With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
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Muhammad Soobadar
With declining kidney function there is increased phosphate . As a result there is increased FGF23/Klotho which promotes phosphate excretion. FGF 23 inhibits 1 alpha hydroxylase and this leads to decreased calcium and increased PTH . This also lead to decreased p042- absorption which is reversed by increased PTH. PTH also increases due to decline in KF and causes increase phosphate excretion. FGF23 inhbibits PTH but with uraemia this stops.
As GFR decrease FGF23 increase lead suppressing 1a hydroxylase and 1,25 (OH)2D production , increase urinary po4 execration .
with CKD patient will have hypocalcemia , hyperphosphatemia and low 1,25(OH)2D
Both PTH and FGF-23 are phosphaturia hormones that increase in case of hyperphosphatemia. PTH is also influenced by hypocalcemia. Hypocalcemia and hyperphosphatemia stimulate the release and synthesis of parathyroid hormones.
An increase in PTH level decreases the Pİ transporters 2a and 2c This increases the phosphorus excretion by kidneys and lowers Pi level.
Increase in FGF-23 after complexing with Klotho: decreases Pi transported 2a and 2c, by this increase renal excretion. Also decrease 1-alpha hydroxylase, and increase 24 hydroxylase. This decreases calcitriol (1,25 oh vit. D) and decreases the intestinal absorption of phosphorus. All lead to a decreased level of Pi in serum
With CKD progression, klotho decreases & FGF23 increases upon Pi retention (aiming to lower S.phosphorus),
FGF23 Inhibits vitamin D activation, hence decreasing intestinal Ca absorption and phosphorus excretion, which all stimulates PTH secretion and synthesis (upon persistent stimulation).
FGF23 also inhibits PTH secretion, but parathyroid gland escapes this inhibition (due to gland resistance), results in SHPT -> bone resorption (indirect osteoclast stimulation) & increase Ca absorption and distal nephron Ca reabsorption -> increases S.Ca level.
PTH also causes Indirect stimulation of Pi absorption (insertion of NaPit2b in the intestinal mucosa under vitamin D control) and Pi reabsorption (insertion of NaPit2a,c in PCT) -> decreases serum phosphate to normal
As CKD continue to progress, compensatory mechanisms fail to mention adequate serum Pi and Ca level
As the GFR falls, free serum calcium levels fall and serum phosphorus increases . The decrease in free serum calcium and increase in serum phosphorus stimulate the parathyroid glands to produce PTH, which decreases the abundance of Npt2a and Npt2c in the renal proximal tubule, leading to increased Pi excretion in the urine that in turn lowers serum Pi levels . Hyperphosphatemia also stimulates production of FGF23, which decreases levels of Npt2a and Npt2c in the kidney, resulting in increased urinary excretion of phosphate. FGF23 also decreases production of 1,25 (OH)2D, which decreases intestinal Pi absorption, further decreasing serum Pi levels.
As GFR continues to fall, however, these compensatory mechanisms fail, leading to hyperphosphatemia.
both of FGF23 and PTH are phosphaturic,
they tend to normalize PO4 in early stages of CKD, but from late CKD3b on, nephron mass becomes so small and kidneys won’t be able to excrete enough PO4 (that comes from diet and bones), so PTH, FGF23, and PO4 rise further
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
PTH: – causes decreased renal reabsorption of phosphate and phosphaturia by: decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane.
FGF-23: – FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter. – FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1hydroxylase. – FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
It is currently accepted that increase in FGF23, the decrease of Klotho, and the reduction of renal mass are possibly the earliest events in the pathogenesis of CKD-MBD. These changes favor the reduction of 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the most active natural activator of VDR, a fact that reduces the absorption of calcium in the intestine and favors the decrease in serum calcium, which in turn acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
Declining nephron mass will cause phosphate retention which stimulate PTH and FGF-23 secretions. PTH decrease expression of NPT a and c,
FGF-23 increase expression of NPT a and c and suppress one alpha hydroxylase decreasing 1,25(oh) vit d decreassing intestinal phosphate absorption
As the GFR falls, free serum calcium levels fall and serum phosphorus increases . The decrease in free serum calcium and increase in serum phosphorus stimulate the parathyroid glands to produce PTH, which decreases the abundance of Npt2a and Npt2c in the renal proximal tubule, leading to increased Pi excretion in the urine that in turn lowers serum Pi levels.
Hyperphosphatemia also stimulates production of FGF23, which decreases levels of Npt2a and Npt2c in the kidney, resulting in increased urinary excretion of phosphate. FGF23 also decreases production of 1,25 (OH)2D, which decreases intestinal Pi absorption,decreasing serum phosphate.
