Vitamin D in patients with chronic kidney disease: a position statement of the Working Group ‘‘Trace Elements and Mineral Metabolism’’ of the Italian Society of Nephrology
Describe mechanism of action and action of vitamin D.
Emphasize physiological regulation of vitamin D.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Describe the different biological effects of different forms of vitamin D therapy.
Analyze the evidence of antiproteinuric effect of VITDRA.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
Mechanism of vitamin D activation
activated by enzymes, firstly in the liver and then in the kidneys.
25 Hydroxycholecalciferol is made by the liver from cholecalciferol by 25 hydroxylase enzymes without a feedback mechanism.
Vitamin D is converted in Kidney from 25- Hydroxycholecalciferol to 1,25 Calcitriol by one alpha-hydroxylase
24hydroxylase from the Kidney deactivates 25 OH Vitamin D.
mechanism of action
vitamin d helps to absorb calcium from the intestine and mineral bone growth,
also stimulates the absorption of phosphate and magnesium
The recommended target vitamin D level is 40-60ng/ml the KDIGO guidelines has highlighted the use of calcitriol reserve after discovering the association between hypercalcemia , hyperphosphatemia and vascular calcification and dynamic bone disease .these guidelines defined clear limits to avoid over treatment
Native form of vitamin d is produced endogenously from cholesterol. 7 dehydrocholesterol is converted into pre vitamin D3 by UV radiation and isomerised to vitamin D3 by body temperature. Vitamin D2 is derived from plant and we obtain it from diet
25 Hydroxycholecalciferol is made by liver from cholecalciferol or ergocalciferol by 25 hydroxylase enzyme without a feedback mechanism. Vitamin D ist converted in Kidney from 25- Hydroxycholecalciferol to 1,25 Calcitriol by 1 alpha hydroxylase 24hydroxylase from kidney deactivate 25 OH Vitamin D Describe mechanism of action and action of vitamin D.
All genomic actions of biologically active vitamin D are mediated by the vitamin D receptor (VDR. It is present in cells and tissues, the VDR exerts an extensive biological response, when activated by ligand-binding, via regulation of gene transcription and stimulation of intra[1]cellular signaling pathways .The major endocrine action of VDR is to regulate mineral and bone homeostasis in intestinal, renal and bone tissues. In fact, VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption Of note, vitamin D activity can directly regulate bone metabolism when insufficient calcium is acquired through diet or absorbed by the intestine, enhancing bone resorption and suppressing bone matrix mineralization In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes Emphasize physiological regulation of vitamin D Cholecalciferol /Ergocholecalciferol is hydroxylated by liver 25 hdyrxoylase to 25 OH Vitamin Dand then hydroxylated by kidneys by 1alpha hydrolxase into calcitriol. The renal enzyme is only one and is substrate independent unlike hepatic enzyme substrate depedendent. PTH stimulates 1 alpha hydroxylase while FGF23 inhibit one alpha hydroxylase as well as high level of 1 25 oh inhibit 1 alpha hhdyroxyalse. Calcium and phosphate can have effect on on 1 alpha hydroxylase by action on PTH and FGF23 Active vitamin D suppress PT H Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients. Vitamin D <30ng/ml range tho its not evidence based Describe the different biological effects of different forms of vitamin D therapy. Cholecalciferol Vitamin D3 and Ergocholecalciferol Vitamin D2 can both be used when vitamin d level <30 and stopped when level are> 100 or hypercalcaemia . Many studies have showed that cholecalciferol is better than Ergocholecalciferol increasing Vitamin D levels. Nice Guidance recommends recommends CKD4/5 active Vitamin D in patient suffering from symptomatic CKDMBD and egfr<30 despite 250h being adequate. Correction of Vitamin D level could delay and onset of progression. There is some data that shows that active vitamin d reduced PTH and improve bone histology. Selective Vitamin Receptors should favour stronger down regulation PTH synthesis with lower impact on calcium phosphate and lower pro calcifying effect on arterial wall. Zeng ET AL meta analysis of observational studies showed that vitamin d in CKD patient showed reduced cardiovascular mortality and there was a signal that selective VDRA might be better than non selective one. However this consideration needs proving by RCT Vitamin D impact on reducing proteinuria is controversial as well as impact on LVH. Vitamin D supplementation has also been showed to reduce inflammation namely by reduction of inflammatory markers such as CRP and Interleukin 6. In the same line it has been proposed that correction of vit d deficiency could help reduce amount of iron/epo as it decreases hepcidin. Analyze the evidence of the antiproteinuric effect of VITDRA. The ongoing VITALE study is comparing the effect of cholecalciferol at high or low J Nephrol 123 dose (respectively 100.000 or 12.000 IU every 2 weeks for 2 months, then monthly for 22 months) on proteinuria and graft survival as secondary outcomes. Data on antiproteinuric effects of VDRA in KTRs look more promising. Paricalcitol at low doses (3 lg/week) was retrospectively associated with a significant reduction of proteinuria at 24 months performed a randomized, crossover study to compare the effect of 6-month treatment with paricalcitol (1 lg/day for 3 months and then uptitrated to 2 lg/day if tolerated) or non-paricalcitol therapy in KTRs with a long-term functioning graft. Compared with baseline, proteinuria showed a significant decrease at 6 months. Amer et al. randomized 100 incident KTRs to oral paricalcitol, 2 lg/day, for the first year post-transplant or no additional therapy [174]. They did not observe lower protein excretion among paracalcitol treated KTRs compared to controls at 1 year post[1]transplantation. However, moderate interstitial fibrosis was observed in 4/38 biopsies in the control group, but was absent in the paricalcitol group. Notably, neither of the previous two RCTs was designed to investigate the effect of paricalcitol on proteinuria as a primary outcome. This trial did not look at proteinuria as secondary outcome.
survival benefits of Vitamin D in CKD patients on dialysis. Observational studies decreased vitamin D associated with increasing mortality. Data from german registry showed increasing deficiency of vitamin D shows increasing rate of mortality. RCT failed to demonstrate any survival benefit. Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis Improves cardiovascular mortality Possibly reduce inflammation , no effect on EPO tho theoretically could reduce epo/iron use Decreases risk of infection Decrease cardiac dysfunction Describe the effects of different immunosuppressives on both vitamin D levels and bone health in KTR.
Steroids directly worsen bone formation by inducing: derangement of vitamin D metabolism, impaired osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/os[1]teoprotegerin (OPG) ratio while . Both cyclosporin and tacrolimus similarly promote bone loss via a direct osteo[1]clast activation [153]. Conversely, sirolimus is taken as a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation.
Discuss the pros & cons of vitamin D therapy in KTRs. Pros; Reduced PTH levels result in an improvement in BMD. This may lead to an increase in allograft survival(scanty data) Anti-proteinuric action by inhibiting RAS Anti-fibrotic ( all above scanty evidence) Cons Can promote hypercalcaemia which can affect graft function
1-Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to the hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D).
2-The action of VDR is to regulate mineral and bone homeostasis in intestinal, renal and bone tissues . In fact,VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption
Vitamin D activity can directly regulate bone metabolism when insufficient calcium is acquired through diet or absorbed by the intestine, enhancing bone resorption and suppressing bone matrix mineralization
VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes
vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells
3-The three main steps in vitamin D metabolism, 25-hydroxylation, 1α-hydroxylation, and 24-hydroxylation are all performed by cytochrome P450 mixed-function oxidases (CYPs). These enzymes are located either in the endoplasmic reticulum (ER) (e.g., CYP2R1) or in the mitochondria (e.g., CYP27A1, CYP27B1, and CYP24A1). The electron donor for the ER enzymes is the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent P450 reductase. The electron donor chain for the mitochondrial enzymes is comprised of ferredoxin and ferredoxin reductase. These are not specific for a given CYP—specificity lies within the CYP. Although of the CYPs involved in vitamin D metabolism, only CYP2R1 and CYP24A1 have been crystallized, it is likely that these enzymes contain a number of common structural features. These include 12 helices (A–L) and loops and a common prosthetic group, namely the iron-containing protoporphyrin IX (heme) linked to the thiolate of cysteine. The I helix runs through the center of the enzyme above the heme where a thr(ser) and asp(glu) pair is essential for catalytic activity (Sugimoto and Shiro, 2012). CYP2R1, like other microsomal CYPs, contains two extra helices that appear to form a substrate channel in the bilayer of the ER (Sugimoto and Shiro, 2012). The B′ helix serves as a gate, closing on substrate binding. Whether a similar substrate channel exists for the mitochondrial CYPs is not clear.
4- The International Osteoporosis Foundation guidelines suggest levels of 25(OH)D [30 ng/ml as normal values inolder adults. The KDOQI guidelines suggest that levels of 25(OH)D [30 ng/ml should be regarded as normal limits for patients with non-dialysis CKD. Thus, 25(OH)D [30 ng/ml may be regarded as a suitable target also for patients on dialysis.
5- Vit D2 is derived from plants while vit D3 is of animal origin, there are two isoform of 1a-hydroxylase that work on vit D3, while vit D2 is is only acted on by one isoform. Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body so has more share of the actions · Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase. Supplemental Active vitamin D increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.Selective VDRA like paricalcitol suppresses PTH and 1a-hydroxylation but it causes less Ca and PO4 to be absorbed from intestines
6-
Effect of vitamin-D analogue on albuminuria in patients with non-dialysed chronic kidney disease stage 4–5: a retrospective single center study:A total of 146 macroalbuminuric patients were identified, and of these, 59 started alfacalcidol treatment during the observation period. A 12% reduction in 24 h albuminuria was seen after starting treatment. In 19 patients with no change in renin-angiotensin-aldosteron-system (RAAS) inhibition, the reduction in albuminuria was 16%. The reduction remained stable over time (9%) in a subgroup of patients (n = 20) with several urine collections before and after the start of alfacalcidol-treatment.
7-comes only in patients with PTH above the median.
Similar results were found by Jean et al. who measured baseline 25(OH)D levels in 648 prevalent hemodialysis patients from the regional ARNOS French cohort [117]. A 42-month survival analysis was performed according to serum 25(OH)D level and calcitriol analog therapy. Base- line 25(OH)D levels above the median value (18 ng/ml) were associated with lower all-cause mortality (hazard
ratio, HR, 0.73 [0.5–0.96], p = 0.02) after adjustment for age, gender, dialysis vintage, calcemia, phosphatemia, CVD, and diabetes. The association between low levels of vitamin D and mortality was evident also in the retro- spective study carried out by Krause et al. [118]. Patients (n = 6518) from the German Renal Registry were matched with 73,919 recorded 25(OH)D measurements. All-cause mortality risk increased with decreasing vitamin D levels. For vitamin D insufficiency—25(OH)D levels ranging from 20 to \30 ng/ml—a moderate increase in risk was observed; for vitamin D deficiency—25(OH)D ranging from 12.5 to \20 ng/ml—the risk was much more pro- nounced; for severe vitamin D deficiency— 25(OH)D \12.5 ng/ml—mortality risk was more than doubled. In addition to all-cause mortality risk, it was observed that the cardiac mortality risk increased among patients with vitamin D deficiency and that mortality risk for cancer was higher in patients with severe vitamin D deficiency
8- HTN better control
Reduced LV mass
good effect on immune system
patient lifestyle because of sun exposure
9-Immunosuppressive therapy may contribute to vitamin D derangement, although the scientific literature is still scanty in this regard. Steroids impair vitamin D metabolism activating the enzymes involved in vitamin D catabolism and increasing PTH and FGF23 levels [149]. In contrast, steroid sparing/withdrawal improves vitamin D metabolism [139]: in particular, cumulative prednisone dose was found to be inversely associated with 1,25(OH)2D levels 2 years after transplantation and low 1,25(OH)2D levels were inversely associated with the higher FGF23 concentrations induced by steroid therapy [150]. In agreement, Sanchez- Fructuoso et al. [146] showed that high levels of FGF23 are associated with higher cumulative doses of steroids and low levels of 1,25(OH)2D. Several discrepancies have been observed between the effects of calcineurin and mam- malian target of rapamycin (mTOR) inhibitors on vitamin J Nephrol
D metabolism. Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels [151]. This finding is in agreement with experimental studies showing vitamin D resistance induced by CNI through VDR downregulation. The loss of VDR removes feedback inhi- bition of vitamin D on 1-a-hydroxylase and increases the 1,25(OH)2D level [152]. Rapamycin does not have any effect on vitamin D metabolism [153]. Substantial evidence has ascertained that the conversion of 25(OH)D to 1,25(OH)2D via 1-a-hydroxylase in osteoblasts, osteocytes and osteoclasts regulates processes such as cell prolifera- tion, mineralization as well as bone resorption
10-Pros:
reduced risk of bone loss , Vitamin D can help prevent osteoporosis and bone loss which are common in KTR due to use of immunosuppressant. There is improvement in Bone mineral density and reduce risk of fracture
There is reduced PTH level under Vitamin D therapy by KTR.
There is some studies that suggest that Vitamin D especially paricalcitol reduce proteinuria waht ca improve long term graft survival.
There is a potential CV benefits .
Cons:
Risk of Hypercalcemia
Drug interaction and increased adverse effect.
Lack of evidence of benefits. Most evidence are conflicting and more research is needed to determine optimal dosing, duration, timing of vitamin D.
Describe mechanisms of vitamin D activation. the kidney is essential for maintaining adequate serum 25(OH)D levels by means of the megalinmediated uptake of 25(OH)D from the glomerular ultrafiltrate and its recycling into to the circulation. The 25(OH)D uptaken from the glomerular ultrafiltrate may also be 1-a-hydroxylated in the kidney to produce the fully active form 1,25(OH)2D (calcitriol). Unlike 25-hydroxylation, there is only one enzyme recognized to have 1a-hydroxylase activity, i.e. CYP27B1 Describe mechanism of action and action of vitamin D.
The major endocrine action of VDR is to regulate mineral and bone homeostasis in intestinal, renal and bone tissues . In fact,VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption
Vitamin D activity can directly regulate bone metabolism when insufficient calcium is acquired through diet or absorbed by the intestine, enhancing bone resorption and suppressing bone matrix mineralization
VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes
vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells
Emphasize physiological regulation of vitamin D.
