A robust plasma protein signature predicts hypertensive chronic kidney disease and identifies FOLR1 and STC1 as potential therapeutic targets.
Does a plasma protein-based risk score improve the prediction of incident CKD in hypertensive individuals compared to clinical models alone?
A 13-protein plasma signature significantly improves the prediction of incident CKD in hypertensive patients beyond standard clinical models.
Absolute Event Rate: 0% vs 0%
Background: Hypertension is a major modifiable risk factor for chronic kidney disease (CKD), yet predicting which hypertensive individuals will progress to CKD remains challenging. We aimed to develop and validate a plasma protein-based risk score for incident CKD in hypertension and to identify causal proteins and potential therapeutic targets. Methods: Using data from the UK Biobank Pharma Proteomics Project, we included 22 258 hypertensive participants without baseline CKD. A protein risk score was developed in a training set (n=11 671) and validated in internal testing (n=7778) and external validation (Scotland/Wales, n=2809) cohorts. Hypothesis-generating Mendelian randomization using cis - protein quantitative trait loci was performed to prioritize proteins for functional follow-up. Results: A 13-protein risk score (C-index ≈0.78) was developed, with a simplified 3-protein panel (RNASE1 pancreatic ribonuclease, IGFBP4 insulin-like growth factor-binding protein 4, GDF15 growth differentiation factor 15) capturing most of its predictive power. Adding the 13-protein score to the clinical model significantly improved the C-index by 0.019 (95% CI, 0.011–0.026) in internal testing and 0.047 (95% CI, 0.013–0.090) in external validation cohorts, with significant net reclassification improvement and integrated discrimination improvement, while an estimated glomerular filtration rate-based polygenic risk score provided no meaningful improvement. Mendelian randomization analysis identified 7 proteins (BMPER BMP-binding endothelial regulator protein, GFRA1 GDNF family receptor alpha-1, CST3 cystatin-C, CXCL16 C-X-C motif chemokine 16, FOLR1 folate receptor alpha, AMBP protein AMBP, and STC1 stanniocalcin-1) with nominally significant associations with hypertensive CKD, all with higher levels increasing risk. Enrichment analyses highlighted protease inhibition and folate metabolism pathways. FOLR1 and STC1 emerged as druggable targets. Conclusions: This study establishes a robust plasma protein signature for predicting hypertensive CKD and provides genetic evidence supporting several proteins as prioritized candidates, revealing novel pathways and nominating FOLR1 and STC1 as potential therapeutic targets for further investigation.
Huang et al. (Wed,) reported a other. A robust plasma protein signature predicts hypertensive chronic kidney disease and identifies FOLR1 and STC1 as potential therapeutic targets.