Calcium & Phosphate Metabolism Flashcards
What happens to the pulse wave velocity in calcified stiff arteries?
Pulse wave increases. It does a bunch of shit that’s bad.
What is CKD-Bone Mineral Disease?
The kidneys fail to maintain proper levels of Ca and PO4 in the blood leading to abnormal bone hormone levels.
What are the 4 functions of phosphorus?
- key component of bony skeleton
- metabolic (i.e. ATP)
- component of nucleic acids
- blood and urinary pH buffer
What is the normal serum phosphorus concentration?
3-4.5 mg/dL
Phosphorus is present in the plasma as what 2 ions?
- HPO4^2-
- H2PO4-
At pH of 7.4, HPO4 is favored 4:1.
What is the distribution of phosphorus in the body?
Bone- 85%
Soft Tissue- 14%
ECF- 1%
What is the metabolic balance of phosphorus?
1400 mg from diet each day. 500 mg lost in feces. 900 mg renally excreted. There is a 200 mg/day turnover of phosphorus from bone (resorption/formation occuring in equal amounts).
What is the renal handling of phosphate?
90% freely filtered. 80-97% reabsorbed with 80% occuring in the proximal tubule.
T or F. Tubular reabsorption of phosphate is saturable.
T: with a GFR<40, hyperphosphatemia results. Note, glucose reabsorption is also saturable.
What is the overall goal of PTH?
To increase serum Ca back to normal. It is secreted in response to hypocalcemia. Secreted by parathyroid.
PTH acts on which 3 organs?
- Kidney
- Small Intestine
- Bone
What is the result of PTH action on the kidney?
- Increased 1-alpha-hydroxylase activity, thus more calcitrol
- Increased excretion of phosphorus
- Increased reabsorption of Ca
What is the result of PTH action on the small intestine?
Increased Ca and PO4 absorption.
What is the result of PTH action on bone?
Increased Ca and PO4 mobilization from bone.
What trade off occurs with Ca with CKD?
High PTH levels in exchange for Ca homeostasis. This is only an adequate correction for a GFR >40.
Hyperphosphatemia isn’t seen in CKD patients until GFR drops below what value?
40 mL/min
T or F. Then he shows some bullshit graph with the key point of “the vast majority of patients with Stage 5 CKD have elevated serum phosphorus.”
T: no shit Sherlock…thanks Kovesdy.
Hyperphosphatemia initiates a cascade of cellular events that results in what?
Calcification of vascular smooth muscle cells.
What is the metabolic balance of Ca?
1000 mg dietary intake per day. 700 mg lost in feces. 300 mg renally excreted. 280 mg/day turnover in bone.
What hormone increases Ca absorption in the small intestine?
Vitamin D. PTH indirectly does this by stimulating 1-alpha-hydroxylase.
T or F. Most CKD patients have a normal serum calcium but there are small decreases seen with worsening kidney function.
T
T or F. His next point is confusing as shit b/c he says CKD patients have higher incidences of hypocalcemia AND hypercalcemia with worsening kidney function.
T: this is the UT way. FMS.
Normally, what percentage of Ca is bound to albumin in the serum?
40%. This is the reason serum Ca concentration measurements must be albumin-adjusted.
An albumin-adjusted serum Ca concentration measurement is important because?
If serum albumin is low, serum Ca could be decreased but if free Ca is normal then the serum concentration would appear to be normal if it wasn’t adjusted.
Does K-DIGO (whoever the eff that is) recommend adjusting Ca concentration for albumin in CKD and ESRD patients?
Nope.
T or F. The risks of both hypo- and hypercalcemia increase with advanced CKD when adjusting for changes in serum albumin and bicarbonate.
T. I can’t even begin to explain this. The next graph shows these patients die or something.
What side effect is seen in CKD patients with hypocalcemia?
Increased neuromuscular excitability.
What side effect is seen in CKD patients with hypercalcemia?
