Explain the old and new trade-off hypothesis regarding pathophysiology of CKD-MBD?
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Ahmed Altalawy
Old hypothesis: -Hyperphosphatemia and hypocalcemia are the only stimulants or drivers of PTH stimulation or secretion. -Secondary hyperparathyroidism occurs only in late CKD New hypothesis:
-PTH could be stimulated separately from increase phosphorus level. -As CKD progress there is a decrease in renal klotho, and increase in FGF-23 and there is a resistance to FGF-23 that will not be able to doing its action as a phosphaturic factor any more.
Although CKD–MBD generally starts early in the course of the CKD,but it becomes apparent only when GFR falls below 45–50 mL/min/1.73 and it worsens with its progression (stage 3b–5)
Since Albright’s first studies on the close relationship between calcium, phosphate, and parathyroid hormone (PTH).
In the 1960 original exposition of the “intact nephron hypothesis Briker et al. stated that although kidney disease consists of a diminished number of nephrons, the remaining nephrons undergo adaptive changes and increase their function to compensate for the damaged nephrons and maintain homeostasis of any given solute. These adaptations consist of an increase in single nephron GFR, decreased tubular reabsorption, and increased tubular secretion, but they can actually carry some consequences on other systems and result in abnormalities of the uremic state (the “trade-off theory”)
And This pathophysiologic theory affects CKD–MBD as well. In fact, during the course of CKD, the progressive decrease in GFR leads to phosphate retention; however, it has been demonstrated that serum phosphate level may remain normal until the advances stages of CKD due to a compensatory increase in PTH and (FGF-23).
Recently FGF-23 and its coreceptor Klotho has resulted in a new perspective of the “trade-off” theory. FGF-23 has both short-term beneficial (reduction in serum phosphate level) and long-term adverse effects, as its circulating concentration progressively increases while GFR falls down, The current understanding is that, as CKD progresses, Klotho expression in the kidney decreases and FGF-23 rises. Higher levels of FGF-23 maintain serum phosphate at normal levels until the final stages of CKD, Calcitriol decreases and PTH subsequently increasese achieving levels that are several hundred times the normal range in late CKD stages.
Thus, FGF-23 is likely involved in the development of SHPT. However, despite the development of new theories that should radically change the therapy for CKD-MBD, as its treatment are observational and have focused on the control of phosphate, PTH, calcium, and vitamin D levels with diet, and the use of phosphate binders, vitamin D analogs, or calcimimetics in order to avoid or attenuate SHPT. But this approach has been associated with frustrating results Current guidelines have been based on survival and quality of life making pain relief and improving quality of life and mortality the main endpoints of a clinical trial, instead of focusing exclusively on the control of calcium,phosphate, and PTH
In the previous pathophysiology, it was only recognized the relationship between calcium, phosphate, and PTH, and then found out hypocalcemia was the primary event caused by vitamin D deficiency which followed by intestinal calcium absorption. In 1960 slatopolsky and bricker were invented to compromise the old theory. And long gap history of CKD-MBD. So the identification of IGF-23 and klotho helped to explain why PTH would elevate in the absence of hyperphosphatemia—and stated shining in new theory,as the CKD advances klotho expression decreases and IGF23 rises and maitain serum phosphate at the normal level
The old (trade- off ) theory relies on the following steps:
– Decreased phosphorus excretion, increased phosphorus level–> increased PTH
– Decreased vit D synthesis –> decrease calcium level and increase PTH level
– Treatment based on this theory focuses on controlling the level of serum calcium, phosphorus, iPTH, and vit D
The new hypothesis:
– The mechanism better defines the start with Decreased klotho expression and increase in the phosphaturic hormone FGF 23 which explains normal phosphorus level with increased PTH level in early CKD stages
– Treatment concepts based on this theory aimed at pain relief, the better quality of life, and less mortality
( old Trade off theory)
Phosphate retention → hyperphosphatemia → hypocalcemia → ↑ PTH
( But Phosphate retention occurs in later stages but ↑ PTH occurs in earlier stages so it doesn’t explain the beginning of the process )
. ( New theory)
↓ klotho → ↑ FGF 23 → normal P despite ↓ renal mass
+ ↓ vit D , ↓ Ca → ↑ PTH earlier to hyperphosphatemia
So the difference is the arrangement of events and the beginning of the process
the framework is the same but there is a new player in new hypothesis. FGF-23 plays a major role in the new one, but no role in the old. both of them starts with nphron mass reductons causing phosphate retention. in the new one this will lead to increase FGF-23 secretion by osteocytes. FGF-23 has a phosphoturic effect, helping to maintain po4 homestasis, but on other hand will reduce calcitrol production, which will result in hyperparathyroidism
Old hypothesis:
-Hyperphosphatemia and hypocalcemia are theonlystimulants or drivers of PTH stimulation or secretion. -Secondary hyperparathyroidism occurs only in late CKD
New hypothesis:
-PTH could be stimulated separately from increase phosphour level.
-As CKD progress there is a decrease in renal klotho, and increase in FGF-23 and there is a resistance to FGF-23 that will not be able to doing its action as a phosphaturic factor any more.
