Data-driven cluster analysis identifies three clinical phenotypes in hemodialysis patients

Clinical heterogeneity among hemodialysis patients necessitates precision medicine approaches transcending conventional single-parameter management. Through machine learning analysis of 1,207 maintenance hemodialysis patients, we developed a novel two-tier phenotyping framework integrating unsupervised K-means clustering across 22 clinical indicators with supervised classification using six universally available biomarkers. Five mechanistically informed composite indicators were constructed, including the Middle-Small Molecule Clearance Index (β₂-microglobulin reduction ratio × <i>Kt</i>/<i>V</i>) and ferritin–hemoglobin ratio, achieving superior discriminatory capacity over traditional approaches. Three distinct metabolic phenotypes emerged with exceptional stability (Adjusted Rand Index = 0.9181): high retention-inflammatory (19.5%) characterized by dialysis inadequacy and functional iron deficiency, optimal clearance (24.3%) demonstrating superior toxin removal, and intermediate-stable (56.0%) maintaining balanced parameters. The simplified six-parameter model achieved clinically acceptable performance (AUC: 0.893–0.919, accuracy &gt;88%) enabling automated EMR integration. This cross-sectional phenotype discovery represents the foundational step toward precision nephrology, establishing classification frameworks essential for subsequent longitudinal validation studies. The methodology facilitates phenotype-guided interventions: intensified dialysis for high retention-inflammatory patients, clearance optimization for optimal clearance patients, and proactive monitoring for intermediate-stable patients, advancing hemodialysis toward algorithm-driven individualized care with potential to optimize clinical outcomes and resource utilization, pending prospective validation of phenotype-outcome associations.