| | |  | | NEWSLETTER ::: NO. 17 ::: DEC 2018 | | CARSTEN WAGNER: IS PHOSPHATE TOXIC? | | Phosphate is essential for many processes inside our bodies and can be absorbed very well by our system. However, too much of it appears to cause organ calcification and heart disease. | Scientists want to find out when and why it becomes harmful for us. Phosphate is an essential mineral for life on earth. Humans require it for a plethora of processes inside the body. Phosphate helps build membranes and synthetize DNA and RNA molecules. It is used for the generation of energy-rich molecules like ATP or GTP, for the transmission of signals by phosphorylation and dephosphorylation and for stabilizing bones. 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.
Phosphate, however, can be dangerous, particularly when reacting with calcium. It can form precipitates and cause aberrant organ calcification or arteriosclerosis.
Again, our body has developed powerful mechanisms to prevent this. Parathyroid hormone, calcitriol and FGF23/a-klotho cooperate to regulate minerals and to prevent phosphate from exceeding its solubility product. Plasma proteins like Fetuin-a reduce the risk of forming precipitates. This balance in our body is being increasingly challenged.
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Over recent decades, food composition and preferences in many regions of the world, particularly in industrialized countries, have dramatically changed. Large percentages of the population consume soft drinks and large quantities of processed food. These food items have in common a substantial amount of inorganic phosphate, mostly added during the production process.
After all, 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. In theory, this excessive phosphate absorption from our diet should not pose a problem if the kidneys are excreting all unwanted phosphate. However, higher phosphate consumption elevates blood phosphate levels.
In nephrology it has been known for decades that in patients with CKD consuming a phosphate-rich diet
increases phosphate plasma levels causing cardiovascular morbidity and increasing mortality due to vascular calcification and left ventricular hypertrophy. Importantly, this association with phosphate consumption has now also been detected in the general population. However, it has remained elusive how phosphate can trigger this dramatic increase in cardiovascular morbidity not only in patients with chronic kidney disease (CKD) but also in people with normal kidney function. Only recently have several lines of evidence emerged that suggest distinct pathomechanisms. In patients with CKD, associations between Fibroblast Growth Factor 23 (FGF23), a phosphaturic hormone highly elevated in these patients, and cardiovascular disease (particularly left ventricular hypertrophy, LVH) have suggested that FGF23 may be a missing link. Animal experiments have also shown the effects of FGF23 on the heart. More recently, this concept has been challenged by the Wagner group at the University of Zurich—as well as by others, which have shown that the isolated elevation of FGF23 without kidney disease is not sufficient to trigger LVH.
Alpha-klotho, a co-receptor for FGF23, may be another link between phosphate, CKD and LVH. Both, high phosphate intake as well as CKD cause a decrease in a-klotho levels. In the heart, a-klotho deficiency may promote LVH whereas reconstitution of a-klotho levels protects the heart in experimental models of CKD and high phosphate intake. Direct effects of phosphate on the cardiovascular system may also contribute to the elevated risk associated with high phosphate intake. Animal experiments have demonstrated that phosphate can increase sympathetic nerve tone. Phosphate also triggers vascular calcification through a variety of mechanisms involving the local production of aldosterone in vessels. Research within the NCCR Kidney.CH points to a bloodpressure- raising effect of phosphate in healthy persons.
Reto Krapf has conducted studies with healthy volunteers, who for six weeks were exposed to normal or high-phosphate diets, the latter demonstrating an increase in systolic blood pressure paralleled by evidence of a higher sympathetic tonus. Blood pressure normalized upon ending the high phosphate diet. Similarly, experiments in mice and healthy humans that consumed diets with high or low phosphate content over a range from a few hours to five days showed increased systolic blood pressure in the high phosphate groups. Simultaneously, the activity of the renal NaCl cotransporter NCC is increased, an effect in part mediated by the sympathetic nerve system and FGF23.
Even though we still do not understand if the associations between high phosphate intake and increased cardiovascular morbidity and mortality in the general population are causative, the picture is becoming clearer. Experimental data from humans and from rodent models provide evidence for direct detrimental effects of high phosphate intake on cardiovascular risks. Many open questions remain to be addressed, including examining whether the association between dietary phosphate and cardiovascular risk includes also other ingredients typically found in phosphate-rich diets, such as high salt or high fructose, both well known risk factors for cardiovascular disease. Also, crosstalk between kidney and bone may further contribute to the overall effects of phosphate.
As clear as it is that we cannot live without phosphate, it also emerges that too much may bear considerable risks for our health.
| | | Carsten Wagner Carsten Wagner is a professor of Physiology at the University of Zurich and new co-director of the NCCR Kidney.CH. His research interest is in renal physiology and particularly in aspects of acid-base balance and phosphate homeostasis. |
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| | | | Kidney - Control of Homeostasis | | is a Swiss research initiative, headquartered at University of Zurich, which brings together leading specialists in experimental and clinical nephrology and physiology from the universities of Bern, Fribourg, Geneva, Lausanne, and Zurich, and corresponding university hospitals. |
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