The concept was that hypocalcemia was the primary event, caused by vitamin D deficiency and accompanied by a decreased intestinal calcium absorption.
In the 1960s, Slatopolsky and Bricker coined the expression trade-off for the theory that explained the elevations in serum PTH through phosphate retention, hyperphosphatemia, and the consequent hypocalcemia. As renal function declines, PTH rises. Accordingly, secondary hyperparathyroidism (SHPT) would be present only at later stages of CKD, which is not the case in the clinical practice.
The identification of FGF-23 and Klotho helped to explain why PTH levels would rise in the absence of hyperphosphatemia and resulted in a new perspective of the trade-off theory. The current understanding is that, as CKD progresses, Klotho expression in the kidney decreases and FGF-23 rises. Higher levels of FGF-23 maintain serum phosphate at normal levels until the final stages of CKD, as calcitriol decreases and PTH subsequently increases.
FGF23 is a ~30 kD protein that is proteolytically processed to a ~18 kD N-terminal fragment and a ~12 kD C-terminal fragment. The receptor-binding domain of FGF23 is present in the N-terminus.
FGF23 is able to suppress the expression of NaPi-2a and NaPi-2c cotransporters either directly or through affecting parathyroid hormone activity, which induces urinary phosphate excretion by reducing NaPi-2a and NaPi-2c co transporter activities.
In proximal renal tubules, blood-borne FGF23 binds to FGFR-klotho complexes and directly activates extracellular signal-regulated kinase (ERK)1/2 and serum/glucocorticoid-regulated kinase (SGK)-1 signals. Subsequently, SGK-1 phosphorylates the Na+/H+ exchange regulatory cofactor (NHERF)-1 to down-regulate membrane expression of the key sodium phosphate cotransporter NaPi-2a, thus leading to an increase in urinary phosphate excretion.
Loss of membrane-bound klotho expression limits FGF23-stimulated signal transduction through FGFR-klotho complexes. It has been shown that a specific deletion of klotho in proximal renal tubules was unable to increase renal phosphate excretion in vivo, suggesting that the effect of FGF23 on phosphate excretion is limited by proximal tubular klotho deficiency.
Furthermore, FGF23 suppresses renal 1α-hydroxylase expression, which is the key enzyme responsible for 1,25(OH)2D production, by a klotho-dependent signalling mechanism in proximal renal tubules.
In addition, soluble klotho directly regulates phosphorus excretion in the kidney and participates in systemic mineral homeostasis by regulating 1α-hydroxylase activity and parathyroid hormone (PTH) and FGF23 secretion.
These results suggest that klotho deficiency limits its regulation of FGF23 production and hyperphosphataemia remains the principal regulator of FGF23 secretion in CKD.
In addition, it has been identified that as with the mineral parameters, FGF23 and phosphate are increased, while klotho and 1,25(OH)2D are decreased in CKD, especially in early stages, except serum phosphate.
Old hypothesis
1/Recognition that Calcium , Phosphate and PTH are related.
2/ Then it was thought that low calcium was triggered by Vitamin D deficiency and decreased intestinal absorption. It did not involve phosphate
3 Later on the trade-off theory was coined and it showed that rising PTH was due to hyperphosphataemia , and hypocalcaemia was a consequence of that.
4 the fault is this theory is that CKD MBD should start at very late stages of CKD and not earlier stages of CKD. So there was a need for further research
New trade off theory
It tries to explain why CKD MBD manifestation occurs at earlier stages of CKD via multiple pathways. As ckd progressed klotho expression decreases and FGF 23 increases which keeps phosphate in normal range of CKD. FG23 decreases calcitriol absorption until eventually PTH increases with consequent decrease in renal mass. It also includes the osteocyte as principal driver of bone turnover . FGF23 excess or deficiency decreases bone mineralisation. FGF23 and Klotho decreases bone formation by Dickkopft related protein 1(DKK1) (a Wnt pathway inhibitor. Dentin matrix protein 1 (DMP1) and X-linked phosphate-regulating endopeptidase (PHEX), two osteocyte-specific proteins, are capable of negatively regulat[1]ing local FGF-23 expression. The other agent is sclerotin that is linked to decreased bone formation and more mineralisation defect with increasing level. CKDMBD can be causing inflammation and that can worsen it as well as inflammation worsening it. CKDMBD is also related to sleep quality and duration and bone turnover.
The old trade-off theory:
Explain the elevated PTH through hypocalcemia as a primary event, which is caused by vitamin D deficiency accompanied by a decreased intestinal calcium absorption. Then the theory coined retention of phosphate and hyperphosphatemia with consequent hypocalcemia as trigger for elevated serum PTH at later stages of CKD. Which is not what happened actually in clinical practice.
The New trade-off theory :
As CKD progresses , Klotho expression decreased in the kidney.
FGF-23 increase which will control phosphate at normal level until the final stage of CKD , when PTH start to increases ,as cacitriol start to decrease.
The aim of the new theory is to focusing on decreasing the pain and improving quality of life and survival instead of concentrating only on controlling ca , p, and PTH level.
