PRESENTED BY
CARSTEN WAGNER

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Carsten Wagner

Phosphorus is an essential nutrient for human health that has a variety of physiological roles mostly in the form of inorganic phosphate. These include structural roles, as phosphate is a major component of cell membranes (i.e. phospholipid bilayer), the sugar-phosphate backbone of nucleic acids, and in the form of hydroxyapatite it is essential in bones and teeth. Additionally, phosphate plays important roles in energy metabolism (e.g. in ATP, GTP, ADP, GDP), in acid/base balance, and in intracellular cell signalling. During evolution, our food always contained small amounts of phosphate. Thus, our body has evolved to absorb phosphate very efficiently from food and to hold on to it by reabsorbing as much as needed from urine [1].

Maintenance of a normal serum phosphate level depends on absorption in the gut, reabsorption and excretion by the kidney, and the flux between the extracellular and skeletal pools. Phosphate homeostasis is a coordinated, complex system of crosstalk between bone, intestine, kidney, and parathyroid gland. Dysfunction of this system has serious clinical consequences in healthy individuals and those with conditions such as chronic kidney disease (CKD), in which hyperphosphatemia is associated with increased risks of cardiovascular and overall mortality [2].

Association between increased serum phosphates and mortality risk
Elevated serum phosphate levels are independently associated with increased mortality risk in patients with impaired kidney function. Among dialysis patients, hyperphosphatemia is linked with calcification of the coronary arteries and aorta, as well as cardiovascular and all-cause mortality in the setting of end-stage renal disease (ESRD). In CKD patients, mortality risk increases linearly with each subsequent 0.5-mg/dl increase in serum phosphate levels [3]. On the other hand, lower serum phosphate levels are associated with improved survival in patients with CKD stages 3 and 4 [4]. However, this association has also been noticed in the general population without pre-existing cardiovascular disease and normal kidney function [5-7].

Since dietary intake prior to measurement can affect serum phosphate levels, Chang et al. hypothesized that the association between serum phosphorus and mortality is the strongest in those who have fasted for longer duration. Authors showed that the association was significantly stronger for those fasting longer (≥ 12 vs. <12 hours). Among those fasting ≥ 12 hours, every 1-mg/dL increase above 3.5 mg/dL was associated with an 84% increased risk of death. Among those fasting < 12 hours, there was no association between serum phosphate levels above 3.5 mg/dL and all-cause mortality. Serum phosphate below 3.5mg/dL was not associated with all-cause mortality in either subgroup [8]. Hyperphosphatemia accelerates renal function decline and significantly increases the risk of ESRD. In those with normal kidney function, every 0.5-mg/dL phosphate increase demonstrates a 40% greater risk for incident ESRD [9]. In pre-dialysis patients, high plasma phosphate is an independent risk factor for a more rapid decline in renal function and a higher mortality during the pre-dialysis phase [10]. Except for promoting CKD progression, high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors among patients with proteinuric CKD [11]. Phosphate toxicity as a multi-system disorder
Excess phosphate exerts toxic effects through a variety of pathways. Hyperphosphatemia directly potentiates vascular calcification and endothelial dysfunction, promotes the progression of kidney disease, and induces cell stress and apoptosis. It may also contribute to adverse outcomes through increases in the levels of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), including left ventricular hypertrophy, renal anemia, immune dysfunction, adipose tissue browning, and skeletal muscle atrophy (Figure 1).

Figure 1. Schematic representation of phosphate toxicity (Slide 11) [13]

 

Our body is very efficient at absorbing phosphate, combining high affinity phosphate transporters (mostly active during times of low phosphate availability) and a high-capacity paracellular pathway that absorbs abundant phosphate. Theoretically, the excessive phosphate absorption from our diet should not pose a problem if the kidneys were excreting all unwanted phosphate. Although we have developed a sophisticated system to regulate phosphate homeostasis, due to the dependence of phosphate elimination on urinary excretion by the kidneys, patients with decreased kidney function are likely to be in a positive phosphate balance [12, 14]. However, findings of phosphate toxicity and positive phosphate balance are also noted even in populations with normal kidney function. A possible cause might be growing consumption of animal-based products rich in phosphates, soft drinks and foods processed with inorganic phosphate additives. In most industrialized countries, daily phosphate intake exceeds recommended daily allowance (RDA) by 2-3 folds. Moreover, phosphate salts from these products are readably absorbable in contrast to phyto-phosphates from vegetables and fruits [15].

