Kidney developmental effects of metal-herbicide mixtures: Implications for chronic kidney disease of unknown etiology

Babich, Remy; Ulrich, Jake C.; Ekanayake, Emil; Massarsky, Andrey; Silva, P. Mangala C.S. De; Manage, P.M.; Jackson, Brian P.; Ferguson, P. Lee; Giulio, Richard T. Di; Drummond, Iain A.; Jayasundara, Nishad

doi:10.1016/j.envint.2020.106019

Cited by 56 publications

(42 citation statements)

References 60 publications

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“…Despite recent studies [54,82], validation of normal levels of NGAL and KIM-1 in larger populations has not been carried out. Previously, Jayasumana et al (year) reported glyphosate and heavy metals (Cd, & As) as the main etiological factor in CKDu among farmers [27] and were shown to affect KIM-1 expression in an animal model [26]. Expression of KIM-1 in response to exposure to toxic metals including As [83], Cd [84], and Hg have been noted in human subjects and Cr [18] in a rat model.…”

Section: Discussionmentioning

confidence: 99%

“…A similar disease is prevalent among sugarcane workers in low lands of Nicaragua, El Salvador, and Honduras (referred to as Meso American Nephropathy-MEN), coconut, sugar, and rice farmers in India (referred to as Uddanam nephropathy) and some other parts of South East Asia and Egypt [23][24][25]. Multiple causes have been suggested such as chronic low dose exposure to multiple heavy metals [26] and agrochemicals [27], heat stress and recurrent dehydration [28][29][30][31] nephrotoxic drugs [32], hyperuricemia and hyperuricosuria [29], leptospirosis [33], and genetic susceptibility [34]. Heat stress and associated dehydration were recently highlighted as main etiological factors mainly in MEN [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

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Occupational Paraquat and Glyphosate Exposure May Decline Renal Functions among Rural Farming Communities in Sri Lanka

Abdul

Silva

Ekanayake

et al. 2021

IJERPH

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Extensive use of herbicides is common among rural agricultural workers in Sri Lanka. Recent studies have postulated their role in the development of chronic kidney disease of unknown etiology (CKDu). Paraquat and glyphosate are leading herbicides used by sugarcane farmers (SF), hence occupational exposure is inevitable. This study examined the expression of urinary paraquat, glyphosate and biomarkers among residential SF in CKDu emerging regions, Warunagama (WA) and Rahathangama (RH), in the Uva Province with non-endemic Matara (MA) in the Southern Province of Sri Lanka. Urinary glyphosate, Paraquat, Kidney injury molecule -1 (KIM-I), Neutrophil gelatinase-associated lipocalin (NGAL) andβ2-microglobulin (B2M) were determined using enzyme-linked immunosorbent assays (ELISA). Urinary creatinine, microalbumin, serum creatinine (SCr), serum cystatin C, estimated glomerular filtration rate (eGFR), and albumin creatinine ratio (ACR) were also assessed. Generally, herbicide residues and kidney injury biomarkers were higher in SF compared to the non-endemic MA. Creatinine-adjusted urinary glyphosate and paraquat levels were significantly higher in WA compared to MA. ACR in RH (median 14.9; IQR 5.4–393.1 mg/g) and WA (23.7; 11.5–64.6) was significantly higher than MA (4.3; 2.2–6.7). This study reports 39 individuals with impaired kidney function among SF in Sri Lanka for the first time. Urinary NGAL levels were significantly higher in both WA (median 2.14; IQR 1.28–6.15 ng/mg Cr) and RH (3.09; 1.15–9.09) compared to MA (1.28; 0.56–2.81). However, urinary KIM-I levels in RH (3.2; 1.29–106.1 ng/g Cr) and WA (3.6; 1.94–115.1) were not significantly higher in MA (1.74; 0.76–116.9). Urinary NGAL (r = 0.493), eGFR (r = −0.147) and ACR (r = 0.171) significantly correlated with urinary glyphosate, but not with urinary paraquat levels. Urinary KIM-1 levels did not correlate with either urinary glyphosate or paraquat, while urinary B2M and serum cystatin C levels showed significant correlation with urinary glyphosate levels. The current study reports higher urinary herbicide levels among sugarcane farmers in WA and RH, and that is potentially linked to the subsequent decline in kidney function, as indicated by ACR, eGFR, and NGAL. We posit that these indicators may serve as markers to detect renal injury among herbicide-exposed SF in Rural Sri Lanka.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Occupational Paraquat and Glyphosate Exposure May Decline Renal Functions among Rural Farming Communities in Sri Lanka

