T he optimal management of disordered mineral metabolism in patients with chronic kidney disease has been among the most controversial topics in clinical nephrology during the past decade. The origins of the current controversies can be traced back to the initial reports from large-scale human studies of important associations between individual mineral metabolites-calcium, phosphorus, parathyroid hormone (PTH)-and adverse clinical outcomes (1,2). The volume of the mineral metabolism discourse

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... scalated with the publication of complex pharmacoepidemiologic studies that suggested that therapy with active forms of vitamin D might improve survival (3,4). In the next wave of individual analyte studies that followed, deficiencies in the vitamin D axis were found to be associated with increased risk of cardiovascular disease and death (5,6). The introduction of cinacalcet into clinical practice doubled the number of available PTH-lowering therapies but, predictably, launched a new layer of jostling to identify the ideal therapeutic cocktail for dialysis patients. Unfortunately, it is doubtful that clear answers will ever emerge if we continue to assume that "better control" of individual mineral metabolism analytes, as judged by national and international practice guidelines, will translate into improved patient survival rather than directly comparing survival rates of different strategies in head-to-head studies. How to best treat dialysis patients' elevated serum phosphate levels is a related quagmire. Again, limited definitive data have promoted a dependence on nonvalidated surrogate markers and expert opinion (educated guessing), which has sparked seemingly never-ending controversy, including calcium versus noncalcium-based binders, metal versus polymer, efficacy versus safety, and so on. These issues have deflected attention from the most fundamental questions for which we also have no answers: Will reducing an elevated serum phosphate level improve survival and, if so, what is the optimal level to target? The imminent bundling of dialysis-related medications into a single dialysis reimbursement will surely add a new dimension of controversy. The only absolute certainty in this area is that the number of patients with renal failure and markedly abnor-mal mineral metabolism who die soon after initiating dialysis will continue to grow. Only randomized trials can defuse these controversies, but we might have already missed several windows of opportunity in mineral metabolism. Although the logistical difficulties of performing large-scale trials are well known, perhaps the greatest impediment in this particular area has been the insidious effect of the nephrology community's propensity to package excellent hypothesis-generating animal and observational human data into plausible "stories" that are then prematurely integrated into clinical practice. For phosphorus and PTH control, the compelling yet unproven "stories" that have been ingrained in the nephrology vernacular and integrated into the standard of care limit our ability to go back and perform the placebo-controlled studies we desperately need but that many would now consider unethical. The argument that we must use the best available data today to treat our current patients is understandable, but it is that argument that engendered the current dilemma in mineral metabolism: we have gone too far (thereby preventing trials) but not far enough (we still do not have clear answers) in our research. The discovery of fibroblast growth factor 23 (FGF23) injected a breath of fresh air and renewed optimism into the mineral metabolism dialogue. Secreted primarily by osteocytes, FGF23 is a phosphaturic hormone that counter-regulates the stimulatory effect of PTH on 1,25-dihydroxyvitamin D, stimulates the catabolism of 1,25-dihydroxyvitamin D by activating the 24hydroxylase, and inhibits PTH secretion (7). The main stimuli of FGF23 secretion are dietary phosphorus intake and 1,25dihydroxyvitamin D, which unite in several newly discovered classical negative endocrine feedback loops. FGF23 levels increase progressively as kidney function declines, which is possibly an adaptation to maintain neutral phosphorus balance and the most likely cause of early 1,25-dihydroxyvitamin D deficiency in chronic kidney disease (8). The FGF23 burden in kidney disease is dramatic: dialysis patients can routinely manifest 100-to 1000-fold elevations in biologically active FGF23 levels compared with healthy individuals (9). As the latest addition to the family of measurable circulating analytes of mineral metabolism, several studies examined the relationship between FGF23 excess and adverse outcomes. Although the field is only in its infancy, FGF23 excess has been already associated with kidney disease progression, ventricular hypertrophy, vascular disease, and mortality (10 -13). The results are strikingly consistent, particularly when contrasted Published online ahead of print. Publication date available at www.cjasn.org.