Outline of ReviewHyperphosphatemia is an inevitable consequence of CKD Stage IV and V, particularly once dialysis has been initiated; large observational cohort studies suggest that significant hyperphosphatemia (>2 mmol/L) carries an increased risk of death. There are plausible biological explanations for the adverse health outcomes, with accelerated vascular calcification conceptually linked to ongoing positive calcium and phosphate balance. The pathophysiology of hyperphosphatemia in chronic kidney disease is briefly described with reference to several reviews on this topic.
This review provides a synopsis of currently available phosphate binders, based on calcium, magnesium, sevelamer, and lanthanum as the cationic binding agent, together with the clinical trials evidence (where available) to support their use. In keeping with international guidelines, and those of the Canadian Society of Nephrology, aluminum-based binders are not considered safe for long-term use due to the associated brain (dementia), bone marrow (anemia), and bone (osteomalacia) toxicity. Several agents under development are mentioned.
The KDIGO guidelines provided an exhaustive systematic review of non-calcium based phosphate binders. Tonelli and colleagues simplify and tabulate the essential evidence base and reiterate the methodological short-comings of the clinical trials published to date. Too many trials have focused on surrogates of morbidity and mortality, limiting endpoints to biochemical markers – serum phosphate, PTH and calcium. Clinical trials with endpoints that included vascular calcification, cardiac / all-cause morbidity or death were available only for sevelamer, for which the outcomes have been inconsistent, limited by inadequate power, and confounded by high drop-out rates. Furthermore, they note that bone histology-based safety data are also extremely limited.
The authors state that they: “consider calcium-based agents to be the first-line phosphate binders for patients undergoing dialysis, since these agents remain the least expensive and best tolerated option”. For patients in whom phosphate levels cannot be controlled with calcium-based agents alone (especially patients with hypercalcemia), short courses of magnesium-based binders are an inexpensive alternative. They do not discuss the very limited evidence supporting either the efficacy or long-term safety of these calcium-based binders, in particular the concerns that increased calcium absorption during their use might contribute to accelerating the severity of vascular calcification. However, the incremental annual cost of sevelamer or lanthanum over calcium-based phosphate binders is at least 10-20 times higher. One cost-effectiveness analysis from the DCOR trial estimated a cost per quality-adjusted life year gained of about $150,000 CD for sevelamer; in the absence of consistent patient-centered outcome data, it is hard to justify recommending sevelamer or lanthanum as a treatment of first choice.
The authors’ conclusions mirror those set out by the KDIGO working group, and those put forward by CSN. The available clinical data are well summarized, and the failings of the clinical trials to date are expertly outlined. There is a focus on dietary counseling (including the mention of food additives), but little mention of prolonged dialysis times (nocturnal) which is associated with excellent phosphate control.
The reviewers do not discuss the complex interplay that exists in chronic kidney disease patients between vitamin D status, vitamin D sterol usage and phosphate absorption; factors which clearly impact on clinic practice and on the choice of phosphate binder. Neither do they make mention of the use of calcimimetics in patients whose hyperphosphatemia is partially driven by PTH mediated bone resorption, although the latter is also a very costly alternative.
Impact on Practice
This review will reinforce the use of calcium-based phosphate binders as the treatment of choice for controlling hyperphosphatemia, without addressing the issue of limited safety data for these agents.