As GFR further decrease so impaired compensatory mechanism lead to hyperphosphatemia.
The impact of CKD progression to level of po4 is differe according to ckd stage In early stages of CKD (2-3A )phosphate homeostasis is maintained by progressive increase in phosphate excretion due to elevated FGF-23 levels in presence of koltho, which subsequently inhibit 1,25(OH)2D3 production. The low production of 1,25(OH)2D3 causing secondary hyperparathyroidism. Both FGF-23 and PTH inhibit reabsorption of phosphate in the proximal tubule and enhance its urinary excretion.
In CKD stages 4 and 5
Klotho’s deficiency with resistance of FGF-23 and decreased phosphate excretion—leads to hyperphosphatemia
As GFR decrease there will be decrease in S. Ca and increase S. Phosphorous these lead to stimulation of PTH which remove the Npt2a and Npt2c so cause phosphate excretion
Increase S. Phosphorous lead to stimulation of FGF23 which remove Npt2a and Npt2c and increase phosphate excretion, also it decrease formation of calcitriol which decrease intestinal absorption of phosphorous.
As GFR further decrease so impaired compensatory mechanism lead to hyperphosphatemia.
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level? In early stages of CKD (2-3A )
phosphate homeostasis is maintained by :
progressive increase in phosphate excretion due to elevated FGF-23 levels, which subsequently inhibit 1,25(OH)2D3 production. The low production of 1,25(OH)2D3 causing secondary hyperparathyroidism. Both FGF-23 and PTH inhibit reabsorption of phosphate in the proximal tubule and enhance its urinary excretion.
In CKD stages 4 and 5
Klotho’s deficiency with resistance of FGF-23 and decreased phosphate excretion—leads to hyperphosphatemia
In patients with chronic kidney disease, FGF-23 and PTH levels increase to regulate phosphate levels. However, as kidney function deteriorates, the effectiveness of FGF-23 and PTH decreases, leading to hyperphosphatemia.
FGF-23 reduces the expression and activity of sodium-phosphate cotransporters in the proximal tubule of the kidneys, which decreases the reabsorption of phosphate, and also decreases the activity of the intestinal sodium-phosphate cotransporter, leading to reduced absorption of dietary phosphate. However, in patients with CKD, FGF-23 levels increase significantly, but its activity becomes impaired due to the development of resistance to its effects(decreased klotho), resulting in decreased ability to regulate phosphate levels.
PTH, on the other hand, acts on the kidneys to decrease the reabsorption of phosphate and increase its excretion in the urine. This helps to lower the serum phosphate levels. However, in CKD patients, the effectiveness of PTH decreases, and it can no longer fully compensate for the impaired kidney function, leading to a rise in serum phosphate levels.
A decrease in GFR may cause high Pi, which stimulates FGF23, and causes an increase in Pi excretion in the urine, which normalizes serum Pi. This happens in the early stages of CKD. A decrease in GFR also leads to a reduction in calcitriol & hypocalcemia. Both low Ca and high Pi serves as stimulants for PTH, which in turn causes an increase in Pi excretion and the synthesis of Vitamin D, thereby correcting early hypocalcemia and hyperphosphatemia. PTH and calcitriol are both stopped in their tracks by FGF23.
As GFR decreases, blood phosphorus levels rise, which encourages the parathyroid glands to produce a more parathyroid-stimulating hormone (PTH). This, in turn, reduces the brush border abundance of Npt2a and Npt2c in the renal proximal tubule, which ultimately results in an increase in the amount of phosphorus that is excreted in the urine. PTH is shorthand for parathyroid hormone.
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level? PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane Fibroblast Growth Factor-23. FGF-23 is produced in osteoblasts in response to increases in serum Pi. FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1 FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter. FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1hydroxylase FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
In early CKD, drop in GFR may lead to high Pi and this stimualte FGF23 which increase Pi excretion in the urine normalizing serum Pi. Fall in GFR also lead to decrease in calcitriol & hypocalcemia. Both low Ca and High Pi are stimulus for PTH which increase Pi excretion & synnthesis of Vit D correcting the early hypocalemia and hpyperphosphatemia. FGF23 inhibit both PTH & Calitriol
In advanced CKD FGF23 increases to higher levels and lost it is phosphaturic effect due to decrease in renal Klotho (maladaptive response). At the same time PTH also inceases significantly without any effect on phosphate reduction or Ca normalization due resistance to PTH.
