The phosphate bucket list
2018; Elsevier BV; Volume: 93; Issue: 5 Linguagem: Inglês
10.1016/j.kint.2018.01.010
ISSN1523-1755
AutoresTamara Isakova, Geoffrey A. Block,
Tópico(s)Magnesium in Health and Disease
ResumoAs 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. 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. The nephrology community has come a long way since the initial reports that linked hyperphosphatemia to adverse outcomes in end-stage renal disease (ESRD).1Block G.A. Hulbert-Shearon T.E. Levin N.W. Port F.K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2109) Google Scholar Breakthroughs in the understanding of the pathogenesis of rare causes of hypophosphatemic rickets have uncovered a new hormone, fibroblast growth factor 23 (FGF23), and knowledge about its effects on the regulation of mineral metabolism and its contribution to elevated cardiovascular disease risk has proliferated.2Wolf M. Mineral (mal)adaptation to kidney disease–Young Investigator Award address: American Society of Nephrology Kidney Week 2014.Clin J Am Soc Nephrol. 2015; 10: 1875-1885Crossref PubMed Scopus (26) Google Scholar Appreciation of the importance of active intestinal phosphate transport has focused attention on designing new drugs and testing old ones that could block this pathway for dietary phosphate absorption.3Larsson T.E. Kameoka C. Nakajo I. et al.NPT-IIb inhibition does not improve hyperphosphatemia in CKD.Kidney Int Rep. 2017; 2: 73-80Google Scholar, 4Isakova T. Ix J.H. Sprague S.M. et al.Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD.J Am Soc Nephrol. 2015; 26: 2328-2339Crossref PubMed Scopus (105) Google Scholar We are also learning that paracellular phosphate transport may be amenable to manipulation through blockade of the intestinal sodium-hydrogen type 3 exchanger by tenapanor.5Block G. Rosenbaum D. Korner P. Yan Z. Chertow G.M. Efficacy of tenapanor to treat hyperphosphatemia in patients on hemodialysis.American Society of Nephrology Kidney Week. 2017; ([abstract])Crossref Scopus (64) Google Scholar These and other fundamental discoveries have paved the way for ongoing development of novel therapeutic approaches for management of hyperphosphatemia.4Isakova T. Ix J.H. Sprague S.M. et al.Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD.J Am Soc Nephrol. 2015; 26: 2328-2339Crossref PubMed Scopus (105) Google Scholar Physiological processes exhibit circadian rhythms, the existence of which may be advantageous from an evolutionary perspective. The clinical implications of the variability in multiple parameters throughout the day have also become apparent. For example, a large body of evidence supports the existence of diurnal variation in blood pressure, the circadian variation in the renin-angiotensin-aldosterone system and the sympathetic nervous system, and the relationship of non-dipping with increased cardiovascular risk. Indeed, as a result of this evidence, some have advocated that blood pressure–lowering medications be administered at nighttime. The importance of circadian rhythms in the mineral and bone system is much less known. Although a diurnal rhythm for serum phosphate exists in health and in CKD,6Isakova T. Xie H. Barchi-Chung A. et al.Daily variability in mineral metabolites in CKD and effects of dietary calcium and calcitriol.Clin J Am Soc Nephrol. 2012; 7: 820-828Crossref PubMed Scopus (43) Google Scholar it has not been linked to changes in parathyroid hormone (PTH), FGF23, or vitamin D levels, which are noted to vary throughout the day. Therefore, the mechanisms for diurnal changes in serum phosphate remain largely unexplained. The results of the experimental studies by Miyagawa et al.7Miyagawa A. Tatsumi S. Takahama W. et al.The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration.Kidney Int. 2018; 93: 1073-1085Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar (2018) reported in this issue of Kidney International shed light on potential regulators of circadian rhythms of plasma and urinary phosphate in mice and have important clinical implications. The investigators previously established the contribution of the nicotinamide phosphoribosyltransferase (Nampt)/nicotinamide adenine dinucleotide (NAD)+ system to regulation of sodium phosphate cotransporters.8Nomura K. Tatsumi S. Miyagawa A. et al.Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis.J Am Soc Nephrol. 2014; 25: 761-772Crossref PubMed Scopus (35) Google Scholar In a rat model of hepatectomy-related hypophosphatemia, they demonstrated that after partial hepatectomy, the ensuing hypophosphatemia is accompanied by increased phosphaturia. This biochemical phenotype is explained by decreased renal and intestinal brush-border membrane active transport of phosphate due to decreased renal and intestinal expression of sodium-dependent phosphate transporters (NaPi-2a, NaPi-2b, and NaPi-2c). Through a series of hypothesis-driven experiments, the investigators established mechanistic links between abnormal nicotinamide metabolism following partial hepatectomy (specifically, increased levels of nicotinic acid derivatives and Nampt activation in renal proximal tubular cells) and negative transcriptional regulation of sodium-dependent phosphate transporters, renal phosphate leak, and hypophosphatemia.8Nomura K. Tatsumi S. Miyagawa A. et al.Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis.J Am Soc Nephrol. 2014; 25: 761-772Crossref PubMed Scopus (35) Google Scholar These experimental observations are consistent with the findings from human studies9Zheng J. Glezerman I.G. Sadot E. et al.Hypophosphatemia after hepatectomy or pancreatectomy: role of the nicotinamide phosphoribosyltransferase.J Am Coll Surg. 2017; 225: 488-497.e482Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar and provide support for phosphate-lowering effects of niacin (vitamin B3) and its derivatives.4Isakova T. Ix J.H. Sprague S.M. et al.Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD.J Am Soc Nephrol. 2015; 26: 2328-2339Crossref PubMed Scopus (105) Google Scholar The investigative team has now gone on to address the mechanistic basis for diurnal variation in plasma phosphate levels and urinary phosphate excretion in mice.7Miyagawa A. Tatsumi S. Takahama W. et al.The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration.Kidney Int. 2018; 93: 1073-1085Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Their results show that in wild-type animals, oscillations in plasma and urinary phosphate are independent of known hormonal regulators, although levels of FGF23 and PTH were only assessed twice daily. The authors do report that diurnal changes in plasma and urinary phosphate are accompanied by expected changes in levels of expression of sodium-dependent phosphate transporters. Using genetic models of inactivation of active phosphate transport, the authors demonstrate that plasma and urinary phosphate diurnal oscillations are blunted somewhat in Npt2a−/− mice and almost completely abolished in the Npt2a−/−/Npt2c−/− mice. In contrast, mice with intestine-specific Npt2b deletion had preserved diurnal variability in plasma and urinary phosphate levels, although the excursions of the latter were attenuated, likely due to compensatory renal response to decreased intestinal phosphate absorption. Further experiments implicated renal and intestinal NAD levels and the activity of the Nampt enzyme, which is integral to cellular NAD synthesis, in controlling the diurnal variability in renal and intestinal phosphate transport. Intriguingly, liver-specific Nampt deletion and systemic reduction in Nampt activity by 30% to 50% resulted in attenuation of oscillations in plasma phosphate levels. Together, these findings suggest that the Nampt/NAD+ system is an important contributor to diurnal variation in plasma phosphate levels through effects on expression of sodium-dependent phosphate transporters and cellular shifts of phosphate from tissues such as the liver. These findings enhance our understanding of the intricate regulation of phosphate homeostasis. Although bone- and parathyroid-specific genetic models were not deployed, the authors show that circadian variation in serum phosphate is not regulated by hormones but is determined by the Nampt/NAD+ system, which affects cellular shifts and renal and intestinal transport. Because the preservation of diurnal variation in serum phosphate levels in patients with CKD and ESRD is well-established,6Isakova T. Xie H. Barchi-Chung A. et al.Daily variability in mineral metabolites in CKD and effects of dietary calcium and calcitriol.Clin J Am Soc Nephrol. 2012; 7: 820-828Crossref PubMed Scopus (43) Google Scholar we could infer from the presented data that the Nampt/NAD+ system is also critical in settings of reduced kidney function. Future studies in animal models of CKD will need to confirm this hypothesis. Whether the attenuation of diurnal peaks in serum phosphate in the genetic models resulted in long-term reductions in FGF23 and PTH is also untested. Several additional questions are important to highlight. If serum phosphate levels could be prevented from rising in the late afternoon in patients with CKD, would this effect also prevent the rise in FGF23 and PTH during the course of CKD and lead to improved long-term clinical outcomes? Could systemic or bone-specific inhibition of Nampt activity prevent the release into the circulation of phosphate stored in bone, especially in patients with severe hyperparathyroidism and bone disease? What are the unexpected consequences of abolishing the oscillation of serum phosphate? If this is accomplished through increasing urinary phosphate excretion, we can speculate that there may be increased risk of nephrocalcinosis and kidney stones. It is less clear what if any the