Mention the causes of vitamin D deficiency in patients with CKD
lack of sunlight
lack of vitamin D in diet
lack of enzymatic activation to active vitamin D
If CKD related proteinuria then loss vitamin D binding protein
Compare the biological effects of novel vitamin D analogous to calcitriol.
they both act on vitamin D receptor to decrease PTH however due to side chain alteration in molecular structure have less side effect on binding to VDR in terms of causing hypercalcaemia and hyperphosphataemia.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is an extended release vitamin D analogue and does not cause deactivation of active vitamin D due to initial rapid surge
Efficacy: it does decrease PTH and increase in VITAMIN D LEVEL WITHOUT STATISTICALLY SIGNIFICANT increase in calcium or phosphate
Safety there has been no safety concerns from phase 3 trial
there is no evidence of that it improves mortality or survival or decrease progression of ckd just biochemical benefit
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
it could cause a transient secondary hyperparathyroid state due to increase na and po42- absorption
it does decrease MACE MARE events tho tho more studies needed to understand more
The causes of vitamin D deficiency in patients with CKD
proteinuria and uremia which cause the vitamin D binding proteins,and 1,25dihydroxyvitamin d ,, poor diet intake ,, decreased sunlight exposure and skin synthesis.
suppression of the 1α-hydroxylase CYP27B1activation The consequences of Vitamin D Deficiency in CKD secondary hyperparathyroidism. hypocalcemia hyperphosphatemia Renal osteodystrophy Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D analogs, such as paricalcitol, doxercalciferol, or paricalcitol, came into play, predominantly in use in Europe and the US. It was declared that these analogs have good properties of vitamin D and showed fewer side effects and significantly less tendency for hypercalcemia. The mechanism of action for these substances was the same as for 1,25-hydroxyvitamin D, namely binding to the VDR to mediate PTH lowering. However, it come up that side-chain modifications would alter the binding affinity to circulating vitamin D binding proteins and the VDR to such a degree that this would allow for better control. Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D. Extended-release calcifediol (ERC) is effectively treat renal HPT without the risk of hypercalcemia and hyperphosphatemia. Extended-release calcifediol is formulated in a lipophilic, wax-like structure that allows for prolonged calcifediol extended release about 12hours.
Calcidiol does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which reduces active vitamin D to inactive forms.
The SGLT2-inhibitors and the non-steroidal mineralocorticoid
receptor blocker finerenone reduce both major cardiovascular events (MACE) and major
renal events (“MAREs”), such as renal death and the initiation of dialysis or renal trans-
plantation [71,72]. Maybe this positive experience could stimulate researchers and industry The reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
IN trials for non-dialysis CKD–MBD patients to provide clear guidance.
regarding the optimal starting point, dosage, and type of future vitamin D treatment, as
well as phosphate management.
In addition to that, the safety, efficacy and widespread usage of SGLT2 inhibitors
in CKD treatment might also stimulate further research in renal HPT, vitamin D, and
CKD–MBD: Interestingly, SGLT2-inhibitors did promote the
development of hyperparathyroidism and changes in other markers of CKD–MBD.
Mention the causes of vitamin D deficiency in patients with CKD.
*impaired skin synthesis
*prescribed dietary restrictions reducing the availability of the 25-hydroxyvitamin D precursors cholecalciferol/ergocalciferol .
*Also, CKD suppresses the 1α-hydroxylase CYP27B1, which catalyzes the activation of 25-hydroxyvitamin D .
*In addition to impaired biosynthesis CKD-associated proteinuria and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxyvitamin D .
Mention the consequences of Vitamin D Deficiency in CKD.
Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D as maxacalcitol, doxercalciferol, & paricalcitol have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
vit D Analogue safe than calcitriol as it may decrease risk of vascular calcification.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is a prohormone of the active vit D, made to be released over 12Hrs period ,It achieves PTH reduction in one third of patients (compared to placebo), and increases Vit D levels to normal in ~ 80%. It reduces PTH in 40% of subjects by a third.
The risk of hypercalcemia and hyperphosphatemia is minimal compared to other VDRAs.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
SGLT2i raises the concentration of Na in the lumen of the PCT, leading to an increase in PO4 reabsorption via the Na PO4 cotransporter. This may be the mechanism through which FGF-23 and PTH exert their phosphaturic impact.
Mention the causes of vitamin D deficiency in patients with CKD.
This might be caused by impaired skin synthesis or prescribed dietary restrictions reducing the availability of the 25-hydroxyvitamin D precursors chole- calciferol/ergocalciferol. Also, CKD suppresses the 1α-hydroxylase CYP27B1, which catalyzes the activation of 25-hydroxyvitamin D. In addition to impaired biosynthe-CKD-associated proteinuria and uremia lead to the loss of vitamin D binding proteins and
1,25-dihydroxyvitamin D. Mention the consequences of Vitamin D Deficiency in CKD. A 1,25-dihydroxyvitamin D deficiency in CKD results in insufficient induction of these genes and thus impedes the transport of active Ca2+ from the intestine to the circulation. The PTH from the parathyroid glands counteracts hypocalcemia by stimulating osteoclasts to initiate calcium resorption from the bone. In CKD, however, several mechanisms lead to PTH overproduction, also known as hyperparathyroidism. Compare the biological effects of novel vitamin D analogous to calcitriol. Novel vitamin D analogues, such as maxacalcitol, doxercalciferol or paricalcitol, came into play, with the latter predominantly in use in Europe and the US. It was claimed that these analogues have all the good properties of vitamin D and showed less unwanted side effects, especially less tendency for hypercalcemia. As vitamin D analogues, the mechanism of action for these substances was basically the same as for 1,25-hydroxyvitamin D, namely binding to the VDR to mediate PTH lowering. However, it was conceived that side-chain modifications would alter the binding affinity to circulating vitamin D binding proteins and/or the VDR to such a degree that this would allow for better control of the biochemical (side) effects. Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D. (ERC; EU term: prolonged-release calcifediol) is an orally administered prohormone of 1,25-dihydroxyvitamin D. The area of indication is secondary HPT in CKD stage G3–G4 patients. The key difference to other vitamin D supplements is the formulation: the calcifediol is encapsulated in a lipophilic, wax-like structure that allows prolonged calcifediol release over an extended 12 h period [42,67]. This has important biochemical implications: By avoiding the rapid rises of 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D levels, as seen with immediate-release calcifediol, ERC does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which degrades active vitamin D to inactive forms. Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD. Interestingly, the above-mentioned SGLT2-inhibitors promote the development of hyperparathyroidism and changes in other markers of CKD–MBD. increase serum phosphate, PTH , FGF23 , and decrease serum 1,25-dihydroxyvitamin D
Mention the causes of vitamin D deficiency in patients with CKD.
Reduced sun light exposure
Diets poor in content
Proteinuria
Uremia
Suppressed CYP27B1
Mention the consequences of Vitamin D Deficiency in CKD.
Hypocalcemia
Hyperphopshatemia
Secondary hyperparathyroidism
Renal osteodystrophy with Poor Bone Health
Compare the biological effects of novel vitamin D analogous to calcitriol.
Vitamin D analogs helps with controlling bone turnover, suppresses parathyroid hormone, and increases FGF-23 in secondary hyperparathyroidism.
They are less likely to cause hypercalcemia and hyperphosphatemia.
Paricalcitol may be associated with better outcomes and better survival compared to calcitriol.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Extended-release calcifediol (ERC) has the potential to effectively treat renal HPT without the risk of hypercalcemia and hyperphosphatemia. ERC is formulated in a lipophilic, wax-like structure that allows for prolonged calcifediol release over an extended 12-hour period.
Calcidiol does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which degrades active vitamin D to inactive forms.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
The prelimanary effects include hyperparathyroidism, hyperphosphatemia increase PTH, and FGF23, and decrease 1,25-dihydroxyvitamin D.
thanks dr Riaan for your effort
1-The clinical consequences of CKD–MBD encompass parathyroid gland hyperplasia, vascular calcification and bone abnormalities which in turn increases the risk of mortality
2-Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Compare the biological effects of novel vitamin D analogous to calcitriol.
lack of reliable superiority compared to calcitriol.same mechanism of action.
Novel vitamin D have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR to a such a degree that would allow for better control of the biochemical side effects.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is oral prohormone of 1,25 hydroxyvitamin D.It has two forms; immediate-release calcifediol (IMR) or extended-release calcifediol (ERC)
Efficacy:
According to the data from 2 phase -3 RCT, PTH reduction was in intervention group 33%, 34% versus 8%, 7 % in placebo group respectively.
> 80% of patients had vitamin D levels > 30 ng/ml.
Another study by Fadda et al. revealed that, 40% of the participant had > 30% reduction in PTH.
Safety:
In this phase-3 data, minimal alterations in Ca & PO4 were noted in both intervention & placebo arm and therefore, a low risk for hypercalcemia and hyperphosphatemia.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
Hyperphosphatemia, sHPT, FGF23, Hypovitaminosis D
SGLT2i increases Na concentration in the lumen of PCT,
lead to increase in Pi reabsorption in the PCT via Na Pi cotransporter.
This may be the trigger for FGF-23 & PTH to exert their phosphaturic effect.
thanks dr Mahmoud for your effort
Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
1. The causes of vitamin D deficiency in CKD patients are:
-reduced sunlight exposure and skin synthesis
-diets reduction of intake
-proteinuria: what causes loss of vitamin D binding proteins
-suppressed activation of 1 alpha hydroxylase
-Uremia: loss of Calcitriol
2. Consequences of Vitamin D in CKD:
-insufficient induction of genes responsible for calcium hemostasis (including epithelial calcium channel and calcium binding proteins), what causes disruption in transport of calcium in circulation.
– Vitamin D deficiency causes secondary hyperparathyroidism in 3 main pathway: The hyperphosphatemia and hypocalcemia upregulate and induce the transcription of PTH and also increase FGF23 stabilisation and upregulation which in turn lead to inhibition of 1 alpha hydroxylase.
Secondly, Decreased Klotho cofactor transcription what causes fgf23 resistance.
Thirdly, decreased production of 1,25 OHvitaminD becauseof decreased CYP27B1 expression.