With declining kidney function there is increased phosphate . As a result there is increased FGF23/Klotho which promotes phosphate excretion. FGF 23 inhibits 1 alpha hydroxylase and this leads to decreased calcium and increased PTH . This also lead to decreased p042- absorption which is reversed by increased PTH. PTH also increases due to decline in KF and causes increase phosphate excretion. FGF23 inhbibits PTH but with uraemia this stops.
As GFR decrease FGF23 increase lead suppressing 1a hydroxylase and 1,25 (OH)2D production , increase urinary po4 execration .
with CKD patient will have hypocalcemia , hyperphosphatemia and low 1,25(OH)2D
Both PTH and FGF-23 are phosphaturia hormones that increase in case of hyperphosphatemia. PTH is also influenced by hypocalcemia. Hypocalcemia and hyperphosphatemia stimulate the release and synthesis of parathyroid hormones.
An increase in PTH level decreases the Pİ transporters 2a and 2c This increases the phosphorus excretion by kidneys and lowers Pi level.
Increase in FGF-23 after complexing with Klotho: decreases Pi transported 2a and 2c, by this increase renal excretion. Also decrease 1-alpha hydroxylase, and increase 24 hydroxylase. This decreases calcitriol (1,25 oh vit. D) and decreases the intestinal absorption of phosphorus. All lead to a decreased level of Pi in serum
With CKD progression, klotho decreases & FGF23 increases upon Pi retention (aiming to lower S.phosphorus),
FGF23 Inhibits vitamin D activation, hence decreasing intestinal Ca absorption and phosphorus excretion, which all stimulates PTH secretion and synthesis (upon persistent stimulation).
FGF23 also inhibits PTH secretion, but parathyroid gland escapes this inhibition (due to gland resistance), results in SHPT -> bone resorption (indirect osteoclast stimulation) & increase Ca absorption and distal nephron Ca reabsorption -> increases S.Ca level.
PTH also causes Indirect stimulation of Pi absorption (insertion of NaPit2b in the intestinal mucosa under vitamin D control) and Pi reabsorption (insertion of NaPit2a,c in PCT) -> decreases serum phosphate to normal
As CKD continue to progress, compensatory mechanisms fail to mention adequate serum Pi and Ca level
As the GFR falls, free serum calcium levels fall and serum phosphorus increases . The decrease in free serum calcium and increase in serum phosphorus stimulate the parathyroid glands to produce PTH, which decreases the abundance of Npt2a and Npt2c in the renal proximal tubule, leading to increased Pi excretion in the urine that in turn lowers serum Pi levels . Hyperphosphatemia also stimulates production of FGF23, which decreases levels of Npt2a and Npt2c in the kidney, resulting in increased urinary excretion of phosphate. FGF23 also decreases production of 1,25 (OH)2D, which decreases intestinal Pi absorption, further decreasing serum Pi levels.
As GFR continues to fall, however, these compensatory mechanisms fail, leading to hyperphosphatemia.
both of FGF23 and PTH are phosphaturic,
they tend to normalize PO4 in early stages of CKD, but from late CKD3b on, nephron mass becomes so small and kidneys won’t be able to excrete enough PO4 (that comes from diet and bones), so PTH, FGF23, and PO4 rise further
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
PTH:
– causes decreased renal reabsorption of phosphate and phosphaturia by: decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane.
FGF-23:
– FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter.
– FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1hydroxylase.
– FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
It is currently accepted that increase in FGF23, the decrease of Klotho, and the reduction of renal mass are possibly the earliest events in the pathogenesis of CKD-MBD. These changes favor the reduction of 1-α-hydroxylase in the kidney, which results in low levels of calcitriol, the most active natural activator of VDR, a fact that reduces the absorption of calcium in the intestine and favors the decrease in serum calcium, which in turn acts as a stimulus for the synthesis and release of PTH. The increase in PTH favors bone turnover and resorption and stimulates the production of 1-α-hydroxylase. All of these mechanisms translate into compensatory increases to normalize serum calcium. Furthermore, the increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
Declining nephron mass will cause phosphate retention which stimulate PTH and FGF-23 secretions. PTH decrease expression of NPT a and c,
FGF-23 increase expression of NPT a and c and suppress one alpha hydroxylase decreasing 1,25(oh) vit d decreassing intestinal phosphate absorption
As the GFR falls, free serum calcium levels fall and serum phosphorus increases . The decrease in free serum calcium and increase in serum phosphorus stimulate the parathyroid glands to produce PTH, which decreases the abundance of Npt2a and Npt2c in the renal proximal tubule, leading to increased Pi excretion in the urine that in turn lowers serum Pi levels.
Hyperphosphatemia also stimulates production of FGF23, which decreases levels of Npt2a and Npt2c in the kidney, resulting in increased urinary excretion of phosphate. FGF23 also decreases production of 1,25 (OH)2D, which decreases intestinal Pi absorption,decreasing serum phosphate.