Old hypothesis :
-The close relationship between calcium, phosphate and PTH
was recognized by a century ago.
– Hypocalcemia was the main event caused by Vitamin D deficiency and decreased intestinal calcium absorption.
– In the 1960s, Latopolsky and Bricker invented the term “trade-off to explain their hypothesis that the causes of an increase in PTH level are hyperphosphatemia and hypocalcemia.
– PTH levels rise when renal function deteriorates. consequently,
– Secondary hyperparathyroidism (SHPT) is only present in later stages of CKD
New hypothesis:
– Focus on controlling phosphate, PTH, calcium, and vitamin D levels with diet and phosphate use
– As CKD progresses, Klotho expression in the kidneys decreases and FGF-23 increases. When calcitriol levels fall and PTH levels rise, higher levels of FGF-23 maintain normal serum phosphate levels.
– Current policy is not based on surrogate markers but on survival
Old hypnosis: explain the role of phosphate in SHPT:
The retained phosphate as a result of decreased in nephron mass leads to a triad of hyperphosphatemia, low calcitriol production by the kidney and hypocalcaemia which are well-known stimuli for PTH secretion.
Increased PTH:
Restored normal Ca through actions on target organs.
Corrected P by ↓ tubular phosphate reabsorption (phosphaturic hormone).
So SHPT is the price paid for correction of Ca and phosphate.
New concept:
Hyperphosphatemia had been considered as the main trigger of SHPT, prior to the discovery of FGF23.FGF23 has been shown to be an early feature of CKD-MBD.
Hyperphosphatemia doesn’t became evidence before CKD4 because of:
Increased of circulatory FGF 23; FGF23 is central hormone in PO4 and vit D homeostasis produced by osteocytes, requires co-factor klotho for optimal binding and function.
Compensatory hyperparathyroidism.
at early stage of CKD
↓GFR
↓
↑FGF-23
↓
Klotho-FGF-23 complex
↓ ↓
↓ NPT2a ↓ 1α hydroxylase
↓ ↓
↓ Renal Po4 excretion ↓ calcitriol
↓
↓ Intestinal absorption of Ca and Po4
The triad of low levels of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion, results in skeletal changes. With progressive declining of kidney function and subsequent of events leading to SPTH.
These discovery ameliorate or stop/delay the development the CKD-MBD
CKD-MBD disordered dtarted with hypocalcemia, as a result of vit D deficiency, which cause reduce intestinal Ca absorption.
In 1960s, Slatopolsky and Bricker, desinged a trade-off theoty , that explain secondary hyperparathyroidism, as a result of phosphate retention, following hypocalcemia.
For decades, there was a gap in the natural history of CKD-MBD, and when the pathological process take place.
The pathology occur contain reduction in Klotho in the impaird kidney, with a resultant increase in FGF-23 to maintain normal phosphorus level till advancing CKD and SHPT.
As this theory are clinically prevalent, it lead to lower traget of management and challenges, in focusing of control PTH,P04, Ca and vit D level, by using P04 binderand vitD analoque or calcimimetics.
This funstration make a study desingner to focus on survival and quality of life other than focusing on serum biochemical and bone profile level.
The New hypothesis:
This new view of pathophysiology of CKD-MBD, should change the way we evaluate and treat bone and cardiovascular disease in CKD patients.
Focusing in improving quality of life and survial.
Causes of death in chroni chemodialysis patient are non-related to hemodialysis, so studies are focusing in this risk factors (cardiovascular, sudden death, cardiac arrysthmia, acute MI, Periphral vascular insufficiency, and stroke, and measures ti reduce it.
Undestanding the pathological process of CKD-MBD and how it can affect negatively patient quality of life, (fracutre, e.t.c..).
Improving pain and patient performance to prevent disability, rather tahn focusing on the lab results.
Recent studies show that bone changes start earlier than previously thought in CKD.
Pereira et al.;
show increase in FGF-23, DMP-1, and MEPE in bone biopsies taken from pediatric patient with CKD.
Higher expression in FF-23 associated with accumulation of osteoid and inhibition of mineralization.
8.Unexpected direct mechanism of action for FGF-23 on the skeletonis via its interaction with Klotho. 9.Recent study show that; the level of Klotho expression in osteocytes is about 500 times lower than in kidneys. 10.Tne mechansim of how FGF-23 and Klotho inhibit bone formation, is by stimulation of Dickkopf-related protein (DKK1), a W nt pathway inhibitor. 11.Activation of W nt pathway increases bone formation and decrease bone resorption. 12.In retrospective study of patient with SHPT on dialysis, compared bone biopsies in patient with and without fracture, they found that; those with bone fracture had a higher expression of sclerstin in cortical bone, lower formation rate, and greater mineralization defect. 13. This open an window of sclerostin inhibition might be a hope to the way to improve both bone remodeling and volume in CKD, and by the end of theday, reduces the risk of fractures. 14.Observation study on effect of scostin on mortality, show a conflicting results, and doubt about sclerostin and vascular calcification, however in one study show that womwn with osteoporosis tretade with anti-sclerostin antibodies, develop cardiovascular events.