– vitamin D deficiency and increased PTH will lead to MBD including nodular hyperplasia of parathyroid gland till complete resistance to medical treatment, vascular calcification and increased cardiovascular events (36 percent in a studdy of Gorriz) due to increase deposition of calcium phosphate saltsin the presence of hyperphosphatemia. And lastly excessive bone resorption due to PTH excess and hypocalcemia.
3. Early on(1970, 1980) the wide use of Calcitriol was the main cause of hyperphophatemia and hypercalcemia. It was reported in the study of memmos that Calcitriol can very effectively lower PTH.
Goodman in year 2000 highlighted the vascular calcification (CAC) side effects and hyperphosphatemia and hypercalcemia due to Calcitriol usage. He systematically quantified the calcification using CT scores. His work lead to shift toward less aggressive usage of avtive vitamin D.
Some studies indicated a relationship between Calcitriol usage and increasing FGF23 level( What give an association to LV hypertrophy).
Novel vitamin D analogue such as maxacalcitol, doxercalciferol or Paricalcitol showed less negative side effects. This is due to more selectivity to VDR, what lead to more local effect on Parathyroid gland causing effective decrease in PTH level, antiinflammatory , antifibrotic effects and decreasing proteinuria.
They have less affinity to circulating vitamin D binding proteins so it is more likely to reach his target tissue.
4. In comparison to other forms of vitamin D , ERC are used and studied in CKD stage 3-4. They are encapsulated in a Wax like, lipophilic structure which causes slow release over 12 hours time. This slow rise in 25OHvitaminD do not stimulate the negative feedback of CYP24A1 which degrade active vitamin D to inactive form.
About1/3 of patient on ERC reached the end point of over 30 % reduction in PTH level ovee 6 months.
Over 80% of patient on ERC reached serum level of 25OH vitamin D above 30.
Hypercalcemia and hyperphosphatemia risk was comparable to Placebo.
There was no adverce effect even with a 25OH level of 92.5 ng/mL.
5. The preliminary effects of SGLT2 on CKD-MBD are:
Reduction of MACE ( major cardiovascular events) and reduction of MARE ( major renal events).
On CKD-MBD: jong et al. has shown that dapagliflozin increased phosphate by 9%, FGF23 by 19،% anddecreased 1,25 OH vitamin D by 12% .
Calcium and 25OH Vitamin D were unaffected. Similar studies shows the same on empagliflozin.
The pathophysiology behind this results is that with inhibition of SGLT2 receptors, there is increased sodium intraluminal of the PCT, which lead to increased phosphate reabsorption via NaPi cotransporters. These changes are transient (for first 3 month).
So in summary they cause transient hyperphosphatemia, increased FGF23 and PTH, Hypovitaminosis D without clear consequences.
thanks dr Nour for comprehensive answers
Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
The causes of vitamin D deficiency in patients with CKD
Progressive decline eGFR.
< 30 ng/dl in CKD G3a by 71%.
< 30 ng/dl in CKD G4 by 84%.
< 30 ng/dl in CKD G5 by 89%.
2. Impaired skin synthesis. 3. Dietary restriction. 4. Suppression of 1 alpha-hydroxylase CYP27B1, catalyzes the activation of 25-hydroxyvitamin D. 5. CKD-associated proteinuria and uremia >>> loss of vitD binding proteins and 1-25, 2(OH) vitD.
The consequences of Vitamin D Deficiency in CKD
First main pathway
Disturbed hemostasis reduces Ca absorption and hypocalcemia.
Decreases biosynthesis of PTH.
Increase production of PTH.
2. The second main pathway
Reduce renal Pi clearance (hyperphosphatemia) with resultants sHPT and other mechanisms of hyperphosphatemia;
a) Hyperphosphatemia directly stimulates sHPT. b) Hyperphosphatemia reduces Ca serum levels by forming Ca/Pi complexes. c) Hyperphosphatemia decreases activation of vitD, >>> hypocalcemia. d) Hyperphosphatemia enhances the secretion of FGF23.
Reduce Kloth with a resultant decrease in Pi clearance.
3. The third main pathway
Decrease Klotho expression
a) Hyperphospahtemia. b) sHPT. Comparison of the biological effects of novel vitamin D analogous to calcitriol. Novel vitamin D analogues;
Have all the good properties of vitD.
Less unwanted side effects, (less hypocalcemia).
The same mechanism of action, binding to VDR to downregulate PTH, with altered affinity binding to vitD and VDR, and lower side effects.
Paricalcitol effectively suppresses PTH in HD patients, with better outcomes and survival compared to calcitriol.
However; there are no sufficient studies and a lack of evidence.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D
It is an oral prohormone of 1,25-(OH)vitD.
Indicated for the treatment of sHPT in CKD G3-G4 patients.
It differs from other vitD supplements in that the calcifediol is encapsulated in a lipophilic, wax-like structure that allowed prolonged calcifediol release over an extended 12 hours period.
This has important biochemical implication
a) Avoiding of the rapid rise of 25-(OH)D, and 1,25(OH)D level. b) ERC does not stimulate the negative feedback loop leading to an increase in the activity of the enzyme CYP24A1, which degrades active vitD to inactive forms. c) Prooved efficacy in treating sHPT in CKD G3-G4. d) Lower risk of hypercalcemia and hyperphosphatemia. The reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
High-quality RCTs in recent years showed that SGLT2 and MCR blocker (Finerenone) reduces both major cardiovascular events (MACE) and major renal events (MAREs), such as renal death and the initiation of dialysis or renal transplantation.
The safety and efficacy of the novel drug stimulate further research in renal HPT, vitD, and CKD-MBD.
De Jong et al; (2019) tested DAPA and EMPA and showed that SGLT2 increase Pi, PTH, and FGF23 while reducing VitD level, finally the concern about the effect of hyperphosphatemia in triggering a cascade of changes of CKD-MBDparameters.
Transient parameter changes in Pi, PTH, and FGF23, and decrease vitD level, which is a negative predictor of SGLT2-i(can affect the overall beneficial outcome improvement of patients with CKD, DM, and HF), but on the other hand a positive effect proved by MACE, and MARE need to be furtherly long-term studied.
thanks dr Kamal for comprehensive answers
1-The clinical consequences of CKD–MBD encompass parathyroid gland hyperplasia, vascular calcification and bone abnormalities which in turn increases the risk of mortality
2-Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Mention the causes of vitamin D deficiency in patients with CKD. 1- low dietary intake or supplement , 2- non exposure to sunlight,
3- loss of vitamin D binding proteins in proteinuria, and uremia 4- and 1,25-dihydroxy vitamin D decrease it’s activation through progression of ckd
-Mention the consequences of Vitamin D Deficiency in CKD. 1- disruption of mineral homeostasis, 2- parathyroid hyperplasia as result of prolonged hypocalcemia, 3- vascular calcification,
-Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D as maxacalcitol, doxercalciferol, & paricalcitol have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
vit d analogue safe than calcitriol as it may decrease risk of vascular calcification. -Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D. extended-release calcifediol an oral prohormone of calcitriol in an prolonged release formulation resulting in a slow and steady release of the drug lead to increase vitamin D and decrease PTH in ND-CKD patients with moderate SHPT. ERC associated with Currently no data on ERC regarding endpoints ie fractures, cardiovascular events so further studies are needed to evaluate the long-term efficacy and safety of ERC for the treatment of SHPT in ND-CKD patients. – Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD. in an RCT. Dapagliflozin increase phosphate, PTH, FGF23, 1,25-dihydroxy vitamin D compared to the placebo but Calcium and 25-hydroxyvitamin D were unchanged
although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitrio, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Mention the causes of vitamin D deficiency in patients with CKD.
Vit D Insufficiencyeceny in CKD patients due to many factors like :
Reduce sun exposure
reduce intake and low diet of vit d
Due to CKD , high FGF23 will reduce the 1 alpha hydroxylation
uraemia and proteinuria will affect the level of ON VDR
Mention the consequences of Vitamin D Deficiency in CKD.
hypocalcemia and SHPTH , high phosphate level due to the FGF23
osteomalacia
High PTH level will lead to refractory anaemia and EPO hyporesponsiveness
Compare the biological effects of novel vitamin D analogous to calcitriol.
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR. These proparities make the noval vit d analogue more safe than calciterol and decrease risk of vascular calcification.
1-Mention the causes of vitamin D deficiency in patients with CKD.
inadequate dietary intake or supplement , decreased exposure to sunlight,
Impaired biosynthesis, proteinuria, and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxy vitamin D decrease it’s activation through progression of ckd also
excessive supplies of vitamin D, calcium, and phosphate,
2-Mention the consequences of Vitamin D Deficiency in CKD.
Vit d deficiency lead to disruption of mineral homeostasis, parathyroid gland hyperplasia dueto hypocalcimia, increase risk for vascular calcification, bone abnormalities.
Also when taken inadequate Vitamin D supplementation can lead to hypercalcemia and hyperphosphatemia, and cause adynamic bone disease.even metastatic calcification.
3-Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D as maxacalcitol, doxercalciferol, & paricalcitol have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
These proparities make the noval vit d analogue more safe than calciterol and decrease risk of vascular calcification.
4-Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Novel vitamin D has numerous advantages: 1,25-dihydroxyvitamin D’s prohormone, extended-release calcifediol (ERC)and taken orally. When administed inSecondary hyperparathyroidism in CKD patients is indicated. Calcifediol is contained in a lipophilic, wax-like structure that releases it over 12 hours, unlike other vitamin D supplements.
5-Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
SGLT2-inhibitors promote the development of hyperparathyroidism and changes in other markers of CKD–MBD via inhibition of the SGLT2 receptor leads to increased sodium concentration in the lumen, which in turn leads to an increased phosphate re-absorption in the proximal tubule by NaPo4 cotransporters. This re-absorption of phosphate into the blood causes the temporal increase in serum phosphate, triggering an increase in FGF23 and PTH,so in end result lead to hyperphosphatemia and hypovitaminosis D
1.Mention the causes of vitamin D deficiency in patients with CKD.
Impaired skin synthesis and reduced exposure to sun of “ill” patients
Dietary restrictions
Reduced dietary intake due to nausea of CKD
Suppression of 1-α-hydroxylase by FGF-23
Proteinuria: loss of vitamin D binding protein in urine
2.Mention the consequences of Vitamin D Deficiency in CKD.
