Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
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Rania Mahmoud
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species. It also induces the calcification of vascular smooth muscle cells,whichincreases the risk of CV and all-cause mortality.Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure9and induce left ventricular hypertrophy.High parathyroid hormone concentrations are associated with hypertensionand increased risk of CV mortality.
A lack of resources may also contribute to the dearth of randomized clinical trial data; welldesigned, adequately powered randomized trials studying hard outcomes are expensive (e.g., $50–$100 million) and time consuming. Single-intervention trials evaluate outcomes specific to the intervention, not hard clinical end points.
phosphate binders were approved based on their ability to lower phosphorus levels in patients with CKD, not impact on morbidity or mortality. Single dialysis-based interventions, such as increasing the dialysis dose increasing dialyzer flux,and increasing hemodialysis frequency,97 have not been found to reduce allcause or CV mortality. No statistically significant impact on all-cause and cause-specific mortality wasrevealed by nondialysis interventions (e.g., lowering cholesterol through statin use, use of noncalcium-basedphosphate binders [sevelamer] vs. calcium-based binders) in patients undergoing hemodialysis
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.
It also induces the calcification of vascular smooth muscle cells, which increases the risk of CV and all-cause mortality.
Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure and induce left ventricular hypertrophy. High parathyroid hormone concentrations are associated with hypertension and increased risk of CV mortality.
Conducting prospective, randomized trials with hard clinical end points in patients with CKD is an established challenge.
Given the guideline-recommended target phosphorus level of <5.5 mg/dl, we believe that it would be unethical to conduct a trial evaluating adverse effects of phosphorus level elevated beyond this threshold.
In addition, CKD is a multifactorial disease associated with complications spanning different physiological processes, such as CVD, dyslipidemia, anemia, and mineral bone disorder.
Lack of resources may also contribute to the dearth of randomized clinical trial data; well designed, adequately powered randomized trials studying hard outcomes are expensive (e.g., $50–$100 million) and time consuming.
Single-intervention trials evaluate outcomes specific to the intervention, not hard clinical endpoints.
Phosphate binders were approved based on their ability to lower phosphorus levels in patients with CKD, not impact on morbidity or mortality.Single dialysis-based interventions, such as increasing the dialysis dose.
Increasing dialyzer flux, and increasing hemodialysis frequency,have not been found to reduce all cause or CV mortality. No statistically significant impact on all-cause and cause-specific mortality was revealed by nondialysis interventions (e.g., lowering cholesterol through statin use, use of non calcium-based phosphate binders [sevelamer] vs. calcium-based binders) in patients undergoing hemodialysis.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms?
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.
It also induces the calcification of vascular smooth muscle cells,which increases the risk of CV and all-cause mortality.
Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and
mortality.
Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure and induce left ventricular hypertrophy.High parathyroid hormone concentrations are associated with hypertension and increased risk of CV mortality.
Improved phosphate management could remove or reduce the stimulus for all these abnormalities, potentially decreasing the risk of CVD.
Why is there a lack in RCTs evaluating solid end-point outcomes?
Given the guideline-recommended target phosphorus level of <5.5 mg/dl, SO it would be unethical to conduct a trial evaluating adverse effects of phosphorus level elevated beyond this threshold.
In addition, CKD is a multifactorial disease associated with complications spanning different physiological processes, such as CVD, dyslipidemia,anemia, and mineral bone disorder evertheless, and the data indicating phosphate drives multiple physiological changes that increase CV rISK
A lack of resources may also contribute
Adequately powered randomized trials studying hard outcomes are expensive and time consuming
A meta-analysis of CV events in patients with CKD explored the association between CV health and nontraditional risk factors, including serum phos- phorus, albumin, hemoglobin, and urate.This study found that increased serum phosphorus concentrations were associated with increased risk of CV events.