The old theory
-Close relation among calcium, phosphorus and PTH then
-Hypocalcemia is the primary event caused by deficiency in vitamin D which causes decrease in intestinal absorption of calcium
-the elevation of PTH caused by the hyperphosphatemia (from phosphorus retention) and subsequently Hypocalcemia and the as ckd progress there will be secondary hyperparathyroidism on later stages
The new theory
– when GFR decrease the klotho expression decrease and subsequently increase in the FGF-23 secretions which act as phosphaturic agent to keep normal level of phosphorus and decrease level of vitamin D level with decrease calcium and subsequently increase PTH
-the question now if the control of calcium, phosphorous and PTH will change the clinical outcome of MBD
OLD THEORY:
the stimulus for hyperparathyroidism is hypocalemia and hyperphosphatemia due to vitamin D deficiency (lack of 1 hydroxlation on the kidney )
new concept :
the process start early in ckd by release of FGF23 FROM OSTEOBLAST as phophaturic effect to increase phosphate excretion as increase dietary phosphate and reduction of nephron mass to maintain serum po4 within normal limit
FGF23 need klotho for his action which released from the kidney by time the klotho reduced
Vit. D deficiency causes a decrease in calcium absorption resulting in hypocalcemia.
hyperphosphatemia causes an elevation in PTH. therefore, 2ry hyperparathyroidism is present only in the later stages of CKD.
the guidelines were based on the control of surrogate markers.
the new trade-off hypothesis :
with CKD progression, FGF-23 expression increases and klotho expression decreases.
FGF-23 is a phosphaturic agent that maintains serum phosphate until the final stages of CKD. Also, it decreases Calcitriol and increases PTH. Therefore, the end result is 2ry hyperparathyroidism without hyperphosphatemia with the diagnosis of CKD-MBD in early CKD.
the current guidelines are not based on surrogate markers but on survival and quality of life.
Old concept: Elevation of serum PTH was mainly associated with hyperphosphatemia and hypocalcemia.
Ner concept: as CKD progresses Klotho expression in the kidney decreases and FGF-23 rises to maintain serum phosphate at normal level
hypothesis depends mainly on low Ca as a stimulus for HPT. So decreased calcium absorption from the GUT, induced by a low level of 1-25 vit D, will lead to high PTH.
New hypothesis:
in CKD KLOTHO expression in kidney decrease and FGF23 increase to maintain normal P at normal level until the final stage of CKD with decrease vit D AND increase PTH
iam proud of attend to this program
lot of new information
old concept hyperphosphatemia is major cause of increase synthesis of pth
new concept
involve kolotho level and fgf-23 factor and osteocyte role
relation between CKD-MBD and inflammatory process
comparison between loop deuritic and thiazide effect on ckd
the old hypothesis
mainly depend on ca and po4 homeostasis and its relation with vit D and PTH hormon
new hypothesis
the effect of kolotho on suppression of FGF23 even in eraly stage of ckd
also other inflammatory cytokines and its role in theses condition and effect of medications such as diuretics and hypoxia inducible factor as in ttt of anemia
I am really enjoying this article with a lot of new information which make me more confident in dealing with CKD-MBD.
The old concipt the main drive of PTH secretion is the hyperphophatemia which lead to increase secretion of PTH to secret the high Phosphorus ( PTH IS PHOSPHATURIC HORMON).then this drive will be shared later on by hypocalcemia.
The new trade off theory As the CKD progress the Kolotho level is decrease and the FGF 23 increase and this is the new drive for the PTH .SHPT is started from this point when the GFR is 40 to 45ml/mint and progress gradually and at this stage PTH increase even with normal phosphates level
The changes in the drive and changing of the PTH,Ca AND po4 is not only for the laporatory finding ,it is also in the chnges of the medications that have been used in dealing with high Phospherus and PTH level starting from the Aluminum chelating agent in early 1960 to ca chelatingg then phophates binder ending up recently with iron chelating tabs for phophore . With regard to the PTH Cinacalcit and Etacalcitide .
The old hypothesis says that the iPTH rise in response to hyperphophatemia and hypocalcemia. The secondary hyperparathyroidism should be only present on late stage CKD but this is not always the case.
New is that the new discovered FGF23 will raise on early stage CKD. This phosphouric hormone will maintain the phosphate hemostasis. This is why pth may rise in the abscence of hyperphophatemia.
This hypothesis depends mainly on hypocalcemia as a driver for high PTH. So decreased calcium absorption from the intestine, induced by a low level of 1-25 vit D, will lead to high PTH.
New trade-off hypothesis:
It happens in the early stages of CKD (as early as stage II) when klotho synthesis by the kidney is decreased. Kletho is an essential FGF-23 cofactor. So low klotho level will cause a rise in FGF-23 levels. FGF-23 is responsible for phosphate homeostasis. At an early stage of CKD, phosphate levels will be normal due to high FGF-23. The phosphate level will creep up with the decreased volume of nephrons with advanced CKD, even in the presence of high FGF-23. FGF-23 also inhibits 1-alpha hydroxylase, leading to a reduced level of 1-25 vit D. A low level of 1-25 vit D will decrease intestinal absorption of Ca and phosphate, and a low level of Ca will lead to high PTH.