Hypocalcemia leading to SHPT
Hyperphosphatemia due bone resorption and inability of kidneys to excrete PO4
Progressive renal osteodystrophy
Osteomalacia
Arteriosclerosis and cardiovascular diseases
High PTH causes resistance to Erythropoietin leading to anemia
Anemia further exacerbates CVDs
3.Compare the biological effects of novel vitamin D analogous to calcitriol.
The added chain of the novel vitamin D analogues alters binding of the molecule to the VDR. It is thought that novel Vitamin D analogues supress PTH but has the added benefit of NOT increasing the absorption of Ca and PO4 from GIT, a feature that is debatable.
4.Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D. Calcifediol is a prohormone of the active vit D, made to be released over 12Hrs period (because of the way it is encapsulated) It achieves PTH reduction in one third of patients (compared to placebo), and increases Vit D levels to normal in ~ 80%. It reduces PTH in 40% of subjects by a third. The risk of hypercalcemia and hyperphosphatemia is minimal compared to other VDRAs 5.Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD. SGLT2i raises the concentration of Na in the lumen of the PCT, leading to an increase in PO4 reabsorption via the Na PO4 cotransporter. This may be the mechanism through which FGF-23 and PTH exert their phosphaturic impact.
thanks dr Hassan for your effort
vitamin D deficiency leads to increased the risk of cardiovascular calcification with consequent increase in mortality
regarding novel vitamin D analogues although preliminary data reported that paricalcitol may have a reasonable safety profile and associated with better outcomes and better survival compared to calcitriol, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development
Mention the causes of vitamin D deficiency in patients with CKD.
CKD patients often face deficiencies in both inactive vitamin D (calcidiol or 25-hydroxyvitamin), as well as active vitamin D (calcitriol or 1,25-dihydroxyvitamin D). This might be caused by impaired skin synthesis or prescribed dietary restrictions reducing the availability of the 25-hydroxyvitamin D precursors cholecalciferol/ergocalciferol. Also, CKD suppresses the 1α-hydroxylase CYP27B1, which catalyzes the activation of 25-hydroxyvitamin D. In addition to impaired biosynthesis, CKD-associated proteinuria and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxyvitamin D.
Mention the consequences of Vitamin D Deficiency in CKD.
Vitamin D deficiency in CKD directly impacts the homeostasis of calcium and phosphate regulatory feedback loops maintain this homeostasis, with vitamin D, the fibroblast growth factor-23 (FGF23), and the parathyroid hormone (PTH) acting as additional regulators . To maintain calcium homeostasis, a complex of vitamin D, the vitamin D receptor (VDR) and the retinoid X receptor binds to the vitamin D response element to regulate the transcription of genes for calcium homeostasis, including epithelial calcium channels and calcium-binding proteins.
A 1,25-dihydroxyvitamin D deficiency in CKD results in insufficient induction of these genes and thus impedes the transport of active Ca2+ from the intestine to the circulation. The PTH from the parathyroid glands counteracts hypocalcemia by stimulating osteoclasts to initiate calcium resorption from the bone.
Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D analogues, such as maxacalcitol, doxercalciferol or paricalcitol, have all the good properties of vitamin D and showed less unwanted side effects, especially less tendency for hypercalcemia
Early studies in humans showed the efficacy of paricalcitol in terms of PTH suppression in hemodialysis patients with HPT. Paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile comparable to placebo.
The nephrology community evaluated with great interest human (non-interventional) data associating the usage of paricalcitol with better outcomes and better survival compared to calcitriol lack of reliable superiority compared to calcitriol.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Extended-release calcifediol (ERC; EU term: prolonged-release calcifediol) is an orally administered prohormone of 1,25-dihydroxyvitamin D. The area of indication is secondary HPT in CKD stage G3–G4 patients. The key difference to other vitamin D supplements is the formulation.
the calcifediol is encapsulated in a lipophilic, wax-like structure that allows prolonged calcifediol release over an extended 12 h period. This has important biochemical implications: By avoiding the rapid rises of 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D levels, as seen with immediate-release calcifediol.
ERC does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which degrades active vitamin D to inactive forms .
The CKD stage did not influence the level of PTH suppression induced by specific total 25-hydroxyvitamin D levels.
As already discussed, the efficacy of vitamin D treatment measured by PTH reduction in secondary HPT .There were minimal changes in serum calcium and phosphate, and hence a low risk for hypercalcemia and hyperphosphatemia was recorded. In summary, these data indicate that on a biochemical level, ERC is a true step forward in HPT treatment
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
The SGLT2-inhibitors and the non-steroidal mineralocorticoid receptor blocker finerenone reduce both major cardiovascular events (MACE) and major renal events (“MAREs”), such as renal death and the initiation of dialysis or renal transplantation .
SGLT2-inhibitors promote the development of hyperparathyroidism and changes in other markers of CKD–MBD
The inhibition of the SGLT2 receptor leads to increased sodium concentration in the lumen, which in turn leads to an increased phosphate re-absorption in the proximal tube by NaPi cotransporters. This re-absorption of phosphate into the blood causes the temporal increase in serum phosphate, triggering an increase in FGF23 and PTH, which counteract elevated phosphate levels
thanks dr Rania
1-the other consequences of vitamin D deficiency include parathyroid gland hyperplasia, vascular calcification and bone abnormalities as well as inreased risk of mortality
2- Compare the biological effects of novel vitamin D analogous to calcitriol
Despite preliminary data in favor of vitamin D analogues, later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
thanks dr Rania
other consequences of vitamin D deficiency include parathyroid gland hyperplasia, vascular calcification and bone abnormalities as well as increased risk of mortality
2- compare novel vitamin D analogues to calcitriol
although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitriol, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development
**Mention the causes of vitamin D deficiency in patients with CKD.
Decrease dietary intake of vitamin D containing foods or drug, decrease sunlight exposure so no skin synthesis of vitamin D, proteinuria which lead to loss of vitamin D binding protein, suppression of 1 alpha hydrxylase so no activation of vitamin D, in Chronic Kidney disease causes decrease biosynthesis and loss of calcitriol
**Mention the consequences of Vitamin D Deficiency in CKD.
Vitamin D important in calcium and phosphorus hemostasis, in vitamin D deficiency leading to decrease Calcium intestinal absorption through regulation of transcription gene for hemostasis like epithelial calcium channel and Calcium binding protein so reduce calcium absorption from intestinal lumen, in addition to that vitamin D deficiency causes increase in PTH which lead to stimulation of osteoclast activity that lead to bone resorption for increasing calcium level
**Compare the biological effects of novel vitamin D analogous to calcitriol.
VD analogue like maxacalcitol, doxercalciferol and paricalcitol has the same mechanism of action as 1,25 Dihydr D in binding to VDR and lower PTH but with a better safety profile including hypercalcimia and hyperphosphatemia this is because the side chain modification causes change in binding affenity to vitamin D binding protein or VDR so there will better control of biochemical side effects
**Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifedol is oral form encapsulated, lipophilic wax like structure allow slow release of extended over 12 hr, causing slow rise 25 OH vitamin D and 1,25dihydroxyvitamin D, lower PTH does not stimulate the negative feedback loop causes increase of CYP24A1 which causes degradation of active vitamin D to inactive form without significant increase in calcium and phosphorus
**Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD
SGLT2 inhibitor reduce the major cardio-vascular event and major renal events. These drug inhibit SGLT2 receptors causes increase luminal sodium and then increase sodium and phosphorus absorption through sodium phosphorous cotransporter lead to increase S. Phosphorous which stimulate FGF23 and PTH with decrease 1,25dihydroxyvitamin without changing in calcium and 25 hydroxy vitamin D.
Mention the causes of vitamin D deficiency in patients with CKD.
Calcidiol and 1,25-dihydroxy vitamin D deficits are common in CKD patients. The 25-hydroxyvitamin D precursors cholecalciferol/ergocalciferol may be unavailable due to decreased skin production or dietary constraints. CKD inhibits the 1α-hydroxylase CYP27B1, which causes D-associated proteinuria and uremia by depleting the vitamin D binding protein a1,25-dihydroxy vitamin D.
Mention the consequences of Vitamin D Deficiency in CKD.
Vitamin D insufficiency in CKD directly affects calcium and phosphate homeostasis, which is maintained via regulatory feedback loops involving vitamin D, FGF23, and PTH. Vitamin D, the vitamin D receptor (VDR), and the retinoid X receptor connect to the vitamin D response element to control calcium homeostasis genes such as epithelial calcium channels and calcium-binding proteins. In CKD, 1,25-dihydroxy vitamin D insufficiency inhibits gene induction and active Ca2+ transfer from the gut to the circulation. Parathyroid PT stimulates osteoclasts to innate calcium to treat hypocalcemia.
Compare the biological effects of novel vitamin D analogous to calcitriol.
Paricalcitol suppressed PTH in HPT hemodialysis patients in early investigations. On hemodialysis, paricalcitol reduced intact PTH serum levels while being as safe as a placebo. Subsequently, the nephrology community examined human (non-interventional) evidence linking paricalcitol to better outcomes and survival than calcitriol.
Paricalcitol did not improve cardiovascular surrogate (intermediate) objectives in well-designed randomized, prospective, interventional studies.
Clinical experience and experimental data showed that even innovative vitamin D mimics might cause hypercalcemia. According to a PubMed search in May 2022, the number of yearly papers using “paricalcitol” has been declining for many years, probably reflecting a decline in clinical and scientific interest owing to the lack of verifiable superiority compared to calcitriol.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Novel vitamin D has numerous advantages: 1,25-dihydroxyvitamin D’s prohormone, extended-release calcifediol (ERC), is taken orally. Secondary HPT in G3–G4 CKD patients is indicated. Calcifediol is contained in a lipophilic, wax-like structure that releases it over 12 hours, unlike other vitamin D supplements.
for 12 weeks, 30 or 60 μg ERC or placebo for 14 weeks, then ERC for up to 52 weeks (extension study). ERC progressively raised blood 25-hydroxyvitamin D levels, with 80% of patients reaching 30 ng/mL (placebo: 7%). A PTH decrease of 30% at week 26 was the main objective. 33% and 34% of ERC patients in each trial met the endpoint, compared to 8% and 7% with the placebo. In the open-label extension phase, placebo-treated patients who converted to ERC saw a similar drop.
