Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

TLDR

Progressive CKD is usually detected late, when eGFR declines or albuminuria becomes significant. The study aimed to improve early risk stratification of CKD patients by analyzing urinary peptides in a large multicenter cohort. Urinary peptides were profiled by proteome analysis in 1990 participants, 522 of whom had follow‑up data. A multipeptide urinary biomarker classifier outperformed urinary albumin, improved CKD risk prediction (AUC 0.831 vs 0.758), and its peptide signatures—derived from circulating protein fragments, collagen, and inflammation/tissue‑repair proteins—highlighted glomerular barrier dysfunction and intrarenal extracellular matrix changes, underscoring the potential of urinary proteome analysis for early CKD detection and outcome prediction.

Abstract

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aimof early and improved risk stratification of patients with CKD,we studied urinary peptides in a large cross-sectionalmulticenter cohort of 1990 individuals, including 522with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of themultipeptide biomarker classifier significantly improvedCKDrisk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±20.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly fromproteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identi-fication of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.