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Background: Chronic hemodialysis (HD) patients face symptoms that significantly impact their quality of life and health outcomes. Longitudinal research on the dynamics of symptom severity and the integration of individual patient characteristics into cluster analyses is limited, hindering understanding of cluster evolution over time. Objective: The objective of this study was to characterize and compare symptom clusters across body systems based on frequency and severity at three time points in chronic HD patients. Methods: This prospective longitudinal study collected self-reported data on 23 symptoms using validated measures from 69 chronic HD patients (age range: 24-87 years) at three time points over a year. Symptoms were rated on a 0-10 scale. Symptom progression and clustering were analyzed using heat maps and principal component analysis. Results: Among 69 HD patients, a substantial symptom burden was identified at baseline, with fatigue, overall perceived health, worry or distress, and sleep disturbance reported as the most severe (mean scores > 4.0 on a 0-10 scale). Hierarchical clustering yielded a five-cluster solution; however, longitudinal analysis revealed poor structural stability in patient symptom profiles over 12 months (ARI < 0.70), indicating significant symptomatic reorganization. Gastrointestinal cluster showed a statistically significant reduction in severity over time (β = -0.914, p = 0.003); fatigue and overall perceived health remained a high burden. Subgroup analyses demonstrated that patients using central venous catheters reported significantly higher severity in pain, fatigue, and nausea compared to patients with arteriovenous fistulas, while Diabetes mellitus was uniquely associated with increased dyspnea (p < 0.001). Conclusions: Chronic HD patients experience a dynamic and multidimensional symptom burden, with significant variations in severity, progression, and clustering of symptoms over time. The observed temporal instability of symptom clusters and the heterogeneity of individual trajectories emphasize the importance of routine, longitudinal symptom assessment and flexible, patient-centered management strategies by nephrology nurse specialists, which may support value-based healthcare approaches.