Calcium & Phosphate Metabolism

Question 1

Where is most phosphate reabsorbed?

Answer 1

Proximal tubule

Question 2

About how much filtered load of phosphate is reabsorbed?

Answer 2

80-97%

Question 3

How is phosphate reabsorbed?

Answer 3

Na/P cotransporter

Question 4

How does hyperphosphatemia occur in CKD?

Answer 4

Low GFR decreases filtration rate of phosphate

Question 5

What are the three effects of PTH during hypocalcemia?

Answer 5

Enhances Ca and P efflux from bone

Enhances 1a-hydroxylase to form active vit D which reabsorbs more Ca stops P reabsorption

Question 6

How does PTH activity in patients with CKD differ?

Answer 6

Diseased kidney cannot make more vitamin D, so the effect of reabsorbing more calcium and less phosphate is lost

Question 7

Elevated serum phosphorus is seen in which CKD patients?

Answer 7

Severe, NOT in mild to moderate

Question 8

How are phosphate levels predictive of mortality in CKD?

Answer 8

The higher the phosphate level, the higher the mortality rate for CKD patients, even within normal phosphate levels

Question 9

How does hyperphosphatemia contribute to vascular disease in CKD patients?

Answer 9

Elevated phosphate levels cause vasculat smooth muscle cell calcification

Question 10

How is serum calcium related to CKD?

Answer 10

Can be high or low; high or low are both associated with increased mortality

Question 11

What is a pathogenic mechanism of hypocalcemia?

Answer 11

Increased neuromuscular excitability

Question 12

What is a pathogenic mechanism of hypercalcemia?

Answer 12

CV and soft tissue calcification

Question 13

Explain vitamin D synthesis in the normal healthy person

Answer 13

Mostly from UV light; some from diet. Hydroxylated once first by the liver and then again by the kidney to active form. There is also some enzyme in tissues to do second step.

Question 14

Explain vitamin D deficiency in someone with normal kidneys

Answer 14

Lack of vitamin D causes low calcium, which activates PTH to stimulate 1a-hydroxylase in the kidneys. As a result, phosphate levels go down but more vitamin D is made into active form.

Question 15

Explain vitamin D deficiency in someone with CKD

Answer 15

Hypocalcemia activates PTH, but it cannot act on depleted kidney to upregulate vitamin D formation. However, PTH remains active due to hypocalcemia, hyperphosphatemia (no way to excrete), and whatever vitamin D is made.

Leads to bone disease because PTH causes efflux of Ca and P from bone –> osteomalacia

Question 16

How do you treat CKD patients to prevent bone disease?

Answer 16

Supplement with vitamin D (calcitrol) which has been shown to increase survival

Question 17

Why is vitamin D a big deal?

Answer 17

Its receptor is located in the nucleus and is important for regulating transcription of many proteins; not just one reaction

Question 18

What are some S/S of FGF23 excess?

Answer 18

Low serum phosphate
aberrant vit D metabolism
rickets/osteomalacia

Question 19

What are some S/S of FGF23 deficiency?

Answer 19

Hyperphosphatemia
Elevated 1,25 vit D
Tissue calcification
Hyperosteosis

Question 20

What are the actions of FGF?

Answer 20

Decreases active vitamin D

Blocks phosphorus reabsorption

Question 21

How do PTH and FGF23 work together to control phosphorus and vitamin D levels?

Answer 21

PTH and FGF23 both decrease renal P reabsorption

FGF23 decreases vitamin D while PTH increases vitamin D

Question 22

Does FGF23 or PTH increase start first?

Answer 22

FGF23

Question 23

Explain secondary hyperparathyroidism in CKD

Answer 23

FGF23 Suppress vitamin D level and inhibits phosphorus reabsorption
Decreased calcium reabsorption in the gut stimulates PTH
In CKD, FGF23 cannot block PTH
PTH increases bone remodeling resulting in efflux of calcium from bone
PTH also targest kidney to increase excretion of phosphorus (good!) and stimulates production of vitamin D which offsets and balances FGF23

Question 24

What are the putative mechanisms of FGF23 adverse effects?

Answer 24

Decrease vitamin D
Increase RAAS
Increase inflammation

Question 25

What is the deal with FGF23

Answer 25

Fibroblast growth factor (FGF)-23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)2D3) levels. It is secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased serum 1,25(OH)2D3 levels. In human chronic kidney disease (CKD), plasma FGF-23 appears to be a sensitive biomarker of abnormal renal phosphate handling, as FGF-23 levels increase during early stages of kidney malfunction. In humans and animals with CKD, elevated FGF-23 levels increase fractional phosphate excretion, reduce serum phosphate levels, and reduce 1α-hydroxylase activity, which reduces 1,25(OH)2D3 formation thereby increasing parathyroid hormone (PTH) secretion. FGF-23 thus has a key adaptive role in maintaining normophosphatemia. Plasma FGF-23 continues to increase as CKD progresses, increasing by orders of magnitude in end-stage renal disease. At the same time, responsiveness to FGF-23 declines as the number of intact nephrons declines, which is associated with reduced expression of Klotho, the co-receptor required for FGF-23 signaling. In late CKD, FGF-23 cannot reduce serum phosphate levels, and abnormally high plasma FGF-23 concentrations appear to exert unwarranted off-target effects, including left ventricular hypertrophy, faster CKD progression, and premature mortality. Lowering serum phosphate levels through the use of oral phosphate binders and/or long-acting PTH agents may reduce FGF-23 levels in early CKD stages, thereby limiting off-target effects, which may improve patient outcomes.