In the kidney the activity of CYP27B1 is primarily stimulated by parathyroid hormone (PTH) and suppressed by both
fibroblast growth factor 23 (FGF23), and 1,25(OH)2D itself
The renal CYP27B1 activity can be secondarily suppressed by calcium via PTH as well as by phosphate viaFGF23, although a direct effect of these ions on renal 1ahydroxylation cannot be excluded. Of note, circulating25(OH)D can also be 1-a-hydroxylated in extrarenal cells that express CYP27B1, such as keratinocytes and macrophages.
Regulation of extrarenal CYP27B1 differs from the renal one: it is site-dependent, and involves several hormones and inflammatory molecules [15]. However the kidney is the major if not sole source of circulating 1,25(OH)2D and its extrarenal percentage is negligible
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The achievement of 25(OH)D levels [30 ng/ml seems a reasonable target for the prevention and treatment of secondary hyperparathyroidism in CKD patients stages 3–5.
In predialysis CKD patients treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in thepresence of 25(OH)D levels [100 ng/ml and/or with persistent serum calcium levels [10.5 mg/dl in the absence ofactive vitamin D administration. Attention should be paid in transplanted patients and in those affected bysarcoidosis or B cell lymphoma, where 25(OH)D levels even lower than 100 ng/ml may result toxic.
The International Osteoporosis Foundation guidelines suggest levels of 25(OH)D [30 ng/ml as normal values inolder adults. The KDOQI guidelines suggest that levels of 25(OH)D [30 ng/ml should be regarded as normal limits for patients with non-dialysis CKD. Thus, 25(OH)D [30 ng/ml may be regarded as a suitable target also for patients on dialysis.
Describe the different biological effects of different forms of vitamin D therapy.
The D2 and D3 differ only in their structure and the differences do not affect the activation process.Both forms function as prohormones and when activated exhibit identical biological responses diverse forms of vitamin D have been used by nephrologists from many years in the prevention and treatment of renal hyperparathyroidism. In the last two decades, selective active vitamin D metabolites (paricalcitol, maxacalcitol) have been used to reduce circulating PTH with minor changes in calcium and phosphate concentrations compared to the non-selective calcitriol.
Active forms of vitamin D are more effective than other forms in correcting secondary hyperparathyroidism. Native and nutritional vitamin D may increase 1,25(OH)2D levels and reduce PTH levels
Analyze the evidence of antiproteinuric effect of VITDRA.
Data on antiproteinuric effects of VDRA in KTRs look more promising. Paricalcitol at low doses (3 lg/week) was retrospectively associated with a significant reduction of proteinuria at 24 months
An important future challenge is the specific antiproteinuric effect of paricalcitol even if, in KTRs as well as inCKD patients, we do not know whether the reduction of proteinuria can be translated into a higher graft survival.Clinical results suggest a promising action of VDRA to reduce post-transplant proteinuria and hyperparathyroidism.
There is a study to compare the effect of 6-month treatment with paricalcitol (1 lg/day for 3 months and then uptitrated to 2 lg/day if tolerated) or non-paricalcitol therapy in KTRs with a long-term functioning graft. Compared with baseline, proteinuria showed a significant decrease at 6 months
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
The International Osteoporosis Foundation guidelines suggest levels of 25(OH)D [30 ng/ml as a suitable target also for patients on dialysis.
There are data from observational studies that linked lower 25(OH)D levels to hypertension and to increased risk for cardiovascular events in both dialysis and non-dialysis patients In addition, an association between vitamin D supplementation and reduced LV mass as well as a positive effect of vitamin D supplementation on the immune system has been reported.
There is no unanimous position on when to start treatment, on which vitamin D to prescribe, on dose to administer and on the route to prefer [112–115]. Furthermore, because most vitamin D comes from the sun and healthier people have more opportunities to spend time outdoors, studies in patients are particularly susceptible to confounding. Therefore the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle. As said before, available studies are certainly interesting but still they do not offer us solid certainties on the use of vitamin D in patients on dialysis. assessed. Studies on the role of baseline 25(OH)D concentration show an association between low serum levels with mortality.
Patients were stratified as ‘‘severely vitamin D deficient’’ (B10.0 ng/ml), ‘‘moderately vitamin D deficient’’ ([ 10 B 30 ng/ml) and ‘‘vitamin D sufficient’’ ([30 ng/ml). Mortality was higher in severely vitamin D deficient patients compared to the other groups. In particular, a strong association was evident between severe vitamin D deficiency and short-term cardiovascular mortality while no significant association was found between non-cardiovascular mortality and vitamin D status. Further, stratifying patients on the basis of PTH, the impact of 25(OH)D on clinical events was modified by PTH levels; low 25(OH)D levels were associated to outcomes only in patients with PTH above the median.Baseline 25(OH)D levels above the median value (18 ng/ml) were associated with lower all-cause mortality after adjustment for age, gender, dialysis vintage, calcemia, phosphatemia,CVD, and diabetes
All-cause mortality risk increased with decreasing vitamin D levels. For vitamin D insufficiency—25(OH)D levels ranging from 20 to\30 ng/ml—a moderate increase in risk was observed; for vitamin D deficiency—25(OH)D ranging from 12.5 to \20 ng/ml—the risk was much more pronounced; for severe vitamin D deficiency— 25(OH)D \12.5 ng/ml—mortality risk was more than doubled.
In addition to all-cause mortality risk, it was observed that the cardiac mortality risk increased among patients with vitamin D deficiency and that mortality risk for cancer was higher in patients with severe vitamin D deficiency
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
The administration of active forms of vitamin D may cause a further decrease of PTH levels.
Active vitamin D administration was associated with a significant reduction of proteinuria. Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and non diabetic patients
Cholecalciferol supplementation may have a prominent anti-inflammatory action with concomitant improvement of cardiac dysfunction. Cholecalciferol supplementation resulted safe and effectivein correcting hypovitaminosis D with a significant reduction of CRP . Serum 25(OH)D levels increased
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR. · on vitamin D level
Immunosuppressive therapy may contribute to vitamin D derangement,
Steroids impair vitamin D metabolism activating the enzymes involved in vitamin D catabolism and increasing PTH and FGF23 levels
Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels
Rapamycin does not have any effect on vitamin D metabolism on bone health
Steroids directly worsen bone formation by inducing: derangement of vitamin D metabolism, impaired osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio
Both cyclosporin and tacrolimus similarly promote bone loss via a direct osteoclast activation. Conversely, sirolimus is taken as a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation
Discuss pros & cons of vitamin D therapy in KTRs Pros
Reduced 25(OH)D levels where independently associated with lower GFR at 12-month follow-up and a higher risk for interstitial fibrosis and tubular atrophy. Accordingly, a worse annual estimated GFR decline was observed in the presence of 25(OH)D levels\12 ng/ ml reducing proteinuria in CKD patients by endocrine suppression of the renin-angiotensin system.
Calcitriol decreases PTH levels and improves BMD in KTRs with osteopenia or osteoporosis. Therefore becoming a well accepted preventive therapy against bone loss in KTRs
**Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Cholecalciferol and ergocalciferol increase 25 OH D without significant change of blood Ca, phosphorous or PTH. Ergocalciferol may increase erythropoietin
Paricalcitol decrease cardiac mortality and overall mortality, increase 25 OH D without increasing Ca, phosphorous and has stronger effect on decreasing PTH.
**Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
Glucocorticoids may impair vitamin D metabolism by activation of the enzyme involved in vitamin D catabolism and increase FGF23 and PTH levels, it impair osteoblastogenesis, increase apoptosis of osteoblast and increase osteoclastogenesis by increasing RNCKL/OPG ratio.
Calcinuron inhibitor associated with lower 25 OH Ddue to vitamin D resistance caused by down regulation of VDR and direct osteoclast activation.
Rabamycin does not have effect on vitamin D metabolism
**Discuss pros & cons of vitamin D therapy in KTRs.
Pros
Decrease PTH and improve BMD in KTR with osteoporosis and osteopenia
With Paricalcitol improve L3 and L4 BMD and decrease bone formation and reabsorption biomarker and not associated with higher level of hypercalcimia and decrease proteinuria
Cons
Hypercalcimia, not modify the progression of GFR, proteinuria, onset of interstitial fibrosis and tubular atrophy.
**Describe the different biological effects of different forms of vitamin D therapy.
The cholecalciferol and ergocalciferol both undergo 25 hydrxylation in the liver to 25 OH vitamin D 3 and 25 OH vitamin D 2 but cholecalciferol show superiority in elevation of 25 OH D level but causes increase levels of Ca and phosphorous level and decrease in PTH
Calcifedol a modefied release formulations increase 25 OH D in a dose dependant manner.
Selective vitamin D receptors activators VDRA causes regulation in PTH synthesis lower impact on ca phosphorous byproduct and lower procalcifying effects on arterial wall
**Analyze the evidence of antiproteinuric effect of VITDRA.
It is associated with significant reduction of about 16 % of proteinuria compared with the 6% among control with >100 fold reduction of proteinuria of >15 %.
**Criticize survival benefits of Vitamin D in CKD patients on dialysis.
The recent data show that low 25 OH D increase risk of hypertension and vitamin D s will decrease LV mass.
Mortality is high with those who have sever vitamin D deficiency of <30ng/ml and even associated with all causes mortality, include cardiac mortality risk and mortality risk for cancer.
Describe mechanisms of vitamin D activation: · From skin as sunlight acts on 7-dehydrocholesterol and convert it vitD3, Vitamin D2 comes from plant source. · 25-hydroxylation happen in the liver by CYP27A1 and CYP2R1 (from Cytochrome P450 family) · it is transferred to the kidneys bound to vitamin D binding protein where further 1a-hydroxylation to active vitamin D happen in the kidneys through CYP27B1 enzyme Describe mechanism of action and action of vitamin D: · Active Vit D bind to a membrane receptor (VDR), the complex is internalized, and travel to nucleus to increase /Decrease gene transcription and translation of protein. · Actions of active vit D includes PTH suppression , FGF23 production by osteocyte. · it also has autocrine and paracrine functions like inhibition of cellular proliferation and stimulation of maturation in immune system , colon, breast and prostate. Emphasize physiological regulation of vitamin D
Produced by sunlight actin on cholesterol in the dermis.Stimulated by PTH. Liver (by 25-Hydroxylation). Kidneys (by 1a-Hydroxylation-affected by PTH). Supressed by FGF-23 (inhibition of 1a-hydroxylation). Regulated Ca, Phosphate levels
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients: recommended to keep vitD > 30 (25-OH-VitD), stop giving if levels are >100. May induce Hypercalcemia in CKD ,deposited in soft tissues. Adynamic bone disease Describe the different biological effects of different forms of vitamin D therapy. · Vit D2 is derived from plants while vit D3 is of animal origin, there are two isoform of 1a-hydroxylase that work on vit D3, while vit D2 is is only acted on by one isoform. Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body so has more share of the actions · Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase. · Supplemental Active vitamin D increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase. · Selective VDRA like paricalcitol suppresses PTH and 1a-hydroxylation but it causes less Ca and PO4 to be absorbed from intestine. Analyze the evidence of antiproteinuric effect of VITDRA:
· There is evidence that cholecalciferol causes a mild but significant reduction of albuminuria among diabetic and non diabetic CKD. Other trials reported negative results. · Recent meta-analysis by de Borst et al included 6 RCTs looking the effect of vitamin D on proteinuria, active vitamin D administration was associated with 16% reduction of proteinuria compared to 6% reduction among controls, the analysis not limited to diabetics but also include IgA Nephropathy Criticize survival benefits of Vitamin D in CKD patients on dialysis: · potential survival benefits of Vitamin D is conflicting and uncertain. · no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescribe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle. · Observational studies varies significantly on number of participants, time and duration of follow up Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis. · weekly ingestion of 40,000 IU D3 for 8 weeks corrected hypovitaminosis D in CKD patients. However, they were not able to demonstrate any effects of vitamin D3 supplementation in HD patients (Marckmann et al.) · cholecalciferol is effective in replenishing deficient hemodialysis patients without toxic effects. · Mean serum 1,25(OH)2D increased significantly in the cholecalciferol-treated group, whereas it decreased in the placebo group (Armas et al). · short-term, high-dose oral cholecalciferol treatment is effective in replenishing deficient hemodialysis patients without toxic effects (Wasse et al) · cholecalciferol increased serum 25(OH)D levels and decreased PTH levels compared to controls without any observed toxicity (Delanaye et al.) · cholecalciferol increased serum 25(OH)D and 1,25(OH)2D levels, but did not significantly modify serum levels of PTH, calcium, or PO4(Massart et al.) · ergocalciferol increased 25(OH)D levels in incident HD patients without significant changes in blood calcium, phosphate, or PTH during a 12-week period (Bhan et al.) Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR: · Vitamin D: CNIs lower levels of Vit D, mTOR-i do not have effects, and glucocorticoids increase PTH and FGF23 · Bone Health: Glucocorticoids Osteoclasts and inhibit Osteoblast thereby reducing bone density. mTORs-i enhance bone health by inhibiting osteoclast, and CNIs enhance osteoclast activities. Discuss pros & cons of vitamin D therapy in KTRs. · suppresses PTH, · antifibrotic, · antiproteinuric effects but .. Vit D3hyperphosphatemia hypercalcemia suppressing bone matrix mineralization .
The native form of vitamin D is produced endogenously from cholesterol as vitamin D3 (cholecalciferol). In skin, 7-dehydrocholesterol is converted to pre-vitamin D3 by a narrow band of solar ultraviolet (UV) radiation (290–315 nm) and thereafter it is isomerized by the body’s temperature to vitamin D3 .On the other hand, vitamin D2 (ergocalciferol) is derived from the sterol ergosterol of plants and the main intake is through diet. However, only less than one-third of the native form of vitamin D origi- nates from food as vitamin D2 or as vitamin D3 .Of note, very few foods contain vitamin D (e.g. fatty fish, fish liver oil, mushrooms and egg yolk) and vitamin D status is generally maintained by exposure to sunlight .
If sunlight exposure is adequate, dietary supplementation of vitamin D can be unnecessary.
