury, and may contribute to chronic kidney disease of uncertain etiology (CKDu) as a risk factor. However, this link remains unclear, and examining the risk of kidney damage from early life fluoride exposure may provide important insights. Hence, this study aimed to investigate associations of fluoride exposure with pediatric kidney health in CKDu impacted and unimpacted communities in Sri Lanka. METHODS: Considering the geographical variations in environmental fluoride, climate, and prevalence of CKDu, four study groups were established within selected education zones in CKDu-endemic dry zone regions (D-En), and CKDu-nonendemic regions within the dry (D-NE), wet (W-NE), and intermediate (I-NE) climatic zones. The study population included 922 school students (11-18 years of age). Participants in each group were divided into four subgroups based on quartiles of respective urinary fluoride (UF) distribution for comparison of urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and albumin-creatinine ratio (ACR). RESULTS: UF levels in participants particularly in CKDu endemic dry zone regions were significantly high compared to the other regions. Significantly high median urinary NGAL (in D-NE) and ACR (in D-EN, and W-NE) levels were observed in subgroups of higher UF quartiles. Albuminuria was not particularly identified in subjects with high UF excretion. Urinary KIM-1 showed no significant variation across the UF quartile subgroups. Linear regression identified weak associations of UF with kidney injury biomarkers. CONCLUSIONS: Fluoride exposure is particularly high in CKDu-endemic dry zone communities. As implied by kidney injury biomarkers, a strong link between fluoride exposure and pediatric kidney health was not evident at the observed exposure levels in the study regions.

Fluoride exposure and pediatric kidney health in dry, wet and intermediate climatic zone communities in Sri Lanka: Implications from urinary Cystatin-C, and albumin-creatinine ratio.

BACKGROUND: High fluoride exposure is increasingly discussed attributing to kidney injury as a causative factor. Depending on geochemistry, differential fluoride levels in drinking water are identified in different regions in Sri Lanka. However, the levels of fluoride exposure, and associations with kidney health has not been adequately studied in Sri Lanka, particularly in pediatric communities. Hence, the present study aimed to assess fluoride exposure in selected pediatric communities in the dry, wet and intermediate climatic zones in Sri Lanka, along with an assessment of renal health using urinary Cystatin-C (uCys-C), and albumin-creatinine ratio (uACR). METHODS: We conducted a cross-sectional study with school students in selected education zones representing dry (N = 331), wet (N = 152), and intermediate (N = 292) climatic zones in Sri Lanka. Fluoride contents in urine and drinking water were assessed as measures of fluoride exposure. RESULTS: The median (interquartile distance) urinary fluoride levels of participants in the dry, wet and intermediate zones were 1.63(1.04-2.85), 1.29(0.85-2.21), and 1.07(0.61-1.98) mg/gCr while the fluoride contents of drinking water samples were 1.76(1.36-2.30), 0.25(0.18-0.37), and 0.43(0.26-0.63) ppm respectively with significant differences among the three groups. Median uCys-C level (ng/mgCr) of the participants in intermediate zone [30.26(8.49-71.44)] was significantly low (p < 0.05) compared to that of the participants in dry zone [56.19(7.08-211.8)], and wet zone [66.29(30.43-125.20)]. The incidences of elevated uCys-C levels above reference intervals in participants of dry zone (47.7%), and wet zone (50.0%) were significantly high (p < 0.001) compared to the intermediate zone (26.4%). CONCLUSION: Relatively high fluoride exposure is likely in dry and wet zone communities compared to the intermediate zone along with significantly higher incidence of uCys-C levels above reference intervals in study groups with higher fluoride exposure. However, to conclude a clear link between fluoride exposure and kidney health we need in-depth studies.

Applicability of Novel Urinary Biomarkers for the Assessment of Renal Injury in Selected Occupational Groups in Sri Lanka: A Comparative Study with Conventional Markers.

Screening approaches with more robust biomarkers, are of the utmost importance in the characterization of renal injuries, particularly among communities with high burdens of chronic kidney disease of uncertain etiology (CKDu). The present study aimed to assess the utility of two emerging biomarkers: kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in predicting renal injury in different occupational groups in Sri Lanka. A cross-sectional study was conducted with six occupational groups (n = 188): fisherfolk (FF), paddy farmers (PF), sugarcane farmers (SF), factory workers (FW) and plantation workers (PW) to assess the predictive performance of KIM-1 and NGAL against a CKDu patient (PT) group (n = 40). The median KIM-1 levels of the study groups; FF, PF, SF, FW, PW and PT were 0.67, 0.59, 0.49, 1.62, 0.67 and 5.24 ng/mgCr, respectively, while the median NGAL levels were 1.16, 2.52, 1.42, 1.71, 1.06 and 22.41 ng/mgCr respectively. In ROC analysis to predict CKDu susceptibility, the area under the curve for KIM-1 ranged from 0.88 to 0.99 for the study groups, and in overall analysis, the sensitivity and specificity were 100% and 96%, respectively, for a cutoff value of 2.76 ng/mgCr. Similarly, for NGAL the range of AUC was 0.78-0.94, and a cutoff value of 3.12 ng/mgCr produced 88% sensitivity and 82% specificity. Compared with conventional markers, KIM-1 was the best biomarker for the characterization of renal injury in the participants of the occupational groups. With further validations, KIM-1 may be adopted as a prognostic marker to identify early renal injury and CKDu susceptibilities in community screening.