There was a gap in the natural history of CKD-MBD for many years because there were no pathophysiological explanations for how this disease started.
The old concept:
Hypocalcemia, which is caused by a lack of vitamin D and a drop in calcium absorption in the gut, was thought to be the main problem.
Slatopolsky and Bricker came up with the term “trade-off” to describe their theory that high serum PTH levels were caused by phosphate retention, hyperphosphatemia, and the low calcium levels that followed.
As renal function declines, PTH rises. So, secondary hyperparathyroidism (SHPT) wouldn’t show up until the later stages of CKD, which isn’t what happens in real life.
The new theory:
The discovery of FGF-23 and Klotho helped explain why PTH levels would rise even when hyperphosphatemia wasn’t present. This gave the trade-off theory a new way to look at things.
As CKD gets worse, Klotho expression in the kidneys goes down and FGF-23 goes up, according to what we know now. Higher levels of FGF-23 keep serum phosphate levels normal until the end stages of CKD, when calcitriol levels drop and PTH levels rise.
Old hypothesis:
-Hyperphosphatemia and hypocalcemia are the only stimulants or drivers of PTH stimulation or secretion. -Secondary hyperparathyroidism occurs only in late CKD
New hypothesis:
-PTH could be stimulated separately from increase phosphorus level.
-As CKD progress there is a decrease in renal klotho, and increase in FGF-23 and there is a resistance to FGF-23 that will not be able to doing its action as a phosphaturic factor any more.
Although CKD–MBD generally starts early in the course of the CKD,but it becomes apparent only when GFR falls below 45–50 mL/min/1.73 and it worsens with its progression (stage 3b–5)
Since Albright’s first studies on the close relationship between calcium, phosphate, and parathyroid hormone (PTH).
In the 1960 original exposition of the “intact nephron hypothesis Briker et al. stated that although kidney disease consists of a diminished number of nephrons, the remaining nephrons undergo adaptive changes and increase their function to compensate for the damaged nephrons and maintain homeostasis of any given solute. These adaptations consist of an increase in single nephron GFR, decreased tubular reabsorption, and increased tubular secretion, but they can actually carry some consequences on other systems and result in abnormalities of the uremic state (the “trade-off theory”)
And This pathophysiologic theory affects CKD–MBD as well. In fact, during the course of CKD, the progressive decrease in GFR leads to phosphate retention; however, it has been demonstrated that serum phosphate level may remain normal until the advances stages of CKD due to a compensatory increase in PTH and (FGF-23).
Recently FGF-23 and its coreceptor Klotho has resulted in a new perspective of the “trade-off” theory. FGF-23 has both short-term beneficial (reduction in serum phosphate level) and long-term adverse effects, as its circulating concentration progressively increases while GFR falls down, The current
understanding is that, as CKD progresses, Klotho expression
in the kidney decreases and FGF-23 rises.
Higher levels of FGF-23 maintain serum phosphate at normal levels until the final stages of CKD,
Calcitriol decreases and PTH subsequently increasese achieving levels that are several hundred times the normal range in late CKD stages.
Thus, FGF-23 is likely involved in the development of SHPT.
However, despite the development of new theories that should radically change the therapy for CKD-MBD, as its treatment are observational and have focused on the control of phosphate, PTH, calcium, and vitamin D levels with diet, and the use of phosphate binders, vitamin D analogs, or calcimimetics in order to avoid or attenuate SHPT.
But this approach has been associated with frustrating results
Current guidelines have been based on survival and quality of life making pain relief and improving quality of life and mortality the main endpoints of a clinical trial, instead of focusing exclusively on the control of calcium,phosphate, and PTH
In the previous pathophysiology, it was only recognized the relationship between calcium, phosphate, and PTH, and then found out hypocalcemia was the primary event caused by vitamin D deficiency which followed by intestinal calcium absorption. In 1960 slatopolsky and bricker were invented to compromise the old theory. And long gap history of CKD-MBD. So the identification of IGF-23 and klotho helped to explain why PTH would elevate in the absence of hyperphosphatemia—and stated shining in new theory,as the CKD advances klotho expression decreases and IGF23 rises and maitain serum phosphate at the normal level
The old (trade- off ) theory relies on the following steps:
– Decreased phosphorus excretion, increased phosphorus level–> increased PTH
– Decreased vit D synthesis –> decrease calcium level and increase PTH level
– Treatment based on this theory focuses on controlling the level of serum calcium, phosphorus, iPTH, and vit D
The new hypothesis:
– The mechanism better defines the start with Decreased klotho expression and increase in the phosphaturic hormone FGF 23 which explains normal phosphorus level with increased PTH level in early CKD stages
– Treatment concepts based on this theory aimed at pain relief, the better quality of life, and less mortality
Great answer. Thanks Dr. Radwa
( old Trade off theory)
Phosphate retention → hyperphosphatemia → hypocalcemia → ↑ PTH
( But Phosphate retention occurs in later stages but ↑ PTH occurs in earlier stages so it doesn’t explain the beginning of the process )
. ( New theory)
↓ klotho → ↑ FGF 23 → normal P despite ↓ renal mass
+ ↓ vit D , ↓ Ca → ↑ PTH earlier to hyperphosphatemia
So the difference is the arrangement of events and the beginning of the process
Good explanation. Thanks Dr. Mohammed
the framework is the same but there is a new player in new hypothesis. FGF-23 plays a major role in the new one, but no role in the old. both of them starts with nphron mass reductons causing phosphate retention. in the new one this will lead to increase FGF-23 secretion by osteocytes. FGF-23 has a phosphoturic effect, helping to maintain po4 homestasis, but on other hand will reduce calcitrol production, which will result in hyperparathyroidism
Thanks Dr. Ahmed.