Improving phosphate management is a rational approach to improving CV health because phosphate retention and elevated phosphorus concentrations trigger multiple pathophysiological derangements associated with increased risk of CVD. High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.It also induces the calcification of vascular smooth muscle cells,which increases the risk of CV and all-cause mortality.Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 con- centrations are associated with congestive heart and induce left ventricular hypertrophy.High parathyroid hormone concentrations are associated with hypertensionand increased risk of CV mortality.Improved phosphate management could remove or reduce the stimulus for all these abnormalities, potentially decreasing the risk of CVD.
Conducting prospective, randomized trials with hard clinical end points in patients with CKD, analogous to those that have led to major therapeutic advances in other fields (e.g., oncology and cardiology), is an established challenge.Given the guideline-recommended target phosphorus level of <5.5 mg/dl, we believe that it would be unethical to conduct a trial evaluating adverse effects of phosphorus level elevated beyond this threshold. In addition, CKD is a multifactorial disease associated with complications spanning different physiological processes, such as CVD,dyslipidemia,anemia,and mineral bone disorder.
Nevertheless, the high volume of evidence connecting
elevated phosphorus level with CV and overall mortality, and the data indicating phosphate drives multiple physiological changes that increase CV risk, establish phosphorus concentrations as a logical target for intervention in CKD. A lack of resources may also contribute to the dearth of randomized clinical trial data; well- designed, adequately powered randomized trials studying hard outcomes are expensive and time consuming.
Single-intervention trials evaluate outcomes specific to the intervention, not hard clinical end points. For example, phosphate binders were approved based on their ability to lower phosphorus levels in patients with CKD, not impact on morbidity or mortality.Single dialysis-based interventions, such as increasing the dialysis dose,increasing dialyzer flux,and increasing hemodialysis frequency,have not been found to reduce all- cause or CV mortality. No statistically significant impact on all-cause and cause-specific mortality was revealed by nondialysis interventions (e.g., lowering cholesterol through statin use, use of noncalcium-based phosphate binders [sevelamer] vs. calcium-based binders) in patients undergoing hemodialysis.
Elevated phosphorus levels are associated with CV adverse events each 1mg/do increase in phosphorus was associated with a 23% increase in mortality risk.
Hyperphophatemia causes endothelial dysfunction, ROS production mediated mitochondrial dysfunction, vascular calcification, increased FGF23 & PTH.
There is lacking in RCT evaluating solid end points as it is unethical to keep pts in hyperphosphatemic state in-spite long term suspected complications although the guideline’s recommended to keep phosphorus at target as possible. Beside CKD is multifactorial disease (traditional and non traditional risk factors brings to CV risk.
Mechanisms
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.It also induces the calcification of vascular smooth muscle cells, which increases the risk of CV and all-cause mortality. Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure and induce left ventricular hypertrophy. High parathyroid hormone concentrations are associated with hypertension and increased risk of CV mortality
The lack in RCT is due to the fact that A lack of resources may also contribute to the dearth of randomized clinical trial data; welldesigned, adequately powered randomized trials studying hard outcomes are expensive (e.g., $50–$100 million) and time consuming.
Hyperphosphatemia leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production( of reactive oxygen species.It also induces the calcification of vascular smooth muscle cells,which increases the risk of CV and all-cause mortality.
Phosphate retention leads to increasing FGF23 and secondary hyperparathyroidism.
Elevated fibroblast growth factor-23 is associated with congestive heart failure and left ventricular hypertrophy.
Hyperparathyroidism is associated with hypertension and increased risk of CV mortality.
Why is there a lack in RCTs evaluating solid end-point outcomes?May be due to presence of traditional risk factors(smoking,DM,HTN) that also increase risk of cardiovascular risk factors
The mechanisms of hyperphosphatemia induced CVD due to hyperphosphatemia induced endothelial dysfunction and increase oxidetive stress substance promote apoptosis, also high phosphorus direct injury on cardiac muscle with metastatic calcification .
