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

Abstract

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.

Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities

“…Importantly, Kolli et al recently were the first to publish on the urinary proteome of CKDu/CINAC patients, reporting findings similar to ours, e.g. roles of mitochondrial, lysosomal, and protein reabsorption processes in disease onset and progression of CINAC 59 .…”

Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease

“…Ten or 11 μLs of peptide digest (∼33 μg from batch 1 and ∼36 μg from batch 2) were analyzed by microflow liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) using data-independent acquisition (DIA) as previously described. 56 Briefly, LC used an ACQUITY LC (Waters) with a 1 × 100 mm, 1.7 μm ACQUITY Premier CSH C18 column using a flow rate of 100 μL/min, a column temperature of 55 °C, and a gradient of 3−28% (v/v) MeCN/ H 2 O with 0.1% formic acid over 60 min. DMSO was delivered postcolumn 57,58 using an M-Class Auxiliary Solvent Manager (Waters) delivering 50/50 (v/v) MeCN/DMSO at a flow rate of 6 μL/min via a PEEK mixing tee (Valco).…”

Chronic kidney disease of unknown aetiology: A comprehensive review of a global public health problem

“…Biomarkers such as kidney injury molecule (KIM)-1, neutrophil gelatinase-associated lipocalin (NGAL) and so forth, can potentially identify renal injury earlier than conventional markers such as creatinine; however, their use has not been validated yet [97,98]. Recently, a potential role of urinary proteome profiling for early diagnosis of CKDu has been suggested [99].…”