Background: Chronic allograft dysfunction (CAD) with interstitial fibrosis-tubular atrophy (IFTA) post kidney transplantation (KT) is one of the most common causes of graft loss. This cross-sectional study analyzed circulating protein profiles associated with IFTA in KT patients aimed to identify noninvasive biomarkers.

Patients and Methods: Peripheral blood plasma samples from KT recipients (n=20) with normal function NFA (n=10) and IFTA (n=10) were studied. Proteomic analyses were performed using Liquid Chromatography followed by MS-MS for peptide identification and quantitation. Separate analysis of variance model was applied to identify significant differentially expressed proteins between IF/TA vs. NFA. Results were expressed as fold changes. Differentially expressed proteins were ranked by the estimated q-value. Priority scores (P1, P2, P3, P4) were assigned to each significant protein depending on peptide number and high or moderate peptide sequence ID confidence. A p-value < 0.05 was considered significant. FDR was controlled at < 5%. IPA tool were used for pathway analysis.

Results: Peptide identity analysis identified 1652 distinct proteins. Of those, 413 proteins (155 increased and 258 decreased) were significantly and differentially expressed between KT recipients with IFTA versus NFA. The 29.3% (121/413) of proteins were identified with high peptide ID confidence and classified as P1 (19.0%; 23/121) and P2 (81.0%; 98/121). The remaining proteins, 7.0% (29/413) were assigned as P3, and 63.7% (263/413) as P4. Positive plasma/serum expression was in silico corroborated for 124 proteins, which included 21 out of 23 P1 proteins. Pathways analyses fit for the 124 significant proteins identified 23 significant canonical pathways (p ≤ 0.05). Top five significant canonical pathways (p ≤ 0.01) included Intrinsic, and Extrinsic Prothrombin Activation Pathway, Acute Phase Response Signaling, LXR/RXR Activation, and Coagulation System. A set of 19 plasma circulating proteins was found to be directly associated with CAD / IF-TA. Interestingly, 7 circulating proteins (AMBP, COL3A1, FGA, FGB, HPX, ITGA4, RBP4) were directly identified as related to proximal tubular renal injury, and validated in a larger IF/TA cohort.

Conclusion: We identified a set of proteins with potential value as non-invasive biomarker associated with CAD-IFTA development post KT.

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