4 in the placebo group, with safety proﬁle and tolerability on a strictly comparable level. The mean dose of lanthanum carbonate after eight weeks was 2,645 ± 97 mg/day. The RIND study provided some more indirect insights into the clinical potential of phosphate binder treatment in predialysis stages [25]. This investigation was designed as a prospective trial observing the progression of coronary artery calciﬁcations in incident hemodialysis patients treated with either sevelamer-HCl or calcium acetate. One central obser- vation was that even though none of the patients who were free of calciﬁcations became positive during the ﬁrst 18 months of dialysis treatment, “progressors” (about 60% of the total cohort) were all calciﬁed prior to initiation of dial- ysis treatment. Thus, prevention strategies targeting car- diovascular calciﬁcation, such as phosphate-lowering app- roaches, must be initiated early in the course of CKD. Currently, there is only one prospective clinical study addressing the biological eﬀect of phosphate binders in CKD patients [29]. Russo and colleagues studied 90 phos- phate binder-naive patients in predialysis CKD stages 3–5 with regard to progression of coronary artery calciﬁcation. Patients were randomized (30 per group) to either a low P diet alone, or to a low P diet in combination with ﬁxed doses of calcium carbonate (2 g/day) or sevelamer (1.6 g/day). Final MSCT-based coronary artery calciﬁcation scores were greater than initial scores in those subjects receiving diet and diet in combination with calcium carbonate, while no progression was observed in the diet plus sevelamer-treated group. Absolute urinary phosphate excretion was higher in the diet- treated patients but lower when compared to baseline in those receiving phosphate binders. FGF23 serum levels were unfortunately not available from this study. 6. Novel Concepts for Phosphate Management in Predialysis CKD Stages One of the key issues in phosphate management in predial- ysis stages of CKD is the fact that serum phosphate levels do not appropriately reﬂect phosphate retention. Because phosphate retention is immediately counterregulated by phosphatonins such as FGF23, PTH, and probably other factors, composite measurements of these parameters may need to ﬁnd their way into diagnostic algorithms, as well as estimates of phosphate excretion in the urine. Nagano et al. recently demonstrated in a uremic rat model that phosphate binding by sevelamer dose-dependently lowered both FGF23 and PTH serum concentrations [30]. In this line, two clinical pilot studies were launched investigating the eﬀect of phosphate binder treatment on these surrogate parameters of phosphate retention. Isakova et al. studied 16 normophosphatemic CKD stage 3 and 4 patients to either lanthanum carbonate or placebo, and to either a 750 mg or 1,500 mg phosphate diet, in a 2 × 2 factorial design [31]. FGF23, PTH, serum levels of calcium and phosphate, and phosphate excretion were measured. While the high phosphate diet and lanthanum treatment lead to decreases in phosphate excretion, no eﬀects were observed with regard to FGF23 and PTH levels, respectively. However, the high phosphate diet caused a signiﬁcant increase in FGF23 levels. International Journal of Nephrology Block and colleagues started a similar, but larger pilot study in >200 normophosphatemic CKD patients (eGFR 20–45 ml/min) using three diﬀerent phosphate binders (lan- thanum carbonate, sevelamer carbonate, calcium acetate) with matching placebos [32]. Follow-up will be nine months, and parameters of interest are serum concentrations of FGF23, PTH, calcium, and phosphate, as well as changes in arterial stiﬀness (pulse wave velocity) and coronary artery celaciﬁcation scores (multislice spiral CT). Data are expected to be available in autumn 2011. The biologically plausible hypothesis that “invisible” phosphate retention may be the earliest and foremost event in the development of secondary hyperparathyroidism was already picked up in concept papers [33]. Here, a “phos- phocentric” (in contrast a “vitamin D-centric”) view was proposed with the consequence that the initial treatment approach must be targeted towards limiting phosphate ingestion and absorption in predialysis patients. This view was recently supported by Evenepoel et al. who demonstrated that urinary phosphate excretion in predialysis CKD patients was indeed highest in individuals with both elevated FGF23 and PTH, respectively, and that increased FGF23 and phos- phate, and decreased 25-OH-vitamin D were independently associated with decreased calcitriol levels [34]. What needs to be determined and better understood though is, whether, or to which degree, secondary hyperparathyroidism (and FGF23 elevations) is a favourable, adaptive or a disadvan- tageous, maladaptive mechanism, prior to basing treatment decisions on this novel concept. Furthermore, age, klotho expression, and potentially klotho resistance (in uremia) may impact on shifting phosphate regulation to dysregulation [3, 9, 10, 12]. 7. Conclusion Much needs to be learned about the assessment and the impact of deranged phosphate homeostasis in predialysis CKD stages. Limited data suggest that phosphate retention may cause harm in these stages even if serum levels do not rise beyond the normal range. Composite measures of serum phosphate, fractional phosphate excretion, and FGF23 may become an integral and improved approach in therapeutic decision making, in contrast to just waiting for hyperphos- phatemia to occur. However, there is a huge gap with regard to prospective clinical trials assessing the eﬀect of phosphate- lowering strategies on clinically meaningful hard endpoints. In addition, since a positive phosphate balance may already tip the balance towards cardiovascular calciﬁcation and damage, we require information on the impact of treatment on cardiovascular surrogate parameters as well. Fortunately, there are initiatives underway attempting to at least partially ﬁll those gaps of knowledge. References [1] T. Isakova, O. Gutierrez, A. Shah et al., “Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD,” Journal of the American Society of Nephrology, vol. 19, no. 3, pp. 615–623, 2008.