Describe mechanism of action and action of vitamin D.
The dermal production of vitamin D is not an enzymatic process .The D2 and D3 differ only in their structure and the differences do not affect the activation process. Both forms function as prohormones and when activated exhibit identical biological responses .Conversely, the main steps in vitamin D metabolism, such as 25-hydroxy- lation, 1a-hydroxylation, and 24-hydroxylation are all enzymatic processes performed by cytochrome P450 mixed-function oxidases (CYPs). The liver is the major if not sole source of 25(OH)D production from native vitamin D. The native vitamin D2 and D3 are both 25-hydroxylated to 25(OH)D (calcidiol or calcifediol) by several 25-hy- droxlases, such as CYP27A1 and CYP2R1 .
The hepatic 25-hydroxylation is induced by the availability of the substrate D2 and D3 and is not inhibited by the concentrations of its product 25(OH)D. Thus regulation of vitamin D 25-hydroxylation is not a major concern, and circulating levels of 25(OH)D are commonly considered useful markers of vitamin D status. Nevertheless, the kidney is essential for maintaining adequate serum 25(OH)D levels by means of the megalin- mediated uptake of 25(OH)D from the glomerular ultrafiltrate and its recycling into to the circulation .
The 25(OH)D uptaken from the glomerular ultrafiltrate may also be 1-a-hydroxylated in the kidney to produce the fully active form 1,25(OH)2D (calcitriol). Unlike 25-hy- droxylation, there is only one enzyme recognized to have 1a-hydroxylase activity, i.e. CYP27B1.
Emphasize physiological regulation of vitamin D.
In the kidney the activity of CYP27B1 is primarily stimulated by parathyroid hormone (PTH) and suppressed by both fibroblast growth factor 23 (FGF23), and 1,25(OH)2D itself .
The renal CYP27B1 activity can be secondarily suppressed by calcium via PTH as well as by phosphate via FGF23, although a direct effect of these ions on renal 1a- hydroxylation cannot be excluded.
circulating 25(OH)D can also be 1-a-hydroxylated in extrarenal cells that express CYP27B1, such as keratinocytes and macrophages.
Regulation of extrarenal CYP27B1 differs from the renal one: it is site-dependent, and involves several hormones and inflammatory molecules .However the kidney is the major if not sole source of circulating 1,25(OH)2D and its extrarenal percentage is negligible.
Both calcidiol and calcitriol are transported in the blood by the vitamin D binding protein (DBP) and are catabolized through a 24-hydroxylation process involving the 24-hydroxylase CYP24A1 .
Most 25(OH)D and 1,25(OH)2D circulates as bound to DBP , while less than 1 % circulates in its free form .
The circulating DBP-bound vitamin D reaches the liver, kidney and other cellular activation sites and is stored in the adipose tissue.
All genomic actions of biologically active vitamin D are mediated by the vitamin D receptor (VDR).
VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption
Finally, the bioactive vitamin D fraction exerts its biological functions in target tissues and is catabolized by 24-hy- droxylase (CYP24A1) to inactive forms.
vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
the achievement of 25(OH)D levels [30 ng/ml seems a reasonable target for the prevention and treatment of secondary hyperparathyroidism in CKD patients.
Regardless of the preferred regime, in predialysis CKD patients treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in the presence of 25(OH)D levels [100 ng/ml and/or with persistent serum calcium levels [10.5 mg/dl in the absence of active vitamin D administration. Attention should be paid in the presence of potentially increased 1-a-hydroxylase activity, as in transplanted patients and in those affected by sarcoidosis or B cell lymphoma, where 25(OH)D levels even lower than 100 ng/ml may result toxic.
Current data suggest a mild impact of nutritional vitamin D on non-severe secondary hyperparathyroidism in pre-dialysis CKD patients ,with a moderately stronger effect when administered at high doses against its mild phenotype .An early replenishment of 25(OH)D levels could delay the onset and progression of secondary hyperparathyroidism .
Selective vitamin D receptor activators (VDRA) should favor a stronger down-
regulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
Significant improvement of osteitis fibrosa together with a low risk of adynamic bone disease was observed among pre-dialysis CKD patients receiving calcitriol or alfacalcidol .
Experimental data using paricalcitol showed better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol ,doxercalciferol and cinacalcet .
vitamin D has received growing interest as a treatment for several targets beyond PTH and bone health control, e.g. proteinuria, LVH and anemia.
Describe the different biological effects of different forms of vitamin D therapy.
Three nutritional forms are currently available for 25(OH)D replenishment: the two pro-drugs cholecalciferol and ergocalciferol (both requiring conversion by hepatic 25-a- hydroxylase to 25(OH)D3 or 25(OH)D2, respectively) and calcifediol (already available as 25(OH)D3). Many studies have indicated a potential superiority of cholecalciferol vs. ergocalciferol in increasing 25(OH)D levels .
calcifediol, in a modified-release formulation, resulted effective in increasing 25(OH)D levels in a dose-dependent manner among non-dialysis CKD patients compared to placebo.
treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in the presence of 25(OH)D levels [100 ng/ml and/or with per- sistent serum calcium levels [10.5 mg/dl in the absence of active vitamin D administration. Attention should be paid in the presence of potentially increased 1-a-hydroxylase activity, as in transplanted patients and in those affected by sarcoidosis or B cell lymphoma, where 25(OH)D levels even lower than 100 ng/ml may result toxic.
An early replenishment of 25(OH)D levels could delay the onset and progression of secondary hyperparathyroidism.
Selective vitamin D receptor activators (VDRA) should favor a stronger down-
regulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
vitamin D has received growing interest as a treatment for several targets beyond PTH and bone health control, e.g. proteinuria, LVH and anemia.
Analyze the evidence of antiproteinuric effect of VITDRA.
Proteinuria is an established biomarker of CKD severity as well as a strong direct pathogenetic factor of progression toward end-stage renal disease (ESRD), and
worse survival .Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and non diabetic patients ,although negative results were also reported .About the impact of nutritional vitamin D on proteinuria reduction and calcium-phosphate balance there is still not concordance between different studies .The recent meta- analysis by de Borst et al. included 6 RCTs investigating the effect of active vitamin D on proteinuria .Active vitamin D administration was associated with a significant 16 % reduction of proteinuria compared to 6 % reduction among controls with a more than 100-fold greater proba- bility to reach a proteinuria reduction >=15 % .The analysis was not limited to diabetics ,but it included patients with immunoglobulin (Ig)A nephropathy and patients with other renal disorders .Sensitivity analysis did not reveal differences between vitamin D compounds, paricalcitol doses, sample size and length of follow-up.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
• Low levels of 25(OH)D are very frequent in the dialysis population. Insufficiency or deficiency of 25(OH)D may affect survival by directly influencing mineral metabolism. Better survival of patients treated with native or nutritional or active vitamin D over and above the effects on mineral metabolism indicates that vitamin D possesses pleiotropic protective actions. For this reason many interventional studies have evaluated the effectiveness of 25(OH)D replenishment with cholecalciferol, ergocalciferol, or calcidiol in correcting deranged mineral metabolism as well as in improving survival.
• Most of the available data come from observational studies which are characterized by significant differences in number of enrolled patients, administered doses of vitamin D sterols, duration of treatment and assessed outcomes. Therefore strong evidence supporting an association between vitamin D sterols and survival is lacking. Large RCTs addressing this issue need to be performed.
• Active forms of vitamin D are more effective than other forms in correcting secondary hyperparathyroidism despite the fact that they are not able to increase and/ or normalize 25(OH)D levels. In contrast, native and nutritional vitamin D may increase 1,25(OH)2D levels and reduce PTH levels. This finding may support the therapeutic strategy of dual administration of active and native/nutritional vitamin D, taking into account that a potential interaction may not be excluded. Beneficial effects of dual supplementation on survival have not been assessed as yet.
• Almost all studies indicate that supplementation does not markedly affect levels of calcium or phosphorus and does not accelerate the vascular calcification process. However, markers of mineral metabolism should be monitored during long-term treatment according to the presence of comorbidities and half- life of supplemented vitamin D. These suggestions should be taken into account particularly in dialysis patients treated with active forms of vitamin D.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
There is an association between vitamin D supplementation and reduced LV mass as well as a positive effect of vitamin D supplementation on the immune system.
the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle.
an association between low serum levels with mortality.
a strong association was evident between severe vitamin D deficiency and short-term cardiovascular mortality while no significant association was found between non-cardiovascular mortality and vitamin D status.
Untreated deficient patients were at increased risk for early mortality compared to patients with the highest 25(OH)D or 1,25(OH)2D levels who received therapy with active vitamin D .
Low-dose oral alfacalcidol improved the survival rate in patients with and without 25(OH)D deficiency.
Cholecalciferol supplementation resulted safe and effective in correcting hypovitaminosis D with a significant reduction of CRP, IL-6 and LVH with minor changes of markers of mineral metabolism. These data suggest that cholecalciferol supplementation may have a prominent anti-inflammatory action with concomitant improvement of cardiac dysfunction.
Short-term, high-dose oral cholecalciferol treatment was effective in replenishing deficient/insufficient hemodialysis patients without toxic effects.
cholecalciferol (50,000 IU, once weekly for 8 weeks and then monthly for 4 months) increased serum 25(OH)D and 1,25(OH)2D levels but had no effect on muscle strength, functional capacity, pulse wave velocity or health-related quality of life (HRQOL), as shown by Hewitt et al. in 60 patients .
Higher serum 25(OH)D was associated with decreased risks of infectious events, cardiac events and all-cause deaths. In addition, high serum FGF23 levels were associated with infectious and cardiac events.
6 months of supplementation with ergocalciferol increased serum 25(OH)D levels in patients on hemodialysis with vitamin D insufficiency or deficiency, but it had no effect on epoetin utilization or secondary biochemical and clinical outcomes.
There was a significant improvement in 25(OH)D levels and reduction of PTH levels. PTH reduction was more evident in dialysis patients. Incidence of hypercalcemia and hyperphosphatemia was irrelevant with vitamin D supplementation.
Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
selective VDRA such as paricalcitol resulted associated with lower mortality compared to calcitriol in some but not all studies.
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR Vitamin D
Immunosuppressive therapy may contribute to vitamin D derangement, although the scientific literature is still scanty in this regard. Steroids impair vitamin D metabolism activating the enzymes involved in vitamin D catabolism and increasing PTH and FGF23 levels .In contrast, steroid sparing/withdrawal improves vitamin D metabolism ,in particular, cumulative prednisone dose was found to be inversely associated with 1,25(OH)2D levels 2 years after transplantation and low 1,25(OH)2D levels were inversely associated with the higher FGF23 concentrations induced by steroid therapy .In agreement, Sanchez- Fructuoso et al. showed that high levels of FGF23 are associated with higher cumulative doses of steroids and low levels of 1,25(OH)2D. Several discrepancies have been observed between the effects of calcineurin and mam- malian target of rapamycin (mTOR) inhibitors on vitaminD metabolism. Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels .This finding is in agreement with experimental studies showing vitamin D resistance induced by CNI through VDR downregulation. The loss of VDR removes feedback inhibition of vitamin D on 1-a-hydroxylase and increases the 1,25(OH)2D level .Rapamycin does not have any effect on vitamin D metabolism .Substantial evidence has ascertained that the conversion of 25(OH)D to 1,25(OH)2D via 1-a-hydroxylase in osteoblasts, osteocytes and osteoclasts regulates processes such as cell proliferation, mineralization as well as bone resorption . Bone health
Various studies have shown that bone loss is considerable during the first year after transplantation, with a rate of 14.5 % in the first 6 months, followed by a mild improvement after the second year post-transplant ,and recovers within the pre-transplant range only 8 years after transplantation .Studies in late KTRs revealed a prevalence of osteoporosis ranging from 11 to 56 % and fractures ranging from 5 to 44 %; at any rate the risk of hip fracture, until 3 years after transplantation, is higher than in HD patients .A few studies have reported histological patterns of post-transplant bone disease, describing a considerable prevalence of adynamic bone disease and of high bone turnover .Immunosuppressive drugs elicit a deep impact on bone loss. Steroids directly worsen bone formation by inducing: derangement of vitamin D metabolism, impaired osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio .Both cyclosporin and tacrolimus similarly promote bone loss via a direct osteoclast activation .Conversely, sirolimus is taken as a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation.
Discuss pros & cons of vitamin D therapy in KTRs.
Pors
a significant improvement of PTH and calcium levels in KTRs receiving nutritional vitamin D.
calcitriol decreases PTH levels and improves BMD in KTRs with osteopenia or osteoporosis ,therefore becoming a well accepted preventive therapy against bone loss in KTRs .
greater PTH reduction and a lower prevalence of hyperparathyroidism (29–63 %) in KTRs receiving paricalcitol .
paricalcitol therapy was not associated with a higher risk of hypercalcemia.
Paricalcitol at low doses (3 lg/week) was ret- rospectively associated with a significant reduction of proteinuria at 24 months
Cons
cholecalciferol supplementation after kidney transplant did not modify the progres- sion of GFR, the onset of interstitial fibrosis, tubular atrophy and proteinuria .
cholecalciferol supplementation after kidney transplant did not modify the progres- sion of GFR, the onset of interstitial fibrosis, tubular atrophy and proteinuria .
VitD either D2 from plant sources or D3 from activation of sun rays through the skin is hydroxylated by 25 hydroxylases from the liver the activated the active form is 1,25 alpha-hydroxylaseby 1 alpha-hydroxylase from the kidney.
2-Describe mechanism of action and action of vitamin D.
The mechanism if action
active Vit D bind to a membrane receptor the complex is internalized, and travel to nucleus to increase /Decrease gene transcription and translation of protein.
Action of vit d regulation of bone mineral homeostasis with pth and lay major role for maintain ca po4 balance via activation of VDR leads to calcium and phosphate intestinal absorption
vitamin D activity regulate bone metabolism ,enhance bone resorption
suppress PTH secretion and enhance FGF23 production
vitamin D exert autocrine or paracrine function in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin ,the immune system and colonic ,breast and prostate cells.
3-Emphasize physiological regulation of vitamin D.
Activated by sunlight action on cholesterol in the dermis.
