Proteomics Signatures of Chronic Kidney Disease in Hypertension

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.

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.

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.

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.