The phase 3 ERC studies showed similar hyperphosphatemia and hypercalcemia. Hypercalcemia and hyperphosphatemia were modest due to limited serum calcium and phosphate alterations.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
SGLT2-inhibitors cause hyperparathyroidism and CKD–MBD indicators. SGLT2-inhibitors affect CKD–MBD characteristics in small prospective studies. De Jong et al. (2019) examined dapagliflozin in 31 diabetic kidney disease patients in an RCT. Dapagliflozin raised blood phosphate, PTH, FGF23, and 1,25-dihydroxy vitamin D compared to the placebo. Calcium and 25-hydroxyvitamin D were unchanged.
1- Mention the causes of vitamin D deficiency in patients with CKD.
1-reduced sun light exposure and skin synthesis
2- reduce intake
3-suppressed activation of 1alfa -hydroxylase
4-proteinuria;- loss of vit.D binding proteins
5- uremia: loss of calcitriol
2.Mention the consequences of Vitamin D Deficiency in CKD.
Hypocalcemia
SHPT
Hyperphosphatemia
Progressive renal osteodystrophy
Vascular calcification
ABD
parathyroid gland hyperplasia.
3-Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D (maxacalcitol, doxercalciferol, & paricalcitol) have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
4- Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D
ERC is encapsulated in lipophilic wax like structure causes prolonged release extended up to 12h .
-ERC not stimulate the negative feedback loop to increased activity
The study confirmed ERC effectiveness in increasing serum25-hydroxyvitamin D and reducing PTH level without impact on serum calcium and phosphate levels.
5-Explain effects of SFLT-2 inhibitor on CKD-MBD
SGLT2-inhibitors increase serum phosphate, PTH, and FGF23, and decrease 1,25-dihydroxyvitamin D.
SGLT2i increases Na concentration in the lumen of PCT, and this will lead to increase in Pi reabsorption in the PCT via Na Pi cotransporter. This may be the trigger for FGF-23 & PTH to exert their phosphaturic effect.
thanks dr Ashraf for your effort
although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitrio, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
1.Mention the causes of vitamin D deficiency in patients with CKD. Causes of vitamin D deficiency in patients with CKD include; Impaired biosynthesis, proteinuria, and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxy vitamin D excessive supplies of vitamin D, calcium, and phosphate, inadequate dietary intake, and decreased exposure to sunlight.
2. Mention the consequences of Vitamin D Deficiency in CKD.
The consequences of Vitamin D Deficiency in CKD include disruption of mineral homeostasis, parathyroid gland hyperplasia, vascular calcification, bone abnormalities, hypocalcemia, and PTH overproduction. Additionally, Vitamin D deficiency can lead to insufficient induction of active Ca2+ from the intestine to the circulation and potentially increase the risk of cardiovascular disease in CKD patients. Furthermore, inadequate Vitamin D supplementation can lead to hypercalcemia and hyperphosphatemia, and cause adynamic bone disease.
3. Compare the biological effects of novel vitamin D analogous to calcitriol.
The novel vitamin D analogs have been developed to provide similar benefits to calcitriol, such as controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. However, unlike calcitriol, they are less likely to cause hypercalcemia and hyperphosphatemia. Additionally, long-term clinical studies have indicated that paricalcitol may be associated with better outcomes and better survival compared to calcitriol. Extended-release calcifediol (ERC) has the potential to effectively treat renal HPT without the risk of hypercalcemia and hyperphosphatemia. ERC is formulated in a lipophilic, wax-like structure that allows for prolonged calcifediol release over an extended 12-hour period. Finally, calcidiol does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which degrades active vitamin D to inactive forms.
4. Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Extended-release Calcifediol(ERC)has several advantages over other types of vitamin D; Calcifediol is encapsulated in a lipophilic, wax-like structure that allows prolonged calcifediol release over an extended 12 hrs period. ERC also helps to transfer the well-known efficacy of calcitriol into a modern HPT treatment with less risk for hypercalcemia and hyperphosphatemia induction. Studies found that ERC was effective in increasing serum 25-hydroxyvitamin D and reducing PTH levels without a statistically significant or notable impact on serum calcium and phosphate levels. Furthermore, the open-label extension phase of the trial found that patients primarily treated with a placebo, and then switched to ERC experienced a comparable decline in plasma PTH levels compared to those patients initially actively treated with ERC in the blinded study phases.
5.Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
The small prospective trials that have been conducted on the usage of SGLT2 inhibitors have shown that they have an influence on CKD-MBD parameters. These preliminary effects include hyperparathyroidism, changes in other markers of CKD-MBD, and hyperphosphatemia.
Small prospective trials suggest that SGLT2-inhibitors increase serum phosphate, PTH, and FGF23, and decrease 1,25-dihydroxyvitamin D. There is evidence that the usage of SGLT2 inhibitors and the non-steroidal mineralocorticoid receptor blocker finerenone reduce both major cardiovascular events (MACE) and major renal events (“MAREs”), such as renal death and the initiation of dialysis or renal transplantation. These findings suggest that SGLT2 inhibitors may have a positive effect on CKD-MBD, although further long-term research is necessary to confirm this. The potential for increased survival in CKD stage G2/G3a patients due to SGLT2-inhibitors and finerenone could create more interest in CKD-MBD research, as CKD MBD is primarily an issue in later CKD-stages.
There is association between vitamin D deficiency with the development of secondary hyperparathyroidism (sHPT) in chronic kidney disease (CKD). There is association between sHPT and important clinical outcomes, such as kidney disease progression, fractures, cardiovascular events, and mortality So three core issues should be solved and answered: (1) What is the optimal parathyroid hormone (PTH) target level for CKD and dialysis patients? (2) What is the optimal vitamin D level to support optimal PTH titration? (3) How can sHPT treatment support reduction in the occurrence of hard renal and cardiovascular events in CKD and dialysis patients? One of the main causes for vitamin D deficiency is chronic kidney disease (CKD) A study by Nigwekar et al. (2012) showed the prevalence of vitamin D levels below 30 ng/ml to be 71% for CKD stage G3a/b, 84% for stage G4 (eGFR of 15–29 mL/min/1.73 m2 ), and 89% for stage G5 (eGFR < 15 mL/min/1.73 m2 )
causes of vit. D deficiency in CKD
1-reduced sun light exposure and skin synthesis 2- diet reducing intake 3-suppressed activation of 1alfa -hydroxylase CYP27B1 4-proteinuria;- loss of vit.D binding proteins 5- uremia;- loss of calcitriol
Consequences of Vitamin D Deficiency in CKD
CKD can lead to SHPTH
The 1st main pathway is deficiency 1-25 (OH)2 vit D
Lead to decrease of intestinal calcium absorption And hypocalcemia increase production PTH which affect on Bone >>>>increase osteoclast activity and mobilizing ca to circulation And effect on TAL and DCT increase ca reabsorption by upregulating TRPV5 On PCT block phosphorus reabsorption , -stimulus and upregulate of alfa 1 hydroxylase This types of over production of PTH is secondary HPTH The 2nd main pathway is the reduced renal phosphate clearance in CKD leading to hyperphosphatemia, which further stimulates the development of SHPT In addition, high phosphate levels also lower serum-Ca2+ levels by forming insoluble Ca—P complexes and by decreasing the expression of the 1α-hydroxylase CYP27B1, which further aggravates vitamin D deficiency-related hypocalcemia. Additionally, phosphate stabilizes intact FGF23 , enhancing the secretion of the FGF23 which also downregulates the expression of CYP27B1 The 3rd main pathway is the CKD-induced suppression of transcription of the FGF23 coreceptor Klotho ; without Klotho FGF23 can not downregulation PTH and serum phosphate The development of sHPTand disruption of vit D are vapert of clinical syndrome called CKD -MBD whtich lead to # Parathyroid hyperplasia >>>>>>nodularity Parathyroid # Bone abnormality >>>ROD Vascular calcification and cardiovascular disease (a study by Górriz et al. identified cardiovascular events as the leading cause of death (36%) in non-dialysis CKD patients)
Use of vit.D KDIGO guidelines defined clear limits to avoid overtreatment with (active) vitamin D (including vitamin D analogues). These limits were PTH oversuppression and the development of hypercalcemia and hyperphosphatemia in CKD Also , more and more data indicated the potential association between active vitamin D overtreatment and the development of adynamic bone disease Novel vitamin D analogues, such as maxacalcitol, doxercalciferol or paricalcitol, came into play, with the latter predominantly in use in Europe and the US. It was claimed that these analogues have all the good properties of vitamin D and showed less unwanted side effects, especially less tendency for hypercalcemia The novel vit.d act as synthetic agonist to VDR no convert to calcitriol before binding to VDR
Extended-Release Calcifediol (ERC ): A Combination of Efficacy and Safety as the Next Step in sHPT Treatment ERC the novel form of VIT.D Used indication in sHPT in CKD stag G3 –G4 #The key difference to other vit.D IS 1-formulation ERC is encapsulated in lipophilic wax like structure that allow prolonged release ERC over extended 12h period So avoid the rapid rising of vit.D level 2-ERC doesn’t stimulate the negative feedback loop to increased activity The study confirmed ERC effectiveness in increasing serum25b-hydroxyvitamin D and reducing PTH level without statistically significant or notable impact on serum calcium and phosphate levels
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
The SGLT2-inhibitors and the non-steroidal mineralocorticoid receptor blocker finerenone reduce both major cardiovascular events (MACE) and major renal events (“MAREs”), such as renal death and the initiation of dialysis or renal trans[1]plantation [71,72]. Maybe this positive experience could stimulate researchers and industry to start comparable trials for non-dialysis CKD–MBD patients to provide clear guidance regarding the optimal starting point, dosage, and type of future vitamin D treatment, as well as phosphate management An RCT by de Jong et al. (2019) hypothesize that the inhibition of the SGLT2 receptor leads to increased sodium concentration in the lumen, which in turn leads to an increased phosphate re-absorption in the proxi[1]mal tube by NaPi cotransporters. Assumingly, this re-absorption of phosphate into the blood causes the temporal increase in serum phosphate, triggering an increase in FGF23 and PTH, which counteract elevated phosphate levels the effect of SGLT2 inhibitor and finerenone on survival; CKD stage G2 , G3 a and investigated on CKD-MBD needs more research and studies
1.Mention the causes of vitamin D deficiency in patients with CKD.