The lack of reach to end point due to the guide line recommended target level of po4 not exceed more than 5.5 and not ethical maintain patient and study the effect of high po4 above this level also hidden amount of po4 in diet and drug cannot be measured proparly
one of the reasons of the lack of RCT evaluating the CV effects of hyperphosphatemia is that the guidelines recommend to keep serum phosphorus below 55 so it is unethical to leave the patient serum phosphorus above this target to evaluate its hazards.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
hyperphosphatemia causes
endothelial dysfunction.
mitochondrial dysfunction
calcification in the vascular smooth muscle cells causes hypertension and increase CV morbidity and mortality.
increase FGF23 and PTH.
Why is there a lack in RCTs evaluating solid end-point outcomes cost effectiveness
The complex pathways and surrogate outcomes with plenty of confounders make it difficult. Cardiovascular events are not a result of only vascular calcifications. Same patients have DM, HT, infşammation, and hyperlipidemia. The association may not mean causation.
High phosphorus may lead to endothelial dysfunction. Secondary hyperparathyroidism may increase blood pressure. Vascular calcifications, including coronary arteries add to that
The mechanism of CVD in patients with hyperphosphatemia as increase S. Phosphorous causes endothelial cell dysfunction and injury which lead to mitochondrial dysfunction due to increase reactive oxygen stress, in addition to the calcification in the vascular smooth muscle cells which increase CV events and mortality.
Elevated Phosphorous are associated with CV adverse event. What are possible mechanisms?
elevated phosphate initiates a cascade of pathophysiological events that lead to increased cardiovascular mortality. At cellular level hyperphosphataemia cause endothelial dysfunction which causes cell injury by inducing endothelial cell apoptosis and generation of oxygen free radical that cause mitochondrial dysfunction. At hormonal level high phosphate cause increase of phosphaturic hormones ( PTH and FGF 23) . High PTH level are associated with HTN and CV mortality while high level FGF23 are linked with LVH and CCF which increases CV events. At a tissue level level it causes calcification of vascular smooth muscle which increases CV and all cause mortality
Why is there a lack in RCTs evaluating solid end-point outcomes?
CKD is multifactorial disease and CV mortality is atrributed to multiple factors and it might not be possible to eliminate co-founders leading to association rather than causality. Single intervention do not look at hard outcomes but rather at just one aspect of the issue.
It might not be ethical to let patient reach phosphate above 5.5 mg/dl which is recommended by KDIGO guidelines.
Finally it might be lack of resources and whether it is cost effective to do reseach in that field
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes? High phosphate levels cause endothelial dysfunction, apoptosis, and mitochondrial dysfunction by increasing reactive oxygen species production. It also causes vascular smooth muscle cell calcification, which raises CV and all-cause mortality. Phosphate retention raises fibroblast growth factor-23 and parathyroid hormone levels, which enhance CV morbidity and mortality.
-It would be unethical to undertake a study investigating the deleterious effects of phosphorus levels beyond the guideline-recommended 5.5 mg/dl. CKD is a complex illness with consequences ranging from CVD, dyslipidemia, anemia, and mineral bone dysfunction. Additionally, there is a lack of resources.
The mechanism of CVD in patients with hyperphosphatemia as increase S. Phosphorous causes endothelial cell dysfunction and injury which lead to mitochondrial dysfunction due to increase reactive oxygen stress, in addition to the calcification in the vascular smooth muscle cells which increase CV events and mortality.
Hyperphosphatemia also causes increase FGF23 and PTH
FGF23 causes congestive heart failure and left ventricular hypertrophy while PTH causes hypertension and increase CV morbidity and mortality
The prevalence of CV disease and mortality in Ckd not decrease in recent years because of the complexity to keep CV health and decrease all causes mortality caused by the traditional factors such as smoking, diabetes, hyperlipidemia and hypertension in addition to the non traditional factors such as s. Phosphorous, hemoglobin, albumin and urate.
Studies show that increases s. Phosphorous associated with CV events.
