Why hyperphosphatemia in renal failure?

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ChessMaster3000

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I know that PTH serves to endocytose Na-Phosphate symporters from the apical surface of renal tubular cells into the cytoplasm. I realize in chronic renal failure the kidney isn't working as well in general, however, if there is increased PTH, then there would be an increase in endocytosis of these symporters and you would think that more phosphate would be wasted in CRF. So why do we see hyperphosphatemia? If your answers is, because less is filtered by the kidneys, well fair, except then why dont we also see hypercalcemia as well?

to put the question another way, even if PTH can't act on the kidney tubular cells because they are messed up, then it follows that there would be phosphate reabsorption (because the tubular cells are messed up). Either way, logic would argue that you should be hypophosphatemic in CRF.

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Focusing on phosphate:
1) Early in CKD, you get hyperphosphatemic due to decreased filtration and excretion.
2) Initially, PTH can compensate by causing increased secretion in the proximal tubule.
3) Once you get to Stage IV (GFR<30), you can no longer pump enough out to handle the amount being put in your blood (see below).

Relating to Calcium:
4) There is absolute 1,25Vit D def-->decreased Ca++ absorption
5) PTH is resorbing both Ca++ and PO4 in the bone
5) Remember that serum Ca++ is determined by the ratio of Ca++ to PO4- in the blood. PTH increasing NET serum Ca++ (relative to PO4) is totally dependent on the fact that the kidney increases excretion of PO4- which it can no longer do. So whatever rise you get in Ca is more than matched by PO4-.

The high PO4-/Ca++ ratio meanwhile keeps hammering away at the parathyroids, and PTH keeps getting made, exacerbating the problem (could transition to tertiary hyperPTH over time)
What calcium does exist in the blood is much more likley to precpitate and be driven into tissues in the form of metastatic calcifications, again further keeping Ca++ low and causing CV morbidity.

This also can all be related to the 3 disorders of renal osteodystrophy:
1) Ostetitis Fibrosa Cystica ( due to PTH)
2) Osteomalacia (due to lack of ability to mineralize bone)
3) Osteoperosis (metabolic acidosis causes leeching of buffer from bone)

Controlling phosphate levels and trending PTH are important in following ESRD patients. Its not unusual I think for their PTH > 100 with an elevated phophate. Eventually calcitriol is given for the hyperPTH and hypocalcemia. Since it causes increased absoprtion of both Ca and phosphate from the gut, dietary restriction +/- phosphate binders are needed.
 
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Focusing on phosphate:
1) Early in CKD, you get hyperphosphatemic due to decreased filtration and excretion.
2) Initially, PTH can compensate by causing increased secretion in the proximal tubule.
3) Once you get to Stage IV (GFR<30), you can no longer pump enough out to handle the amount being put in your blood.
Relating to Calcium:
4) There is absolute 1,25Vit D def-->decreased Ca++ absorption (this as a driving force of both hypocalcemia and hyperphosphatemia)
5) PTH is resorbing both Ca++ and PO4 in the bone
5) Remember that serum Ca++ is determined by the ratio of Ca++ to PO4- in the blood. PTH increasing NET serum Ca++ (relative to PO4) is totally dependent on the fact that the kidney increases excretion of PO4- which it can no longer do. So whatever rise you get in Ca is more than matched by PO4-.
The high PO4-/Ca++ ratio meanwhile keeps hammering away at the parathyroids, and PTH keeps getting made, exacerbating the problem (could transition to tertiary hyperPTH over time)
What calcium does exist in the blood is much more likley to precpitate and be driven into tissues in the form of metastatic calcifications, again further keeping Ca++ low and causing CV morbidity.

This also can all be related to the 3 disorders of renal osteodystrophy:
1) Ostetitis Fibrosa Cystica ( due to PTH)
2) Osteomalacia (due to lack of ability to mineralize bone)
3) Osteoperosis (metabolic acidosis causes leeching of buffer from bone)

Controlling phosphate levels and trending PTH are important in following ESRD patients. Its not unusual I think for their PTH > 100 with an elevated phophate.


I suppose I am likely overthinking it--but I understand how PTH decreases Phosphate in the normal kidney, but it seems like a contradiction that the increased PTH can affect the calcium reabsorption in the kidney in CRF but not the phosphate excretion--or are you arguing that the increase in calcium in CRF is ONLY with GI and bone reabsorption, and the kidney reabsorption of calcium is not significant in CRF even with an elevated PTH (
 
The driver for hypocalcemia in ESRD is loss of the ability of the kidneys to convert 25OH VitD-->1,25VitD via alpha hydroxylase and the increase in PO4 relative to Ca. The net increase in Ca due to PTH requires the ability of the kidney to secrete PO4, which is lost.

