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 .
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 .
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 . 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 .
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 . 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 .
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 . 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 .