Dietary Phosphate: is it toxic? Essam Elsayed, MD MSc FACP FASN
Consultant Physician Medical Subspecialties Institute/ Nephrology
Cleveland Clinic Abu Dhabi
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Objectives Describe Klotho-FGF23-endocrine axis Analyze
evidence of phosphotoxicity Discuss dietary phosphate food content
and challenges to lower its intake
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60 year old stage 2 CKD obese male with h/o CVD, DM,
hyperlipidemia and Pi level of 4mg/dL heard about possible toxic
effects of phosphate in the news and asked you, Doc, what should I
do? A)The average diet has much lower phosphate than recommended
daily dose B) Try to avoid soda and eat more dairy products and
beans C) Chewing gum can lower your phosphate D) Limit processed
food but no enough data to go on a starvation diet Clinical
Case
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Phosphate in the news Not aging fast enough? Drink a soda
Another Reason To Avoid Diet Soda
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Phosphate homeostasis
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Nishida et al. KI 2007 Renal phosphate excretion 1200 mg 800 mg
400 mg
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FGF23 is a phosphaturic hormone
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Phosphate Klotho is an obligatory co-receptor for FGF23 Kidney
KlothoFGFR Intestine FGFR Others FGFR Bone FGFR Liver FGFR FGF23
Phosphate excretion Kurosu et al. J Biol Chem 2006
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Klotho and aging Klotho gene was shown to affect life span in
animal models Mice with a genetic deletion of Klotho or FGF23
exhibit hyperphosphatemia associated with multiple aging-like
phenotypes Klotho -/- mouse
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The klotho -/- mouse Short lifespan Age (weeks) Cumulative
Survival WT (wild type) Klotho
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The klotho -/- mouse Short lifespan Growth retardation WT
Klotho Body Weight (g) Age (weeks)
FemurTibia WTKlothoWTKlotho Bone X-p The klotho mouse Short
lifespan Growth retardation Hypogonadism Premature thymus Skin
atrophy Muscle atrophy Vascular calcification Osteoporosis WTKlotho
Micro CT
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The klotho -/- mouse Short lifespan Growth retardation
Hypogonadism Premature thymus Skin atrophy Muscle atrophy Vascular
calcification Osteoporosis Pulmonary emphysema Ectopic
calcification Motor neuron degeneration Hearing loss klotho
-/-
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Phenotypes of Klotho -/- mice and Fgf23 -/- mice Short lifespan
Growth retardation Hypogonadism Premature thymic involution Skin
atrophy Muscle atrophy Arteriosclerosis Osteoporosis Aging lung
Ectopic calcification Klotho -/- miceFgf23 -/- mice
Hyperphosphatemia Hypervitaminosis D Hypercalcemia Hypoglycemia
Short lifespan Growth retardation Hypogonadism Premature thymic
involution Skin atrophy Muscle atrophy Arteriosclerosis
Osteoporosis Aging lung Ectopic calcification Hyperphosphatemia
Hypervitaminosis D Hypercalcemia Hypoglycemia
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The Bone-Kidney Endocrine Axis Bone FGF23 Phosphate
reabsorption Vitamin D biosynthesis Vitamin D Kidney Klotho
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Low phosphate diet rescues Klotho -/- phenotypes Rescued Short
lifespan Growth retardation Hypogonadism Premature thymic
involution Skin atrophy Muscle atrophy Vascular calcification
Osteoporosis Aging lung Ectopic calcification Motor neuron
degeneration LP: Low phosphate diet (0.02% Pi) NP: Normal diet
(0.54% Pi) X X X X X X X X X X ?
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But not serum Ca and vitamin D LP: Low phosphate diet, NP:
Normal diet * P < 0.01 vs. WT on NP, # P < 0.01 vs. Klotho
-/- on NP NP LP WTKlotho -/- NPLP NPLP WTKlotho -/- NPLPNPLP
WTKlotho -/- NPLP P (mM) Vitamin D (pg/ml ) Ca (mg/dl ) * * * * ***
# *
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Deletion of Na-phosphate cotransporters in Klotho mice reverse
aging-like phenotypes
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Klotho over-expression extends lifespan in mice Kurosu et al.
Science, 2005
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Klotho-deficient mice exhibit molecular signatures of aging
Phosphate may be responsible for the aging-like phenotypes Many of
these phenotypes are alleviated by a low phosphate diet But, is the
data reproducible in other models and humans? What did we learn
from Klotho -/- mouse so far?
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Low phosphate diet extends life span in flies Ken-ichi Miyamoto
(Tokushima Univ) High P (0.2%) Normal P (0.1%) Low P (0.02%) No P
(0.0%) Average Life Span (Days) * * *
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Phosphate accelerates aging in mammals SpeciesLongevity (year)
Serum Pi (mg/dL) Klotho mouse0.1514 Hamster46.5 Rabbit106.4 Guinea
pig125.3 Squirrel245.2 Bear504.9 Rhino504.7 Elephant704.3
Human753.6 Human (centenarian) 1003.1
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Block GA, et al. Am J Kidney Dis. 1998
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CKD is a state of Klotho deficiency urine
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Connolly et al. Transplantation 2009 High Pi level decreases
survival after transplant --- 1.1mmol/l (>3.4 mg/dL) (2.8- 3.4
mg/dL) (
