Abstract End-stage kidney disease patients on in-center hemodialysis (HD) experience a substantial symptom burden, which is associated with poor health-related quality of life (HRQOL), hospitalizations and mortality. Fatigue, pain and depression are among the most debilitating symptoms, reported by more than 60%, 50% and 20% of patients, respectively. Despite the significant prevalence and impact of these symptoms, treatment options remain limited. The management of symptoms has been identified as a high research priority advocated by patient advocacy groups and in both the National Institute of Health's scientific workshop and Kidney Disease Improving Global Outcomes conferences. Recently, we successfully completed a randomized controlled trial, Technology Assisted Stepped Collaborative Care (TĀCcare), to test an intervention to improve symptom burden among 160 diverse patients on HD from Western Pennsylvania and New Mexico. Our intervention had unique strengths that included targeting symptom cluster (fatigue, pain and depression), a shared decision-making approach for pharmaco- and/or cognitive behavioral-therapy (CBT), stepped approach for treatment, telemedicine delivered CBT in dialysis units, and a collaborative care model that integrated symptom management with patients' dialysis and primary care teams. Our results showed clinically significant improvements in fatigue and pain, and small improvement in depression, after a 12-week intervention that were sustained for 6 months, as compared to an attention control arm. The goal of this proposal is to conduct a hybrid Type II effectiveness-implementation, cluster randomized trial of TĀCcare 2.0 facilitated by dialysis staff in a real-world setting. The TĀCcare 2.0 intervention will build on successful design elements of the original intervention, enhance depression management strategies and increase durability of effect by incorporating monthly longitudinal telemedicine-delivered booster sessions to complete a total 12-month intervention. This proposal leverages our team's experience, collaboration, unique institutional resources, and stakeholder advisory board (dialysis unit leadership, staff and patients) input, and will recruit 424 diverse patients from 36 dialysis units (diverse in academic affiliation, rural/urban location) in Pennsylvania, New Mexico, Tennessee, Alabama, Nebraska and New Jersey. We aim to 1) evaluate effectiveness of TĀCcare 2.0 in reducing fatigue, pain or depression (co-primary outcomes) after 12-week intervention compared to usual care in HD patients (Aim 1); and 2) examine implementation barriers and facilitators at patient, provider and organizational levels using Practical Implementation Sustainability Model (PRISM) based mixed-methods (Aim 2). If successful, this study will provide transformative evidence and a blueprint to dialysis clinics and policy makers for an integrated, scalable intervention and a set of implementation strategies and facilitation toolkit t...