increase PTH in chronic renal failure?

[cali7925]

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Why is there increased PTH in chronic renal failure? Could anyone help me out with the mechanism behind this?

 

[dynx]

you can't think this one through?
What things regulate PTH?
Which one of these things is unable to be excreted in renal failure?
There's your answer.

 

[16846]

you can't think this one through?
What things regulate PTH?
Which one of these things is unable to be excreted in renal failure?
There's your answer.

I'll take a stab at phosphate?

 

[Idiopathic]

Thats correct. While calcium is a major stimulus also for PTH release (espceially with normal renal fxn), and calcium can be down (due to vitamin D deficiency), phosphate excess is the more important stimulus for PTH release in this case.

 

[RS6]

The mechanism by which PTH increases secondary to renal disease is several fold. (btw, this is a mechanism of secondary hyperparathyroidism)

1. Renal disease causes the PTH molecule to no longer stimulate the receptor for active resorption of calcium in the distal tubule. (Remember the PTH sensitive calcium channel located here that is activated via cAMP.) Therefore, calcium will be excreted in the urine because it is not actively reabsorped and serum calcium will decrease causing the compensatory rise in PTH.

2. Renal disease also causes the inability of the kidney to excrete phosphate. Not only because it cannot secrete the phosphate but also becasue the kidney is no longer sensitive to PTH. Remember that the PTH molecule is responsible for inhibiting renal phosphate reabsorption in the PCT, this is called the "phosphaturic effect". (It acts via the cAMP pathway that is actually located within the lumen of the PCT. You can get a urinary cAMP level that will tell you if this mechansim of reducing serum phosphate is working properly or not.) Without this phosphate resorption inhibition, phosphate will continue to be reasborbed and cause a rise in serum phosphate. The rise of phosphate levels in the serum causes a reciprocal decrease in serum calcium.

3. But the most important mechanism by which the PTH is increased secondary to renal disease is due to the fact that the kidney can no longer convert 25-Vitamin D into it's active form 1,25-Vitamin D because the enzyme 1-alpha hydroxylase is no longer functioning. This then leads to a decreased intestinal absorption of calcium because active 1,25-Vitamin D is needed. The low calcium causes the compensatory rise in PTH.

Overall, the chronic low calcium and the elevated PTH will cause hyperplasia of the PTH glands and can result in some serious side effects. The most important of which is Renal Osteodystrophy. The high levels of PTH will cause the bones to actively turnover by acting directly on the osteoblasts. This increased bone turnover causes bone weakness and instability. You can see this on X-Ray as many bony lesions. You can also get an alkaline phosphatase, level which will be elevated.

Hope this helps.

 

[dynx]

Hmmmm, the idea sounds good but the details are a bit skewed. The major factor is phosphate retention due to decreased filtered load of phosphate, not in ability to NOT reabsorb phosphate. If you decrease intake of phosphate in proportion to your decrease in GFR you can pretty much eliminate the rise in PTH seen in renal failure. Everything else is secondary to this...the loss of Vitamin D activation is due to inhibition by hyperphospatemia (an overall minor effect till GFR is bottomed out, I think this effect isn't even consistant untill a GFR of about 30)...the decrease in Ca++ is mostly secondary to binding by phosphate but there is also some evidence of decreased feedback inhibition of parathyroid Ca receptors so that what calcium there is present does not have as much of an effect as it should in lowering PTH. That last sentance my be a little convoluted but I think this is what you were trying to refer to in #1.

The mechanism by which PTH increases secondary to renal disease is several fold. (btw, this is a mechanism of secondary hyperparathyroidism)

1. Renal disease causes the PTH molecule to no longer stimulate the receptor for active resorption of calcium in the distal tubule. (Remember the PTH sensitive calcium channel located here that is activated via cAMP.) Therefore, calcium will be excreted in the urine because it is not actively reabsorped and serum calcium will decrease causing the compensatory rise in PTH.

