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A response by G. A. Block, D. Spiegel and P. Raggie to a letter to the editor about their article "Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients" in the previous issue.

As our understanding of phosphate homeostasis has expanded over the last 20 years, additional quandaries have surfaced. Though the phosphate bucket list remains full, we are confident that the next 20 years will lead to major fundamental discoveries. In this commentary, we provide an example of how findings from a basic study that examined the mechanisms for circadian rhythms of plasma and urinary phosphate sheds light on important pathways that can be harnessed for novel therapeutic approaches in the future., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stages 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To evaluate this, we used Cox proportional hazards models to assess associations of baseline 24-h urine phosphate excretion with risk of end-stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease [CVD] and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24-h urinary phosphate excretion with risk of ESRD, CVD, non-CVD, or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dl higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stages 3-5, and there was no evidence that greater phosphate intake, assessed by 24-h phosphate excretion, is associated with ESRD, CVD, non-CVD, or all-cause mortality in CKD stages 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation., (Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Conventional risk factors of cardiovascular disease and mortality in the general population such as body mass, serum cholesterol, and blood pressure are also found to relate to outcome in maintenance dialysis patients, but often in an opposite direction. Obesity, hypercholesterolemia, and hypertension appear to be protective features that are associated with a greater survival among dialysis patients. A similar protective role has been described for high serum creatinine and possibly homocysteine levels in end-stage renal disease (ESRD) patients. These findings are in contrast to the well-known association between over-nutrition and poor outcome in the general population. The association between under-nutrition and adverse cardiovascular outcome in dialysis patients, which stands in contrast to that seen in non-ESRD individuals, has been referred to as "reverse epidemiology." Publication bias may have handicapped or delayed additional reports with such paradoxical findings in ESRD patients. The etiology of this inverse association between conventional risk factors and clinical outcome in dialysis patients is not clear. Several possible causes are hypothesized. First, survival bias may play a role since only a small number of patients with chronic kidney disease (CKD) survive long enough to reach ESRD. Hence, the dialysis patients are probably a distinctively selected population out of CKD patients and may not represent the risk factor constellations of their CKD predecessors. Second, the time discrepancy between competitive risk factors may play a role. For example, the survival disadvantages of under-nutrition, which is frequently present in dialysis patients, may have a major impact on mortality in a shorter period of time, and this overwhelms the long-term negative effects of over-nutrition on survival. Third, the presence of the "malnutrition-inflammation complex syndrome" (MICS) in dialysis patients may also explain the existence of reverse epidemiology in dialysis patients. Both protein-energy malnutrition and inflammation or the combination of the two are much more common in dialysis patients than in the general population and many elements of MICS, such as low weight-for-height, hypocholesterolemia, or hypocreatininemia, are known risk factors of poor outcome in dialysis patients. The existence of reverse epidemiology may have a bearing on the management of dialysis patients. It is possible that new standards or goals for such traditional risk factors as body mass, serum cholesterol, and blood pressure should be considered for these individuals.