Chronic kidney disease 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 CKDu patients and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins (DAPs). In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in CKDu patients was evinced by the increase in albumin, cystatin C and β2-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-N-acetylglucosaminidase, were decreased in CKDu patients. Further, 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, CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Further, 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 DAPs in CKDu patients 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.
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