Even if PTH increases reabsorption of calcium in the DCT of the failing kidney, you can only resorb what you filter (which isn't much) and you can only filter what you have in the blood (which isn't much due to low 1,25OHVitD and high PO4).

Right or wrong, in end stage renal disease just assume that whatever the kidney did before it no longer does. No PO4 secretion, no vitamin D production, no Ca re-absorption. That right there intuitively gets you to high PO4, Low Ca.
 
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The driver for hypocalcemia in ESRD is loss of the ability of the kidneys to convert 25OH VitD-->1,25VitD via alpha hydroxylase and the increase in PO4 relative to Ca. The net increase in Ca due to PTH requires the ability of the kidney to secrete PO4, which is lost.

Even if PTH increases reabsorption of calcium in the DCT of the failing kidney, you can only resorb what you filter (which isn't much) and you can only filter what you have in the blood (which isn't much due to low 1,25OHVitD and high PO4).

Right or wrong, in end stage renal disease just assume that whatever the kidney did before it no longer does. No PO4 secretion, no vitamin D production, no Ca re-absorption. That right there intuitively gets you to high PO4, Low Ca.

thanks @alicealicealice I also came across in FA that alkaline phosphatase is increased in secondary hyperPTH. This makes sense-I was wondering if you knew if that rule applied to primary and tertiary hyperPTH. On the subject of tertiary hyperPTH, given your previous excellent explanation (thanks for that), I would infer that even though calcium is now increased (this is the definition of conversion from secondary to tertiary hyerPTH), that the phosphate is still in fact low. It is possible that the phosphate is now high though because the only reason calcium is increased must be due to massive Ca reabsorption (kidneys still dont work, therefore no D, must be coming from the bone); if that is the case, then phosphate could in fact be elevated in this situation as well. What do you think? I could see phosphate going either way
 
thanks @alicealicealice I also came across in FA that alkaline phosphatase is increased in secondary hyperPTH. This makes sense-I was wondering if you knew if that rule applied to primary and tertiary hyperPTH. On the subject of tertiary hyperPTH, given your previous excellent explanation (thanks for that), I would infer that even though calcium is now increased (this is the definition of conversion from secondary to tertiary hyerPTH), that the phosphate is still in fact low. It is possible that the phosphate is now high though because the only reason calcium is increased must be due to massive Ca reabsorption (kidneys still dont work, therefore no D, must be coming from the bone); if that is the case, then phosphate could in fact be elevated in this situation as well. What do you think? I could see phosphate going either way

Not 100% sure by the Tertiary HyperPTH in ESRD is due to secretion of PTH by the parathyroids completely independent of serum calcium, i.e. a complete loss of regulatory feedback because the PTH has been pounded so long it stops listening. Edit: these patients will have hypercalcemia.

In general, due to your inability to excrete PO4, at no point in the normal natural history ESRD does a patient become Hypophosphatemic. It can be iatrogenically induced, but at our level I think Kidney failure = High phosphate till the end unless you treat it, because your body absorbs it avidly, its in most of our diet, its pouring out of your bones do to PTH, and theres just no way to get it out besides dialysis or in your poop using Rx binders.

Someone please correct me if Im wrong...also I think this is beyond the scope of step1, but nevertheless worth discussing.
 
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Not 100% sure by the Tertiary HyperPTH in ESRD is due to secretion of PTH by the parathyroids completely independent of serum calcium, i.e. a complete loss of regulatory feedback because the PTH has been pounded so long it stops listening. Clinically this does not manifest as a high calcium per se, but what happens is that the patients PTH does not drop despite you giving them calcium in the form of activated Vitamin D.
Basically, it is just the natural history of ESRD if you catch it to late. A Patient comes is with a GFR or 10, a PTH int eh 100s, hypocalcemic and hyperphosphatemic. You replete their calcium but the PTH doesn't budge = tertiary hyperPTH.

In general, due to your inability to excrete PO4, at no point in the normal natural history ESRD does a patient become Hypophosphatemic. It can be iatrogenically induced, but at our level I think Kidney failure = High phosphate till the end unless you treat it, because your body absorbs it avidly, its in most of our diet, its pouring out of your bones do to PTH, and theres just no way to get it out besides dialysis or in your poop using Rx binders.

Someone please correct me if Im wrong...also I think this is beyond the scope of step1, but nevertheless worth discussing.

