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-1), neutrophil gelatinase-associated lipocalin (NGAL) and β2-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-1 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.

Chronic Kidney Disease (CKD) is a globally prevalent non-communicable disease with significant mortality and morbidity. It is typically associated with diabetes and hypertension; however, over the last two decades, an emergence of CKD of unknown etiology (CKDu) has claimed thousands of lives in several tropical agricultural communities. CKDu is associated with gradual loss of renal function without initial symptoms until reaching complete kidney failure and eventually death. The most impacted are young adult males of lower socio-economic strata. Since the disease progression can be successfully attenuated through early detection, the development of superior screening and management measures is of utmost importance. In contrast to the conventional biomarkers, novel biomarkers with improved sensitivity and specificity are being discussed as promising tools for early diagnosis of the disease. This review summarizes emerging novel biomarkers used in assessing CKD and discusses the current utility and diagnostic potential of such biomarkers for CKDu screening in clinical settings of different communities impacted by CKDu. Our goal is to provide a framework for practitioners in CKDu impacted regions to consider the use of these novel biomarkers through this synthesis. The increased use of these biomarkers will not only help to validate their diagnostic power further and establish potential prognostic value but may also provide critical insights into sites and mechanisms of renal damage.

Pediatric renal injury is an emerging health concern in communities affected by chronic kidney disease of uncertain etiology (CKDu). Early detection of susceptibilities through highly sensitive and specific biomarkers can lead to effective therapeutic and preventive interventions against renal diseases. Here, we aimed to investigate the utility of kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in early detection of renal abnormalities in selected pediatric communities in Sri Lanka. The study areas were stratified as CKDu endemic, emerging, and non-endemic based on the prevalence of CKDu, and a total of 804 school students (10–18 years of age) participated in the study. The median (IQR) urinary KIM-1 levels of the participants were 0.193 (0.026–0.338), 0.082 (0.001–0.220) and 0.040 (0.003–0.242) ng/mgCr for CKDu endemic, emerging and non-endemic regions respectively. Participants from CKDu endemic regions reported elevated (p < 0.0001) urinary KIM-1 expression compared to those from the other regions. The median (IQR) NGAL levels in participants from CKDu endemic (2.969; 1.833–5.641), emerging (3.374; 1.766–6.103), and non-endemic (3.345; 1.742–5.128 ng/mgCr) regions showed no significant difference. Also, urinary albumin-creatinine ratio (UACR) showed no significant differences across gender or residency. The prevalence of albuminuria was 1–2% in the locations irrespective of CKDu burden. Albuminuric participants reported higher (p < 0.05) urinary KIM-1 levels in comparison to normoalbuminuric participants. Significantly elevated urinary KIM-1 expression in a pediatric population from CKDu affected regions, especially in the presence of albuminuria, may indicate low-grade early renal damage supporting the utility of KIM-1 as a quantifiable biomarker.

CKDu is a global health concern debilitating a number of tropical rural farming communities. In the absence of typical risk factors like diabetes and hypertension and the lack of molecular markers, it is crucial to identify potential early disease markers. Here, we detail the first urinary proteome profile to distinguish CKDu from CKD. Our data and in silico pathway analyses infer the roles of mitochondrial, lysosomal, and protein reabsorption processes in disease onset and progression.

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.