Impaired skin synthesis
Dietary restrictions
Suppressed alpha-1 hydroxlayse
Proteinuria: loss of vitamin D binding in urine
Uremia: loss of calcitriol
2.Mention the consequences of Vitamin D Deficiency in CKD.
Hypocalcemia
Secondary hyperparathyroidism (sHPT)
Hyperphosphatemia
Progressive renal osteodystrophy
Bone demineralization
Uncontrolled PTH
3.Compare the biological effects of novel vitamin D analogous to calcitriol.
This is debatable issue.
Both have the same mechanism of action.
Up to-date no high quality RCT regarding the relevant hard end points such as MI, stroke, or survival
Novel vitamin D (maxacalcitol, doxercalciferol, & paricalcitol) have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR to a such a degree that would allow for better control of the biochemical side effects.
In general, there is lack of reliable superiority compared to calcitriol.
4.Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is oral prohormone of 1,25 hydroxyvitamin D.
It has two forms; immediate-release calcifediol (IMR) or extended-release calcifediol (ERC)
-Features of ERC
Encapsulated in a lipophilic, wax like structure.
Which allows prolonged calcifediol release over an extended period of 12 hours.
Does not activate negative feedback loop that leads to increase activity of 24 hydroxylase which degrades vitamin D into inactive forms.
-Efficacy of ERC
According to the data from 2 phase -3 RCT, PTH reduction was in intervention group 33%, 34% versus 8%, 7 % in placebo group respectively.
> 80% of patients had vitamin D levels > 30 ng/ml.
Another study by Fadda et al. revealed that, 40% of the participant had > 30% reduction in PTH.
-Safety
In this phase-3 data, minimal alterations in Ca & PO4 were noted in both intervention & placebo arm and therefore, a low risk for hypercalcemia and hyperphosphatemia.
5.Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD. -Transient changes in CKD-MBD profile (de Jong et al.) in the form of;
Hyperphosphatemia
sHPT
FGF23
Hypovitaminosis D
-Possible mechanism
SGLT2i increases Na concentration in the lumen of PCT, and this will lead to increase in Pi reabsorption in the PCT via Na Pi cotransporter. This may be the trigger for FGF-23 & PTH to exert their phosphaturic effect.
Causes of vit D deficiency in CKD 1- Decreased sun exposure leads to decreased cholecalciferol production 2- Diet restriction limits ergocholecalciferol and cholecalciferol 3- Reduced functioning renal mass causes decreased alpha one hydroxylase activity 4- Increase FGF-23 which suppress alpha one hydroxylase 5- Proteinuria and uremia cause loss of vit-D binding proteins Consequences of vit D deficiency in CKD 1- Hypocalcemia: Decrease calcitrol leads to decreased transcription of genes involved in calcium homestasis like gnenes encoding epithelial calcium channels and calcium binding protein, decreasing calcium absorption form intestine 2- Hypoparathyroidism: vit D deficiency release negative feedback effect of vit d on parathyroid gland which in addition to hypocalcemia will cause hyperparathyroidism 3- 2ry HPT, vit D deficiency and mineral disturbance will lead CKD-BMD COMPARE the biologic effects of novel vit analogue Synthetic vit D analogues like parcalcitol a vitamin D2 analog, and oxacalcitriol, a vitamin D3 analog, have many beneficial effects by different machanisms: 1- Action on parathyroid: inhibit PTH secretion and supress parathyroid hyperplasia 2- Action on calcium and phosphorus level: minimal hypercalcemia and hyperphosphatemia Extended release calcifedol It is a prohormone of calcitrol, kept in a lipophilic, wax- like capsule, so released over 12 hours, inhibiting rapid rise of serum vit D, preventing negative feedback, thus prevent convention of active vit D to inactive form due to inactivation of CYP14A1 Explain effects of SFLT-2 inhibitor on CKD-MBD 1-SFLT-2 inhibitor activate phosphorus and sodium absorption by proximal tubules, leading to hyperphosphatemia, which in turn causes hyperparathyroidism, and increase FGF-23. 2-these changes cumulate in inhibition of alpha hydroxylase, decreasing 1,25(OH)2VIT D. 3- serum calcium and 25OH vit D remain unaffected all these changes will accelerate CKD-BMD in the first 3 months post initiation of ttt, after that no differences in these parameter
thanks dr Ahmed vitamin D deficiency is also associated with increased risk of vascular calcification and mortality
regarding novel vitamin D analogues: although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitriol, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Mention the causes of vitamin D deficiency in patients with CKD
lack of sunlight
lack of vitamin D in diet
lack of enzymatic activation to active vitamin D
If CKD related proteinuria then loss vitamin D binding protein
Mention the consequences of Vitamin D Deficiency CKD.
Hypocalcaemia
Hyperphosphataemia
Secondary Hyperparathyroid
Tertiary Hypeparathyroid
Increased PTH, Increased FGF 23 Decreased Klotho decreased 1 alpha hydroxylase
Renal Osteodystrophy
Vascular Calcification
increased cardiovascular mortality
Compare the biological effects of novel vitamin D analogous to calcitriol.
they both act on vitamin D receptor to decrease PTH however due to side chain alteration in molecular structure have less side effect on binding to VDR in terms of causing hypercalcaemia and hyperphosphataemia.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is an extended release vitamin D analogue and does not cause deactivation of active vitamin D due to initial rapid surge
Efficacy: it does decrease PTH and increase in VITAMIN D LEVEL WITHOUT STATISTICALLY SIGNIFICANT increase in calcium or phosphate
Safety there has been no safety concerns from phase 3 trial
there is no evidence of that it improves mortality or survival or decrease progression of ckd just biochemical benefit
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
it could cause a transient secondary hyperparathyroid state due to increase na and po42- absorption
it does decrease MACE MARE events tho tho more studies needed to understand more
The causes of vitamin D deficiency in patients with CKD
proteinuria and uremia which cause the vitamin D binding proteins,and 1,25dihydroxyvitamin d ,, poor diet intake ,, decreased sunlight exposure and skin synthesis.
suppression of the 1α-hydroxylase CYP27B1activation
The consequences of Vitamin D Deficiency in CKD
secondary hyperparathyroidism.
hypocalcemia
hyperphosphatemia
Renal osteodystrophy
Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D analogs, such as paricalcitol, doxercalciferol, or paricalcitol, came into play, predominantly in use in Europe and the US. It was declared that these analogs have good properties of vitamin D and showed fewer side effects and significantly less tendency for hypercalcemia. The mechanism of action for these substances was the same as for 1,25-hydroxyvitamin D, namely binding to the VDR to mediate PTH lowering. However, it come up that side-chain modifications would alter the binding affinity to circulating vitamin D binding proteins and the VDR to such a degree that this would allow for better control.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Extended-release calcifediol (ERC) is effectively treat renal HPT without the risk of hypercalcemia and hyperphosphatemia. Extended-release calcifediol is formulated in a lipophilic, wax-like structure that allows for prolonged calcifediol extended release about 12hours.
The SGLT2-inhibitors and the non-steroidal mineralocorticoid
receptor blocker finerenone reduce both major cardiovascular events (MACE) and major
renal events (“MAREs”), such as renal death and the initiation of dialysis or renal trans-
plantation [71,72]. Maybe this positive experience could stimulate researchers and industry
The reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
IN trials for non-dialysis CKD–MBD patients to provide clear guidance.
regarding the optimal starting point, dosage, and type of future vitamin D treatment, as
well as phosphate management.
In addition to that, the safety, efficacy and widespread usage of SGLT2 inhibitors
in CKD treatment might also stimulate further research in renal HPT, vitamin D, and
CKD–MBD: Interestingly, SGLT2-inhibitors did promote the
development of hyperparathyroidism and changes in other markers of CKD–MBD.
Mention the causes of vitamin D deficiency in patients with CKD.
*impaired skin synthesis
*prescribed dietary restrictions reducing the availability of the 25-hydroxyvitamin D precursors cholecalciferol/ergocalciferol .
*Also, CKD suppresses the 1α-hydroxylase CYP27B1, which catalyzes the activation of 25-hydroxyvitamin D .
*In addition to impaired biosynthesis CKD-associated proteinuria and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxyvitamin D .
Mention the consequences of Vitamin D Deficiency in CKD.
*Hypocalcemia
*Hyperphopshatemia
*Secondary hyperparathyroidism
*Renal osteodystrophy .
Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D as maxacalcitol, doxercalciferol, & paricalcitol have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
vit D Analogue safe than calcitriol as it may decrease risk of vascular calcification.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is a prohormone of the active vit D, made to be released over 12Hrs period ,It achieves PTH reduction in one third of patients (compared to placebo), and increases Vit D levels to normal in ~ 80%. It reduces PTH in 40% of subjects by a third.
The risk of hypercalcemia and hyperphosphatemia is minimal compared to other VDRAs.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
SGLT2i raises the concentration of Na in the lumen of the PCT, leading to an increase in PO4 reabsorption via the Na PO4 cotransporter. This may be the mechanism through which FGF-23 and PTH exert their phosphaturic impact.
Mention the causes of vitamin D deficiency in patients with CKD.
This might be caused by impaired skin synthesis or prescribed dietary restrictions reducing the availability of the 25-hydroxyvitamin D precursors chole- calciferol/ergocalciferol. Also, CKD suppresses the 1α-hydroxylase CYP27B1, which catalyzes the activation of 25-hydroxyvitamin D. In addition to impaired biosynthe-CKD-associated proteinuria and uremia lead to the loss of vitamin D binding proteins and
1,25-dihydroxyvitamin D.
Mention the consequences of Vitamin D Deficiency in CKD.
A 1,25-dihydroxyvitamin D deficiency in CKD results in insufficient induction of these genes and thus impedes the transport of active Ca2+ from the intestine to the circulation. The PTH from the parathyroid glands counteracts hypocalcemia by stimulating osteoclasts to initiate calcium resorption from the bone. In CKD, however, several mechanisms lead to PTH overproduction, also known as hyperparathyroidism.
Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D analogues, such as maxacalcitol, doxercalciferol or paricalcitol, came into play, with the latter predominantly in use in Europe and the US. It was claimed that these analogues have all the good properties of vitamin D and showed less unwanted side effects, especially less tendency for hypercalcemia. As vitamin D analogues, the mechanism of action for these substances was basically the same as for 1,25-hydroxyvitamin D, namely binding to the VDR to mediate PTH lowering. However, it was conceived that side-chain modifications would alter the binding affinity to circulating vitamin D binding proteins and/or the VDR to such a degree that this would allow for better control of the biochemical (side) effects.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
(ERC; EU term: prolonged-release calcifediol) is an orally administered prohormone of 1,25-dihydroxyvitamin D. The area of indication is secondary HPT in CKD stage G3–G4 patients. The key difference to other vitamin D supplements is the formulation: the calcifediol is encapsulated in a lipophilic, wax-like structure that allows prolonged calcifediol release over an extended 12 h period [42,67]. This has important biochemical implications: By avoiding the rapid rises of 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D levels, as seen with immediate-release calcifediol, ERC does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which degrades active vitamin D to inactive forms.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
Interestingly, the above-mentioned SGLT2-inhibitors promote the development of hyperparathyroidism and changes in other markers of CKD–MBD.
increase serum phosphate, PTH , FGF23 , and decrease serum 1,25-dihydroxyvitamin D
Mention the causes of vitamin D deficiency in patients with CKD.
Mention the consequences of Vitamin D Deficiency in CKD.
Compare the biological effects of novel vitamin D analogous to calcitriol.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
thanks dr Riaan for your effort
1-The clinical consequences of CKD–MBD encompass parathyroid gland hyperplasia, vascular calcification and bone abnormalities which in turn increases the risk of mortality
2-Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Mention the causes of vitamin D deficiency in patients with CKD.
Mention the consequences of Vitamin D Deficiency in CKD.
Compare the biological effects of novel vitamin D analogous to calcitriol.
lack of reliable superiority compared to calcitriol.same mechanism of action.
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Efficacy:
Safety:
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
thanks dr Mahmoud for your effort
Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
1. The causes of vitamin D deficiency in CKD patients are:
-reduced sunlight exposure and skin synthesis
-diets reduction of intake
-proteinuria: what causes loss of vitamin D binding proteins
-suppressed activation of 1 alpha hydroxylase
-Uremia: loss of Calcitriol
2. Consequences of Vitamin D in CKD:
-insufficient induction of genes responsible for calcium hemostasis (including epithelial calcium channel and calcium binding proteins), what causes disruption in transport of calcium in circulation.
– Vitamin D deficiency causes secondary hyperparathyroidism in 3 main pathway: The hyperphosphatemia and hypocalcemia upregulate and induce the transcription of PTH and also increase FGF23 stabilisation and upregulation which in turn lead to inhibition of 1 alpha hydroxylase.
Secondly, Decreased Klotho cofactor transcription what causes fgf23 resistance.
Thirdly, decreased production of 1,25 OHvitaminD becauseof decreased CYP27B1 expression.
– vitamin D deficiency and increased PTH will lead to MBD including nodular hyperplasia of parathyroid gland till complete resistance to medical treatment, vascular calcification and increased cardiovascular events (36 percent in a studdy of Gorriz) due to increase deposition of calcium phosphate saltsin the presence of hyperphosphatemia. And lastly excessive bone resorption due to PTH excess and hypocalcemia.
3. Early on(1970, 1980) the wide use of Calcitriol was the main cause of hyperphophatemia and hypercalcemia. It was reported in the study of memmos that Calcitriol can very effectively lower PTH.
Goodman in year 2000 highlighted the vascular calcification (CAC) side effects and hyperphosphatemia and hypercalcemia due to Calcitriol usage. He systematically quantified the calcification using CT scores. His work lead to shift toward less aggressive usage of avtive vitamin D.
Some studies indicated a relationship between Calcitriol usage and increasing FGF23 level( What give an association to LV hypertrophy).
Novel vitamin D analogue such as maxacalcitol, doxercalciferol or Paricalcitol showed less negative side effects. This is due to more selectivity to VDR, what lead to more local effect on Parathyroid gland causing effective decrease in PTH level, antiinflammatory , antifibrotic effects and decreasing proteinuria.
They have less affinity to circulating vitamin D binding proteins so it is more likely to reach his target tissue.
4. In comparison to other forms of vitamin D , ERC are used and studied in CKD stage 3-4. They are encapsulated in a Wax like, lipophilic structure which causes slow release over 12 hours time. This slow rise in 25OHvitaminD do not stimulate the negative feedback of CYP24A1 which degrade active vitamin D to inactive form.
About1/3 of patient on ERC reached the end point of over 30 % reduction in PTH level ovee 6 months.
Over 80% of patient on ERC reached serum level of 25OH vitamin D above 30.
Hypercalcemia and hyperphosphatemia risk was comparable to Placebo.
There was no adverce effect even with a 25OH level of 92.5 ng/mL.
5. The preliminary effects of SGLT2 on CKD-MBD are:
Reduction of MACE ( major cardiovascular events) and reduction of MARE ( major renal events).
On CKD-MBD: jong et al. has shown that dapagliflozin increased phosphate by 9%, FGF23 by 19،% anddecreased 1,25 OH vitamin D by 12% .
Calcium and 25OH Vitamin D were unaffected. Similar studies shows the same on empagliflozin.
The pathophysiology behind this results is that with inhibition of SGLT2 receptors, there is increased sodium intraluminal of the PCT, which lead to increased phosphate reabsorption via NaPi cotransporters. These changes are transient (for first 3 month).
So in summary they cause transient hyperphosphatemia, increased FGF23 and PTH, Hypovitaminosis D without clear consequences.
thanks dr Nour for comprehensive answers
Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
The causes of vitamin D deficiency in patients with CKD
2. Impaired skin synthesis.
3. Dietary restriction.
4. Suppression of 1 alpha-hydroxylase CYP27B1, catalyzes the activation of 25-hydroxyvitamin D.
5. CKD-associated proteinuria and uremia >>> loss of vitD binding proteins and 1-25, 2(OH) vitD.
The consequences of Vitamin D Deficiency in CKD
2. The second main pathway
a) Hyperphosphatemia directly stimulates sHPT.
b) Hyperphosphatemia reduces Ca serum levels by forming Ca/Pi complexes.
c) Hyperphosphatemia decreases activation of vitD, >>> hypocalcemia.
d) Hyperphosphatemia enhances the secretion of FGF23.
3. The third main pathway
a) Hyperphospahtemia.
b) sHPT.
Comparison of the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D analogues;
Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D
a) Avoiding of the rapid rise of 25-(OH)D, and 1,25(OH)D level.
b) ERC does not stimulate the negative feedback loop leading to an increase in the activity of the enzyme CYP24A1, which degrades active vitD to inactive forms.
c) Prooved efficacy in treating sHPT in CKD G3-G4.
d) Lower risk of hypercalcemia and hyperphosphatemia.
The reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
thanks dr Kamal for comprehensive answers
1-The clinical consequences of CKD–MBD encompass parathyroid gland hyperplasia, vascular calcification and bone abnormalities which in turn increases the risk of mortality
2-Compare the biological effects of novel vitamin D analogous to calcitriol.
Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Mention the causes of vitamin D deficiency in patients with CKD.
1- low dietary intake or supplement ,
2- non exposure to sunlight,
3- loss of vitamin D binding proteins in proteinuria, and uremia
4- and 1,25-dihydroxy vitamin D decrease it’s activation through progression of ckd
-Mention the consequences of Vitamin D Deficiency in CKD.
1- disruption of mineral homeostasis,
2- parathyroid hyperplasia as result of prolonged hypocalcemia,
3- vascular calcification,
-Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D as maxacalcitol, doxercalciferol, & paricalcitol have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
vit d analogue safe than calcitriol as it may decrease risk of vascular calcification.
-Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
extended-release calcifediol an oral prohormone of calcitriol in an prolonged release formulation resulting in a slow and steady release of the drug lead to increase vitamin D and decrease PTH in ND-CKD patients with moderate SHPT. ERC associated with Currently no data on ERC regarding endpoints ie fractures, cardiovascular events so further studies are needed to evaluate the long-term efficacy and safety of ERC for the treatment of SHPT in ND-CKD patients.
–
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
in an RCT. Dapagliflozin increase phosphate, PTH, FGF23, 1,25-dihydroxy vitamin D compared to the placebo but Calcium and 25-hydroxyvitamin D were unchanged
although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitrio, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
Vit D Insufficiencyeceny in CKD patients due to many factors like :
Reduce sun exposure
reduce intake and low diet of vit d
Due to CKD , high FGF23 will reduce the 1 alpha hydroxylation
uraemia and proteinuria will affect the level of ON VDR
Mention the consequences of Vitamin D Deficiency in CKD.
hypocalcemia and SHPTH , high phosphate level due to the FGF23
osteomalacia
High PTH level will lead to refractory anaemia and EPO hyporesponsiveness
Compare the biological effects of novel vitamin D analogous to calcitriol.
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
These proparities make the noval vit d analogue more safe than calciterol and decrease risk of vascular calcification.
1-Mention the causes of vitamin D deficiency in patients with CKD.
inadequate dietary intake or supplement , decreased exposure to sunlight,
Impaired biosynthesis, proteinuria, and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxy vitamin D decrease it’s activation through progression of ckd also
excessive supplies of vitamin D, calcium, and phosphate,
2-Mention the consequences of Vitamin D Deficiency in CKD.
Vit d deficiency lead to disruption of mineral homeostasis, parathyroid gland hyperplasia dueto hypocalcimia, increase risk for vascular calcification, bone abnormalities.
Also when taken inadequate Vitamin D supplementation can lead to hypercalcemia and hyperphosphatemia, and cause adynamic bone disease.even metastatic calcification.
3-Compare the biological effects of novel vitamin D analogous to calcitriol.