Abdul

Silva

Ekanayake

et al. 2021

IJERPH

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“…This is highlighted in an emergence of chronic kidney disease of unknown etiology (CKDu) (also termed as chronic interstitial nephritis among agricultural communities) that is closely associated with agricultural lifestyle in several global hotspots mainly in Central America, and south-east Asia [4]. Although the causes of CKDu are unknown, a childhood-onset coupled to repeated acute kidney injury is suspected [5,6], highlighting the need for early-stage markers of kidney damage and dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Urinary Biomarkers of Renal Injury KIM-1 and NGAL: Reference Intervals for Healthy Pediatric Population in Sri Lanka

et al. 2021

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Emerging renal biomarkers (e.g., kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) are thought to be highly sensitive in diagnosing renal injury. However, global data on reference intervals for emerging biomarkers in younger populations are lacking. Here, we aimed to determine reference intervals for KIM-1 and NGAL across a pediatric population in Sri Lanka—a country significantly impacted by the emergence of chronic kidney disease of unexplained etiology (CKDu). Urine samples were collected from children (10–18 years) with no prior record of renal diseases from the dry climatic zone of Sri Lanka (N = 909). Urinary KIM-1 and NGAL concentrations were determined using the enzyme-linked immunosorbent assay (ELISA) and adjusted to urinary creatinine. Biomarker levels were stratified by age and gender, and reference intervals derived with quantile regression (2.5th, 50th, and 97.5th quantiles) were expressed at 95% CI. The range of median reference intervals for urinary KIM-1 and NGAL in children were 0.081–0.426 ng/mg Cr, 2.966–4.850 ng/mg Cr for males, and 0.0780–0.5076 ng/mg Cr, 2.0850–3.4960 ng/mg Cr for females, respectively. Renal biomarkers showed weak correlations with age, gender, ACR, and BMI. Our findings provide reference intervals to facilitate screening to detect early renal damage, especially in rural communities that are impacted by CKDu.

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“…The safe levels of heavy metals in drinking water in endemic areas can indeed cause kidney dysfunction due to its unique hydrogeochemistry resulting in CKDu. Hence, use of spring water is encouraged at least for drinking purposes (Babich et al 2020;Chandrajith et al 2011;Jayasekara et al 2015). Consumption of untreated well water and history of drinking water from an abandoned well were found to be causative factors for CKDu (Balasubramanya et al 2020;de Silva et al 2017;Jayasumana et al 2014.…”

Section: Etiologic Studiesmentioning

confidence: 99%

Multi-pronged research on endemic chronic kidney disease of unknown etiology in Sri Lanka: a systematic review

Arambegedara

Jayasinghe

Udagama

2021

Environ Sci Pollut Res

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Kidney developmental effects of metal-herbicide mixtures: Implications for chronic kidney disease of unknown etiology

Cited by 56 publications

References 60 publications

Occupational Paraquat and Glyphosate Exposure May Decline Renal Functions among Rural Farming Communities in Sri Lanka

Occupational Paraquat and Glyphosate Exposure May Decline Renal Functions among Rural Farming Communities in Sri Lanka

Urinary Biomarkers of Renal Injury KIM-1 and NGAL: Reference Intervals for Healthy Pediatric Population in Sri Lanka

Multi-pronged research on endemic chronic kidney disease of unknown etiology in Sri Lanka: a systematic review

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