Hey folks,
I recently wrote this for my blog (it helps me understand) and I thought I would post it here.Source: http://hanswuhealth....-phosphate.html
In the Ohnishi et al (2010) paper they took mice and made 4 groups
- wild-type (WT) mice,
- klotho−/− mice,
- NaPi2a−/−/klotho−/− mice fed with a normal-phosphate diet (DKO+NPD),
- and NaPi2a−/−/klotho−/− mice fed with a high-phosphate diet (DKO+HPD)
Klotho is a protein that is found in the membrane and is also secreted by release from ectodomains. Its importance with relation to phosphate metabolism is that it associates with the FGF receptor (FGFR) thus creating a high affinity complex that will bind to FGF23. This latter protein's function is to decrease phosphate reabsorption in the kidneys (it also has other functions)
Besides the kidneys it also acts on the brain (no one knows what this is involved with yet) and the parathyroid.
NaPi2a stands for, Sodium-dependent phosphate transport protein 2A, and is involved in absorbing phosphate from the gut and kidney. With these groups of mice, this is what they found in terms of serum phopshate and calcium:
As you can see, the Klotho-/- mice had the highest serum phosphate. By knocking out Klotho, the ability of the body to regulate phosphate serum levels is removed, this resulting in high phosphate levels. What is seen in these mice are shortened lifespan and "numerous physical, biochemical, and morphological features consistent with premature aging, including kyphosis, uncoordinated movement, hypogonadism, infertility, severe skeletal muscle wasting, emphysema, and osteopenia, as well as generalized atrophy of the skin, intestine, thymus, and spleen". If you also knockout the NaPi2a transporter (which decreases absorption and reabsorption) of phosphate on the normal phosphate diet, the phenotype is normal (as with the phosphate serum level). HOWEVER if you feed these DKO mice with a high phosphate diet (thus bringing phosphate serum levels on par with Klotho-/-) you get the same phenotype as the Klotho-/-. This effect is also seen for FGF23 knockout mice (2).
(The injections in this case are of FGF23, thus Klotho is required for action)
This relationship between klotho and aging is not a new idea by the way. A paper back in 1997 which identified the gene and also the phenotype of klotho-/- (3) is the first I can find about this relationship. The first author of this original paper published a very recent paper on this topic (4).
In our classes we were taught this very simple regulation of calcium and phosphate:
When in reality it probably looks more like this:
OR
We can clearly see that this relationship of phosphate to morbidities exist in mice. How about humans? Well we can look at illness that affect the kidneys which end up affecting phosphate homeostasis resulting in high serum phosphate levels e.g. Chronic Kidney Disease, they experience many problems, however the disease also affects FGF23 ending up with the same physiology as the mice above. What about healthy individuals?
In (6) they measured baseline serum phosphorus levels in mean age 25yr (N=3000) and followed-up 15 years later and this is what they found:
In patients with cardiovascular disease researchers found this relationship. As you can see there the higher the phosphate serum the greater your risk (7).
One also sees these associations with increased PTH and FGF23, and even Vitamin D3 levels.
For those of us interested in Vitamin D (I am going to write a post on this next) I'm sure we have all seen this graph before:
So we know about serum phosphate, but for those of us with healthy kidneys, does dietary phosphate play a role? In a study where Shuto et al (9) took 11 healthy males and compared a meal load of 400mg of phosphate to 1200mg and % change measured flow-mediated dilatation (%FMD):
Pre-prandial closed circle, Post-prandial open circle
The 1200mg significantly impaired FMD and also significantly increased serum phosphate levels.
In my previous post on this issue I mention both decreasing my bioavailable dietary phosphate and also introducing phosphate binders (non-pharmaceutical) into my meals (e.g. calcium). We know that dietary phosphate loads can alter post-prandial phosphate, but it alter long-term phosphate levels.