2. Renal disease also causes the inability of the kidney to excrete phosphate. Not only because it cannot secrete the phosphate but also becasue the kidney is no longer sensitive to PTH. Remember that the PTH molecule is responsible for inhibiting renal phosphate reabsorption in the PCT, this is called the "phosphaturic effect". (It acts via the cAMP pathway that is actually located within the lumen of the PCT. You can get a urinary cAMP level that will tell you if this mechansim of reducing serum phosphate is working properly or not.) Without this phosphate resorption inhibition, phosphate will continue to be reasborbed and cause a rise in serum phosphate. The rise of phosphate levels in the serum causes a reciprocal decrease in serum calcium.

3. But the most important mechanism by which the PTH is increased secondary to renal disease is due to the fact that the kidney can no longer convert 25-Vitamin D into it's active form 1,25-Vitamin D because the enzyme 1-alpha hydroxylase is no longer functioning. This then leads to a decreased intestinal absorption of calcium because active 1,25-Vitamin D is needed. The low calcium causes the compensatory rise in PTH.

Overall, the chronic low calcium and the elevated PTH will cause hyperplasia of the PTH glands and can result in some serious side effects. The most important of which is Renal Osteodystrophy. The high levels of PTH will cause the bones to actively turnover by acting directly on the osteoblasts. This increased bone turnover causes bone weakness and instability. You can see this on X-Ray as many bony lesions. You can also get an alkaline phosphatase, level which will be elevated.

Hope this helps.

 

[RS6]

I just read an article explicitly stating that high levels of phosphate directly inhibit the 1-hydroxylation reaction. In addition, there is a loss of the enzyme itself seen in renal disease. Both of these mechanisms cause the decreased activation of vitamin D to it's active form, which will cause low calcium and a rise in PTH. So, I guess we are both right in a way. Thanks dynx for pointing out that hyperphosphatemia has a direct inhibitory effect on the 1-hydroxylation reaction.

Also, I would like to add one thing about when we see hyperphosphatemia in renal disease. And this has to do with the phosphaturic effect I mentioned earlier. It is only when our GFR falls to around 20 to 30 that phosphate reabsorption is maximally suppressed and we start to see a rise in phosphate levels. i.e. Our kidneys have lost the ability to excrete phosphate in light of hyperphosphatemia because the increasing levels of PTH, which promotes phosphate excretion (via the phosphaturic effect), have reached their 'Vmax.' So in actuality, it is the reduced GFR that is the main contributor of elevated phosphate levels, like dynx said. However, just be aware that our kidney's have an extraordinary ability to regulate phosphate balance up until sever renal disease.

Bottomline, dynx is right. Everything we see - decreased active vitamin d, decreased hydroxylation, elevated PTH, low calcium - is all secondary to hyperphosphatemia via multiple mechanisms.

 

[cali7925]

thank you both so much....u are very good teachers. I have one more question though.....in chronic renal failure, is the PCT still able to reabsorb phosphate? Thank you both!

I just read an article explicitly stating that high levels of phosphate directly inhibit the 1-hydroxylation reaction. In addition, there is a loss of the enzyme itself seen in renal disease. Both of these mechanisms cause the decreased activation of vitamin D to it's active form, which will cause low calcium and a rise in PTH. So, I guess we are both right in a way. Thanks dynx for pointing out that hyperphosphatemia has a direct inhibitory effect on the 1-hydroxylation reaction.

Also, I would like to add one thing about when we see hyperphosphatemia in renal disease. And this has to do with the phosphaturic effect I mentioned earlier. It is only when our GFR falls to around 20 to 30 that phosphate reabsorption is maximally suppressed and we start to see a rise in phosphate levels. i.e. Our kidneys have lost the ability to excrete phosphate in light of hyperphosphatemia because the increasing levels of PTH, which promotes phosphate excretion (via the phosphaturic effect), have reached their 'Vmax.' So in actuality, it is the reduced GFR that is the main contributor of elevated phosphate levels, like dynx said. However, just be aware that our kidney's have an extraordinary ability to regulate phosphate balance up until sever renal disease.