Cardiovascular and soft tissue calcification.
T or F. He then has the gumption to call vitamin D a hormone…involved in the regulation of a wide range of physiologic processes.
T. He then asks if it is the holy grail of medicine or rat poison. I can’t make this stuff up.
Describe vitamin D metabolism.
UVB stimulates vitamin D synthesis. Intake is another source. Then you hydroxylate in the liver. Then hydroxylate again in the kidney (or tissue) to its active form.
Describe calcitrol’s MOA.
Calcitrol binds VDR. VDR goes to the nucleus and heterodimerizes with RXR. This complex binds DNA and regulates transcription of those genes.
Tell me about classical FGFs.
- paracrine mediators
- binds to FGF receptor tyrosine kinases
- binding requires heparin as a cofactor
Tell me about the FGF19 subfamily.
- endocrine mediators
- heparin INdependent
- members are FGF19, FGF21, and FGF23
FGF19 is involved in the homeostasis of what?
Energy and bile acid.
FGF21 is involved in the metabolism of what?
Glucose and lipids.
FGF23, the one we talk about, is involved in the homeostasis of what?
Phosphate and vitamin D.
What kind of activity does FGF23 have in vivo?
Phosphaturic activity
Where is FGF23 expressed?
Mainly in osteocytes. Also by ventrolateral thalamic nucleus, central venous sinusoids, and the thymus.
What 3 things stimulate FGF23?
- calcitrol
- PTH
- bone metabolism
What 4 things does FGF23 do?
- decreases activity (or levels?) of 1-alpha-hydroxylase thus lowering calcitrol
- decreases PTH
- decreases Klotho expression
- decreases renal phosphate reabsorption
What is the overall goal of FGF23?
To lower serum phosphorus levels back to normal.
What is unique about FGF23 in regards to calcitrol?
It is stimulated by calcitrol but its activity is to lower calcitrol. Closed feedback loop.
T or F. FGF23 levels become very high in CKD patients thus explaining the very low calcitrol levels also seen in those patients.
T
Panda’s Notes about FGF23.
- PHEX gene mutation decreases degradation of FGF23
- Increased FGF23 downregulates phosphate transporter activity
- It also inhibits activation of vitamin D
- Inc FGF23 leads to dec calcitrol which inc PTH which leads to hypophosphatemia.
T or F. FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.
T. From one of the BS graphs.
How does FGF23 lead to hyperparathyroidism in CKD patients?
FGF23 lowers calcitrol levels which decreases Ca absorption in the gut. Decreased Ca triggers PTH secretion.
T or F. The effects of FGF23 to suppress PTH is blocked by downregulation of FGFR1/Klotho in CKD patients.
T: this combined with the decreased Ca culminates in hyperparathyroidism. Moral of the story: CKD patients have hyperparathyroidism. I think.
T or F. Increased FGF23 levels are linked to an increased mortality rate in CKD patients.
T. Cool story bro. I don’t even think this is proven but it’s part of his crappy research.
T or F. Then he shows another graph showing elevated FGF23 levels are associated with LVH in CKD patients.
T. Then he found $20.
In summary, what 5 bad things does elevated FGF23 levels do? What is the consequence of each?
- Dec calcitrol: CV disease, metabolic disorders, infections, malignancies
- Inc RAAS: CV disease, metabolic disorders
- Dec Klotho expression: vascular and metabolic disorders
- Inc inflammation: CV disease, protein-energy wasting
- Inc LVH: arrhthymias, CV mortality
Summary Slide of CKD-MBD. Just watch.
Decreased renal function leads to decreased calcitrol production and phosphate retention. This leads to decreased VDR expression, increased PTH, hypo- or hypercalcemia, hyperphosphatemia, elevated FGF23, and increased ALP. The consequences of all that shit= renal osteodystrophy, fractures, calcification, and CV disease. Thus, increased morbidity and mortality.