Elevated phosphorus levels are associated with CV adverse events. the possible mechanismshyperphosphatemia trigger multiple pathophysiological derangement associated with increase CVD
1-Endothelial dysfunction
2-disrupting of mitochondrial function by production of reactive oxygen species
3- also hyperphosphatemia induce calcification of vascular smooth muscle cell
4- also phosphate retention triggered increase of FGF-23 which lead to congestive HF and left ventricular hypertrophy
also phosphate retention triggered PTH which induced hypertension Why is there a lack in RCTs evaluating solid end-point outcomes? costly CKD pt. associated with multimorbidity disorder and multi risk factor complication so need resources , manpower ,and cost
.increase serum phosphate associated with increase risk of CV events .
high phosphate level lead to
1- endothelial dysfunction ,
2-increase production of ROS ,
3-induce vascular calcification which increases the risk of cv and all cause mortality .
phosphate retension triggers increases in FGF23 and PTH concentrations
–
-elevated FGF23 associated with congestive heart failure and LVH
-high PTH associated with hypertension and increased cv risk
=======================
Why is there a lack in RCTs evaluating solid end-point outcomes?1-it would be unethical to conduct atrial evaluating adverse effects of phosphorous level
2-multifactorial disease associated with complications
3-cost
Elevated phosphate is lead to increase FGF23 and increase PTH.
There is a direct relationship between LV hypertrophy and Fgf23 level.
Then , increased phosphate will lead to increased calcium phosphate deposit in tissues including vascular calcification and valvular calcification.
It is expensive to lead RCT trial(50to 100 million dollars). It is unethical to let patient group without phosphate control with our current knowledge.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
the possible mechanisms are as following :
1- endothelial dysfunction.
2- vascular calcification.
3- induction of FGF-23 that is associated with excess mortality.
4- induction of hyperparathyroidism with excess bone resorption and soft tissue calcification.
lack of RCTs is due to :
1- it is unethical to conduct comparative studies with keeping some patients with high serum phosphorus above the targets.
2- CKD is a multifactorial disease with multiple interacting pathophysiologic pathways, not only CKD-MBD.
3- lack of resources will limit adequately high powered studies.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.
It also induces the calcification of vascular smooth muscle cells, which increases the risk of CV and all-cause mortality.
Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure and induce left ventricular hypertrophy. High parathyroid hormone concentrations are associated with hypertension and increased risk of CV mortality.
Conducting prospective, randomized trials with hard clinical end points in patients with CKD is an established challenge.
Given the guideline-recommended target phosphorus level of <5.5 mg/dl, we believe that it would be unethical to conduct a trial evaluating adverse effects of phosphorus level elevated beyond this threshold.
In addition, CKD is a multifactorial disease associated with complications spanning different physiological processes, such as CVD, dyslipidemia, anemia, and mineral bone disorder.
Lack of resources may also contribute to the dearth of randomized clinical trial data; well designed, adequately powered randomized trials studying hard outcomes are expensive (e.g., $50–$100 million) and time consuming.
Single-intervention trials evaluate outcomes specific to the intervention, not hard clinical endpoints.
Phosphate binders were approved based on their ability to lower phosphorus levels in patients with CKD, not impact on morbidity or mortality.Single dialysis-based interventions, such as increasing the dialysis dose.
Increasing dialyzer flux, and increasing hemodialysis frequency,have not been found to reduce all cause or CV mortality. No statistically significant impact on all-cause and cause-specific mortality was revealed by nondialysis interventions (e.g., lowering cholesterol through statin use, use of non calcium-based phosphate binders [sevelamer] vs. calcium-based binders) in patients undergoing hemodialysis.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms?
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.
It also induces the calcification of vascular smooth muscle cells,which increases the risk of CV and all-cause mortality.
Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and
mortality.
Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure and induce left ventricular hypertrophy.High parathyroid hormone concentrations are associated with hypertension and increased risk of CV mortality.
Improved phosphate management could remove or reduce the stimulus for all these abnormalities, potentially decreasing the risk of CVD.
Why is there a lack in RCTs evaluating solid end-point outcomes?
Given the guideline-recommended target phosphorus level of <5.5 mg/dl, SO it would be unethical to conduct a trial evaluating adverse effects of phosphorus level elevated beyond this threshold.
