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Discovery of kidney damage serum biomarkers in canine babesiosis potentially translational to renal dysfunction in human malaria

Canine babesiosis is an infectious disease of dogs caused by protozoan parasites of Babesia genus which infect the red blood cells causing a disease clinically similar to human malaria. Malaria represents a great public health problem as it is potentially lethal and affects millions of people living in tropical areas. Kidney dysfunction can occur as a complication in both babesiosis and malaria, ranging from mild proteinuria to severe azotemia with acute renal failure. Mechanisms of kidney damage may be comparable in babesiosis and malaria, such as hemodynamic dysfunction and immune response, making renal involvement in canine babesiosis a suitable model for the study of human malaria kidney injury. Studies using high- resolution quantitative proteomic approach hold a promise to discover early biomarkers of kidney dysfunction before renal failure with potentially lethal outcome occurs. Comparison of serum proteome profiles of dogs naturally infected with Babesia canis (N=22) and healthy dogs (N=8) was carried out using tandem mass tags (TMT) isobaric labelling with high- resolution liquid chromatography/tandem mass spectrometry. Dogs with babesiosis were divided in 3 groups according to classical renal damage biomarkers: the first group consisted of 6 non- azotemic dogs (serum creatinine < 140 μmol/L) without proteinuria, the second group of 10 non- azotemic dogs with proteinuria and the third group of 6 azotemic dogs with marked proteinuria. Serum samples were individually processed by reduction, alkylation, trypsin digestion, labelling using TMT reagents and then analysed using nanoLC System and Q Exactive Plus mass spectrometer. Proteome Discoverer software was used for protein identification and relative quantification. Differential serum proteins between healthy and all diseased dogs were assessed by Mann–Whitney test, and between the 4 groups by Kruskal–Wallis test, with p-value < 0.05 considered as statistically significant. There were 216 master serum proteins identified with high and medium confidence with at least one unique peptide, of which 58 were statistically different between the dogs with babesiosis and healthy dogs and 59 between the 4 groups. Differential proteins are involved in several pathways such as acute phase response, complement cascade, apolipoproteins dynamics and blood coagulation. Among differential proteins, there were some which could serve as serum biomarkers of kidney damage in canine babesiosis, such as leucine-rich alpha-2- glycoprotein and fetuin-B, but this awaits further validation. Also, findings of our study could be potentially translational to acute renal failure in human malaria.

babesiosis, kidney dysfunction, serum, proteome, biomarker

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