A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease

The diagnosis of chronic kidney disease (CKD) confers dismal clinical outcomes regardless of whether patients are initiating dialysis and face a median survival of only 2-3 years or they have earlier-stage CKD and face a risk of death that is greater than the risk of progression to dialysis. These poor outcomes are driven by extraordinarily high rates of cardiovascular disease that historically have not responded to risk-factor modification strategies proven to attenuate risk in the general population. Nor have measures aimed at increasing the dose or quality of dialysis made an appreciable dent in mortality. Still worse, interventions that were expected to be beneficial resulted in increased mortality in recent trials. Although this apparent lack of progress in advancing the care of CKD is discouraging, resignation is not an option. On the contrary, with the rising rates of CKD worldwide, there is an urgent need to rigorously test novel therapeutic strategies in randomized trials. The breadth of accumulating evidence linking disordered phosphorus metabolism to adverse outcomes spans in vitro, animal, and human studies, and positions phosphorus management as an attractive target for intervention. Although opinion-based practice guidelines promote phosphorus management strategies that are widely accepted in dialysis patients, there is a clear need to perform randomized controlled trials to prove or disprove the benefits of therapy. Perhaps even more important, the discovery of fibroblast growth factor 23 (FGF23) and its potential as a novel diagnostic to identify disordered phosphorus metabolism at an early, subclinical state has presented the opportunity to develop placebo-controlled randomized trials in pre-dialysis CKD patients with normal serum phosphate levels. This commentary considers the justification and challenges for such trials and presents a 'first-draft' blueprint of distinct trial approaches to initiate a dialog that will ultimately culminate in studies aimed at improving survival across the spectrum of CKD.