Abstract
Background. Retrospective, observational studies link high phosphate with mortality in dialysis patients. This generates research hypotheses but does not establish “cause-and-effect.” A large randomised controlled trial (RCT) of about 3000 patients randomised 50 : 50 to lower or higher phosphate ranges is required to answer the key question: does reducing phosphate levels improve clinical outcomes? Whether such a trial is technically possible is unknown; therefore, a study is necessary to inform the design and conduct of a future, definitive trial. Methodology. Dual centre prospective parallel group study: 100 dialysis patients randomized to lower (phosphate target 0.8 to 1.4 mmol/L) or higher range group (1.8 to 2.4 mmol/L). Non-calcium-containing phosphate binders and questionnaires will be used to achieve target phosphate. Primary endpoint: percentage successfully titrated to required range and percentage maintained in these groups over the maintenance period. Secondary endpoints: consent rate, drop-out rates, and cardiovascular events. Discussion. This study will inform design of a large definitive trial of the effect of phosphate on mortality and cardiovascular events in dialysis patients. If phosphate lowering improves outcomes, we would be reassured of the validity of this clinical practice. If, on the other hand, there is no improvement, a reassessment of resource allocation to therapies proven to improve outcomes will result. Trial Registration Number. This trial is registered with ISRCTN registration number ISRCTN24741445.
Highlights
Retrospective, observational studies link high phosphate with mortality in dialysis patients
Serum phosphate increases in chronic kidney disease and by the time the patients are on dialysis, high serum phosphate is found in more than 40% of dialysis patients and is linked with a 40– 100% increased mortality risk in retrospective, observational studies [5, 6]
Opinion-based serum phosphate of less than 1.7 mmol/L is the target for treatment in dialysis patients [7]. 27 observational studies were included in a meta-analysis which examined the relationship between dysregulated mineral metabolism and all-cause or cardiovascular mortality or cardiovascular events in patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD, which is when they need to start dialysis treatment) [8]
Summary
Dialysis requires more “self-management” than any other medical treatment to control risk factors associated with increased mortality. 27 observational studies were included in a meta-analysis which examined the relationship between dysregulated mineral metabolism and all-cause or cardiovascular mortality or cardiovascular events in patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD, which is when they need to start dialysis treatment) [8]. Jamal et al published a meta-analysis of 11 such studies, 9 of them in dialysis patients, and compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders and those taking noncalcium-based binders. They concluded that non-calciumbased phosphate binders were associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease [10]. A review of all available evidence by the international “Kidney Disease Improving Global Outcomes (KDIGO)” expert group [7] concluded, “the extensive review. . . exposed significant gaps in our knowledge. . . robust studies of a large sample size addressing the following issues should be given priority: Does lowering phosphate. . . improve clinical outcomes including mortality?” Our trial will examine the feasibility of conducting such a study of large sample size, which we hope will answer the questions posed by KDIGO
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