The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration

Miyagawa, Atsumi; Tatsumi, Sawako; Takahama, Wako; Fujii, Osamu; Nagamoto, Kenta; Kinoshita, Emi; Nomura, Kazuki; Ikuta, Kayo; Fujii, Tomoyuki; Hanazaki, Ai; Kaneko, Ichiro; Segawa, Hiroko; Miyamoto, Ken‐ichi

doi:10.1016/j.kint.2017.11.022

Cited by 39 publications

(36 citation statements)

References 60 publications

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“…Our findings could also represent an effect of dapagliflozin on the Nampt/NAD + pathway, which regulates the circadian rhythm of phosphate (25). The nadir of this circadian rhythm occurs around 8:00-11:00 AM (26)(27)(28), coinciding with sample collection in this study.…”

Section: Discussionsupporting

confidence: 63%

“…Previous studies indicated that SGLT-2 inhibitors also increase serum phosphate levels (8,9), fueling the hypothesis that these drugs also influence regulators of bone and mineral homeostasis (10). This hypothesis was recently confirmed in a randomized, crossover study in healthy individuals, which showed that canagliflozin influences the fibroblast growth factor 23 (FGF23)/1,25-dihydroxyvitamin D (1,25[OH] 2 D)/parathyroid hormone (PTH) axis (11). These effects may be of relevance for patients with diabetes and kidney disease, who are susceptible to develop hyperphosphatemia (12).…”

Section: Introductionmentioning

confidence: 94%

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Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis

Jong¹,

Petrykiv²,

Laverman³

et al. 2018

CJASN

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Background and objectives The sodium glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin is a novel drug for the treatment of diabetes mellitus. Recent studies suggest that SGLT-2 inhibitors affect phosphate homeostasis, but their effects on phosphate-regulating hormones in patients with diabetic kidney disease are still unclear. Design, setting, participants, & measurements We performed a post-hoc analysis of a double-blind, randomized, crossover trial in patients with type 2 diabetes with early-stage diabetic kidney disease on stable reninangiotensin-aldosterone system blockade, with an albumin-to-creatinine ratio between 100 and 3500 mg/g, eGFR$45 ml/min per 1.73 m 2 , and glycosylated hemoglobin$7.2% and ,11.4%. Patients were randomized to dapagliflozin 10 mg/d or placebo during consecutive 6-week study periods, separated by a 6-week wash-out. We investigated effects on circulating phosphate, calcium, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH] 2 D) levels. Results Thirty-one patients (age 62 years; 23% female) were analyzed. Compared with placebo, dapagliflozin increased serum phosphate by 9% (95% confidence interval, 4% to 15%; P=0.002), PTH increased by 16% (3% to 30%; P=0.01), FGF23 increased by 19% (0.3% to 42%; P=0.05), and serum 1,25(OH) 2 D decreased by 212% (225% to 4%; P=0.12). Calcium and 25(OH)D were unaffected. We found no correlation between changes in markers of phosphate homeostasis and changes in eGFR or 24-hour albumin excretion during dapagliflozin treatment. Conclusions Dapagliflozin increases serum phosphate, plasma PTH, and FGF23. This effect was independent of concomitant changes in eGFR or 24-hour albumin excretion.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 94%

Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis

Jong¹,

Petrykiv²,

Laverman³

et al. 2018

CJASN

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“…Elegant work has demonstrated that the nicotinamide phosphoribosyl transferase (Nampt)/ (NAD + ) intracellular pathway plays a fundamentally important role in the expression of renal and intestinal phosphate transporters (NaPi-2a, NaPi-2b, and NaPi-2c), and likely plays an additional role in the transcellular shifts from other organs that occur independent of oral phosphate ingestion, and which determine diurnal variation in serum phosphate concentration. [25][26][27] Even our understanding of what constitutes a "phosphate-restricted diet" is now known to be on the basis of basic misunderstandings about the relative contribution of animal-versus plant-versus additive-based phosphate exposure. 9,28 Our findings here indicate a clear and substantial contribution of paracellular phosphate transport to net phosphate absorption.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial

Block

Rosenbaum

Yan

et al. 2019

JASN

117

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Background Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. Methods In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. Results Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. Conclusions Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.

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“…Advances in our understanding of P physiology suggest that determinants of serum P concentrations are complex and are likely related to alterations in tissue-specific concentration of nicotinamide phosphoribosyltransferase (Nampt)/NAD+ effecting expression of sodium P transporters and transcellular P flux in active/nonactive periods. 17,18 Nonetheless, serum P concentrations above or near the upper end of the population reference range have been associated with mortality, CV disease, vascular calcification, and incidence and progression of CKD in diverse populations. [19][20][21][22] A meta-analysis of 12 cohort studies including 25,546 patients with non-dialysis-dependent CKD observed a 20% (95% CI, 5% to 37%) increase in mortality and a 36% (95% CI, 20% to 55%) increase in the risk of progressive CKD, defined as a doubling of serum creatinine, 50% decline in eGFR, or ESRD with each 1 mg/dl increase in serum P. 23 Serum P was identified in the Chronic Renal Insufficiency Cohort (CRIC) study as the strongest CKD-specific risk factor for the development of coronary artery calcification in patients without coronary artery calcification at baseline.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Randomized Trial of Ferric Citrate Coordination Complex for the Treatment of Advanced CKD

Block

Smits

et al. 2019

JASN

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BackgroundResearchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population.Methods To investigate whether fixed-dose ferric citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR#20 ml/min per 1.73 m 2 2:1 to receive a fixed dose of ferric citrate coordination complex (two tablets per meal, 210 mg ferric iron per tablet) or usual care for 9 months or until 3 months after starting dialysis. No single biochemical end point was designated as primary; sample size was determined empirically. ResultsThe two groups had generally similar baseline characteristics, although diabetes and peripheral vascular disease were more common in the usual-care group. Ferric citrate coordination complex significantly increased hemoglobin, transferrin saturation, and serum ferritin, and it significantly reduced serum phosphate and intact FGF23 (P,0.001 for all). Of the 133 patients randomized to ferric citrate coordination complex, 31 (23%) initiated dialysis during the study period, as did 32 of 66 (48%) patients randomized to usual care (P=0.001). Compared with usual care, ferric citrate coordination complex treatment resulted in significantly fewer annualized hospital admissions, fewer days in hospital, and a lower incidence of the composite end point of death, provision of dialysis, or transplantation (P=0.002). ConclusionsThe beneficial effects of fixed-dose ferric citrate coordination complex on biochemical parameters, as well as the exploratory results regarding the composite end point and hospitalization, suggest that fixed-dose ferric citrate coordination complex has an excellent safety profile in an unselected population with advanced CKD and merits further study.

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The sodium phosphate cotransporter family and nicotinamide phosphoribosyltransferase contribute to the daily oscillation of plasma inorganic phosphate concentration

Cited by 39 publications

References 60 publications

Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis

Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis

Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial

A Pilot Randomized Trial of Ferric Citrate Coordination Complex for the Treatment of Advanced CKD

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