Ok, just as an fyi according to FA and other sources there is hypercalcemia in tertiary hyperPTH. I actually dont think tertiary hyperPTH is a very testable item as it is pretty hard to distinguish from secondary. But i missed a pretty easy question on an NBME related to this so Im trying to hit that concept hard. I agree that you will be hyperphosphatemic all the way even in tertiary. Thanks for your help
 
Yeah you're right even in ESRD they will have hypercalcemia. Thanks, I'll revise above. Also a search shows that a common scenario for teritiary hyperPTH is after renal transplant presumably for ESRD


Pathophysiology


Tertiary hyperparathyroidism is observed most commonly in patients with chronic secondary hyperparathyroidism and often after renal transplantation. The hypertrophied parathyroid glands fail to return to normal and continue to oversecrete parathyroid hormone, despite serum calcium levels that are within the reference range or even elevated. In these cases, the hypertrophied glands become autonomic and cause hypercalcemia, even after withdrawal of calcium and calcitriol therapy. They also may become resistant to calcimimetic treatment.[31, 32]This type of tertiary disease is particularly dangerous because the phosphate level is often elevated. If the calcium value multiplied by the phosphate value yields a high product, diffuse calcinosis may occur.
 
Yeah you're right even in ESRD they will have hypercalcemia. Thanks, I'll revise above. Also a search shows that a common scenario for teritiary hyperPTH is after renal transplant presumably for ESRD

Pathophysiology


Tertiary hyperparathyroidism is observed most commonly in patients with chronic secondary hyperparathyroidism and often after renal transplantation. The hypertrophied parathyroid glands fail to return to normal and continue to oversecrete parathyroid hormone, despite serum calcium levels that are within the reference range or even elevated. In these cases, the hypertrophied glands become autonomic and cause hypercalcemia, even after withdrawal of calcium and calcitriol therapy. They also may become resistant to calcimimetic treatment.[31, 32]This type of tertiary disease is particularly dangerous because the phosphate level is often elevated. If the calcium value multiplied by the phosphate value yields a high product, diffuse calcinosis may occur.
Yes, I actually saw that yesterday as well, I should have mentioned the renal txp thing. I think the only way tertiary PTH would show up on the exam is in the context of a post-renal transplant. However, while that paragraph mentioned the phosphate level being elevated (man, that phosphate is really messing everythinggg up), I still think you have a renal transplant your phosphate would be normal or low in tertiary--that line must have been referring to tertiary hyperPTH resulting from CHRONIC secondary hyperPTH without a renal transplant.
 
Yes, I actually saw that yesterday as well, I should have mentioned the renal txp thing. I think the only way tertiary PTH would show up on the exam is in the context of a post-renal transplant. However, while that paragraph mentioned the phosphate level being elevated (man, that phosphate is really messing everythinggg up), I still think you have a renal transplant your phosphate would be normal or low in tertiary--that line must have been referring to tertiary hyperPTH resulting from CHRONIC secondary hyperPTH without a renal transplant.

Yeah I totally see what you're saying: after the transplant the patient has functioning kidneys but high PTH, so in that case (apparently the most common way to see tertiary hyperPTH) a low normal phosphate is to be expected, I think thats right
 
Bumping this thread but just want to make sure I understand this concept clearly for an upcoming test. The reason Ca2+ is low but PO4 3- is high in renal failure is bc the renal failure causes diminished excretion of phosphate, which then increases serum levels of phosphate. And serum phosphate binds to free calcium, lowering serum levels of calcium. I got this from Pathoma (for secondary parathyroidism) but the explanation is different from what's been discussed here. Is this perhaps the actual reason for why calcium is low in CKD-MBD?
 
Bumping this thread but just want to make sure I understand this concept clearly for an upcoming test. The reason Ca2+ is low but PO4 3- is high in renal failure is bc the renal failure causes diminished excretion of phosphate, which then increases serum levels of phosphate. And serum phosphate binds to free calcium, lowering serum levels of calcium. I got this from Pathoma (for secondary parathyroidism) but the explanation is different from what's been discussed here. Is this perhaps the actual reason for why calcium is low in CKD-MBD?

To me it seems like this is decent reasoning (correct me if I'm wrong):
1. Kidney damage --> 1-alpha-hydroxylase isn't functioning correctly --> low vitD
2. Low vitD causes a decrease in Ca2+ and PO4 from GIT
3. Low Ca2+ leads to increase in PTH
4. PTH causes increased resorption of Ca2+ and PO4 from bone
5. Note: Most Ca2+ is excreted in the feces, while the principal mech for PO4 excretion is through the kidneys!! PO4 will have an issue exiting the body and will therefore build up as its taken out of bone. And in reference to Ca2+, hyperphosphatemia can lead to precipitation of phosphate with Ca2+ in tissues, reducing free serum calcium levels. PO4 also stimulates osteocytes and osteoclasts to release FGF-23, which, along with high phosphate levels, reduces calcitriol synthesis. Low calcitriol decreases intestinal Ca2+ and PO4 reabsorption. So, this worsens the hypocalcemia, but doesn't really decrease PO4 levels because the kidney is diseased.
 
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