The SLC34 family of sodium-driven phosphate cotransporters comprises three members: NaPi-IIa (SLC34A1), NaPi-IIb (SLC34A2), and NaPi-IIc (SLC34A3). NaPi-IIa and NaPi-IIc are predominantly expressed in the brush border membrane of the proximal tubule, whereas NaPi-IIb is found in many more organs including the small intestine, lung, liver, and testis. All three transporters are highly regulated by factors including dietary phosphate status, hormones like PTH, 1,25-OH2 vitamin D3 or FGF23, electrolyte, and acid–base status. PTH and FGF23 are the most important of these hormones, reducing the activity of both NaPi-IIa and NaPi-IIc, resulting in increased urinary phosphate excretion [16].

In acute situations, excess phosphates intake leads to dose-dependent increase in serum phosphate levels. Eight hours after ingestion, 50% of phosphate will still be in our system [17]. One prospective outpatient study investigated the effects of chronic high-phosphate diet on 20 healthy young adults for 11 weeks. After 6 weeks, all subjects received vitamin D3 (600,000 U) by intramuscular injection. Despite the fact that the all participants on high-phosphate diet were healthy volunteers with normal kidney function and with elevated FGF23 and PTH levels, their serum phosphate levels remained increased after 11 weeks [18].

In the kidney, excess amount of phosphates can form precipitates with calcium, provoking aberrant organ calcification or arteriosclerosis. Prevalence rates of nephrocalcinosis have been shown to increase with increasing CKD stage, reaching more than 50% in ESRD patients [19]. Upon strong supersaturation of blood with calcium and phosphate, mineral-laden fetuin-A and other proteins self-assemble to form primary calciprotein particles (CPP1). The main function of CPP1 is to keep surplus amounts of calcium phosphate suspended until it is cleared. Over time, CPP1 may undergo a characteristic phase transformation into CPP2, which appears to induce oxidative stress, inflammation, and calcification in aortic smooth muscle cells [20].

In addition, an increasing number of studies have linked high dietary phosphate intake to hypertension. Animal experiments have demonstrated that phosphate can increase sympathetic nerve tone and trigger vascular calcification through a variety of mechanisms involving the local production of aldosterone in blood vessels [21]. Similar finding have been also observed in an already mentioned prospective study. Increased phosphate intake significantly increased systolic blood pressure, diastolic blood pressure, and pulse rates in young adults with normal renal function, paralleled by increasing sympathoadrenergic activity [18].

References

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2. Ritter CS, Slatopolsky E. Phosphate Toxicity in CKD: The Killer among Us. Clin J Am Soc Nephrol. 2016;11(6):1088–1100. doi:10.2215/CJN.11901115

3. Kestenbaum B, Sampson JN, Rudser KD et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16(2):520-8.

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7. Chang AR, Lazo M, Appel LJ, Gutiérrez OM, Grams ME. High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am J Clin Nutr. 2014;99(2):320-7. doi: 10.3945/ajcn.113.073148.

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11. Zoccali C, Ruggenenti P, Perna A, et al. Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition. J Am Soc Nephrol. 2011;22(10):1923–1930. doi:10.1681/ASN.2011020175

12. Komaba H, Fukagawa M. Phosphate-a poison for humans? Kidney Int. 2016;90(4):753-63. doi: 10.1016/j.kint.2016.03.039.

13. Wagner C. Phosphate toxicity in the kidney. Presentation at ERA-EDTA 2019, Budapest, Hungary, June 13, 2019. Available on ERA-EDTA Virtual Meeting

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16. Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch. 2014;466(1):139-53. doi: 10.1007/s00424-013-1418-6.

17. Nishida Y, Taketani Y, Yamanaka-Okumura H et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. 2006;70(12):2141-7.

18. Mohammad J, Scanni R, Bestmann L, Hulter HN, Krapf R. A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects. J Am Soc Nephrol. 2018;29(8):2089-2098. doi: 10.1681/ASN.2017121254.

19. Evenepoel P, Daenen K, Bammens B et al. Microscopic nephrocalcinosis in chronic kidney disease patients. Nephrol Dial Transplant. 2015;30(5):843-8. doi: 10.1093/ndt/gfu400

20. Pasch A, Jahnen-Dechent W, Smith ER. Phosphate, Calcification in Blood, and Mineral Stress: The Physiologic Blood Mineral Buffering System and Its Association with Cardiovascular Risk. Int J Nephrol. 2018;2018:9182078. Published 2018 Sep 2. doi:10.1155/2018/9182078

21. Mizuno M, Mitchell JH, Crawford S et al. High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats. Am J Physiol Regul Integr Comp Physiol. 2016;311(1):R39-48. doi: 10.1152/ajpregu.00124.2016.

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