As GFR further decrease so impaired compensatory mechanism lead to hyperphosphatemia.
The impact of CKD progression to level of po4 is differe according to ckd stage In early stages of CKD (2-3A )phosphate homeostasis is maintained by progressive increase in phosphate excretion due to elevated FGF-23 levels in presence of koltho, which subsequently inhibit 1,25(OH)2D3 production. The low production of 1,25(OH)2D3 causing secondary hyperparathyroidism. Both FGF-23 and PTH inhibit reabsorption of phosphate in the proximal tubule and enhance its urinary excretion.
In CKD stages 4 and 5
Klotho’s deficiency with resistance of FGF-23 and decreased phosphate excretion—leads to hyperphosphatemia
As GFR decrease there will be decrease in S. Ca and increase S. Phosphorous these lead to stimulation of PTH which remove the Npt2a and Npt2c so cause phosphate excretion
Increase S. Phosphorous lead to stimulation of FGF23 which remove Npt2a and Npt2c and increase phosphate excretion, also it decrease formation of calcitriol which decrease intestinal absorption of phosphorous.
As GFR further decrease so impaired compensatory mechanism lead to hyperphosphatemia.
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
In early stages of CKD (2-3A )
phosphate homeostasis is maintained by :
progressive increase in phosphate excretion due to elevated FGF-23 levels, which subsequently inhibit 1,25(OH)2D3 production. The low production of 1,25(OH)2D3 causing secondary hyperparathyroidism. Both FGF-23 and PTH inhibit reabsorption of phosphate in the proximal tubule and enhance its urinary excretion.
In CKD stages 4 and 5
Klotho’s deficiency with resistance of FGF-23 and decreased phosphate excretion—leads to hyperphosphatemia
In patients with chronic kidney disease, FGF-23 and PTH levels increase to regulate phosphate levels. However, as kidney function deteriorates, the effectiveness of FGF-23 and PTH decreases, leading to hyperphosphatemia.
FGF-23 reduces the expression and activity of sodium-phosphate cotransporters in the proximal tubule of the kidneys, which decreases the reabsorption of phosphate, and also decreases the activity of the intestinal sodium-phosphate cotransporter, leading to reduced absorption of dietary phosphate. However, in patients with CKD, FGF-23 levels increase significantly, but its activity becomes impaired due to the development of resistance to its effects(decreased klotho), resulting in decreased ability to regulate phosphate levels.
PTH, on the other hand, acts on the kidneys to decrease the reabsorption of phosphate and increase its excretion in the urine. This helps to lower the serum phosphate levels. However, in CKD patients, the effectiveness of PTH decreases, and it can no longer fully compensate for the impaired kidney function, leading to a rise in serum phosphate levels.
With advance CKD
A decrease in GFR may cause high Pi, which stimulates FGF23, and causes an increase in Pi excretion in the urine, which normalizes serum Pi. This happens in the early stages of CKD. A decrease in GFR also leads to a reduction in calcitriol & hypocalcemia. Both low Ca and high Pi serves as stimulants for PTH, which in turn causes an increase in Pi excretion and the synthesis of Vitamin D, thereby correcting early hypocalcemia and hyperphosphatemia. PTH and calcitriol are both stopped in their tracks by FGF23.
As GFR decreases, blood phosphorus levels rise, which encourages the parathyroid glands to produce a more parathyroid-stimulating hormone (PTH). This, in turn, reduces the brush border abundance of Npt2a and Npt2c in the renal proximal tubule, which ultimately results in an increase in the amount of phosphorus that is excreted in the urine. PTH is shorthand for parathyroid hormone.
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
PTH causes decreased renal reabsorption of phosphate and phosphaturia by decreasing the abundance of Npt2a, Npt2c, and PiT-2 in the renal proximal tubule brush border membrane
Fibroblast Growth Factor-23. FGF-23 is produced in osteoblasts in response to increases in serum Pi.
FGF23 requires the presence of a cofactor, Klotho, which is produced in the kidney and activates FGF receptor 1
FGF23 reduces the expression and activity of the sodium phosphate cotransporters in the renal proximal tubule
and is also thought to decrease the activity of the intestinal sodium phosphate cotransporter.
FGF23 also reduces serum levels of calcitriol by decreasing the renal expression of 1hydroxylase
FGF23 suppresses PTH synthesis, although the parathyroid glands are believed to become resistant to FGF23 as kidney disease progresses.
With progression of CKD, FGF-23 and PTH levels increase. How could this impact phosphorus level?
Excellent article