2 signiﬁcantly associated with mortality. Further, mortality risk progressively increased with each 0.5-mg/dL increase in phosphate serum levels. In a prospective, community-based, noninterventional, prospective cohort study (SEEK study, n = 1814 CKD patients), Levin and colleagues were able to demonstrate similar ﬁndings with regard to the incidence of “visible” hyperphosphatemia—phosphate serum levels rose perceptibly in subjects in CKD stage 4 [7]. Therefore, both studies support the assumption that hyperphosphatemia may just be the ﬁnal indicator (tip of an iceberg) of an already previously failing phosphate balance. 3. Phosphate Homeostasis in CKD Up to 80% of the estimated daily phosphate intake of 20 mg/kg b.w. per day is intestinally absorbed in healthy individuals and circulates into an “extracellular phosphate pool” [3]. 3 mg/kg b.w. phosphate per day are exchanged between this virtual pool and the bone, if bone turnover is physiologically balanced. Two-thirds of the daily intake is excreted via healthy kidneys, the other third is excreted by the faeces resulting in a neutral phosphate balance. Kidney disease interferes with the ability to excrete phosphate loads; however, excretion remains surprisingly stable until the late stages of CKD. The fact that there is a delayed onset of hyperphos- phatemic episodes in CKD is probably based on counterregu- latory actions of FGF23 and PTH [8–11]. Both hormones are causing phosphaturia when elevated and apparently become stimulated as early as in CKD stage 3, connected to vitamin D status and dietary phosphate intake. Both in animal models as well as in human studies, it was shown that increases in serum FGF23 levels were paralleled by rises in renal fractional (relative) phosphate excretion counteracting increases in phosphate retention and subsequent hyperphosphatemia [8– 11]. It is currently considered that a positive phosphate balance triggers an osteocyte “phosphate sensor” towards signalling release of FGF23. In this context, it is yet unknown, whether phosphate itself is the circulating messenger, or whether for example intestinal phosphatonins may serve as FGF23 inducers [3]. Furthermore, FGF23 and PTH secretion may be linked to each other. FGF23 actively sup- presses calcitriol synthesis, thus antagonizing a central PTH- suppressive mechanism [9, 10]. Therefore, the organism employs two diﬀerent hormonal systems in order to shelter the body from phosphate accumulation, that is, hyperphos- phatemia. There are also data that PTH and FGF23 secretion are directly interconnected, that is, that FGF23 inhibits PTH release via stimulating the dimeric klotho/FGF-receptor at the parathyroid gland [12]. PTH may vice versa inhibit FGF23 release from the osteocyte [12]. With this in mind, the question arises how acute dietary phosphate ingestion may inﬂuence phosphate, FGF23, and PTH regulation in CKD? Isakova et al. studied a group of CKD patients (GFR 20–45 ml/min) versus healthy individ- uals ingesting a meal with a phosphate content of 500 mg of phosphate [1]. Within 4 hours following ingestion, they found no increase in serum phosphate levels in both groups, but a rapid augmentation of fractional phosphate excretion International Journal of Nephrology in the healthy control group, while the baseline level of uri- nary excretion was already twice as high in the CKD cohort, with a nonsigniﬁcant trend towards a further increase. This phosphaturic response was not acutely accompanied by increases in FGF23 or PTH levels, while at baseline these two parameters were also already signiﬁcantly elevated in the CKD group versus the healthy controls. This study had a few limitations including the fact that the exact timing of interventions was not presented. Nevertheless, this response excludes FGF23 as the predominant “acute-phase” phospha- tonin regulating phosphate excretion, but FGF23 may work as a “memory hormone” and a long-term regulator of a positive phosphate balance. This behaviour may be more comparable to the marker protein of diabetes control, HbA1C, with the additional property that FGF23 not just represents, but also acts on phosphate control. Thus, these insights suggest the existence of additional acute regulatory factors of phosphate balance which remain to be identiﬁed in the future. 4. Treatment of Phosphate Retention in Predialysis CKD: Diets Therapeutic approaches aiming at phosphate lowering (i.e., serum levels as well as phosphate load) include reducing oral intake of phosphate by dietary modiﬁcations as well as intestinal absorption using phosphate binders. Phosphate- restricted diets should be designed in a manner that avoids simultaneous protein malnutrition. In this context, there are a couple of studies supporting that at least moderate phosphate restriction is well tolerated in most individuals. The use of phosphate-restricted diets in combination with oral phosphate binders has become well established in the management of patients with CKD Stages 3–5 CKD (including CKD Stage 5D). Recent epidemiological studies in larger cohorts of dialysis patients are uniequivocal regard- ing associations between dietary phosphate restriction and survival beneﬁts [13, 14]. Two prospective studies are available speciﬁcally evaluat- ing the impact of phosphate-restricted diets in CKD patients. Zeller et al. showed that the restriction of dietary protein plus phosphate intake was welltolerated and maintained nutri- tional parameters in a satisfying range in a study of 35 Type I diabetes patients with associated nephropathy [15]. Here, a signiﬁcant reduction in urinary phosphate excretion in the group assigned to a protein/phosphate restriction as com- pared to subjects receiving a control diet was found. There was no evaluation of other CKD-MBD-related parameters performed in this investigation. Lafage-Proust and colleagues reported in another study featuring a very strict low-protein, low-phosphorus diet (supplemented with essential amino acids and their ketoanalogs) that after a follow-up of ﬁve years bone formation rate was normal or high in 10 patients, and low in the remaining 6, without observing low-protein- associated malnutrition in any of the participants [16]. A new view on phosphate restriction currently develops based on considerations that there might be a signiﬁcant diﬀerence between naturally occuring phosphate and phos- phate supplements in food [17–19]. Natural phosphate is