In addition, CKD is a multifactorial disease associated with complications spanning different physiological processes, such as CVD, dyslipidemia,anemia, and mineral bone disorder evertheless, and the data indicating phosphate drives multiple physiological changes that increase CV rISK
A lack of resources may also contribute
Adequately powered randomized trials studying hard outcomes are expensive and time consuming
A meta-analysis of CV events in patients with CKD explored the association between CV health and nontraditional risk factors, including serum phos- phorus, albumin, hemoglobin, and urate.This study found that increased serum phosphorus concentrations were associated with increased risk of CV events.
Improving phosphate management is a rational approach to improving CV health because phosphate retention and elevated phosphorus concentrations trigger multiple pathophysiological derangements associated with increased risk of CVD. High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.It also induces the calcification of vascular smooth muscle cells,which increases the risk of CV and all-cause mortality.Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 con- centrations are associated with congestive heart and induce left ventricular hypertrophy.High parathyroid hormone concentrations are associated with hypertensionand increased risk of CV mortality.Improved phosphate management could remove or reduce the stimulus for all these abnormalities, potentially decreasing the risk of CVD.
Conducting prospective, randomized trials with hard clinical end points in patients with CKD, analogous to those that have led to major therapeutic advances in other fields (e.g., oncology and cardiology), is an established challenge.Given the guideline-recommended target phosphorus level of <5.5 mg/dl, we believe that it would be unethical to conduct a trial evaluating adverse effects of phosphorus level elevated beyond this threshold. In addition, CKD is a multifactorial disease associated with complications spanning different physiological processes, such as CVD,dyslipidemia,anemia,and mineral bone disorder.
Nevertheless, the high volume of evidence connecting
elevated phosphorus level with CV and overall mortality, and the data indicating phosphate drives multiple physiological changes that increase CV risk, establish phosphorus concentrations as a logical target for intervention in CKD. A lack of resources may also contribute to the dearth of randomized clinical trial data; well- designed, adequately powered randomized trials studying hard outcomes are expensive and time consuming.
Single-intervention trials evaluate outcomes specific to the intervention, not hard clinical end points. For example, phosphate binders were approved based on their ability to lower phosphorus levels in patients with CKD, not impact on morbidity or mortality.Single dialysis-based interventions, such as increasing the dialysis dose,increasing dialyzer flux,and increasing hemodialysis frequency,have not been found to reduce all- cause or CV mortality. No statistically significant impact on all-cause and cause-specific mortality was revealed by nondialysis interventions (e.g., lowering cholesterol through statin use, use of noncalcium-based phosphate binders [sevelamer] vs. calcium-based binders) in patients undergoing hemodialysis.
rise in FGF23 and PTH
endothelial dysfunction and vascular calcifications.
Elevated phosphorus levels are associated with CV adverse events each 1mg/do increase in phosphorus was associated with a 23% increase in mortality risk.
Hyperphophatemia causes endothelial dysfunction, ROS production mediated mitochondrial dysfunction, vascular calcification, increased FGF23 & PTH.
There is lacking in RCT evaluating solid end points as it is unethical to keep pts in hyperphosphatemic state in-spite long term suspected complications although the guideline’s recommended to keep phosphorus at target as possible. Beside CKD is multifactorial disease (traditional and non traditional risk factors brings to CV risk.
The mechanism by which high phosphorus levels can induce cardiac injury and CV events
Why is there a lack in RCTs evaluating solid end-point outcomes ?
cost effectiveness .
Mechanisms
High phosphate level leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production of reactive oxygen species.It also induces the calcification of vascular smooth muscle cells, which increases the risk of CV and all-cause mortality. Phosphate retention triggers increases in fibroblast growth factor-23 and parathyroid hormone concentrations, which are both linked to CV morbidity and mortality. Elevated fibroblast growth factor-23 concentrations are associated with congestive heart failure and induce left ventricular hypertrophy. High parathyroid hormone concentrations are associated with hypertension and increased risk of CV mortality
The lack in RCT is due to the fact that A lack of resources may also contribute to the dearth of randomized clinical trial data; welldesigned, adequately powered randomized trials studying hard outcomes are expensive (e.g., $50–$100 million) and time consuming.