Old hypothesis:
-Hyperphosphatemia and hypocalcemia are theonlystimulants or drivers of PTH stimulation or secretion. -Secondary hyperparathyroidism occurs only in late CKD
New hypothesis:
-PTH could be stimulated separately from increase phosphour level.
-As CKD progress there is a decrease in renal klotho, and increase in FGF-23 and there is a resistance to FGF-23 that will not be able to doing its action as a phosphaturic factor any more.
Great job. Thanks Dr. Mahmoud.
The concept was that hypocalcemia was the primary event, caused by vitamin D deficiency and accompanied by a decreased intestinal calcium absorption.
In the 1960s, Slatopolsky and Bricker coined the expression trade-off for the theory that explained the elevations in serum PTH through phosphate retention, hyperphosphatemia, and the consequent hypocalcemia. As renal function declines, PTH rises. Accordingly, secondary hyperparathyroidism (SHPT) would be present only at later stages of CKD, which is not the case in the clinical practice.
The identification of FGF-23 and Klotho helped to explain why PTH levels would rise in the absence of hyperphosphatemia and resulted in a new perspective of the trade-off theory.
The current understanding is that, as CKD progresses, Klotho expression in the kidney decreases and FGF-23 rises. Higher levels of FGF-23 maintain serum phosphate at normal levels until the final stages of CKD, as calcitriol decreases and PTH subsequently increases.
FGF23 is a ~30 kD protein that is proteolytically processed to a ~18 kD N-terminal fragment and a ~12 kD C-terminal fragment. The receptor-binding domain of FGF23 is present in the N-terminus.
FGF23 is able to suppress the expression of NaPi-2a and NaPi-2c cotransporters either directly or through affecting parathyroid hormone activity, which induces urinary phosphate excretion by reducing NaPi-2a and NaPi-2c co transporter activities.
In proximal renal tubules, blood-borne FGF23 binds to FGFR-klotho complexes and directly activates extracellular signal-regulated kinase (ERK)1/2 and serum/glucocorticoid-regulated kinase (SGK)-1 signals. Subsequently, SGK-1 phosphorylates the Na+/H+ exchange regulatory cofactor (NHERF)-1 to down-regulate membrane expression of the key sodium phosphate cotransporter NaPi-2a, thus leading to an increase in urinary phosphate excretion.
Loss of membrane-bound klotho expression limits FGF23-stimulated signal transduction through FGFR-klotho complexes. It has been shown that a specific deletion of klotho in proximal renal tubules was unable to increase renal phosphate excretion in vivo, suggesting that the effect of FGF23 on phosphate excretion is limited by proximal tubular klotho deficiency.
Furthermore, FGF23 suppresses renal 1α-hydroxylase expression, which is the key enzyme responsible for 1,25(OH)2D production, by a klotho-dependent signalling mechanism in proximal renal tubules.
In addition, soluble klotho directly regulates phosphorus excretion in the kidney and participates in systemic mineral homeostasis by regulating 1α-hydroxylase activity and parathyroid hormone (PTH) and FGF23 secretion.
These results suggest that klotho deficiency limits its regulation of FGF23 production and hyperphosphataemia remains the principal regulator of FGF23 secretion in CKD.
In addition, it has been identified that as with the mineral parameters, FGF23 and phosphate are increased, while klotho and 1,25(OH)2D are decreased in CKD, especially in early stages, except serum phosphate.
Great answer Dr. Alaa. Thanks
Old hypothesis
1/Recognition that Calcium , Phosphate and PTH are related.
2/ Then it was thought that low calcium was triggered by Vitamin D deficiency and decreased intestinal absorption. It did not involve phosphate
3 Later on the trade-off theory was coined and it showed that rising PTH was due to hyperphosphataemia , and hypocalcaemia was a consequence of that.