Stimulated by PTH at Liver and Kidneys
Supressed by FGF-23,Ca levels
and Phosphate levels
4-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
It is recommended to keep vitD > 30and stop giving if levels are >100.
This is limited by the fact that it may induce Hypercalcemia in CKD and +ve Calcium balance where Ca is deposited in soft tissues. Supplementation may also result in Adynamic bone disease especially with normal level of pth.
5-Describe the different biological effects of different forms of vitamin D therapy.
Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body .
Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.
Recently selective VDRA like paricalcitol potant suppression of PTH and prevent ca absorption.
6-Analyze the evidence of antiproteinuric effect of VITDRA.
There is evidence that cholecalciferol causes a mild but significant reduction of albuminuria among diabetic and non diabetic CKD
Other trials reported negative results.
active vitamin D administration was associated with 16% reduction of proteinuria compared to 6% reduction among controls so still debay from study and no conclusive role of vit D and proteinuria.
7-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
There is no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescribe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle.
8-Enumerate reported benefits of
vitamin D therapy in CKD patients on dialysis.
Low vitD levels are associated with HTN, cardiovascular events, and reduced left ventricular mass.
VitD supplements are associated with an improved immune system.
VitD supplements improve renal anemia.
9-Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
The CNIs lower levels of Vit D, mTOR-i do not have effects, and glucocorticoids increase PTH and FGF23 and decrease Vit D
Bone Health: Glucocorticoids stimulate Osteoclasts and inhibit Osteoblast thereby reducing bone density. mTORs-i enhance bone health by inhibiting osteoclast, and CNIs enhance osteoclast activities.
10-Discuss pros & cons of vitamin D therapy in KTRs.
Pros Vit D3 suppresses PTH, is antifibrotic, and has antiproteinuric effect
Cons Vit D3hyperphosphatemia
hypercalcemia suppressing bone matrix mineralization .
Native vitamin D produced endogenously from the conversion of 7 dehdrocholestrol in the skin to previtamin D after exposure to UVB light 290-315nm, then isomerized in the body to form cholecaciferol. While ergocalciferol formed from sterol ergosterol from plant food the vitamin D2 and D3 undergo 25 hydroxyl action in the liver by enzyme CYP2R1 and CYP27B1 then undergo 1 alfa hydrxylation in the kidney to active form calcitriol, which pass to circulation by vitamin D binding protein, it also catabolized by 24 hydrxylation to inactive form.
**Describe mechanism of action and action of vitamin D.
Active vitamin D bind to the VDR where it is activated by regulation of gene transcription and stimulation of intracellular signaling.
This lead to increase Ca and phosphorous intestinal absorption and renal tubular ca absorption. Also causes suppress PTH secretion by PT gland and increase FGF23 production by the osteocyte in addition to it’s paracrine and autocrine function it inhibit cellular proliferation and increase cell maturation in the skin, prostate, colon, breast and immune system.
***Emphasize physiological regulation of vitamin D.
Vitamin D after skin exposure to sunlight form cholecaciferol and from plant ergocalciferol activated in the liver by 25 hdroxylase enzy to 25 OH vitamin D which then undergo hydrxylation by kidney to active form which is bind to VDR once activated produce its action, then it catabolized by 24 hydrxylase enzyme to inactive form.
**Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The target above 30ng/ml and less than 100 ng/ml after which will causes hypercalcimia and xs suppression of PTH.
Describe mechanisms of vitamin D activation. most vitamin D comes from skin as sunlight acts on 7-dehydrocholesterol and convert it vitD3, Vitamin D2 comes from plant source. 25-hydroxylation happen in the liver by CYP27A1 and CYP2R1 (from Cytochrome P450 family), it is transferred to the kidneys bound to vitamin D binding protein where further 1a-hydroxylation to active vitamin D happen in the kidneys through CYP27B1 enzyme Describe mechanism of action and action of vitamin D Like all Cholesterol derived hormones, active Vit D bind to a membrane receptor (VDR), the complex is internalized, and travel to nucleus to increase /Decrease gene transcription and translation of protein. Actions of active vit D includes PTH suppression , FGF23 production by osteocyte. it also has autocrine and paracrine functions like inhibition of cellular proliferation and stimulation of maturation in immune system , colon, breast and prostate. Emphasize physiological regulation of vitamin D
Produced by sunlight actin on cholesterol in the dermis.
Stimulated by PTH
Liver (by 25-Hydroxylation)
Kidneys (by 1a-Hydroxylation-affected by PTH)
Supressed by FGF-23 (inhibition of 1a-hydroxylation)
Ca levels
Phosphate levels
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients It is recommended to keep vitD > 30 (25-OH-VitD), and stop giving if levels are >100. This is limited by the fact that it may induce Hypercalcemia in CKD and +ve Calcium balance where Ca is deposited in soft tissues. Supplementation may also result in Adynamic bone disease Describe the different biological effects of different forms of vitamin D therapy. · Vit D2 is derived from plants while vit D3 is of animal origin, there are two isoform of 1a-hydroxylase that work on vit D3, while vit D2 is is only acted on by one isoform.
Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body so has more share of the actions
Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.
Supplemental Active vitamin D increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.
Selective VDRA like paricalcitol suppresses PTH and 1a-hydroxylation but it causes less Ca and PO4 to be absorbed from intestine.
Analyze the evidence of antiproteinuric effect of VITDRA. There is evidence that cholecalciferol causes a mild but significant reduction of albuminuria among diabetic and non diabetic CKD Other trials reported negative results. the recent meta-analysis by de Borst et al included 6 RCTs looking the effect of vitamin D on proteinuria active vitamin D administration was associated with 16% reduction of proteinuria compared to 6% reduction among controls the analysis not limited to diabetics but also include IgA Nephropathy Criticize survival benefits of Vitamin D in CKD patients on dialysis. potential survival benefits of Vitamin D is conflicting and uncertain. There is no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescribe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle. Observational studies varies significantly on number of participants, time and duration of follow up
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
– weekly ingestion of 40,000 IU D3 for 8 weeks corrected hypovitaminosis D in CKD patients. However, they were not able to demonstrate any effects of vitamin D3 supplementation in HD patients (Marckmann et al.)
– cholecalciferol is effective in replenishing deficient hemodialysis patients without toxic effects. Mean serum 1,25(OH)2D increased significantly in the cholecalciferol-treated group, whereas it decreased in the placebo group (Armas et al). – short-term, high-dose oral cholecalciferol treatment is effective in replenishing deficient hemodialysis patients without toxic effects (Wasse et al)
– cholecalciferol increased serum 25(OH)D levels and decreased PTH levels compared to controls without any observed toxicity (Delanaye et al.)
– cholecalciferol increased serum 25(OH)D and 1,25(OH)2D levels, but did not significantly modify serum levels of PTH, calcium, or PO4(Massart et al.)
– found that ergocalciferol increased 25(OH)D levels in incident HD patients without significant changes in blood calcium, phosphate, or PTH during a 12-week period (Bhan et al.) Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR · Vitamin D: CNIs lower levels of Vit D, mTOR-i do not have effects, and glucocorticoids increase PTH and FGF23 · Bone Health: Glucocorticoids Osteoclasts and inhibit Osteoblast thereby reducing bone density. mTORs-i enhance bone health by inhibiting osteoclast, and CNIs enhance osteoclast activities.
Discuss pros & cons of vitamin D therapy in KTRs. Pros Vit D3 suppresses PTH, is antifibrotic, and has antiproteinuric effects (Debatable) Cons Vit D3hyperphosphatemia hypercalcemia suppressing bone matrix mineralization .
1- Vitamine D (either D2 or D3) is hydroxylated by 25 hydroxylases from the liver the activated (the active form is 1,25 alpha-hydroxylase) by 1 alpha-hydroxylase from the kidney.
2-Both calcidiol and calcitriol are transported in the blood by vitamin-binding protein. Alpha-hydroxylase of the kidney is stimulated by PTH and suppressed by FGF-23 and itself. The active particle of active vitamin is deactivated by 24 alpha-hydroxylase to prevent toxicity. Vitamin D exerts its action by binding to vitamin d receptors, which are activated by ligand binding via gene transcription and regulation of intracellular signalling pathways. Vitamin suppresses PTH secretion by parathyroid glands and suppresses osteocyte release of FGF-23.
3- vitamin D is dependent mainly on its level evaluated as 25(OH) vitamin d. it increases calcium absorption from the intestines
4- Normal level of vitamin D differs among different guidelines (20-30 ng/ml) is enough. In a normal population, less than 30 ng/ml is deficient. but in CKD patients 20 can be accepted. The early stages of CKD have compensator hyperparathyroidism because of hypocalcemia and hyperphosphatemia. 3-5 times the normal PTH is accepted.
5- Vitamin d can be administered in form of normal vitamin d (cholecalceferol, ergocalceferol or calcefediol), active vitamin d (calcitriol) or vitamin d receptor analogue (Paricaltol e.g). paricalcitol is said to have less hypercalcemia and hyperphosphatemia with a potent suppression effect on PTH release. The debate about this is still an issue.
6- In a metanalysis of 6 RCTs, Both in diabetics and non-diabetics, a 16% reduction of proteinuria was observed (controls %6).
7- vitamin d has many benefits and pleiotropic effects in both normal persons as well as CKD patients including those on dialysis. In ESRD , activation of vitamin D is a problem so, calcitroil od . normal vitamin D, though, may increase 1-25 OH vitamin d and suppress PTH
8- vitamin d deficiency or insufficiency is common in Kidney transplant recipients. CNIs have been recently associated with lower vitamin d levels. Experimental studies showed resistance to vitamin D in CNI users by VDR downregulation. The level of 1,25 OH vitamin d is increased because of the absence of a decrease in VDR (downregulated). Rapamycin was found to have no effect on vitamin D metabolism. . Steroids directly worsen bone formation by inducing derangement of vitamin D metabolism and impair osteogenesis through an increased receptor activator of nuclear factor kappa (RANKL)/OPG (osteopetrogerin) ratio. Both tacrolimus and cyclosporin promote bone loss via direct osteoclast activation. Sirolimus is thought of as bone-sparing immunosuppressive. It has the ability to inhibit osteoclast generation.
9-
Vitamin D replacement may have the advantage of protecting bone and increasing calcium absorption. It may have a useful effect on blood pressure and cardiac function, but translation into graft survival is not known. It may have a risk of hypercalcemia and calcium overload. The optimal dose needs to be reevaluated.
we have prohormones D2and D3 from skin (sun exposure by UV rays )and diet
which activated by 25 hydroxylation in the liver to 25 (OH )D3 calcidiol
then 1 alfa hydroxylation on the kidney to active calcitriol 1,25 (OH )2D3
Describe mechanism of action and action of vitamin D.
the genomic actions of active vitamin D are mediated by the vitamin D receptors (the VDR)
VDR produce extensive biological response when activated by ligand binding via regulation of gene transcription and stimulation of intracellular signaling pathways .
the major endocrine action of VDR IS TO REGULATE MINERAL AND BONE HEMOSTASIS IN INTESTINAL ,RENAL AND BONE
activation of VDR leads to calcium and phosphate intestinal absorption
vitamin D activity regulate bone metabolism ,enhance bone resorption
suppress PTH secretion and enhance FGF23 production
vitamin D exert autocrine or paracrine function in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin ,the immune system and colonic ,breast and prostate cells.
.Emphasize physiological regulation of vitamin D.
vitamin D increase calcium and posphate intestinal reabsorption
increase bone resorption
increase calcium reabsorption from kidney
suppress PTH secretion
stimulate FGF23 production
===========================
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
therapy with nutritional and active vitamin D in predialysis patients depend on :
1-how to deal with 25(OH)D deficiency 2-how and when to treat SHPT and CKD -MBD3- potential efficacy of different formulation of vitamin D on proteinuria ,LVH and anaemia ,
the optimal target of 25(OH)D and the best approach to obtain adequate vitamin D remain unknown .
different guidelines have heterogenous defintions of 25(OH)d DEFICIENCY AND THEY SUGGEST DIFFERENT THERAPEUTIC STRATEGIES FOR TREATMENT
KDOQI and ERBP >>TARGET 25(oh)D IS >30 ng/ml
NICE >>> target >20 ng/ml
=====================
Analyze the evidence of antiproteinuric effect of VITDRA.
cholecalciferol induceed a mild but significant reduction of albuminuria among diabetics and non diabetics
although negative results were also reported ,
about the impact of nutritional vitamin D on proteinuria reduction and calcium -phosphate balance
the recent meta analysis iby de Borst et al included 6 RCTs investigating the effect of vitamin D on proteinuria
active vitamin D administration was associated with asignificant 16% reduction of proteinuria compared to 6% reduction among controls
the analysis not limited to diabetics but also include IGAN
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
STEROID >directly worsen bone formation by inducing bone derangement of vitamin D METABOLISM
CNI >promote bone loss by direct osteoclast activation
SIROLIMUS >.inhibit osteoclast generation
================
mTORi>no effect on vitamin D metabolism
CNI >>lower 25(OH)d
Discuss pros & cons of vitamin D therapy in KTRs.
according to KDIGO vitamin D deficiency and insufficiency should be corrected
PRO
1-significant improvement of PTH and calcium levels
2-calcitriol decrease PTH levels and improve BMD in KTRs with osteopenia or osteoprosis 3-paricalcitol improve L3-L4 vertebral BMD without risk of hypercalcemia.
CONS
risk of hypercalcemia
7 Dehydrocholesterol is transformed to cholecalciferol via UV Light.
25 Hydroxycholecalciferol ist made by liver from cholecalciferol or ergocalciferol without a feedback mechanism.
Vitamin D ist converted in Kidney from 25- Hydroxycholecalciferol to 1,25 Hydroxcholecalciferol . The responsable Enzyme is 1alpha hydroxylase in renal tubule. 24hydroxylase from kidney deactivate 25 OH Vitamin D
The 1,25Vitamin D3 level have a inhibitory effect on 1alpha hydroxylase.
PTH stimulate 1 alpha hydroxylase
FGF23 inhibit 1 apha hydroxylase
Describe mechanism of action and action of vitamin D.