-increased endothelial dysfunction
-increased cell injury by reactive oxygen radicals
-increased FGF 23 and PTH secretion
-increased vascular calcification
hyperphosphatemia induces Cardiovascular Diseases through several mechanisms
lack of RCTs tackling hyperphosphatemia is multifactorial:
Why is there a lack in RCTs evaluating solid end-point outcomes
cost effectiveness/ unethical isues and patient safey
Hyperphosphatemia leads to endothelial dysfunction, causing cell injury by inducing endothelial cell apoptosis and disrupting mitochondrial function by increased production( of reactive oxygen species.It also induces the calcification of vascular smooth muscle cells,which increases the risk of CV and all-cause mortality.
Phosphate retention leads to increasing FGF23 and secondary hyperparathyroidism.
Elevated fibroblast growth factor-23 is associated with congestive heart failure and left ventricular hypertrophy.
Hyperparathyroidism is associated with hypertension and increased risk of CV mortality.
Why is there a lack in RCTs evaluating solid end-point outcomes?May be due to presence of traditional risk factors(smoking,DM,HTN) that also increase risk of cardiovascular risk factors
The mechanisms of hyperphosphatemia induced CVD due to hyperphosphatemia induced endothelial dysfunction and increase oxidetive stress substance promote apoptosis, also high phosphorus direct injury on cardiac muscle with metastatic calcification .
The lack of reach to end point due to the guide line recommended target level of po4 not exceed more than 5.5 and not ethical maintain patient and study the effect of high po4 above this level also hidden amount of po4 in diet and drug cannot be measured proparly
The mechanism by which high phosphorus levels can induce cardiac injury and CV events
one of the reasons of the lack of RCT evaluating the CV effects of hyperphosphatemia is that the guidelines recommend to keep serum phosphorus below 55 so it is unethical to leave the patient serum phosphorus above this target to evaluate its hazards.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
hyperphosphatemia causes
Why is there a lack in RCTs evaluating solid end-point outcomes
cost effectiveness
The complex pathways and surrogate outcomes with plenty of confounders make it difficult. Cardiovascular events are not a result of only vascular calcifications. Same patients have DM, HT, infşammation, and hyperlipidemia. The association may not mean causation.
High phosphorus may lead to endothelial dysfunction. Secondary hyperparathyroidism may increase blood pressure. Vascular calcifications, including coronary arteries add to that
The mechanism of CVD in patients with hyperphosphatemia as increase S. Phosphorous causes endothelial cell dysfunction and injury which lead to mitochondrial dysfunction due to increase reactive oxygen stress, in addition to the calcification in the vascular smooth muscle cells which increase CV events and mortality.
Elevated Phosphorous are associated with CV adverse event. What are possible mechanisms?
elevated phosphate initiates a cascade of pathophysiological events that lead to increased cardiovascular mortality. At cellular level hyperphosphataemia cause endothelial dysfunction which causes cell injury by inducing endothelial cell apoptosis and generation of oxygen free radical that cause mitochondrial dysfunction. At hormonal level high phosphate cause increase of phosphaturic hormones ( PTH and FGF 23) . High PTH level are associated with HTN and CV mortality while high level FGF23 are linked with LVH and CCF which increases CV events. At a tissue level level it causes calcification of vascular smooth muscle which increases CV and all cause mortality
Why is there a lack in RCTs evaluating solid end-point outcomes?
CKD is multifactorial disease and CV mortality is atrributed to multiple factors and it might not be possible to eliminate co-founders leading to association rather than causality. Single intervention do not look at hard outcomes but rather at just one aspect of the issue.
It might not be ethical to let patient reach phosphate above 5.5 mg/dl which is recommended by KDIGO guidelines.