4 the fault is this theory is that CKD MBD should start at very late stages of CKD and not earlier stages of CKD. So there was a need for further research
New trade off theory
It tries to explain why CKD MBD manifestation occurs at earlier stages of CKD via multiple pathways. As ckd progressed klotho expression decreases and FGF 23 increases which keeps phosphate in normal range of CKD. FG23 decreases calcitriol absorption until eventually PTH increases with consequent decrease in renal mass. It also includes the osteocyte as principal driver of bone turnover . FGF23 excess or deficiency decreases bone mineralisation. FGF23 and Klotho decreases bone formation by Dickkopft related protein 1(DKK1) (a Wnt pathway inhibitor. Dentin matrix protein 1 (DMP1) and X-linked phosphate-regulating endopeptidase (PHEX), two osteocyte-specific proteins, are capable of negatively regulat[1]ing local FGF-23 expression. The other agent is sclerotin that is linked to decreased bone formation and more mineralisation defect with increasing level. CKDMBD can be causing inflammation and that can worsen it as well as inflammation worsening it. CKDMBD is also related to sleep quality and duration and bone turnover.
Great answer Dr. Muhammad. Thanks
The old trade-off theory:
Explain the elevated PTH through hypocalcemia as a primary event, which is caused by vitamin D deficiency accompanied by a decreased intestinal calcium absorption. Then the theory coined retention of phosphate and hyperphosphatemia with consequent hypocalcemia as trigger for elevated serum PTH at later stages of CKD. Which is not what happened actually in clinical practice.
The New trade-off theory :
As CKD progresses , Klotho expression decreased in the kidney.
FGF-23 increase which will control phosphate at normal level until the final stage of CKD , when PTH start to increases ,as cacitriol start to decrease.
The aim of the new theory is to focusing on decreasing the pain and improving quality of life and survival instead of concentrating only on controlling ca , p, and PTH level.
Good job Asmaa.
Old hypothesis :
-The close relationship between calcium, phosphate and PTH
was recognized by a century ago.
– Hypocalcemia was the main event caused by Vitamin D deficiency and decreased intestinal calcium absorption.
– In the 1960s, Latopolsky and Bricker invented the term “trade-off to explain their hypothesis that the causes of an increase in PTH level are hyperphosphatemia and hypocalcemia.
– PTH levels rise when renal function deteriorates. consequently,
– Secondary hyperparathyroidism (SHPT) is only present in later stages of CKD
New hypothesis:
– Focus on controlling phosphate, PTH, calcium, and vitamin D levels with diet and phosphate use
– As CKD progresses, Klotho expression in the kidneys decreases and FGF-23 increases. When calcitriol levels fall and PTH levels rise, higher levels of FGF-23 maintain normal serum phosphate levels.
– Current policy is not based on surrogate markers but on survival
Great, thanks Rania.
Old hypnosis: explain the role of phosphate in SHPT:
The retained phosphate as a result of decreased in nephron mass leads to a triad of hyperphosphatemia, low calcitriol production by the kidney and hypocalcaemia which are well-known stimuli for PTH secretion.
Increased PTH:
So SHPT is the price paid for correction of Ca and phosphate.
New concept:
Hyperphosphatemia doesn’t became evidence before CKD4 because of:
at early stage of CKD
↓GFR
↓
↑FGF-23
↓
Klotho-FGF-23 complex
↓ ↓
↓ NPT2a ↓ 1α hydroxylase
↓ ↓
↓ Renal Po4 excretion ↓ calcitriol
↓
↓ Intestinal absorption of Ca and Po4
The triad of low levels of calcium, calcitriol and hyperphosphatemia further enhances excessive PTH secretion, results in skeletal changes. With progressive declining of kidney function and subsequent of events leading to SPTH.
These discovery ameliorate or stop/delay the development the CKD-MBD
Perfect, thanks Amna.
The old hypothesis in the treatment of CKD:
The New hypothesis:
8.Unexpected direct mechanism of action for FGF-23 on the skeletonis via its interaction with Klotho.
9.Recent study show that; the level of Klotho expression in osteocytes is about 500 times lower than in kidneys.
10.Tne mechansim of how FGF-23 and Klotho inhibit bone formation, is by stimulation of Dickkopf-related protein (DKK1), a W nt pathway inhibitor.
11.Activation of W nt pathway increases bone formation and decrease bone resorption.
12.In retrospective study of patient with SHPT on dialysis, compared bone biopsies in patient with and without fracture, they found that; those with bone fracture had a higher expression of sclerstin in cortical bone, lower formation rate, and greater mineralization defect.
13. This open an window of sclerostin inhibition might be a hope to the way to improve both bone remodeling and volume in CKD, and by the end of theday, reduces the risk of fractures.
14.Observation study on effect of scostin on mortality, show a conflicting results, and doubt about sclerostin and vascular calcification, however in one study show that womwn with osteoporosis tretade with anti-sclerostin antibodies, develop cardiovascular events.
Excellent explanation, thanks Kamal.