In a cross-over trial from a non-vegetarian diet to a vegetarian diet (with similiar phosphate intake, but the difference lies in the bioavailability), there was a statistically significant decrease in both serum phosphate AND FGF23 (10). [Also see (11)].Beware Extra-Phosphate in Additives
Besides what you see in the nutrition data one really has to beware of extra-phosphate due to additives. For example in (13):
The empty bars are the same food with additives. If the food you consume has additives it may underestimate phosphate intake by as much as 70%!
If you are interested in looking at more foods look up the Hidden Phosphorus series by Lisa Murphy-Gutekunst @ the Journal of Renal Nutrition. [STAY AWAY FROM COLAS, other carbonated beverages are fine, and as always drink diet]
Also for a great read on this issue read (14).
Conclusion
Decrease phosphate absorption by decreasing animal food products, avoiding processed foods, and supplementing calcium with meals.
References
01. FASEB J. 2010 Sep;24(9):3562-71. Epub 2010 Apr 23.Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging.Ohnishi M, Razzaque MS.
02. FASEB J. 2009 Feb;23(2):433-41. Epub 2008 Oct 3.In vivo genetic evidence for klotho-dependent, fibroblast growth factor 23 (Fgf23) -mediated regulation of systemic phosphate homeostasis.Nakatani T, Sarraj B, Ohnishi M, Densmore MJ, Taguchi T, Goetz R, Mohammadi M, Lanske B, Razzaque MS.
03. Nature. 1997 Nov 6;390(6655):45-51.Mutation of the mouse klotho gene leads to a syndrome resembling ageing.Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI.
04. Korean J Intern Med. 2011 Jun;26(2):113-22. Epub 2011 Jun 1.Klotho and the aging process.Kuro-o M.
05. J Ren Nutr. 2011 Jul;21(4):303-8. Epub 2010 Nov 5.Extra-phosphate load from food additives in commonly eaten foods: a real and insidious danger for renal patients.Benini O, D'Alessandro C, Gianfaldoni D, Cupisti A.
06.J Am Soc Nephrol. 2009 February; 20(2): 397–404. Serum Phosphorus Levels Associate with Coronary Atherosclerosis in Young Adults
07. Circulation. 2005 Oct 25;112(17):2627-33.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G; Cholesterol And Recurrent Events Trial Investigators.
08. Adv Chronic Kidney Dis. 2011 Mar;18(2):113-9.Phosphate and cardiovascular disease.Kendrick J, Kestenbaum B, Chonchol M.
09. J Am Soc Nephrol. 2009 Jul;20(7):1504-12. Epub 2009 Apr 30.Dietary phosphorus acutely impairs endothelial function.Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki M, Sato M, Nashiki K, Amo K, Yamamoto H, Higashi Y, Nakaya Y, Takeda E.
10. Clin J Am Soc Nephrol. 2011 Feb;6(2):257-64. Epub 2010 Dec 23.Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease.Moe SM, Zidehsarai MP, Chambers MA, Jackman LA, Radcliffe JS, Trevino LL, Donahue SE, Asplin JR.
11. Clin J Am Soc Nephrol. 2011 Feb;6(2):383-9. Epub 2010 Oct 28.Effects of dietary phosphate and calcium intake on fibroblast growth factor-23.Vervloet MG, van Ittersum FJ, Büttler RM, Heijboer AC, Blankenstein MA, ter Wee PM.
12. Clin J Am Soc Nephrol. 2010 Sep;5(9):1710-6. Epub 2010 May 27.Fibroblast growth factor 23 and disordered vitamin D metabolism in chronic kidney disease: updating the "trade-off" hypothesis.Gutiérrez OM.
13. J Ren Nutr. 2011 Jul;21(4):303-8. Epub 2010 Nov 5.Extra-phosphate load from food additives in commonly eaten foods: a real and insidious danger for renal patients.Benini O, D'Alessandro C, Gianfaldoni D, Cupisti A.
14. Iran J Kidney Dis. 2010 Apr;4(2):89-100.Organic and inorganic dietary phosphorus and its management in chronic kidney disease.Noori N, Sims JJ, Kopple JD, Shah A, Colman S, Shinaberger CS, Bross R, Mehrotra R, Kovesdy CP, Kalantar-Zadeh K.