Urinary cystatin C: pediatric reference intervals and comparative assessment as a biomarker of renal injury among children in the regions with high burden of CKDu in Sri Lanka.

BACKGROUND: Cystatin C (Cys-C) is an emerging biomarker of renal diseases and its clinical use, particularly for screening the communities affected by chronic kidney disease of unknown etiology (CKDu), is hindered due to the lack of reference intervals (RIs) for diverse ethnic and age groups. The present study aimed to define RIs for urinary Cys-C (uCys-C) for a healthy pediatric population in Sri Lanka and in turn compare the renal function of the residential children in CKDu endemic and non-endemic regions in Sri Lanka. METHODS: A cross-sectional study was conducted with 850 healthy children (10-17 years) from selected locations for reference interval establishment, while a total of 892 children were recruited for the comparative study. Urine samples were collected and analyzed for Cys-C, creatinine (Cr) and albumin. Cr-adjusted uCys-C levels were partitioned by age, and RIs were determined with quantile regression (2.5th, 50th and 97.5th quantiles) at 90% confidence interval. RESULTS: The range of median RIs for uCys-C in healthy children was 45.94-64.44 ng/mg Cr for boys and 53.58-69.97 ng/mg Cr for girls. The median (interquartile range) uCys-C levels of children in the CKDu endemic and non-endemic regions were 58.18 (21.8-141.9) and 58.31 (23.9-155.3) ng/mg Cr with no significant difference (P = 0.781). A significant variation of uCys-C was noted in the children across age. CONCLUSIONS: Notably high uCys-C levels were observed in children with elevated proteinuria. Thus, uCys-C could be a potential biomarker in identifying communities at high risk of CKDu susceptibility.

Urinary Biomarkers KIM-1 and NGAL for Detection of Chronic Kidney Disease of Uncertain Etiology (CKDu) among Agricultural Communities in Sri Lanka.

Chronic Kidney Disease of uncertain etiology (CKDu) is an emerging epidemic among farming communities in rural Sri Lanka. Victims do not exhibit common causative factors, however, histopathological studies revealed that CKDu is a tubulointerstitial disease. Urine albumin or albumin-creatinine ratio is still being used as a traditional diagnostic tool to identify CKDu, but accuracy and prevalence data generated are questionable. Urinary biomarkers have been used in similar nephropathy and are widely recognised for their sensitivity, specificity and accuracy in determining CKDu and early renal injury. However, these biomarkers have never been used in diagnosing CKDu in Sri Lanka. Male farmers (n = 1734) were recruited from 4 regions in Sri Lanka i.e. Matara and Nuwara Eliya (farming locations with no CKDu prevalence) and two CKDu emerging locations from Hambantota District in Southern Sri Lanka; Angunakolapelessa (EL1) and Bandagiriya (EL2). Albuminuria (ACR ≥ 30mg/g); serum creatinine based estimation of glomerular filtration rate (eGFR); creatinine normalized urinary kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured. Fourteen new CKDu cases (18%) from EL1 and nine CKDu cases (9%) from EL2 were recognized for the first time from EL1, EL2 locations, which were previously considered as non-endemic of the disease and associated with persistent albuminuria (ACR ≥ 30mg/g Cr). No CKDu cases were identified in non-endemic study locations in Matara (CM) and Nuwara Eliya (CN). Analysis of urinary biomarkers showed urinary KIM-1 and NGAL were significantly higher in new CKDu cases in EL1 and EL2. However, we also reported significantly higher KIM-1 and NGAL in apparently healthy farmers in EL 1 and EL 2 with comparison to both control groups. These observations may indicate possible early renal damage in absence of persistent albuminuria and potential capabilities of urinary KIM-1 and NGAL in early detection of renal injury among farming communities in Southern Sri Lanka.

Arsenic and human health effects: A review.

Arsenic (As) is ubiquitous in nature and humans being exposed to arsenic via atmospheric air, ground water and food sources are certain. Major sources of arsenic contamination could be either through geological or via anthropogenic activities. In physiological individuals, organ system is described as group of organs that transact collectively and associate with other systems for conventional body functions. Arsenic has been associated with persuading a variety of complications in body organ systems: integumentary, nervous, respiratory, cardiovascular, hematopoietic, immune, endocrine, hepatic, renal, reproductive system and development. In this review, we outline the effects of arsenic on the human body with a main focus on assorted organ systems with respective disease conditions. Additionally, underlying mechanisms of disease development in each organ system due to arsenic have also been explored. Strikingly, arsenic has been able to induce epigenetic changes (in utero) and genetic mutations (a leading cause of cancer) in the body. Occurrence of various arsenic induced health effects involving emerging areas such as epigenetics and cancer along with their respective mechanisms are also briefly discussed.