Bottomline, dynx is right. Everything we see - decreased active vitamin d, decreased hydroxylation, elevated PTH, low calcium - is all secondary to hyperphosphatemia via multiple mechanisms.

 

[RS6]

Chronic renal disease means that the kidney is no longer doing it's job. (i.e. it is no longer able to maintain an adequate GFR and clearance to filter the body's blood and maintain certain electrolyte balances, phosphate being one of them)

Phosphate is completely filtered across the glomerular membrane. And normally about 85% to 95% of it is reabsorbed in the PCT. When renal disease occurs, our GFR is reduced and we start holding on to phosphate (and other electrolytes). Because of this elevation in blood phosphate levels, our kidneys start getting rid of the excess phosphate. The way our body does this is via the increase in PTH, which causes the inhibition of phosphate reabsorbtion in the PCT (the phosphaturic effect). The hyperPTH state can lower the reabsorbtion of phosphate to as low as 15%. Therefore, this is a good thing because now we are starting to get rid of phosphate by inhibiting reabsorption. This remains effective until about a GFR of about 25 to 30 ml, when the hyperPTH has reached it's max and can no longer fully compensate for the elevated phosphate. This is when we start to see consequences of hyperPTH, with renal osteodystrophy being the main one.

So to answer your question, i guess the kidney still can reabsorb a little phosphate in the PCT. It will still reabsorb 10% to 15% of the phosphate in the PCT, but my guess is that this is purely obligatory. I mean, the kideny really doesn't want to reabsorb it but might have to, due to the concentration gradient of phosphate generated between the lumen of the kidney and the blood in the peritubular capillaries. However, this is not that relevant and will not be extensitvely tested on step 1. They are more interested in renal osteodystrophy. Don't worry about all the little details.

Hope this helps and good luck....

 

[Command]

The mechanism by which PTH increases secondary to renal disease is several fold. (btw, this is a mechanism of secondary hyperparathyroidism)

1. Renal disease causes the PTH molecule to no longer stimulate the receptor for active resorption of calcium in the distal tubule. (Remember the PTH sensitive calcium channel located here that is activated via cAMP.) Therefore, calcium will be excreted in the urine because it is not actively reabsorped and serum calcium will decrease causing the compensatory rise in PTH.

2. Renal disease also causes the inability of the kidney to excrete phosphate. Not only because it cannot secrete the phosphate but also becasue the kidney is no longer sensitive to PTH. Remember that the PTH molecule is responsible for inhibiting renal phosphate reabsorption in the PCT, this is called the "phosphaturic effect". (It acts via the cAMP pathway that is actually located within the lumen of the PCT. You can get a urinary cAMP level that will tell you if this mechansim of reducing serum phosphate is working properly or not.) Without this phosphate resorption inhibition, phosphate will continue to be reasborbed and cause a rise in serum phosphate. The rise of phosphate levels in the serum causes a reciprocal decrease in serum calcium.

3. But the most important mechanism by which the PTH is increased secondary to renal disease is due to the fact that the kidney can no longer convert 25-Vitamin D into it's active form 1,25-Vitamin D because the enzyme 1-alpha hydroxylase is no longer functioning. This then leads to a decreased intestinal absorption of calcium because active 1,25-Vitamin D is needed. The low calcium causes the compensatory rise in PTH.

Overall, the chronic low calcium and the elevated PTH will cause hyperplasia of the PTH glands and can result in some serious side effects. The most important of which is Renal Osteodystrophy. The high levels of PTH will cause the bones to actively turnover by acting directly on the osteoblasts. This increased bone turnover causes bone weakness and instability. You can see this on X-Ray as many bony lesions. You can also get an alkaline phosphatase, level which will be elevated.

Hope this helps.

Thanks, this was a really good explanation.