International Journal of Nephrology 3 Table 1: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) [14]: recommendations for the management of phosphate in predialysis patients. (4.1.1) In patients with CKD stages 3–5, we suggest maintaining serum phosphorus in the normal range (2C). In patients with CKD stages 3–5 (2D) and 5D (2B), we suggest using phosphate binding agents in the treatment of (4.1.4) hyperphosphatemia. It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD-MBD, concomitant therapies, and side eﬀect proﬁle (not graded). (4.1.5) In patients with CKD stage 3–5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binder and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia (1B). In patients with CKD stage 3–5D and hyperphosphatemia, we suggest restricting the dose of calcium-based phosphate binders in the presence of arterial calciﬁcation (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C). (4.1.6) In patients with CKD stage 3–5D we recommend avoiding long term use of aluminum containing phosphate binders and in patients with CKD stage 5D avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C). (4.1.7) iInn cpoamtiebnintsawtioitnhwCiKthDostthaegrestr3e–at5mDe,nwtes s(u2Dgg)e.st limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or mostly contained in food as organic esters or as phytates (hexa-phospho-inosites), and this bound phosphate is only absorbed at a rate between 40–60% at maximum [20–22]. In contrast, phosphate-containing food additives include polyphosphates, diphosphates, triphosphates, potassium phosphate, calcium phosphate and so on, while this “free” phosphate is quite readily absorbed [19]. Recently, it became evident from longitudinal observations of the “Chronic Renal Insuﬃciency Cohort” (CRIC) cohort that patients with mild to moderate renal insuﬃciency had a 2.5–2.7-fold increased risk of hyperphosphatemia (> 4,6 mg/dL) when the tlowest income tertile was compared to the highest income tertile, despite equal amounts of phosphate intake (1,156 versus 1,190 mg/Tag) [23]. This diﬀerence could only be explained by diﬀerences in “phosphate quality,” with a higher intake of the so-called “fast food” (which is particularly rich in phosphate additives) in the lower income group. 5. Treatment of Phosphate Retention in Predialysis CKD: Phosphate Binders Phosphate binders are pragmatically used in predialysis patients when hyperphosphatemia becomes apparent how- ever, thresholds for treatment initiation vary a lot and are mostly based on preferences at the discretion of the indi- vidual physician. The KDIGO guidelines 2009 (Table 1) suggest to maintain phosphate serum levels within the normal range in CKD patients in stages 3–5 [24], but mild hyperphosphatemia can still be considered an under- recognized and underestimated phenomenon in predialysis patients. Calcium-containing binders may globally play a predominant role as the ﬁrst-line choice of phosphate binder therapy in these predialysis stages, because they are relatively inexpensive and because these patients tend to have calcium serum levels in the lower or even below the normal range. Since many CKD patients suﬀer from a low mineral den- sity, there is also the question, whether a negative calcium balance must be avoided anyway, but there is no answer on the harmless or even beneﬁcial calcium intake quantities that can be permitted. However, we also know quite well that increased calcium exposure, or a positive net calcium bal- ance, may predispose CKD patients for the risk of developing cardiovascular calciﬁcation [25, 26]. Of note, with the exception of calcium carbonate in many European countries, phosphate binder treatment had gener- ally been an oﬀ-label use in these CKD stages tolerated by most authorities until recently. In 2009, however, sevelamer carbonate was approved by the EMA in the indication of treating CKD patients not on dialysis with phosphate serum levels of above 1.78 mmol/L in Europe. The same label was also approved for lanthanum carbonate a few months later. There are only few publications available on phosphate binder use in predialysis patients. Such studies are furthers hampered by the fact that phosphate-lowering eﬀects are not clearly visible, because a decline in phosphaturia may blunt the changes in circulating phosphate levels. The eﬃcacy of sevelamer carbonate in predialysis CKD patients was recently examined in 19 nephrology centers across Northern Europe and Australia in a single-arm study approach with a poststudy washout period [27]. Investigators initially screened 129 patients, 41 of whom completed the study. Recruitment was heavily inﬂuenced by screening failure, because the cutoﬀ of phosphate serum levels was set very high (5.5 mg/dL), according to authority requirements in the study protocol, which also caused a high inclusion percentage of patients in CKD stage 5. Sevelamer carbonate lowered serum phosphorus levels by a mean of 1.4 ± SD 1.0 mg/dL (P < .001) during an eight-week observation period. 70% of those patients with stage 4 CKD achieved normal serum levels of 2.7–4.6 mg/dL. Serum bicarbonate concentrations rose signiﬁcantly from 16.6 ± 3.6 mEq/L to 18.2 ± 3.7 mEq/L (P = .005) which may be clinically meaningful given the high prevalence of metabolic acidosis in CKD stage 4-5 patients. The mean prescribed dosage after dosage titration was 7.8 g/day sevelamer carbonate at the end of the study. Lanthanum carbonate was also studied recently in a Phase II trial in CKD stage 3 and 4 patients [28]. 121 hyper- phosphatemic patients were randomized in a 2 : 1 manner to lanthanum or placebo, respectively. 44.6% of lanthanum- treated patients reached normophosphatemia versus 26.5%