The urinary proteome infers dysregulation of mitochondrial, lysosomal, and protein reabsorption processes in chronic kidney disease of unknown etiology (CKDu).

Chronic kidney disease (CKD) of uncertain etiology (CKDu) is a global health concern affecting tropical farming communities. CKDu is not associated with typical risk factors (e.g., diabetes) and strongly correlates with environmental drivers. To gain potential insights into disease etiology and diagnosis, here we report the first urinary proteome comparing patients with CKDu and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins. In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in patients with CKDu was evinced by increases in albumin, cystatin C, and ß2-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-N-acetylglucosaminidase, were decreased in patients with CKDu. Furthermore, urinary excretion of aquaporins found higher in CKD was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, the CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Furthermore, we report a decrease in endocytic receptor proteins responsible for protein reabsorption (megalin and cubilin) that correlated with an increase in abundance of 15 of their cognate ligands. Functional pathway analyses identified kidney-specific differentially abundant proteins in patients with CKDu denoted significant changes in the complement cascade and coagulation systems, cell death, lysosomal function, and metabolic pathways. Overall, our findings provide potential early detection markers to diagnose and distinguish CKDu and warrant further analyses on the role of lysosomal, mitochondrial, and protein reabsorption processes and their link to the complement system and lipid metabolism in CKDu onset and progression.NEW & NOTEWORTHY 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.

A review of molecular mechanisms linked to potential renal injury agents in tropical rural farming communities.

The chronic kidney disease of unknown etiology (CKDu) is a global health concern primarily impacting tropical farming communities. Although the precise etiology is debated, CKDu is associated with environmental exposures including heat stress and chemical contaminants such as fluoride, heavy metals, and herbicide glyphosate. However, a comprehensive synthesis is lacking on molecular networks underpinning renal damage induced by these factors. Addressing this gap, here we present key molecular events associated with heat and chemical exposures. We identified that caspase activation and lipid peroxidation are common endpoints of glyphosate exposure, while vasopressin and polyol pathways are associated with heat stress and dehydration. Heavy metal exposure is shown to induce lipid peroxidation and endoplasmic reticulum stress from ROS activated MAPK, NFĸB, and caspase. Collectively, we identify that environmental exposure induced increased cellular oxidative stress as a common mechanism mediating renal cell inflammation, apoptosis, and necrosis, likely contributing to CKDu initiation and progression.