-All Genomic actions of biologically active Vitamin D are mediated with VDR.
VDR regulate gene transcription and stimulate intracellular signaling pathway.
-The Major sites of VDR are in bones , intestine and Kidney.
VDR Activation lead to phosphate and calcium intestinal absorption as well as to renal calcium tubular reabsorption.
*In Bones the effect is dependent on calcium. When calcium is insufficient acquired , it enhance calcium resorption from bone and supress bone matrix mineralization.
if calcium is sufficient, it induce bone mineralisation.
-VDR suppress PTH Secretion , VDR activation enhance FGF23 production by osteocyte.Other new function: Paracrine and autocrine activity of VDR, inhibition of cellular proliferation and stimulation of maturation in immune system , colon, breat and prostate.
Emphasize physiological regulation of vitamin D.
Active vitamin D suppress PTH
Active Vitamin D stimulate FGF23
PTH stimulate 1 alpha hydroxylase
FGF23 inhibit 1 alpha hydroxylase
High level of 1,25 OHVitaminD3 inhibit 1 alpha hydroxylase( Negative Feed back mechanism)
24alpha hydroxylase deactivate the 25OHVitaminD3.
Low calcium can stimulate PTH Secretion. (So effect of Ca threw PTH)
High calcium can inhibit PTH Low Phosphate can inhibit PTH and FGF23 High Phosphate can stimulate both PTH and FGF23 affecting indirectly Vitamin D activation.
Approximatly 90% of Vitamin D is binded to Vitamin D Binding Proteind(DBP). it is secreted by liver.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Vitamin D is measured through the level of 25OHVitaminD (As standard)
Sufficient is above 30 ng/mL.
Limiting factor for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD Patient are :
-Hypercalcemia and Hyperphosphatemia in patients.
-Attention should be paid in the presence of potentially increased 1 alpha hydroxylase activity like in B Cell lymphoma and sarcoidosis.
-Cost of some active form of Vitamin D like Paricalcitol.
-limited Sunexposure, seasonal variation should be taken in cosideration and measurement should be done in late winter and late summer.
Describe the different biological effects of different forms of vitamin D therapy.
There is not difference between Vit D2 (from vegetable) and Vitamin D3 (from meat)
The ergocalciferol , Cholecalciferol and calcidiol (So not active) exercice pleiotropic effect more (e.g. antineoplastic, antiinflammatory, regulating immune system, preventing depression,gestational diabetes and preeclampsia, low vitamin D assosiated with incread risk of cardiovascular death.)
Calcitriol has low pleiotropic effect and because is more selective.
Paricalcitol is the most selective , it lower PTH level the most without inducing hypercalcemia or hyperphosphatemia in low-moderate dosage.
Examples:
Encouraging data about paricalcitol, ergocalciferol and calcitriol suggesting adjuvant affect against renal anemia.
Cholecalciferol was more effective than ergocalciferol in providing 25OH Vit D replenishment (Daroux) but other studies did not confirm that.
Cholecalciferol reduced IL6, CRP and LVH (Bucharles et al.)
Analyze the evidence of antiproteinuric effect of VITDRA.
Recent metaanalysis by de Borst et al. included 6 RCTs investigating the effect of active vitamin D on protienuria. it was associated with a significant 16% reduction of protienuria compared to 6% reduction among controls with more than 100 fold greater probabiltiy to reach a proteinuria reduction >15%. The analysis included diabetics and Ig A Nephropathy patient and other renal disorders
-In KTR the evidence look more promising: Paricalcitol at low doses (3µg/week) was retrospectively associated with a significant reduction of proteinuria at 24 months
-Trillini et al. performed a randomized , crosssectional study and showed a significant decrease in proteinuria on paricalcitol by KTR.
Amr et al. showed decreased intersitial fibrosis in KTR on paricalcitol.
these studies was not designed to investigate the proteinuria as a primary outcome.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
The current evidence on the potential survival benefits of Vitamin D is conflicting and uncertain. There is no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescirbe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle. Observational studies varies significantly on number of participants, time and duration of follow up .
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
-Marckmann et al. found that weekly ingestion of 40,000 IU D3 for 8 weeks corrected hypovitaminosis D in CKD patients. However, they were not able to demonstrate any effects of vitamin D3 supplementation in HD patients (except for a rise of FGF23).
-Armas et al. supplemented patients with cholecalciferol and found that it was effective in replenishing deficient/insufficient hemodialysis patients without toxic effects. Mean serum 1,25(OH)2D increased significantly in the cholecalciferol-treated group, whereas it decreased in the placebo group.
-Wasse et al. found that short-term, high-dose oral cholecalciferol treatment was effective in replenishing deficient/insufficient hemodialysis patients without toxic effects.
-Delanaye et al. found that cholecalciferol supplementation increased serum 25(OH)D levels and decreased PTH levels compared to controls without any observed toxicity.
Hewitt et al. found that cholecalciferol therapy had no effect on muscle strength, functional capacity, pulse wave velocity, or health-related quality of life (HRQOL).
-Massart et al. reported that supplementation with cholecalciferol increased serum 25(OH)D and 1,25(OH)2D levels, but did not significantly modify serum levels of PTH, calcium, or phosphorus.
-Bhan et al. found that ergocalciferol increased 25(OH)D levels in incident HD patients without significant changes in blood calcium, phosphate, or PTH during a 12-week period. When the two ergocalciferol arms were combined, the authors noted a trend toward reduction in all-cause mortality among ergocalciferol-treated participants compared to placebo-treated participant
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
Vitamin D Level
-25 OH D Deficiency and insufficiency are common in KTRs with prevalence of 30% and 81% respectively
-1,25(OH)2D reach normal level within 3 to 6 month after transplantation
-High FGF23 levels inhibit 1-a-Hydroxylase and enhance 24 alpha hydroxylase, leading to reduced 1,25ohD and 25ohD initialy in KTR.
-Steroids impair vitamin D metabolism by activating the enzyme involved in Vitamin D Catabolism and increasing PTH and FGF23.
-Calcineurin inhibitor(CNI) suggest that vitamin D resistance induced by CNI through VDR Downregulation (Low 25 OH VitaminD).
-Rapamycin does not have any effect on vitamin D metabolism
Bone Health
Bone loss is considerable during the first year after transplantation, with a rate of 14,5% in the first 6 months followed by a mild improvement after the second year post transplant.
-The risk of hip fracture, until 3 years after transplantation is higher than in HD patients.
-Steroids directly worsen bone formation by inducing derangement of VitD metabolism, impaired osteoblastogenesis , increased apoptosis of osteoblasts, and enhanced osteoclastogeneisis through increased RANKL/OPG ratio.
-Both Cyclosporin and tacrolimus similarly promote bone loss via a direct osteoclast activation
-Sirolimus is a bone sparing immunosuppresive to to its capability to inhibit osteoclast activity.
Discuss pros & cons of vitamin D therapy in KTRs
Pros:
reduced risk of bone loss , Vitamin D can help prevent osteoporosis and bone loss which are common in KTR due to use of immunosuppressant. There is improvement in Bone mineral density and reduce risk of fracture
There is reduced PTH level under Vitamin D therapy by KTR.
There is some studies that suggest that Vitamin D especially paricalcitol reduce proteinuria waht ca improve long term graft survival.
There is a potential CV benefits .
Cons:
Risk of Hypercalcemia
Drug interaction and increased adverse effect.
Lack of evidence of benefits. Most evidence are conflicting and more research is needed to determine optimal dosing, duration, timing of vitamin D.
thanks doctor Nour for your excellent answers.
just few notions to remind
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
2-Describe the different biological effects of different forms of vitamin D therapy.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with KD not yet on dialysis, regression of osteitis fibrosa WITH limited Increase in the hazard of tr adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. Notably, experimental studies also suggested that the use of paricalcitol was assoiated with better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol, doxercalciferol and cinacalcet.
● Zheng et al. performed a meta-analysis from 20 studies that compared several forms of vitamin D. Participants that received calcitriol \and paricalcitol had a lower cardiovascular mortality.
3-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Stimulate cellular maturation, in different systems (skin, immune system, colon, breast, and prostate).
VitD target level in CKD
Therapy with nutritional and active form should be based on the following;
Act with 25(vitD) deficiency.
When and how to treat 2ndary hyperparathyroidism and CKD-MBD.
The potential efficacy of vitD on proteinuria, LFHT, and anemia.
Existing evidence-based effects of vitD on clinical hard endpoints.
2. Although recommended to treat the VitD deficiency, the optimum target level is not clear till now.
3. Different definitions with different therapeutic recommendations by several studies. 4. KDOGI 2003; for treatment of CKD3-5, target vitD > 30 with PTH above the target range. 5. KDIGO 2009; CKD3-5, as suggested for the general population.
6. KDIGO 2012; do not assess routinely, not to be subscribed in the absence of deficiency. 7. ERBP 2010, at least once in CKD 3-4, target vitD>30, replenish if <12.5. 8. NICE 2014, In all patients with CKD 4-5, target >20. Evidence of the antiproteinuric effect of vitD
Data on the antiproteinuric effect of vitD is promising.
A low dose of paricalcitol was retrospectively shown to be associated with a significant reduction at 24 months.
Trillini et al; performed a randomized cross-over study for the effect of 6 months of treatment with paricalcitol (1 micro/week)for 3 months and titrated up to 2 micro/day, if tolerated, or a non-paricalcitol therapy in KTRs with a long-term functioning graft, show a significant reduction of proteinuria at 6 months.
Amer et al; randomize 100 KTRs to oral paricalcitol 2 micro/day for the 1st year post-transplantation or no additional therapy, Did not show any significant lower in protein excretion, Moderate interstitial nephritis observed in 4 biopsies in the non-paricalcitol group.
Survival benefit and reported benefit of vitD on CKD patients on dialysis
Low vitD levels are associated with HTN, cardiovascular events, and reduced left ventricular mass.
VitD supplements are associated with an improved immune system.
VitD supplements improve renal anemia.
Wolfetal; show baseline deficiency of vitD level was associated with 90-day mortality.
NECOSAD study showed that the mortality was higher in the patients with severe vitD deficiency.
Thanks dr Kamal for comprehensive answers, just few notions
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
2-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Crucially, in patients with relatively high 1-a-hydroxylase activity, as transplanted patients and in those with sarcoidosis or B cell lymphoma, are more prone to toxicity therefore, lower targets of 25(OH)D levels are recommend.
The amount of 7-dehydrocholesterol that is changed into pre-vitamin D3 in the skin as a result of exposure to the sun’s ultraviolet B rays is highest at levels of sun exposure that do not cause the skin to burn. After that, it undergoes an isomerization process in which the warmth of the body converts it to vitamin D3.
Vitamin D2 (also known as ergocalciferol) comes from the plant sterol known as ergosterol, and the main way that people get it is through their food. However
Within the organ of the liver Both vitamin D2 and vitamin D3 are converted to 25-OHD, also known as calcidiol or calcifediol when they are exposed to the 25-hydroxylases CYP27A1 and CYP2R1.
The kidney is absolutely necessary for the maintenance of sufficient blood 25(OH)D levels because of the megalin-mediated absorption of 25(OH)D from the glomerular ultrafiltrate and its recycling back into circulation. This process takes place in the kidney.
The 25(OH)D that is created by the liver must go through a process called 1-a-hydroxylation in the kidney before it can be converted into the fully active form 1,25(OH)2D. (calcitriol).
Describe the mechanism of action and action of vitamin D.
The further metabolism of vitamin D to its major circulating form also takes place in other tissues where the 1,25(OH)2D that is produced serves a paracrine or autocrine function. Some examples of these tissues include the skin, cells of the immune system, the parathyroid gland, the intestinal epithelium, the prostate, and the breast.
Parathyroid hormone, FGF23, calcium, and phosphate are the primary regulators of the renal 1-hydroxylase (CYP27B1, the enzyme responsible for the production of 1,25(OH)2D); the regulation of the extrarenal 1-hydroxylase is different from that of the kidney and includes cytokines.
The 24-hydroxylase is the primary enzyme that is responsible for catabolizing 25(OH)D and 1,25(OH)2D. Similar to the 1-hydroxylase, it is tightly controlled in the kidney in a manner that is diametrically opposed to that of the 1-hydroxylase. However, similar to the 1-hydroxylase, it is widespread in other tissues where its regulation is distinct from that of the kidney.
Emphasize physiological regulation of vitamin D.
It is possible for calcium, acting via PTH, and phosphate, acting through FGF23, to have a secondary suppressive effect on renal CYP27B1.
The primary mechanism by which 1,25(OH)2D lowers the levels of 1,25(OH)2D in cells is by increasing its catabolism via the activation of CYP24A1.
This enzyme hydroxylates 5- 25OHD and 1,25(OH)2D at the 24 position, resulting in the formation of 24,25(OH)2D and 1,24,25(OH)3D.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for the prevention and treatment of secondary hyperparathyroidism in CKD patients.
In individuals with CKD, it is possible that a goal of achieving 25(OH)D levels of more than 30 ng/ml is an appropriate aim for the prevention and treatment of secondary hyperparathyroidism.
Reaching 25(OH)D levels of [30 ng/ml appears to be a reasonable first-step intervention to avoid vitamin D deficiency and/or treat secondary hyperparathyroidism in CKD stages 3–5. Optimal 25(OH)D levels are still not well defined; however, achieving these levels seems like a reasonable first-step intervention.
Describe the different biological effects of different forms of vitamin D therapy.
Supplementation looks beneficial. Untreated deficient individuals had a higher risk of early death than those with the highest 25(OH)D or 1,25(OH)2D levels who received active vitamins. Intriguingly, even inactive vitamin D improved mortality. Low-dose oral alfacalcidol enhanced survival in 25-OHD-deficient and non-deficient patients. In Bucharles et al.’s trial, 30 patients received oral cholecalciferol once a week (50,000 IU) for the first 12 weeks and 20,000 IU for the remaining 12 weeks. Inflammation indicators included high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, and serum albumin.
Cholecalciferol supplementation corrected hypovitaminosis D safely and effectively, reducing CRP, IL-6, and LVH with little mineral metabolism alterations. These findings indicate that cholecalciferol supplementation may reduce inflammation and enhance heart function.
