Two phosphAte taRGets in End-stage renal disease Trial (TARGET): A Randomized Controlled Trial

Abstract

Background and objectives: Hyperphosphatemia is common among recipients of maintenance dialysis and is associated with a higher risk of mortality and cardiovascular events. A large randomized trial is needed to determine whether lowering phosphate concentrations with binders improves patient-important outcomes. To inform such an effort we conducted a pilot randomized controlled trial.

Design, setting, participants, & measurements: We conducted a randomized controlled trial of prevalent hemodialysis recipients already receiving calcium carbonate as a phosphate binder at five Canadian centers between March 31, 2014 and October 2, 2014. Participants were randomly allocated to 26 weeks of an intensive phosphate goal of 2.33-4.66 mg/dl (0.75-1.50 mmol/L) or a liberalized target of 6.20-7.75 mg/dl (2.00-2.50 mmol/L) by titrating calcium carbonate using a dosing nomogram. The primary outcome was the difference in the change in serum phosphate from randomization to 26 weeks.

Results: Fifty-three participants were randomized to the intensive group and 51 to the liberalized group. The median (interquartile range) daily dose of elemental calcium at 26 weeks was 1800 (1275-3000) mg in the intensive group, and 0 (0-500) mg in the liberalized group. The mean (SD) serum phosphate at 26 weeks was 4.53 (1.12) mg/dl (1.46 [0.36] mmol/L) in the intensive group and 6.05 (1.40) mg/dl (1.95 [0.45] mmol/L) in the liberalized group. Phosphate concentration in the intensive group declined by 1.24 (95% confidence interval, 0.75 to 1.74) mg/dl (0.40 [95% confidence interval, 0.24 to 0.56] mmol/L) compared with the liberalized group. There were no statistically significant differences between the two groups in the risk of hypercalcemia, hypocalcemia, parathyroidectomy, or major vascular events.

Conclusions: It is feasible to achieve and maintain a difference in serum phosphate concentrations in hemodialysis recipients by titrating calcium carbonate. A large trial is needed to determine if targeting a lower serum phosphate concentration improves patient-important outcomes.

Keywords: Calcium Carbonate; Calcium, Dietary; Canada; Goals; Hemodialysis; Humans; Hypercalcemia; Hypocalcemia; Kidney Failure, Chronic; Nomograms; Parathyroidectomy; Phosphates; Pilots; Prevalence; Random Allocation; hyperphosphatemia; phosphate binders; randomized controlled trials; renal dialysis; renal insufficiency, chronic.

Figure 1.

Participant flow in the TARGET trial.

Figure 2.

Sustained separation in the dose of elemental calcium administered as calcium carbonate in patients randomized to a liberalized phosphate target (>2.00 mmol/L) or an intensive serum phosphate target (0.75–1.00 mmol/L). Dots represent medians and whiskers represent 2.5th and 97.5th percentile. The numbers under the x-axis represent the number of participants under active follow-up and with evaluable data at each time point.

Figure 3.

Sustained separation in serum phosphate concentration in patients randomized to a liberalized serum phosphate target (>2.00 mmol/L) or an intensive serum phosphate target (0.75–1.00 mmol/L). Dots represent medians and whiskers represent 2.5th and 97.5th percentile. 1 mmol/L phosphate = 3.10 mg/dl. The numbers under the x-axis represent the number of participants under active follow-up and with evaluable data at each time point.

Figure 4.

Modest decline in albumin-adjusted serum calcium concentration in patients randomized to a liberalized serum phosphate target (>2.00 mmol/L) or an intensive serum phosphate target (0.75–1.00 mmol/L). Dots represent medians and whiskers represent 2.5th and 97.5th percentile. 1 mmol/L calcium = 4.01 mg/dL. The numbers under the x-axis represent the number of participants under active follow-up and with evaluable data at each time point.

Figure 5.

Lack of difference in intact parathyroid hormone concentration in patients randomized to a liberalized serum phosphate target (>2.00 mmol/L) or an intensive serum phosphate target (0.75–1.00 mmol/L). Dots represent medians and whiskers represent 2.5th and 97.5th percentile. The numbers under the x-axis represent the number of participants under active follow-up and with evaluable data at each time point. ULN, upper limit of normal.