untoward effects of tissue retention of phosphate may be. While we await additional evidence from basic and human studies, clinicians should carefully consider the compelling body of research that illustrates the contribution of multiple processes to regulation of serum phosphate levels throughout the day (Figure 1). While labeling hyperphosphatemic patients noncompliant with phosphate-lowering therapy may be expeditious, it belies the complexity of the problem. For example, based on the findings presented by Miyagawa et al.7Miyagawa A. Tatsumi S. Takahama W. et al.The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration.Kidney Int. 2018; 93: 1073-1085Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, we might speculate that one of the reasons for the commonly observed heterogeneity in response to phosphate binders may be due to inter-individual variability in transcellular phosphate movement. Taking it a step further, it is tempting to hypothesize that inter-individual differences in intracellular phosphate levels may be more proximally linked to phosphate-induced toxicity than are levels of serum phosphate. Indeed, it is important to remember that the plethora of observational studies reporting on the association of elevated serum phosphate levels with mortality in patients undergoing hemodialysis relied on serum phosphate levels measured in morning fasting blood samples, a time of day when serum phosphate levels are at their nadir. If we can comprehensively assess all components that regulate serum phosphate levels, we might be able to determine the true risk associated with abnormal phosphate handling. The implications for clinical therapeutics are also numerous. The data from Npt2a−/− mice and Npt2a−/−/Npt2c−/− mice suggest that perhaps urinary phosphate excretion could be leveraged as a potential target for phosphate management in patients with residual renal function. Further examination of the Nampt/NAD+ system may perhaps lead to identification of additional novel therapeutic modalities that could be used in patients with CKD and ESRD. Finally, although the intestine-specific Npt2b deletion in this study resulted in preserved diurnal variability in plasma and urinary phosphate levels and a human study of a specific small molecule Npt2b inhibitor did not lower serum phosphate levels in ESRD,3Larsson T.E. Kameoka C. Nakajo I. et al.NPT-IIb inhibition does not improve hyperphosphatemia in CKD.Kidney Int Rep. 2017; 2: 73-80Google Scholar there is ongoing interest in developing new agents that reduce dietary phosphate absorption through a mechanism that is different from luminal phosphate binding that is common to all classes of phosphate binders. The exciting findings summarized in the manuscript by Miyagawa et al.7Miyagawa A. Tatsumi S. Takahama W. et al.The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration.Kidney Int. 2018; 93: 1073-1085Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar illustrate how far we have come. We are also reminded that the phosphate bucket list remains full, and many challenges remain in the management of hyperphosphatemia in patients with advanced CKD and those undergoing dialysis. The optimal serum phosphate target is unknown, and existing therapeutic approaches are associated with risks. Yet, hyperphosphatemia is a nearly universal complication of ESRD, and more than 80% of patients are treated with phosphate binders. Continued efforts at the bench and bedside are needed to lead to therapeutic advances in this important area. TI received grant support from Shire and an honorarium from Bayer. GB has served as a consultant for Akebia, Amgen, Ardelyx, AstraZeneca, Celgene, Daiichi Sankyo, Keryx, Relypsa, Sanfit, and ZS Pharma; has ownership interest in Ardelyx and Nephroceuticals; and has received research support from Keryx and honoraria from Akebia, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Keryx, and Sanofi. TI is supported by grants R01DK110087, R01DK102438, and U01DK099930 from the National Institutes of Health. GB is supported by grants U01DK097093 and R01DK102438 from the National Institutes of Health. The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentrationKidney InternationalVol. 93Issue 5PreviewCirculating inorganic phosphate exhibits a remarkable daily oscillation based on food intake. In humans and rodents, the daily oscillation in response to food intake may be coordinated to control the intestinal absorption, renal excretion, cellular shifts, and extracellular concentration of inorganic phosphate. However, mechanisms regulating the resulting oscillation are unknown. Here we investigated the roles of the sodium phosphate cotransporter SLC34 (Npt2) family and nicotinamide phosphoribosyltransferase (Nampt) in the daily oscillation of plasma inorganic phosphate levels. Full-Text PDF Open Archive
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