Analyze the evidence of the antiproteinuric effect of VITDRA.
KTR VDRA antiproteinuric data are encouraging. Low-dose paricalcitol (3 lg/week) significantly reduced proteinuria at 24 months. Trillini et al. conducted a randomized, crossover research to examine the effects of 6-month paricalcitol (1 lg/day for 3 months and then up-titrated to 2 mg/day if tolerated) vs non-paricalcitol therapy in KTRs with long-term functioning grafts. Proteinuria decreased significantly after 6 months. Amer et al. randomized 100 incident KTRs to oral paricalcitol, 2 lg/day, or no treatment for the first year post-transplant. After one year post-transplantation, paricalcitol-treated KTRs did not excrete less protein than controls.
survival benefits of Vitamin D in CKD patients on dialysis.
Serum 25(OH)D and calcitriol analog treatment determined a 42-month survival study. After adjusting for age, gender, dialysis vintage, calcemia, phosphatemia, CVD, and diabetes, 25(OH)D levels above the median (18 ng/ml) were related with decreased all-cause mortality (HR, 0.73 [0.5–0.96], p = 0.02). Krause et alretrospective .’s investigation found a link between low vitamin D and mortality. 6518 German Renal Registry patients matched with 73,919 25(OH)D readings. Vitamin D deficiency increases all-cause mortality. Vitamin D insufficiency—25(OH)D levels ranging from 20 to ±30 ng/ml—increased risk somewhat; vitamin D deficiency—25(OH)D ranging from 12.5 to ±20 ng/ml—increased risk significantly; and severe vitamin D deficiency—25(OH)D <12.5 ng/ml—doubled mortality risk. Vitamin D deficiency increased all-cause death, cardiac mortality, and cancer mortality.
Supplementation looks beneficial. Untreated deficient individuals had a higher risk of early death than those with the highest 25(OH)D or 1,25(OH)2D levels who received active vitamin D. Intriguingly, even inactive vitamin D improved mortality. Low-dose oral alfacalcidol enhanced survival in 25(OH)D-deficient and non-deficient individuals.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Ergocalciferol and cholecalciferol were supplemented in patients with non-dialysis-dependent CKD, dialysis-dependent CKD, and renal transplant recipients. Serum 25(OH)D, intact PTH, 1,25(OH)2D, calcium, and phosphorus were biochemical objectives. Clinical objectives included cardiovascular events, bone disease, and all-cause death. 25(OH)D and PTH improved significantly. Dialysis patients reduced their PTH more.
Describe the effects of different immunosuppressives on both vitamin D levels and bone health in KTR.
Steroids activate vitamin D catabolism enzymes and raise PTH and FGF23 [149]. Steroid sparing/withdrawal increases vitamin D metabolism [139]: cumulative prednisone dosage was inversely linked with 1,25(OH)2D levels 2 years after transplantation, and low 1,25(OH)2D levels were inversely associated with greater FGF23 concentrations caused by steroid treatment.
Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels.
Rapamycin does not have any effect on vitamin D metabolism
Discuss the pros & cons of vitamin D therapy in KTRs.
Pros;
Reduced PTH levels result in an improvement in BMD.
This may lead to an increase in allograft survival(scanty data)
Anti-proteinuric action
Anti-fibrotic
Cons:
Stavroulopoulos et al. found that hypercalcemia after kidney transplantation ranges from 11–66%, depending on time post-transplantation. Vitamin D medication may aggravate hypercalcemia, which may limit patient eligibility.
THANKS dr Weam for your effort, just few notions
1-Describe mechanism of action and action of vitamin D.
I- Mechanism of Action
All genomic actions of biologically active vitamin D are mediated by the vitamin D receptor (VDR). This occurs via ligand binding to VDR leading to modification of gene transcription and activation of intracellular signaling pathways.
II- Action
Principally, vitamin D main action is regulation of mineral and bone homeostasis in intestinal, renal and bone tissues. This is mainly achieved by VDR activation leading to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption. On the other hand, its effect on bone health is dependent on level of calcium. In case of calcium deficiency, VDR activation leads to bone resorption and suppressing bone matrix mineralization. In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes.
2-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Crucially, in patients with relatively high 1-a-hydroxylase activity, as transplanted patients and in those with sarcoidosis or B cell lymphoma, are more prone to toxicity therefore, lower targets of 25(OH)D levels are recommend.
3-Describe the different biological effects of different forms of vitamin D therapy.
Describe the different biological effects of different forms of vitamin D therapy.
● The positive effects of cholecalciferol seem to be limited to replenishment of deficiency/insufficiency of 25(OH)D.
.
● Selective vitamin D receptor activators (VDRA) should favor a stronger downregulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
● The positive effects of cholecalciferol seem to be limited to replenishment of deficiency/insufficiency of 25(OH)D.
.
● Selective vitamin D receptor activators (VDRA) should favor a stronger downregulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with cKD not yet on dialysis, regression of osteitis fibrosa with limited Increase in the hazard of adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. .
4-Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
● An association between vitamin D supplementation and reduced LV mass as well as a positive effect of vitamin D supplementation on the immune system has been reported in patients with ESRD
● There was a significant improvement in 25(OH)D levels and reduction of PTH levels. PTH reduction was more evident in dialysis patients.
● The active forms of vitamin D have been successfully used for a long time to treat secondary hyperparathyroidism in dialysis patients. The main characteristics of selective VDRA are their stronger effect in reducing serum concentration of PTH, lower impact on concentrations of calcium and phosphate, and reduced toxicity.
● Supplementation therapy appears to offer controversial survival advantages.
pRE Vit D is primarily synthesised in the skin after exposure to sunlight, which in turn forms 25 HO of Vit D without the help of the enzymes.
Then through the blood will go for first hydroxylation in the liver 25 HO vit D , THEN TO THE SECOND hydroxylation, which takes place in the kidneys.
One of the important rules of the kidney is to keep a level of 25 HOD constant by continuous reabsorption from the glomerular filtrate.
The kidney will do the second hydroxylation to 1,25 HO (calcitriol). PTH , FGF23,Ca and po4 is the main regulator for 1, hydroxylation.
Emphasise physiological regulation of vitamin D.
PTH controls the kidney’s production of 1,25 VIT D Calcitrole and is inhibited by Ca ,po4 and FGF23.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The optimal level for Vit D level in CKD patients is >then 30 and less than 100
30 is a good level to treat and prevent SHPTH.
iT was advised to discontinue the Vit D in the. Following conditions:
hyper Ca
high and high trends for PTH
Describe the different biological effects of different forms of vitamin D therapy.
The two confusing forms of Vit D needs liver hydroxylation to be active :
Ergocalciferol is Vit D from the plant D2, and Cholecalciferol D3 is vit D from animal sources, both of them will be hydroxylated in the liver to 25(OH) D3 and 25(oh) D2, respectively.The third form is the calcifediol, which is the 25 (OH) D3 THE SYNTHETIC .1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR).
The major function of 1,25(OH)2D is to regulate calcium homeostasis
other biological activities include the regulation of proliferation and differentiation of several cell lines, including keratinocytes, endothelial cells, osteoblasts, and lymphocytes. Most of these biological functions are mediated via the vitamin D nuclear receptor (VDR), which acts as a transcription factor regulating the transcription of target genes.
Analyze the evidence of the antiproteinuric effect of VITDRA.
meta analysis concluded that Active vitamin D administration was associated with a significant 16 % reduction of proteinuria compared to 6 % reduction among controls with a more than 100-fold greater probability to reach a proteinuria reduction C15 %.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.
the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle. available studies are certainly interesting but still they do not offer us solid certainties on the use of vitamin D in patients on dialysis. Observational studies show great differences in duration of follow-up and number of enrolled patients; indeed, observation time varies from 90 days to 3 years and the number patients varies from a few tens to thousands. Further differences between studies are the aims to be assessed. They do not give specific algorithms or guidelines for practice
thanks dr Rihab for your effort, just few notions:
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D
2-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Crucially, in patients with relatively high 1-a-hydroxylase activity, as transplanted patients and in those with sarcoidosis or B cell lymphoma, are more prone to toxicity therefore, lower targets of 25(OH)D levels are recommend.
3-Describe the different biological effects of different forms of vitamin D therapy.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with KD not yet on dialysis, regression of osteitis fibrosa WITH limited Increase in the hazard of tr adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. Notably, experimental studies also suggested that the use of paricalcitol was assoiated with better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol, doxercalciferol and cinacalcet.
Analyze the evidence of antiproteinuric effect of VITDRA.
Evidence of antiproteinuric effect of VITDRA is ontroversial
● Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and non-diabetic patients, although negative results were also reported.
· Describe mechanisms of vitamin D activation. 1- In skin 7-dehydrocholesterol is converted to pre-vitamin D3 under the influence of sunlight (UVB) is maximized at levels of sunlight exposure that do not burn the skin. and thereafter it is isomerized by the body’s temperature to vitamin D3 2- Vitamin D2 (ergocalciferol) is derived from the sterol ergosterol of plants and the main intake is through diet. However
3- In the liver The native vitamin D2 and D3 are both 25-hydroxylated to 25(OH)D (calcidiol or calcifediol) by 25-hydroxlases,CYP27A1 and CYP2R1
4- the kidney is essential for maintaining adequate serum 25(OH)D levels by means of the megalin mediated uptake of 25(OH)D from the glomerular ultrafiltrate and its recycling into to the circulation,
5- The 25(OH)D produced by liver be 1-a-hydroxylated in the kidney to produce the fully active form 1,25(OH)2D (calcitriol). 6- Further metabolism of vitamin D to its major circulating form takes place also in other tissues where the 1,25(OH)2D produced serves a paracrine/autocrine function: examples include the skin, cells of the immune system, parathyroid gland, intestinal epithelium, prostate, and breast. 7- Parathyroid hormone, FGF23, calcium and phosphate are the major regulators of the renal 1-hydroxylase (CYP27B1, the enzyme producing 1,25(OH)2D); regulation of the extra renal 1-hydroxylase differs from that in the kidney and involves cytokines. 8- The major enzyme that catabolizes 25(OH)D and 1,25(OH)2D is the 24-hydroxylase; like the 1-hydroxylase it is tightly controlled in the kidney in a manner opposite to that of the 1-hydroxylase, but like the 1-hydroxylase it is widespread in other tissues where its regulation is different from that of the kidney.
· Emphasize physiological regulation of vitamin D.
1- The production of 1,25(OH)2D in the kidney being stimulated by parathyroid hormone (PTH),
2- The production of 1,25(OH)2D inhibited by calcium, phosphate and FGF23.
3- Extra renal production of 1,25(OH)2D as in keratinocytes and macrophages is under different control, being stimulated primarily by cytokines such as tumor necrosis factor alfa (TNFα) and interferon gamma (IFNg).
4- 1,25(OH)2D reduces 1,25(OH)2D levels in cells primarily by stimulating its catabolism through the induction of CYP24A1(24-hydroxylase).
5- 25OHD and 1,25(OH)2D are hydroxylated in the 24 position by this enzyme to form 24,25(OH)2D and 1,24,25(OH)3D, respectively.
6- This 24-hydroxylation is generally the first step in the catabolism of these active metabolites to the final end product of calcitroic acid, although 24,25(OH)2D and 1,24,25(OH)3D have their own biologic activities.
7- CYP24A1 also has 23-hydroxylase activity that leads to a different end product.
· Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The optimal targets of 25(OH)D circulating levels and the best approach to obtain vitamin D replenishment remain unknown.,
1- 30 ng/ml seems a reasonable target for the prevention and treatment of secondary hyperparathyroidism in CKD patients.
discontinue vit D when
25(OH) levels more than 100 ng/ml .
Hypercalcemia.
continuous elevation of PTH .
Describe the different biological effects of different forms of vitamin D therapy.
Two pro-drugs cholecalciferol and ergocalciferol (both requiring conversion by hepatic 25-ahydroxylase to 25(OH)D3 or 25(OH)D2, respectively) and calcifediol (already available as 25(OH)D3). Many studies have indicated a potential superiority of cholecalciferol vs. ergocalciferol in increasing 25(OH)D levels.
The levels of 25(OH)D are not always completely corrected; therefore alternative regimens with cholecalciferol and ergocalciferol supplementation have been proposed to reach the therapeutic levels of 25(OH)D as suggested by the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines a modified-release calcifediol formulation, resulted in effective increasing 25(OH)D levels in a dose dependent manner among non-dialysis CKD patients compared to placebo
Regardless of the preferred regime, in predialysis CKD patients treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in the presence of 25(OH)D levels[100 ng/ml and/or with persistent serum calcium levels 10.5 mg/dl in the absence of active vitamin D administration. Attention should be paid in the presence of potentially increased 1-a-hydroxylase
A potential superiority of selective VDRA, e.g. paricalcitol, with respect to non-selective VDRA such as calcitriol, alfacalcidol or doxercalciferol is still the subject of debate. Despite encouraging experimental data, not all the available active vitamin D formulations have been tested in head-to-head RCTs on hard endpoints, PTH control, bone histology and vascular aging.
Describe how control of cardiovascular risk factors is different in patients with CKD in comparison to the general population?
1- CKD mainly medial layer which is affected in the vessel wall(arteriosclerosis) previously called Mönckeberg’s arteriosclerosis calcification 2- in general population where intima mainly affected with atherosclerotic plaque. 3- Control of traditional cardiovascular risk have limited success in patients with CKD. 4- cholesterol control has not been conclusively proven to be of benefit in patients with advanced CKD. 5- Trials that target CKD-specific; nontraditional risk factors have failed to show benefit.
Using vitamin D in general population is associated with improvement in cardiovascular outcome and mortality. Analyze the evidence supporting vitamin D use in general population.
1- there is relationship of vitamin D deficiency with cardiovascular disease, including A) carotid intima-media thickness, B) peripheral vascular disease, and c) cardiovascular death.
2- Vitamin D supplementation improves BP and endothelial function and reduces levels of inflammatory markers and lipids (particularly triglycerides) in the general population with or without vitamin D deficiency.
3- a prospective, randomized trial Vitamin D supplementation did not improve incident cardiovascular disease and death, or myocardial infarction, angina, heart failure, and arrhythmia.
