A large-scale, pragmatic clinical trial comparing two phosphate management strategies for patients undergoing hemodialysis as a result of end-stage kidney disease (ESKD) has been launched by the Duke Clinical Research Institute and Duke Nephrology under the direction of Myles Wolf, MD, MMSc, chief of nephrology.

The National Institutes of Health provides the funding for the study, known as HiLo, which was featured in December 2020 in the American Journal of Kidney Diseases.

The primary goal of the HiLo trial is to determine whether maintaining serum phosphate levels at under 5.5 mg/dl—the current standard target—yields better or worse outcomes than a higher target of at least 6.5 mg/dl among patients with ESKD. The primary outcome of the trial is a hierarchical composite outcome of all-cause mortality and all-cause hospitalization rate.

Approximately 500,000 individuals in the U.S. have ESKD; the annual mortality rate ranges from 15% to 20% and patients average one to two hospitalizations per year. Although some patients can use a home-based dialysis treatment, most opt for three weekly visits to a dialysis center.

“Our standard, three-times-a-week dialysis is simply not adequate to remove a sufficient amount of phosphate that comes into the body from the diet,” Wolf says. “As a result, most patients receiving dialysis experience hyperphosphatemia and require treatment with dietary phosphate binders.” A common occurrence for many patients on dialysis in the U.S., hyperphosphatemia has been linked to cardiovascular disease, arterial calcification, and left ventricular hypertrophy.

Despite the intense attention paid to managing hyperphosphatemia in patients with ESKD, Wolf says physicians do not have clinical trial-based knowledge regarding the optimal serum phosphate target. The HiLo clinical trial is designed to help answer that question.

Launched in February 2020 with eight sites in North Carolina, the trial includes partnerships with DaVita, an international dialysis provider serving approximately 100,000 patients across the U.S., and the University of Utah, which manages approximately 20 dialysis facilities across Utah. Eventually, Wolf expects to enroll 4,400 patients. Much of the data will come from the DaVita and Utah EHRs, which will simplify collection and reduce the burden on caregivers in dialysis clinics, Wolf says. The trial has been slowed by COVID-19, but participation began to increase in summer 2020.

Wolf says he hopes the project will help answer key questions about the effectiveness of serum phosphate management strategies. He highlights potential hidden risks in the use of phosphate binders to lower serum phosphate levels that may unnecessarily result in poor outcomes:

• Increasing risk to patients by inducing calcium, lanthanum or iron overload as a result of excessive use of phosphate binders.
• Causing gastrointestinal side effects that exacerbate malnutrition in a population that is vulnerable to nutritional deficits.
• Impacting patients’ quality of life by adding high daily pill burdens and costs for phosphate binders.

“We may or may not be managing hyperphosphatemia correctly,” he says. “We have no randomized trials to inform the best way to treat this condition. We know from clinical trials that phosphate binders can lower serum phosphate levels—knowledge that allows us to ‘treat the numbers.’

“But we do not have trial data that tell us whether treating the numbers improves outcomes. Nor do we have data about what matters most to patients, such as hospitalizations, death, and quality of life,” Wolf says.

Created with a pragmatic design to lowers barriers to entry, the trial has incorporated a patient advisory group—known as “HiLo ambassadors”—and solicited advice and support about trial design from key stakeholders, including dietitians and dialysis center coordinators, who play important roles.