Use of phosphate binders in chronic kidney disease

Abstract

Hyperphosphatemia is a paradigmatic finding in late-stage chronic kidney disease (CKD) and consistently associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causative role of hyperphosphatemia for cardiovascular complications, especially with regard to vascular, valvular and soft-tissue calcifications, and for subsequent mortality. Therefore, phosphate management is thought to play a pivotal role in health and longevity of CKD patients. In this regard, phosphate binders are considered the prime option; however, dietary phosphate restriction and intensified dialysis are also valuable supportive tools. Studies on available calcium-free phosphate binders demonstrate potential to interfere with phosphate regulatory factors, such as fibroblast growth factor-23 (FGF23). Magnesium-containing phosphate binding may possess a pleiotropic potential due to its calcification inhibitory properties. Novel phosphate lowering compounds, including colestilan, iron-containing binders and nicotinamide, are underway to extend the armamentarium of phosphate-lowering strategies. An open question remains when to therapeutically counteract phosphate retention by binders. A recent prospective randomized trial in patients with moderate CKD (stages 3b-4) and phosphate levels in the upper normal range demonstrated only moderate reductions in serum phosphate levels, no effects on FGF23, but increased vascular calcification progression with active treatment versus placebo. Another small trial in patients with similar renal function given diets containing approximately 1 g of calcium and 1.4 g of phosphate per day showed neutral calcium and phosphate balances, whereas addition of calcium carbonate as a phosphate binder only caused a positive calcium, but no negative phosphate balance. Adequate phosphate management in end-stage CKD remains a mainstay of our therapeutic approaches in this population, and additional promising drugs are in development and may shortly be available. The timing and indication for phosphate-lowering strategies in predialysis CKD is currently unclear.