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The role of phosphate in kidney disease

Key Points

  • High phosphate concentrations are associated with an increased incidence of cardiovascular complications and mortality in the general population and in patients with chronic kidney disease (CKD)

  • Serum phosphate concentrations are influenced by circadian rhythm and diet

  • The predictive value of a single serum phosphate measurement for cardiovascular risk is greatest for fasting morning concentrations

  • Fibroblast growth factor 23 is a key hormone involved in phosphate homeostasis and an independent predictor of cardiovascular events with a potential causal role in the development of these events

  • Frequently neglected sources of phosphate are bone in patients with CKD and food additives in all populations

  • Definitive proof of a clinical benefit of dietary or pharmacological interventions that lower phosphate exposure is lacking, mainly owing to a paucity of well-designed clinical trials

Abstract

The importance of phosphate homeostasis in chronic kidney disease (CKD) has been recognized for decades, but novel insights — which are frequently relevant to everyday clinical practice — continue to emerge. Epidemiological data consistently indicate an association between hyperphosphataemia and poor clinical outcomes. Moreover, compelling evidence suggests direct toxicity of increased phosphate concentrations. Importantly, serum phosphate concentration has a circadian rhythm that must be considered when interpreting patient phosphate levels. Detailed understanding of dietary sources of phosphate, including food additives, can enable phosphate restriction without risking protein malnutrition. Dietary counselling provides an often underestimated opportunity to target the increasing exposure to dietary phosphate of both the general population and patients with CKD. In patients with secondary hyperparathyroidism, bone can be an important source of serum phosphate, and adequate appreciation of this fact should impact treatment. Dietary and pharmotherapeutic interventions are efficacious strategies to lower phosphate intake and serum concentration. However, strong evidence that targeting serum phosphate improves patient outcomes is currently lacking. Future studies are, therefore, required to investigate the effects of modern dietary and pharmacological interventions on clinically meaningful end points.

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Figure 1: Disruption of phosphate homeostasis in chronic kidney disease (CKD).
Figure 2: Circadian variation of serum phosphate levels in healthy individuals on a normal diet.
Figure 3: Serum phosphate level is associated with all-cause and cardiovascular mortality in the general population.
Figure 4: Model of changes in the serum levels of fibroblast growth factor 23 (FGF-23), 1,25 dihydroxyvitamin D (1,25D), parathyroid hormone (PTH) and phosphate during progression of chronic kidney disease.
Figure 5: Potential roles of phosphate and fibroblast growth factor 23 (FGF-23) in the development of cardiovascular disease in patients with chronic kidney disease (CKD).
Figure 6: The bioavailability of phosphate differs according to the protein source.
Figure 7: The efficacy of phosphate-binder therapy in patients with chronic kidney disease, including those on dialysis.

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Acknowledgements

Board members of the ERA–EDTA Working Group on Chronic Kidney Disease–Mineral and Bone Disorders: David Goldsmith, Pieter Evenepoel, Vincent Brandenburg, Jordi Bover, Sandro Mazzaferro, Pablo Ureña-Torres, and Adrian Covic. Board members of the European Renal Nutrition Working Group: Juan Jesus Carrero, Vincenzo Bellizzi, Philippe Chauveau, Pablo Molina, Daniel Teta, Christoph Wanner, and Piet Ter Wee.

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All authors researched the data for the article, wrote the manuscript, contributed to discussions of the content and reviewed or edited the manuscript before submission.

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Correspondence to Marc G. Vervloet or Denis Fouque.

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Glossary

Hyperphosphataemia

A serum phosphate concentration higher than the upper limit of the normal range, that is > 4.5 mg/dl (> 1.5 mmol/l).

Paracellular route

Transport of ions or other substances between two adjacent cells that are part of a cell layer.

Transcellular route

Transport of ions or other substances through a cell by passing through both the apical and basolateral membrane.

Phosphaturia

Renal excretion of phosphate in the urine.

Circadian rhythm

A day–night pattern of variation in a biological process.

Hyperdynamic bone disease

Bone disease resulting from an abnormally high rate of bone formation by osteoblasts and increased bone degradation by osteoclasts.

Calcimimetics

A class of agents that increase the sensitivity of the calcium-sensing receptor for extracellular calcium. Calcimimetics are used to treat hyperparathyroidism.

Protein–energy wasting

Depletion of body stores owing to insufficient nutrient intake, chronic inflammation and acute or chronic catabolism that can eventually lead to cachexia and death. An insufficient dialysis dose can contribute to protein–energy wasting in patients receiving maintenance dialysis.

CKD–mineral and bone disorder

A syndrome characterized by the co-occurrence of derangements in the levels of calcium, phosphate and the hormones that regulate these minerals, with fractures, vascular calcifications and cardiovascular disease in patients with CKD.

Osteogenic transdifferentiation

The phenotype switch of vascular smooth muscle cells to osteoblast-like bone-forming cells.

Left ventricular hypertrophy

A usually pathological growth of cardiomyocytes that occurs following chronic exposure of the heart to mechanical or non-mechanical stress and leads to heart failure.

Adynamic bone disease

Bone disease resulting from an abnormally low rate of bone formation by osteoblasts and decreased bone degradation by osteoclasts.

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Vervloet, M., Sezer, S., Massy, Z. et al. The role of phosphate in kidney disease. Nat Rev Nephrol 13, 27–38 (2017). https://doi.org/10.1038/nrneph.2016.164

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