4- More recently, in 25,871 patients with baseline vitamin D concentration of 77 nmol/L, use of 2000 IU/daily of cholecalciferol did not improve cardiovascular outcomes
Criticize the cardiovascular benefits of using vitamin D supplement in patients with CKD.
No adequately powered, randomized, controlled trials have not been conducted. Hence, the impact of vitamin D therapy on cardiovascular health in patients with CKD is unknown 1- Vitamin D deficiency associated with all-cause and cardiovascular mortality in patients with CKD, 2- improvement of cardiovascular and all-cause mortality after treatment with vitamin D and its analogs in patients with CKD.
Impact of Vitamin D on Vascular Function in CKD 1- vitamin D supplementation improve on brachial artery flow-mediated dilatation, 2- reduce markers of inflammation, 3- effect on arterial stiffness, 4- decrease parathyroid hormone, 5- Modulate intracellular cell adhesion molecule, vascular cell adhesion molecule.
6- In CKD eGFR of 15–45 ml/min per 1.73 m2 pulse wave velocity improved after 6-month supplementation with 25-hydroxy vitamin D 7- and brachial artery flow-mediated dilatation improved with 12-week paricalcitol therapy in patients with CKD stages 3 and 4.
8- On the other hand, two studies failed to find any change in flow-mediated dilatation and pulse wave velocity, respectively. Although the effects are inconsistent,
9- a recent meta-analysis showed that vitamin D treatment led to an improvement of endothelial function.
Impact of Vitamin D on Cardiac Structure and Function. 1-year active vitamin D supplementation failed to improve cardiac structure and function in patients with CKD.
2- there is improvement of left atrial volume, diastolic function, and significant improvement in the number of hospitalizations due cardiovascular events.
3- Epidemiology suggests a link between of vitamin D deficiency with cardiovascular events in patients with CKD.
4- Observational cohorts and small, randomized, placebo controlled trials have shown some benefits with supplementation.
5- There is no randomized trial evidence to justify supplementation in patients with CKD patients to improve cardiovascular function in regular clinical careand there is lack of strong evidence for vitamin D therapy to prevent cardiovascular disease in CKD.
· Analyze the evidence of antiproteinuric effect of VITDRA.
1- vitamin D has received growing interest as a treatment for several targets beyond PTH and bone health control, e.g. proteinuria, LVH and anemia.
2- Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and nondiabetic patients, although negative results were also reported
3- meta analysis concluded that Active vitamin D administration was associated with a significant 16 % reduction of proteinuria compared to 6 % reduction among controls with a more than 100-fold greater probability to reach a proteinuria reduction C15 %
4- The analysis was not limited to diabetics but it included patients with immunoglobulin (Ig)A nephropathy and patients with other renal disorders.
· Criticize survival benefits of Vitamin D in CKD patients on dialysis.
available data ABOUT survival benefits of Vitamin D in CKD patients on dialysis are conflicting and, uncertain. Not known when to start treatment, on which vitamin D to prescribe, on dose to administer and on the route to prefer
because most vitamin D comes from the sun and healthier people have more opportunities to spend time outdoors, studies in patients are particularly susceptible to confounding. Therefore, the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle. available studies are certainly interesting but still they do not offer us solid certainties on the use of vitamin D in patients on dialysis.
Observational studies show great differences in duration of follow-up and number of enrolled patients; indeed, observation time varies from 90 days to 3 years and the number patients varies from a few tens to thousands. Further differences between studies are the aims to be assessed. They do not give specific algorithms or guidelines for practice · Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
there is an association between 25(OH)D low serum levels and mortality.
Mortality was higher in severely vitamin D deficient patients compared to the other groups.
while no significant association was found between non-cardiovascular mortality and vitamin D.
Patients (n = 6518) from the German Renal Registry were matched with 73,919 recorded 25(OH)D measurements. All-cause mortality risk increased with decreasing vitamin D levels,
1- for vitamin D insufficiency—25(OH)D levels ranging from 20 to\30 ng/ml—a moderate increase in risk was observed;
2- for vitamin D deficiency—25(OH)D ranging from 12.5 to\20 ng/ml—the risk was much more pronounced;
3- for severe vitamin D deficiency—25(OH)D\12.5 ng/ml—mortality risk was more than doubled.
· Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
1- the impairment of vitamin D metabolism reflects allograft function, FGF23 and PTH levels, immunosuppressive therapy and environmental factors (nutritional deficiency, decreased sun exposure) Vitamin D level
Steroids: increase PTH & FGF23
CNIs: lower levels of 25(OH)D
mTORi: Is neutral on vitamin D metabolism
bone level
Steroids: increase bone loss by suppress action of increase osteoclast .
CNIs :activate the osteoclast causing bone lose.
No interactions were found between tacrolimus and Vitamin D3
· Discuss pros & cons of vitamin D therapy in KTRs.
· the effects of ergocalciferol and cholecalciferol and calcifediol on BMD remains controversial
· No specific guidelines have been released to orient nutritional vitamin D replenishment in KTRs,
· Although several authors reported a significant improvement of PTH and calcium levels in KTRs receiving nutritional vitamin D,
· cholecalciferol supplementation after kidney transplant did not modify the progression of GFR, the onset of interstitial fibrosis, tubular atrophy and proteinuria
· Pros
suppress PTH
antifibrotic
Anti-proteinuric effect
exert autocrine activities in cell function .
anti-depreesion effect.
B.Cons
hyperphosphatemia
hypercalcemia
suppressing bone matrix mineralization .
thanks dr Ahmed for your comprehensive answers just few notions
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
2-Describe the different biological effects of different forms of vitamin D therapy.
● Selective vitamin D receptor activators (VDRA) should favor a stronger downregulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with KD not yet on dialysis, regression of osteitis fibrosa WITH limited Increase in the hazard of tr adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. Notably, experimental studies also suggested that the use of paricalcitol was assoiated with better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol, doxercalciferol and cinacalcet.
3-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Finally, considering the inherent limitations of retrospective analyses characterized by significant differences in number of enrolled patients, administered doses of vitamin D sterols, duration of treatment and assessed outcomes, the benefit of VDRA treatment on survival in hemodialysis patients still remains to be confirmed by prospective RCTs.
D3 is produced in the skin from 7-DHC in a non enzymatic process in which the B ring is broken by UVB radiation.
the pre-D3 formed isomerizes to D3 in a thermo-sensitive process.
D3 is converted to 25OHD3 in the liver and elsewhere by a number of enzymes of which CYP2R1 is the most important. The regulation of this step is modest at best.
The kidney and other tissues metabolize 25OHD to the active metabolite 1,25(OH)2D3 or the first step in the catabolic process 24,25(OH)2D3. The enzymes responsible, CYP27B1 and CYP24A1, respectively, are tightly controlled.
in the kidney, CYP27B1 is stimulated by PTH and inhibited by FGF23 and high calcium (Ca) and phosphate (P).
The regulation of CYP24A1 is just the opposite. 1,25(OH)2D3 also regulates its own production directly and by inhibiting PTH production, stimulating FGF23 production and inducing CYP24A1.
Describe mechanism of action and action of vitamin D.
Most effects of 1,25(OH)2D are mediated by VDR acting primarily by regulating the expression of genes whose promoters contain specific DNA sequences known as vitamin D response elements (VDREs).
some actions of 1,25(OH)2D are more immediate, and may be mediated by a membrane bound vitamin D receptor that has been less well characterized than the nuclear VDR or by the VDR acting outside of the nucleus.
Emphasize physiological regulation of vitamin D.
in the kidney, CYP27B1 is stimulated by PTH and inhibited by FGF23 and high calcium (Ca) and phosphate (P).
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients
30 ng/ml is the minimum level of 25(OH)D .
discontinue vit D when
25(OH) levels more than 100 ng/ml .
Hypercalcemia.
continuous elevation of PTH .
Describe the different biological effects of different forms of vitamin D therapy.
The two forms of vitamin D differ depending on their food sources. Vitamin D3 is only found in animal-sourced foods, whereas D2 mainly comes from plant sources and fortified foods.
1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR).
The major function of 1,25(OH)2D is to regulate calcium homeostasis other biological activities include regulation of proliferation and differentiation of several cell lines including keratinocytes, endothelial cells, osteoblasts, and lymphocytes. Most of these biological functions are mediated via the vitamin D nuclear receptor (VDR) which acts as a transcription factor regulating transcription of target genes .
Analyze the evidence of antiproteinuric effect of VITDRA.
antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis. The information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
thanks dr Ashraf for your effort, just few notions:
1-Describe mechanism of action and action of vitamin D.
II- Action
Principally, vitamin D main action is regulation of mineral and bone homeostasis in intestinal, renal and bone tissues. This is mainly achieved by VDR activation leading to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption. On the other hand, its effect on bone health is dependent on level of calcium. In case of calcium deficiency, VDR activation leads to bone resorption and suppressing bone matrix mineralization. In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes. More recently, vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells.
2-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Finally, considering the inherent limitations of retrospective analyses characterized by significant differences in number of enrolled patients, administered doses of vitamin D sterols, duration of treatment and assessed outcomes, the benefit of VDRA treatment on survival in hemodialysis patients still remains to be confirmed by prospective RCTs.
3-Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
II- bone health
Immunosuppressive drugs elicit a deep impact on bone loss.
● Steroids may harm the bone health by direct suppression of bone formation through impairment of vitamin D metabolism, inhibited osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio.
● Both cyclosporine and tacrolimus may indue bone loss via a direct osteoclast activation.
● Conversely, sirolimus is a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation.
The kidney play important for maintaining adequate blood levels of 25(OH)D through megalin-mediated uptake from the glomerular ulfiltrate and then recycling it back into the circulation
The 25(OH) uptaken from the glomerular ultrafitrate may also be alpha-1 hydroxlated(CYP27B1) in the kidney to produce the fully active form 1,25(OH)2D or calcitriol
Describe mechanism of action and action of vitamin D.
Regulation of mineral and bone homeostasis in intestine, kidney & bone tissues
Inhibition of cellular proliferation & stimulation of cell maturation in the skin,immune system, colon, breast and prostate cells
Emphasize physiological regulation of vitamin D.
The renal CYP27B1{major source of circulating 1,25(OH)D} is stimulated by PTH and suppressed by FGF23 & 1,25(OH) itself
The renal CYP27B1 can be secondarily suppressed by Ca through PTH and by phosphate through FGF23
Circulating 25(OH)D can also be hydroxylated in extra-renal cells that express CYP27B1 e.g., macrophage and keratinocytes. However, the regulation of extra-renal CYP27 B1 is different from the renal one,it is site dependent and involves several hormones and inflammatory molecules
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The achievement of 25(OH)D levels > 30 ng/ml may be a acceptable target for prevention and treatment of secondary hyperparathyroidism in CKD patients
Treatment should be discontinued when 25(OH) levels >100 ng/ml and/or with persistent serum Ca > 10.5 mg/dl. We have to be cautious with the situations of increased alpha 1 hydroxylase activity e.g., transplant patient, sarcoidosis
Describe the different biological effects of different forms of vitamin D therapy.
D2 and D3 differ ony in their structure and the differences do not affect the active process. Both function as prohormone and when activated exhibit identical biological responses
Over the last two selective active vitamin D metabloites (paricalcitol, maxacalcitol) have been used to reduce PTH with minor changes in Ca and PO4 compared to non-selective (calcitriol)
Active forms of vitamin D are more effective than the other forms of vitamin D (native/nutritional vitamin D) in managing secondary hyperparathyroidism with no ability to increase or normalize 25(OH)D. Native/Nutritional vitamin D may increase 25(OH)D and reduce PTH. Therefore, combination of both active and native/nutritional vitamin D may be effective but so far here is no survival benefits.
Analyze the evidence of antiproteinuric effect of VITDRA.
De Borst et al RCT of 6 studies showed that, active vitamin D was associated with with a significant reduction in proteinuria ( 16% on active form of vitamin D versus 6% on the control arm). This was true for diabetic nephropathy, IgA nephropathy and other glomerular diseases.However, more RCT are badly required to confirm this.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Observational data
Differences in the number of the patients involved
Differences in the doses of vitamin D and duration of treatment
Differences in the outcomes being assessed
Therefore, RCTs are needed to figure out this issue
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis
LV mass: reduction of the LV mass
Immune system: improvement of the immune system
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
A.Vitamin D level
Steroids: Increase vitamin D degradation leading to increase PTH & FGF23
CNIs: Down regulate VDR resulting in vitamin D resistance and lower levels of 25(OH)D
mTORi: Is neutral on vitamin D metabolism
B.Bone health
Steroids: promote bone loss by inhibition osteoblast, increase osteoblast apoptosis, and enhance osteoclast through elevation of RANKL/OPG ratio
CNIs: promote bone loss by direct effect on osteoclast
mTORI: Promote bone formation by inhibition of osteoclast generation
Discuss pros & cons of vitamin D therapy in KTRs.
A.Pros
Decrease PTH
Improves BMD
May improve allograft survival (more data are needed)
Anti-proteinuric effect
Anti-fibrotic
B.Cons
Hypercalcemia: ranges between 11 to 66% depending on the time transplantation
thanks dr Ben Lomatayo for your effort, just few notions
1-Describe mechanisms of vitamin D activation.
A- Hepatic hydroxylation
Mechanism: The liver is the major if not sole source of 25 (OH) D productions from native vitamin D. The native vitamin D2 and D3 are both 25-hydroxylated to 25(OH)D (calcidiol or calcifediol) by several 25-hydroxlases, such as CYP27A1 and CYP2R1.
C- Extrarenal extrahepatic
Mechanism: circulating 25(OH)D can also be 1-a-hydroxylated in extrarenal cells that express CYP27B1, such as keratinocytes and macrophages.
2-Describe mechanism of action and action of vitamin D.
Principally, vitamin D main action is regulation of mineral and bone homeostasis in intestinal, renal and bone tissues. This is mainly achieved by VDR activation leading to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption. On the other hand, its effect on bone health is dependent on level of calcium. In case of calcium deficiency, VDR activation leads to bone resorption and suppressing bone matrix mineralization. In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes
3-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
4-
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Mechanism of vitamin D activation
activated by enzymes, firstly in the liver and then in the kidneys.