Finally it might be lack of resources and whether it is cost effective to do reseach in that field
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
High phosphate levels cause endothelial dysfunction, apoptosis, and mitochondrial dysfunction by increasing reactive oxygen species production. It also causes vascular smooth muscle cell calcification, which raises CV and all-cause mortality. Phosphate retention raises fibroblast growth factor-23 and parathyroid hormone levels, which enhance CV morbidity and mortality.
-It would be unethical to undertake a study investigating the deleterious effects of phosphorus levels beyond the guideline-recommended 5.5 mg/dl. CKD is a complex illness with consequences ranging from CVD, dyslipidemia, anemia, and mineral bone dysfunction. Additionally, there is a lack of resources.
The mechanism of CVD in patients with hyperphosphatemia as increase S. Phosphorous causes endothelial cell dysfunction and injury which lead to mitochondrial dysfunction due to increase reactive oxygen stress, in addition to the calcification in the vascular smooth muscle cells which increase CV events and mortality.
Hyperphosphatemia also causes increase FGF23 and PTH
FGF23 causes congestive heart failure and left ventricular hypertrophy while PTH causes hypertension and increase CV morbidity and mortality
moreover, dr Israa, it is unethical to leave the patient’s serum phosphorus above the target to evaluate its hazards
The prevalence of CV disease and mortality in Ckd not decrease in recent years because of the complexity to keep CV health and decrease all causes mortality caused by the traditional factors such as smoking, diabetes, hyperlipidemia and hypertension in addition to the non traditional factors such as s. Phosphorous, hemoglobin, albumin and urate.
Studies show that increases s. Phosphorous associated with CV events.
Elevated phosphorus levels are associated with CV adverse events. the possible mechanismshyperphosphatemia trigger multiple pathophysiological derangement associated with increase CVD
1-Endothelial dysfunction
2-disrupting of mitochondrial function by production of reactive oxygen species
3- also hyperphosphatemia induce calcification of vascular smooth muscle cell
4- also phosphate retention triggered increase of FGF-23 which lead to congestive HF and left ventricular hypertrophy
also phosphate retention triggered PTH which induced hypertension
Why is there a lack in RCTs evaluating solid end-point outcomes?
costly
CKD pt. associated with multimorbidity disorder and multi risk factor
complication so need resources , manpower ,and cost
.increase serum phosphate associated with increase risk of CV events .
high phosphate level lead to
1- endothelial dysfunction ,
2-increase production of ROS ,
3-induce vascular calcification which increases the risk of cv and all cause mortality .
phosphate retension triggers increases in FGF23 and PTH concentrations
–
-elevated FGF23 associated with congestive heart failure and LVH
-high PTH associated with hypertension and increased cv risk
=======================
Why is there a lack in RCTs evaluating solid end-point outcomes?1-it would be unethical to conduct atrial evaluating adverse effects of phosphorous level
2-multifactorial disease associated with complications
3-cost
Elevated phosphate is lead to increase FGF23 and increase PTH.
There is a direct relationship between LV hypertrophy and Fgf23 level.
Then , increased phosphate will lead to increased calcium phosphate deposit in tissues including vascular calcification and valvular calcification.
It is expensive to lead RCT trial(50to 100 million dollars). It is unethical to let patient group without phosphate control with our current knowledge.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms? Why is there a lack in RCTs evaluating solid end-point outcomes?
1- endothelial dysfunction.
2- vascular calcification.
3- induction of FGF-23 that is associated with excess mortality.
4- induction of hyperparathyroidism with excess bone resorption and soft tissue calcification.
1- it is unethical to conduct comparative studies with keeping some patients with high serum phosphorus above the targets.
2- CKD is a multifactorial disease with multiple interacting pathophysiologic pathways, not only CKD-MBD.
3- lack of resources will limit adequately high powered studies.
Elevated phosphorus levels are associated with CV adverse events. What are the possible mechanisms?
Why is there a lack in RCTs evaluating solid end-point outcomes?