*3.1. Phosphate Binder*

Hyperphosphatemia is a major clinical challenge in CKD–MBD. Phosphate binders (PB) are classified into calcium-based PB (CBB; e.g., calcium acetate, calcium carbonate) and non-calcium-based PB (e.g., sevelamer, lanthanum). The administration of PB reduces serum phosphate levels, thereby improving hyperphosphatemia in CKD patients. In two independent experimental CKD models, treatment with sevelamer attenuated vascular calcification (Table 1) [31,32]. The PB calcium acetate/magnesium carbonate (CaMg) reduced CV calcification without a ffecting bone mineral density in adenine-induced CKD rats (Table 1) [33].

In CKD patients, a meta-analysis of eight di fferent PB (sevelamer, lanthanum, iron, calcium, colestilan, bixalomer, nicotinic acid, magnesium) showed that the PB reduced serum phosphate levels compared to placebo controls, but had no e ffect on all-cause mortality and CV events [34]. Another systematic review and meta-analysis revealed decreased all-cause mortality by non-calcium-based PB, compared to CBB in CKD patients [35]. A Cochrane systematic review and meta-analysis of randomized clinical trials (RCT) showed that sevelamer compared to CBB decreased all-cause mortality in ESRD patients [36], while sevelamer had no effect on CV mortality [37].


**Table 1.** Therapeutic strategies that attenuate CV calcification in non-transgenic animal CKD models.

CaMg: acetate/magnesium carbonate; Ref: Reference.

Based on these findings, the Kidney Disease: Improving Global Outcomes (KDIGO) 2017 guideline recommends PB treatment for progressively elevated phosphate and a restriction of CBB treatment [11], with a limited dietary phosphate intake [11]. Given a lack of evidence that PB reduce all-cause mortality, longer placebo-controlled trials are required. It also remains uncertain to which extent pre-dialysis patients would benefit from PB treatment, since adverse effects like nausea, constipation, diarrhea, and abdominal pain are reported [34].
