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CKD 273 CLASSIFIER AS EARLY MARKER FOR TUBULOINTERSTITIAL FIBROSIS

Introduction and Aims: Regardless of the underlying etiology, progressive tubulointerstitial fibrosis (TIF) is a final common pathway leading to terminal chronic kidney disease (CKD). Moreover, the decrease in the glomerular filtration rate (GFR) is better correlated with tubulointerstitial injury than with glomerulosclerosis. Capillary electrophoresis coupled to mass spectrometry (CE-MS) has been extensively used for discovering and validating non-invasive biomarkers of CKD. The CKD 273 classifier, identified by CE-MS, is a CKD-specific biomarker based on 273 sequenced urinary peptides able to identify patients with established CKD and allows prediction of CKD progression.The aim of this study was to investigate the association of the CKD 273 score with the in situ lesions such as the degree of TIF.

Methods: We examined clinical/biochemical data of 66 patients with biopsy proven primary glomerulonephritis and different CKD stages 1-5 and 16 healthy controls. Their urine samples were analysed by CE-MS to obtain CKD 273 classifier scores. Sections from blocks with bioptic tissues were analysed and the level of TIF was scored by a pathologist according to the percentage of affected tissue: 0 (0-5%), 1 (6-25%), 2 (26-50%) and 3 (>50%). The study cohort was stratified in three groups - healthy controls, patients with <5% fibrosis (score = 0) and patients with >5% fibrosis (score = 1-3). The mean score of CKD 273 classifier and differences among the groups for all parameters were analysed.

Results: Post-hoc analysis showed that patients with >5% fibrosis had a higher serum creatinine and lower eGFR in comparison to the other groups. The CKD 273 score was the sole parameter that differed significantly between each group. In addition, the CKD 273 classifier enabled diagnosing of patients with <5% vs. no fibrosis, showing an area under the curve (AUC) of 0.921, significantly higher (p<0.01) than eGFR, showing AUC=0.702.

Conclusions: The CKD 273 classifier score showed a higher association to the level of TIF than eGFR, suggesting that the score detects at an early stage changes in the interstitial extracellular matrix (ECM) composition which is key in progression of CKD. This is probably explained by the fact that the majority of the peptides in the CKD 273 classifier are derived from proteins from the ECM. In contrast, eGFR did not significantly differ between healthy controls and patients with <5% fibrosis, confirming that eGFR is not adequate to identify onset of CKD. Overall this in situ data confirm that the CKD 273 classifier can be considered as a sensitive and early marker for assessing the severity of the disease and possibly predict CKD progression.