The old theory
-Close relation among calcium, phosphorus and PTH then
-Hypocalcemia is the primary event caused by deficiency in vitamin D which causes decrease in intestinal absorption of calcium
-the elevation of PTH caused by the hyperphosphatemia (from phosphorus retention) and subsequently Hypocalcemia and the as ckd progress there will be secondary hyperparathyroidism on later stages
The new theory
– when GFR decrease the klotho expression decrease and subsequently increase in the FGF-23 secretions which act as phosphaturic agent to keep normal level of phosphorus and decrease level of vitamin D level with decrease calcium and subsequently increase PTH
-the question now if the control of calcium, phosphorous and PTH will change the clinical outcome of MBD
Good Job Israa. Thanks
OLD THEORY:
the stimulus for hyperparathyroidism is hypocalemia and hyperphosphatemia due to vitamin D deficiency (lack of 1 hydroxlation on the kidney )
new concept :
the process start early in ckd by release of FGF23 FROM OSTEOBLAST as phophaturic effect to increase phosphate excretion as increase dietary phosphate and reduction of nephron mass to maintain serum po4 within normal limit
FGF23 need klotho for his action which released from the kidney by time the klotho reduced
vitamin D DEFICIENCY LEAD TO MILD HYPOCALCEMIA
Well-Explained Emad. Thanks
the old hypothesis :
the new trade-off hypothesis :
Very good answer Ibrahim. Thanks
Old concept: Elevation of serum PTH was mainly associated with hyperphosphatemia and hypocalcemia.
Ner concept: as CKD progresses Klotho expression in the kidney decreases and FGF-23 rises to maintain serum phosphate at normal level
Thanks Mohammed.
old hypothesis:
New hypothesis:
in CKD KLOTHO expression in kidney decrease and FGF23 increase to maintain normal P at normal level until the final stage of CKD with decrease vit D AND increase PTH
Great job Dr. Ashraf. Thanks
With CKD progresses the action of FGF23 is decreased due to FGF23 resistance .
iam proud of attend to this program
lot of new information
old concept hyperphosphatemia is major cause of increase synthesis of pth
new concept
involve kolotho level and fgf-23 factor and osteocyte role
relation between CKD-MBD and inflammatory process
comparison between loop deuritic and thiazide effect on ckd
Good Job Elsayed.
the old hypothesis
mainly depend on ca and po4 homeostasis and its relation with vit D and PTH hormon
new hypothesis
the effect of kolotho on suppression of FGF23 even in eraly stage of ckd
also other inflammatory cytokines and its role in theses condition and effect of medications such as diuretics and hypoxia inducible factor as in ttt of anemia
Thanks Rabab for your explanation.
I am really enjoying this article with a lot of new information which make me more confident in dealing with CKD-MBD.
The old concipt
the main drive of PTH secretion is the hyperphophatemia which lead to increase secretion of PTH to secret the high Phosphorus ( PTH IS PHOSPHATURIC HORMON).then this drive will be shared later on by hypocalcemia.
The new trade off theory
As the CKD progress the Kolotho level is decrease and the FGF 23 increase and this is the new drive for the PTH .SHPT is started from this point when the GFR is 40 to 45ml/mint and progress gradually and at this stage PTH increase even with normal phosphates level
The changes in the drive and changing of the PTH,Ca AND po4 is not only for the laporatory finding ,it is also in the chnges of the medications that have been used in dealing with high Phospherus and PTH level starting from the Aluminum chelating agent in early 1960 to ca chelatingg then phophates binder ending up recently with iron chelating tabs for phophore . With regard to the PTH Cinacalcit and Etacalcitide .
Well-done Rihab. Very nice comprehensive answer.
The old hypothesis says that the iPTH rise in response to hyperphophatemia and hypocalcemia. The secondary hyperparathyroidism should be only present on late stage CKD but this is not always the case.
New is that the new discovered FGF23 will raise on early stage CKD. This phosphouric hormone will maintain the phosphate hemostasis. This is why pth may rise in the abscence of hyperphophatemia.
Nice, however FGF-23 suppresses PTH secretion. Secondary hyperpara happens mainly because of the failure to activate 25 to 1:25 Dihydroxy Vit D.
Old hypothesis:
New trade-off hypothesis:
I am proud of you Asma, you are a very good add to this program.
Old trade-off hypothesis:
New trade-off hypothesis:
Nice explanation Dr. Ben. Thanks
Most welcome,Eman
There was a gap in the natural history of CKD-MBD for many years because there were no pathophysiological explanations for how this disease started.
The old concept:
Hypocalcemia, which is caused by a lack of vitamin D and a drop in calcium absorption in the gut, was thought to be the main problem.
Slatopolsky and Bricker came up with the term “trade-off” to describe their theory that high serum PTH levels were caused by phosphate retention, hyperphosphatemia, and the low calcium levels that followed.
As renal function declines, PTH rises. So, secondary hyperparathyroidism (SHPT) wouldn’t show up until the later stages of CKD, which isn’t what happens in real life.
The new theory:
The discovery of FGF-23 and Klotho helped explain why PTH levels would rise even when hyperphosphatemia wasn’t present. This gave the trade-off theory a new way to look at things.
As CKD gets worse, Klotho expression in the kidneys goes down and FGF-23 goes up, according to what we know now. Higher levels of FGF-23 keep serum phosphate levels normal until the end stages of CKD, when calcitriol levels drop and PTH levels rise.
Great Weam, nice explanation.
abggh