Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients on Maintenance Hemodialysis

Abstract Rationale & Objective Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend lowering serum phosphate towards the normal range in patients on maintenance dialysis using phosphate binders and dietary phosphate restriction, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. Study Design Multicenter, pragmatic, cluster-randomized clinical trial. Setting & Participants HiLo will randomize 80-120 dialysis facilities operated by DaVita and the University of Utah to enroll 4400 patients undergoing three times weekly, in-center hemodialysis. Intervention(s) Phosphate binder prescriptions and dietary recommendations to achieve, either ‘Hi’ serum phosphate target (≥6.5 mg/dl) or ‘Lo’ serum phosphate target ( Outcomes Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization; Main secondary outcomes: Individual components of the primary outcome. Results The trial is currently enrolling. Limitations HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. Conclusions HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design; liberal eligibility criteria; use of electronic informed consent (“eConsent”); engagement of dietitians to implement the interventions in real-world practice; leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms; and use of a novel hierarchical composite outcome.