Novel vitamin D as maxacalcitol, doxercalciferol, & paricalcitol have the side-chain modifications that would alter the binding affinity to circulating binding proteins and/or the VDR
The novel vitD act as synthetic agonist to VDR no convert to calcitriol before binding to VDR.
These proparities make the noval vit d analogue more safe than calciterol and decrease risk of vascular calcification.
4-Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Novel vitamin D has numerous advantages: 1,25-dihydroxyvitamin D’s prohormone, extended-release calcifediol (ERC)and taken orally. When administed inSecondary hyperparathyroidism in CKD patients is indicated. Calcifediol is contained in a lipophilic, wax-like structure that releases it over 12 hours, unlike other vitamin D supplements.
5-Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
SGLT2-inhibitors promote the development of hyperparathyroidism and changes in other markers of CKD–MBD via inhibition of the SGLT2 receptor leads to increased sodium concentration in the lumen, which in turn leads to an increased phosphate re-absorption in the proximal tubule by NaPo4 cotransporters. This re-absorption of phosphate into the blood causes the temporal increase in serum phosphate, triggering an increase in FGF23 and PTH,so in end result lead to hyperphosphatemia and hypovitaminosis D
1.Mention the causes of vitamin D deficiency in patients with CKD.
2.Mention the consequences of Vitamin D Deficiency in CKD.
3.Compare the biological effects of novel vitamin D analogous to calcitriol.
The added chain of the novel vitamin D analogues alters binding of the molecule to the VDR. It is thought that novel Vitamin D analogues supress PTH but has the added benefit of NOT increasing the absorption of Ca and PO4 from GIT, a feature that is debatable.
4.Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifediol is a prohormone of the active vit D, made to be released over 12Hrs period (because of the way it is encapsulated)
It achieves PTH reduction in one third of patients (compared to placebo), and increases Vit D levels to normal in ~ 80%. It reduces PTH in 40% of subjects by a third.
The risk of hypercalcemia and hyperphosphatemia is minimal compared to other VDRAs
5.Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
SGLT2i raises the concentration of Na in the lumen of the PCT, leading to an increase in PO4 reabsorption via the Na PO4 cotransporter. This may be the mechanism through which FGF-23 and PTH exert their phosphaturic impact.
thanks dr Hassan for your effort
vitamin D deficiency leads to increased the risk of cardiovascular calcification with consequent increase in mortality
regarding novel vitamin D analogues although preliminary data reported that paricalcitol may have a reasonable safety profile and associated with better outcomes and better survival compared to calcitriol, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development
Please use your own words rather than coping and pasting from the article.
thanks dr Rania
1-the other consequences of vitamin D deficiency include parathyroid gland hyperplasia, vascular calcification and bone abnormalities as well as inreased risk of mortality
2- Compare the biological effects of novel vitamin D analogous to calcitriol
Despite preliminary data in favor of vitamin D analogues, later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
thanks dr Rania
other consequences of vitamin D deficiency include parathyroid gland hyperplasia, vascular calcification and bone abnormalities as well as increased risk of mortality
2- compare novel vitamin D analogues to calcitriol
although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitriol, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development
**Mention the causes of vitamin D deficiency in patients with CKD.
Decrease dietary intake of vitamin D containing foods or drug, decrease sunlight exposure so no skin synthesis of vitamin D, proteinuria which lead to loss of vitamin D binding protein, suppression of 1 alpha hydrxylase so no activation of vitamin D, in Chronic Kidney disease causes decrease biosynthesis and loss of calcitriol
**Mention the consequences of Vitamin D Deficiency in CKD.
Vitamin D important in calcium and phosphorus hemostasis, in vitamin D deficiency leading to decrease Calcium intestinal absorption through regulation of transcription gene for hemostasis like epithelial calcium channel and Calcium binding protein so reduce calcium absorption from intestinal lumen, in addition to that vitamin D deficiency causes increase in PTH which lead to stimulation of osteoclast activity that lead to bone resorption for increasing calcium level
**Compare the biological effects of novel vitamin D analogous to calcitriol.
VD analogue like maxacalcitol, doxercalciferol and paricalcitol has the same mechanism of action as 1,25 Dihydr D in binding to VDR and lower PTH but with a better safety profile including hypercalcimia and hyperphosphatemia this is because the side chain modification causes change in binding affenity to vitamin D binding protein or VDR so there will better control of biochemical side effects
**Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Calcifedol is oral form encapsulated, lipophilic wax like structure allow slow release of extended over 12 hr, causing slow rise 25 OH vitamin D and 1,25dihydroxyvitamin D, lower PTH does not stimulate the negative feedback loop causes increase of CYP24A1 which causes degradation of active vitamin D to inactive form without significant increase in calcium and phosphorus
**Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD
SGLT2 inhibitor reduce the major cardio-vascular event and major renal events. These drug inhibit SGLT2 receptors causes increase luminal sodium and then increase sodium and phosphorus absorption through sodium phosphorous cotransporter lead to increase S. Phosphorous which stimulate FGF23 and PTH with decrease 1,25dihydroxyvitamin without changing in calcium and 25 hydroxy vitamin D.
Calcidiol and 1,25-dihydroxy vitamin D deficits are common in CKD patients. The 25-hydroxyvitamin D precursors cholecalciferol/ergocalciferol may be unavailable due to decreased skin production or dietary constraints. CKD inhibits the 1α-hydroxylase CYP27B1, which causes D-associated proteinuria and uremia by depleting the vitamin D binding protein a1,25-dihydroxy vitamin D.
Vitamin D insufficiency in CKD directly affects calcium and phosphate homeostasis, which is maintained via regulatory feedback loops involving vitamin D, FGF23, and PTH. Vitamin D, the vitamin D receptor (VDR), and the retinoid X receptor connect to the vitamin D response element to control calcium homeostasis genes such as epithelial calcium channels and calcium-binding proteins. In CKD, 1,25-dihydroxy vitamin D insufficiency inhibits gene induction and active Ca2+ transfer from the gut to the circulation. Parathyroid PT stimulates osteoclasts to innate calcium to treat hypocalcemia.
Paricalcitol suppressed PTH in HPT hemodialysis patients in early investigations. On hemodialysis, paricalcitol reduced intact PTH serum levels while being as safe as a placebo. Subsequently, the nephrology community examined human (non-interventional) evidence linking paricalcitol to better outcomes and survival than calcitriol.
Paricalcitol did not improve cardiovascular surrogate (intermediate) objectives in well-designed randomized, prospective, interventional studies.
Clinical experience and experimental data showed that even innovative vitamin D mimics might cause hypercalcemia. According to a PubMed search in May 2022, the number of yearly papers using “paricalcitol” has been declining for many years, probably reflecting a decline in clinical and scientific interest owing to the lack of verifiable superiority compared to calcitriol.
Novel vitamin D has numerous advantages: 1,25-dihydroxyvitamin D’s prohormone, extended-release calcifediol (ERC), is taken orally. Secondary HPT in G3–G4 CKD patients is indicated. Calcifediol is contained in a lipophilic, wax-like structure that releases it over 12 hours, unlike other vitamin D supplements.
for 12 weeks, 30 or 60 μg ERC or placebo for 14 weeks, then ERC for up to 52 weeks (extension study). ERC progressively raised blood 25-hydroxyvitamin D levels, with 80% of patients reaching 30 ng/mL (placebo: 7%). A PTH decrease of 30% at week 26 was the main objective. 33% and 34% of ERC patients in each trial met the endpoint, compared to 8% and 7% with the placebo. In the open-label extension phase, placebo-treated patients who converted to ERC saw a similar drop.
The phase 3 ERC studies showed similar hyperphosphatemia and hypercalcemia. Hypercalcemia and hyperphosphatemia were modest due to limited serum calcium and phosphate alterations.
SGLT2-inhibitors cause hyperparathyroidism and CKD–MBD indicators. SGLT2-inhibitors affect CKD–MBD characteristics in small prospective studies. De Jong et al. (2019) examined dapagliflozin in 31 diabetic kidney disease patients in an RCT. Dapagliflozin raised blood phosphate, PTH, FGF23, and 1,25-dihydroxy vitamin D compared to the placebo. Calcium and 25-hydroxyvitamin D were unchanged.
1- Mention the causes of vitamin D deficiency in patients with CKD.
2.Mention the consequences of Vitamin D Deficiency in CKD.
3-Compare the biological effects of novel vitamin D analogous to calcitriol.
4- Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D
The study confirmed ERC effectiveness in increasing serum25-hydroxyvitamin D and reducing PTH level without impact on serum calcium and phosphate levels.
5-Explain effects of SFLT-2 inhibitor on CKD-MBD
thanks dr Ashraf for your effort
although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitrio, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.
1.Mention the causes of vitamin D deficiency in patients with CKD.
Causes of vitamin D deficiency in patients with CKD include;
Impaired biosynthesis, proteinuria, and uremia lead to the loss of vitamin D binding proteins and 1,25-dihydroxy vitamin D
excessive supplies of vitamin D, calcium, and phosphate, inadequate dietary intake, and decreased exposure to sunlight.
2. Mention the consequences of Vitamin D Deficiency in CKD.
The consequences of Vitamin D Deficiency in CKD include disruption of mineral homeostasis, parathyroid gland hyperplasia, vascular calcification, bone abnormalities, hypocalcemia, and PTH overproduction.
Additionally, Vitamin D deficiency can lead to insufficient induction of active Ca2+ from the intestine to the circulation and potentially increase the risk of cardiovascular disease in CKD patients.
Furthermore, inadequate Vitamin D supplementation can lead to hypercalcemia and hyperphosphatemia, and cause adynamic bone disease.
3. Compare the biological effects of novel vitamin D analogous to calcitriol.
The novel vitamin D analogs have been developed to provide similar benefits to calcitriol, such as controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism. However, unlike calcitriol, they are less likely to cause hypercalcemia and hyperphosphatemia. Additionally, long-term clinical studies have indicated that paricalcitol may be associated with better outcomes and better survival compared to calcitriol.
Extended-release calcifediol (ERC) has the potential to effectively treat renal HPT without the risk of hypercalcemia and hyperphosphatemia. ERC is formulated in a lipophilic, wax-like structure that allows for prolonged calcifediol release over an extended 12-hour period.
Finally, calcidiol does not stimulate the negative feedback loop leading to increased activity of the enzyme CYP24A1, which degrades active vitamin D to inactive forms.
4. Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
Extended-release Calcifediol(ERC)has several advantages over other types of vitamin D;
Calcifediol is encapsulated in a lipophilic, wax-like structure that allows prolonged calcifediol release over an extended 12 hrs period.
ERC also helps to transfer the well-known efficacy of calcitriol into a modern HPT treatment with less risk for hypercalcemia and hyperphosphatemia induction. Studies found that ERC was effective in increasing serum 25-hydroxyvitamin D and reducing PTH levels without a statistically significant or notable impact on serum calcium and phosphate levels. Furthermore, the open-label extension phase of the trial found that patients primarily treated with a placebo, and then switched to ERC experienced a comparable decline in plasma PTH levels compared to those patients initially actively treated with ERC in the blinded study phases.
5.Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
The small prospective trials that have been conducted on the usage of SGLT2 inhibitors have shown that they have an influence on CKD-MBD parameters.
These preliminary effects include hyperparathyroidism, changes in other markers of CKD-MBD, and hyperphosphatemia.
Small prospective trials suggest that SGLT2-inhibitors increase serum phosphate, PTH, and FGF23, and decrease 1,25-dihydroxyvitamin D.
There is evidence that the usage of SGLT2 inhibitors and the non-steroidal mineralocorticoid receptor blocker finerenone reduce both major cardiovascular events (MACE) and major renal events (“MAREs”), such as renal death and the initiation of dialysis or renal transplantation. These findings suggest that SGLT2 inhibitors may have a positive effect on CKD-MBD, although further long-term research is necessary to confirm this.
The potential for increased survival in CKD stage G2/G3a patients due to SGLT2-inhibitors and finerenone could create more interest in CKD-MBD research, as CKD MBD is primarily an issue in later CKD-stages.
There is association between vitamin D deficiency with the development of secondary hyperparathyroidism (sHPT) in chronic kidney disease (CKD).
There is association between sHPT and important clinical outcomes, such as kidney disease progression, fractures, cardiovascular events, and mortality
So three core issues should be solved and answered:
(1) What is the optimal parathyroid hormone (PTH) target level for CKD and dialysis patients?
(2) What is the optimal vitamin D level to support optimal PTH titration?
(3) How can sHPT treatment support reduction in the occurrence of hard renal and cardiovascular events in CKD and dialysis patients?
One of the main causes for vitamin D deficiency is chronic kidney disease (CKD)
A study by Nigwekar et al. (2012) showed
the prevalence of vitamin D levels below 30 ng/ml
to be 71% for CKD stage G3a/b,
84% for stage G4 (eGFR of 15–29 mL/min/1.73 m2 ),
and 89% for stage G5 (eGFR < 15 mL/min/1.73 m2 )
causes of vit. D deficiency in CKD
1-reduced sun light exposure and skin synthesis
2- diet reducing intake
3-suppressed activation of 1alfa -hydroxylase CYP27B1
4-proteinuria;- loss of vit.D binding proteins
5- uremia;- loss of calcitriol
Consequences of Vitamin D Deficiency in CKD
CKD can lead to SHPTH
The 1st main pathway is deficiency 1-25 (OH)2 vit D
Lead to decrease of intestinal calcium absorption
And hypocalcemia increase production PTH which affect
on Bone >>>>increase osteoclast activity and mobilizing ca to circulation
And effect on TAL and DCT increase ca reabsorption by upregulating TRPV5
On PCT block phosphorus reabsorption ,
-stimulus and upregulate of alfa 1 hydroxylase
This types of over production of PTH is secondary HPTH
The 2nd main pathway is the reduced renal phosphate clearance in CKD leading to hyperphosphatemia, which further stimulates the development of SHPT
In addition, high phosphate levels also lower serum-Ca2+ levels by forming insoluble Ca—P complexes and by decreasing the expression of the 1α-hydroxylase CYP27B1, which further aggravates vitamin D deficiency-related hypocalcemia. Additionally, phosphate stabilizes intact FGF23 , enhancing the secretion of the FGF23 which also downregulates the expression of CYP27B1
The 3rd main pathway is the CKD-induced suppression of transcription of the FGF23 coreceptor Klotho ; without Klotho FGF23 can not downregulation PTH and serum phosphate
The development of sHPTand disruption of vit D are vapert of clinical syndrome called CKD -MBD whtich lead to
# Parathyroid hyperplasia >>>>>>nodularity Parathyroid
# Bone abnormality >>>ROD
Vascular calcification and cardiovascular disease
(a study by Górriz et al. identified cardiovascular events as the leading cause of death (36%) in non-dialysis CKD patients)
Use of vit.D
KDIGO guidelines defined clear limits to avoid overtreatment with (active) vitamin D (including vitamin D analogues). These limits were PTH oversuppression and the development of hypercalcemia and hyperphosphatemia in CKD
Also , more and more data indicated the potential association between active vitamin D overtreatment and the development of adynamic bone disease
Novel vitamin D analogues, such as maxacalcitol, doxercalciferol or paricalcitol, came into play, with the latter predominantly in use in Europe and the US. It was claimed that these analogues have all the good properties of vitamin D and showed less unwanted side effects, especially less tendency for hypercalcemia
The novel vit.d act as synthetic agonist to VDR no convert to calcitriol before binding to VDR
Extended-Release Calcifediol (ERC ): A Combination of Efficacy and Safety as the Next Step in sHPT Treatment
ERC the novel form of VIT.D
Used indication in sHPT in CKD stag G3 –G4
#The key difference to other vit.D IS
1-formulation
ERC is encapsulated in lipophilic wax like structure that allow prolonged release ERC over extended 12h period
So avoid the rapid rising of vit.D level
2-ERC doesn’t stimulate the negative feedback loop to increased activity
The study confirmed ERC effectiveness in increasing serum25b-hydroxyvitamin D and reducing PTH level without statistically significant or notable impact on serum calcium and phosphate levels
Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
The SGLT2-inhibitors and the non-steroidal mineralocorticoid receptor blocker finerenone reduce both major cardiovascular events (MACE) and major renal events (“MAREs”), such as renal death and the initiation of dialysis or renal trans[1]plantation [71,72]. Maybe this positive experience could stimulate researchers and industry to start comparable trials for non-dialysis CKD–MBD patients to provide clear guidance regarding the optimal starting point, dosage, and type of future vitamin D treatment, as well as phosphate management
An RCT by de Jong et al. (2019)
hypothesize that the inhibition of the SGLT2 receptor leads to increased sodium concentration in the lumen, which in turn leads to an increased phosphate re-absorption in the proxi[1]mal tube by NaPi cotransporters. Assumingly, this re-absorption of phosphate into the blood causes the temporal increase in serum phosphate, triggering an increase in FGF23 and PTH, which counteract elevated phosphate levels
the effect of SGLT2 inhibitor and finerenone on survival; CKD stage G2 , G3 a
and investigated on CKD-MBD needs more research and studies
Please use your own words rather than coping and pasting from the articles.
1.Mention the causes of vitamin D deficiency in patients with CKD.
2.Mention the consequences of Vitamin D Deficiency in CKD.
3.Compare the biological effects of novel vitamin D analogous to calcitriol.
4.Discriminate efficacy and safety of Extended-Release Calcifediol from other forms of vitamin D.
-Features of ERC
-Efficacy of ERC
-Safety
5.Explain the reported preliminary effects of SGLT2 inhibitors on CKD-MBD.
-Transient changes in CKD-MBD profile (de Jong et al.) in the form of;
-Possible mechanism
thanks dr Ben Lomatayo for your comprehensive answers
Causes of vit D deficiency in CKD
1- Decreased sun exposure leads to decreased cholecalciferol production
2- Diet restriction limits ergocholecalciferol and cholecalciferol
3- Reduced functioning renal mass causes decreased alpha one hydroxylase activity
4- Increase FGF-23 which suppress alpha one hydroxylase
5- Proteinuria and uremia cause loss of vit-D binding proteins
Consequences of vit D deficiency in CKD
1- Hypocalcemia: Decrease calcitrol leads to decreased transcription of genes involved in calcium homestasis like gnenes encoding epithelial calcium channels and calcium binding protein, decreasing calcium absorption form intestine
2- Hypoparathyroidism: vit D deficiency release negative feedback effect of vit d on parathyroid gland which in addition to hypocalcemia will cause hyperparathyroidism
3- 2ry HPT, vit D deficiency and mineral disturbance will lead CKD-BMD
COMPARE the biologic effects of novel vit analogue
Synthetic vit D analogues like parcalcitol a vitamin D2 analog, and oxacalcitriol, a vitamin D3 analog, have many beneficial effects by different machanisms:
1- Action on parathyroid: inhibit PTH secretion and supress parathyroid hyperplasia
2- Action on calcium and phosphorus level: minimal hypercalcemia and hyperphosphatemia
Extended release calcifedol
It is a prohormone of calcitrol, kept in a lipophilic, wax- like capsule, so released over 12 hours, inhibiting rapid rise of serum vit D, preventing negative feedback, thus prevent convention of active vit D to inactive form due to inactivation of CYP14A1
Explain effects of SFLT-2 inhibitor on CKD-MBD
1-SFLT-2 inhibitor activate phosphorus and sodium absorption by proximal tubules, leading to hyperphosphatemia, which in turn causes hyperparathyroidism, and increase FGF-23.
2-these changes cumulate in inhibition of alpha hydroxylase, decreasing 1,25(OH)2VIT D.
3- serum calcium and 25OH vit D remain unaffected
all these changes will accelerate CKD-BMD in the first 3 months post initiation of ttt, after that no differences in these parameter
thanks dr Ahmed vitamin D deficiency is also associated with increased risk of vascular calcification and mortality
regarding novel vitamin D analogues: although preliminary data reported that paricalcitol effectively lowered intact PTH serum levels in hemodialysis while having a safety profile and assoiated with better outcomes and better survival compared to calcitriol, Later well-designed randomized, prospective, interventional trials failed to show cardiovascular significant benefits of paricalcitol. Moreover, there is recent evidence even the novel vitamin D analogues may have equivalent risk for hypercalcemia development.