25 Hydroxycholecalciferol is made by the liver from cholecalciferol by 25 hydroxylase enzymes without a feedback mechanism.
Vitamin D is converted in Kidney from 25- Hydroxycholecalciferol to 1,25 Calcitriol by one alpha-hydroxylase
24hydroxylase from the Kidney deactivates 25 OH Vitamin D.
mechanism of action
vitamin d helps to absorb calcium from the intestine and mineral bone growth,
also stimulates the absorption of phosphate and magnesium
The recommended target vitamin D level is 40-60ng/ml
the KDIGO guidelines has highlighted the use of calcitriol reserve after discovering the association between hypercalcemia , hyperphosphatemia and vascular calcification and dynamic bone disease .these guidelines defined clear limits to avoid over treatment
25 Hydroxycholecalciferol is made by liver from cholecalciferol or ergocalciferol by 25 hydroxylase enzyme without a feedback mechanism.
Vitamin D ist converted in Kidney from 25- Hydroxycholecalciferol to 1,25 Calcitriol by 1 alpha hydroxylase
24hydroxylase from kidney deactivate 25 OH Vitamin D
Describe mechanism of action and action of vitamin D.
All genomic actions of biologically active vitamin D are mediated by the vitamin D receptor (VDR. It is present in cells and tissues, the VDR exerts an extensive biological response, when activated by ligand-binding, via regulation of gene transcription and stimulation of intra[1]cellular signaling pathways .The major endocrine action of VDR is to regulate mineral and bone homeostasis in intestinal, renal and bone tissues. In fact, VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption Of note, vitamin D activity can directly regulate bone metabolism when insufficient calcium is acquired through diet or absorbed by the intestine, enhancing bone resorption and suppressing bone matrix mineralization In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes
Emphasize physiological regulation of vitamin D
Cholecalciferol /Ergocholecalciferol is hydroxylated by liver 25 hdyrxoylase to 25 OH Vitamin Dand then hydroxylated by kidneys by 1alpha hydrolxase into calcitriol. The renal enzyme is only one and is substrate independent unlike hepatic enzyme substrate depedendent. PTH stimulates 1 alpha hydroxylase while FGF23 inhibit one alpha hydroxylase as well as high level of 1 25 oh inhibit 1 alpha hhdyroxyalse. Calcium and phosphate can have effect on on 1 alpha hydroxylase by action on PTH and FGF23
Active vitamin D suppress PT H
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Vitamin D <30ng/ml range tho its not evidence based
Describe the different biological effects of different forms of vitamin D therapy.
Cholecalciferol Vitamin D3 and Ergocholecalciferol Vitamin D2 can both be used when vitamin d level <30 and stopped when level are> 100 or hypercalcaemia . Many studies have showed that cholecalciferol is better than Ergocholecalciferol increasing Vitamin D levels.
Nice Guidance recommends recommends CKD4/5 active Vitamin D in patient suffering from symptomatic CKDMBD and egfr<30 despite 250h being adequate. Correction of Vitamin D level could delay and onset of progression. There is some data that shows that active vitamin d reduced PTH and improve bone histology. Selective Vitamin Receptors should favour stronger down regulation PTH synthesis with lower impact on calcium phosphate and lower pro calcifying effect on arterial wall. Zeng ET AL meta analysis of observational studies showed that vitamin d in CKD patient showed reduced cardiovascular mortality and there was a signal that selective VDRA might be better than non selective one. However this consideration needs proving by RCT Vitamin D impact on reducing proteinuria is controversial as well as impact on LVH. Vitamin D supplementation has also been showed to reduce inflammation namely by reduction of inflammatory markers such as CRP and Interleukin 6. In the same line it has been proposed that correction of vit d deficiency could help reduce amount of iron/epo as it decreases hepcidin.
Analyze the evidence of the antiproteinuric effect of VITDRA.
The ongoing VITALE study is comparing the effect of cholecalciferol at high or low J Nephrol 123 dose (respectively 100.000 or 12.000 IU every 2 weeks for 2 months, then monthly for 22 months) on proteinuria and graft survival as secondary outcomes. Data on antiproteinuric effects of VDRA in KTRs look more promising. Paricalcitol at low doses (3 lg/week) was retrospectively associated with a significant reduction of proteinuria at 24 months performed a randomized, crossover study to compare the effect of 6-month treatment with paricalcitol (1 lg/day for 3 months and then uptitrated to 2 lg/day if tolerated) or non-paricalcitol therapy in KTRs with a long-term functioning graft. Compared with baseline, proteinuria showed a significant decrease at 6 months. Amer et al. randomized 100 incident KTRs to oral paricalcitol, 2 lg/day, for the first year post-transplant or no additional therapy [174]. They did not observe lower protein excretion among paracalcitol treated KTRs compared to controls at 1 year post[1]transplantation. However, moderate interstitial fibrosis was observed in 4/38 biopsies in the control group, but was absent in the paricalcitol group. Notably, neither of the previous two RCTs was designed to investigate the effect of paricalcitol on proteinuria as a primary outcome. This trial did not look at proteinuria as secondary outcome.
survival benefits of Vitamin D in CKD patients on dialysis.
Observational studies decreased vitamin D associated with increasing mortality. Data from german registry showed increasing deficiency of vitamin D shows increasing rate of mortality. RCT failed to demonstrate any survival benefit.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis
Improves cardiovascular mortality
Possibly reduce inflammation , no effect on EPO tho theoretically could reduce epo/iron use
Decreases risk of infection
Decrease cardiac dysfunction
Describe the effects of different immunosuppressives on both vitamin D levels and bone health in KTR.
Steroids directly worsen bone formation by inducing: derangement of vitamin D metabolism, impaired osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/os[1]teoprotegerin (OPG) ratio while . Both cyclosporin and tacrolimus similarly promote bone loss via a direct osteo[1]clast activation [153]. Conversely, sirolimus is taken as a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation.
Discuss the pros & cons of vitamin D therapy in KTRs.
Pros;
Reduced PTH levels result in an improvement in BMD.
This may lead to an increase in allograft survival(scanty data)
Anti-proteinuric action by inhibiting RAS
Anti-fibrotic
( all above scanty evidence)
Cons
Can promote hypercalcaemia which can affect graft function
1-Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to the hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D).
2-The action of VDR is to regulate mineral and bone homeostasis in intestinal, renal and bone tissues . In fact,VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption
Vitamin D activity can directly regulate bone metabolism when insufficient calcium is acquired through diet or absorbed by the intestine, enhancing bone resorption and suppressing bone matrix mineralization
VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes
vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells
3-The three main steps in vitamin D metabolism, 25-hydroxylation, 1α-hydroxylation, and 24-hydroxylation are all performed by cytochrome P450 mixed-function oxidases (CYPs). These enzymes are located either in the endoplasmic reticulum (ER) (e.g., CYP2R1) or in the mitochondria (e.g., CYP27A1, CYP27B1, and CYP24A1). The electron donor for the ER enzymes is the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent P450 reductase. The electron donor chain for the mitochondrial enzymes is comprised of ferredoxin and ferredoxin reductase. These are not specific for a given CYP—specificity lies within the CYP. Although of the CYPs involved in vitamin D metabolism, only CYP2R1 and CYP24A1 have been crystallized, it is likely that these enzymes contain a number of common structural features. These include 12 helices (A–L) and loops and a common prosthetic group, namely the iron-containing protoporphyrin IX (heme) linked to the thiolate of cysteine. The I helix runs through the center of the enzyme above the heme where a thr(ser) and asp(glu) pair is essential for catalytic activity (Sugimoto and Shiro, 2012). CYP2R1, like other microsomal CYPs, contains two extra helices that appear to form a substrate channel in the bilayer of the ER (Sugimoto and Shiro, 2012). The B′ helix serves as a gate, closing on substrate binding. Whether a similar substrate channel exists for the mitochondrial CYPs is not clear.
4- The International Osteoporosis Foundation guidelines suggest levels of 25(OH)D [30 ng/ml as normal values inolder adults. The KDOQI guidelines suggest that levels of 25(OH)D [30 ng/ml should be regarded as normal limits for patients with non-dialysis CKD. Thus, 25(OH)D [30 ng/ml may be regarded as a suitable target also for patients on dialysis.
5- Vit D2 is derived from plants while vit D3 is of animal origin, there are two isoform of 1a-hydroxylase that work on vit D3, while vit D2 is is only acted on by one isoform. Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body so has more share of the actions
· Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase. Supplemental Active vitamin D increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.Selective VDRA like paricalcitol suppresses PTH and 1a-hydroxylation but it causes less Ca and PO4 to be absorbed from intestines
6-
Effect of vitamin-D analogue on albuminuria in patients with non-dialysed chronic kidney disease stage 4–5: a retrospective single center study:A total of 146 macroalbuminuric patients were identified, and of these, 59 started alfacalcidol treatment during the observation period. A 12% reduction in 24 h albuminuria was seen after starting treatment. In 19 patients with no change in renin-angiotensin-aldosteron-system (RAAS) inhibition, the reduction in albuminuria was 16%. The reduction remained stable over time (9%) in a subgroup of patients (n = 20) with several urine collections before and after the start of alfacalcidol-treatment.
7-comes only in patients with PTH above the median.
Similar results were found by Jean et al. who measured baseline 25(OH)D levels in 648 prevalent hemodialysis patients from the regional ARNOS French cohort [117]. A 42-month survival analysis was performed according to serum 25(OH)D level and calcitriol analog therapy. Base- line 25(OH)D levels above the median value (18 ng/ml) were associated with lower all-cause mortality (hazard
ratio, HR, 0.73 [0.5–0.96], p = 0.02) after adjustment for age, gender, dialysis vintage, calcemia, phosphatemia, CVD, and diabetes. The association between low levels of vitamin D and mortality was evident also in the retro- spective study carried out by Krause et al. [118]. Patients (n = 6518) from the German Renal Registry were matched with 73,919 recorded 25(OH)D measurements. All-cause mortality risk increased with decreasing vitamin D levels. For vitamin D insufficiency—25(OH)D levels ranging from 20 to \30 ng/ml—a moderate increase in risk was observed; for vitamin D deficiency—25(OH)D ranging from 12.5 to \20 ng/ml—the risk was much more pro- nounced; for severe vitamin D deficiency— 25(OH)D \12.5 ng/ml—mortality risk was more than doubled. In addition to all-cause mortality risk, it was observed that the cardiac mortality risk increased among patients with vitamin D deficiency and that mortality risk for cancer was higher in patients with severe vitamin D deficiency
8- HTN better control
Reduced LV mass
good effect on immune system
patient lifestyle because of sun exposure
9-Immunosuppressive therapy may contribute to vitamin D derangement, although the scientific literature is still scanty in this regard. Steroids impair vitamin D metabolism activating the enzymes involved in vitamin D catabolism and increasing PTH and FGF23 levels [149]. In contrast, steroid sparing/withdrawal improves vitamin D metabolism [139]: in particular, cumulative prednisone dose was found to be inversely associated with 1,25(OH)2D levels 2 years after transplantation and low 1,25(OH)2D levels were inversely associated with the higher FGF23 concentrations induced by steroid therapy [150]. In agreement, Sanchez- Fructuoso et al. [146] showed that high levels of FGF23 are associated with higher cumulative doses of steroids and low levels of 1,25(OH)2D. Several discrepancies have been observed between the effects of calcineurin and mam- malian target of rapamycin (mTOR) inhibitors on vitamin J Nephrol
D metabolism. Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels [151]. This finding is in agreement with experimental studies showing vitamin D resistance induced by CNI through VDR downregulation. The loss of VDR removes feedback inhi- bition of vitamin D on 1-a-hydroxylase and increases the 1,25(OH)2D level [152]. Rapamycin does not have any effect on vitamin D metabolism [153]. Substantial evidence has ascertained that the conversion of 25(OH)D to 1,25(OH)2D via 1-a-hydroxylase in osteoblasts, osteocytes and osteoclasts regulates processes such as cell prolifera- tion, mineralization as well as bone resorption
10-Pros:
reduced risk of bone loss , Vitamin D can help prevent osteoporosis and bone loss which are common in KTR due to use of immunosuppressant. There is improvement in Bone mineral density and reduce risk of fracture
There is reduced PTH level under Vitamin D therapy by KTR.
There is some studies that suggest that Vitamin D especially paricalcitol reduce proteinuria waht ca improve long term graft survival.
There is a potential CV benefits .
Cons:
Risk of Hypercalcemia
Drug interaction and increased adverse effect.
Lack of evidence of benefits. Most evidence are conflicting and more research is needed to determine optimal dosing, duration, timing of vitamin D.
Describe mechanisms of vitamin D activation.
the kidney is essential for maintaining adequate serum 25(OH)D levels by means of the megalinmediated uptake of 25(OH)D from the glomerular ultrafiltrate and its recycling into to the circulation. The 25(OH)D uptaken from the glomerular ultrafiltrate
may also be 1-a-hydroxylated in the kidney to produce the fully active form 1,25(OH)2D (calcitriol). Unlike 25-hydroxylation, there is only one enzyme recognized to have 1a-hydroxylase activity, i.e. CYP27B1
Describe mechanism of action and action of vitamin D.
Emphasize physiological regulation of vitamin D.
fibroblast growth factor 23 (FGF23), and 1,25(OH)2D itself
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Describe the different biological effects of different forms of vitamin D therapy.
Analyze the evidence of antiproteinuric effect of VITDRA.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
· on vitamin D level
Discuss pros & cons of vitamin D therapy in KTRs
Pros
Cons
**Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Cholecalciferol and ergocalciferol increase 25 OH D without significant change of blood Ca, phosphorous or PTH. Ergocalciferol may increase erythropoietin
Paricalcitol decrease cardiac mortality and overall mortality, increase 25 OH D without increasing Ca, phosphorous and has stronger effect on decreasing PTH.
**Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
Glucocorticoids may impair vitamin D metabolism by activation of the enzyme involved in vitamin D catabolism and increase FGF23 and PTH levels, it impair osteoblastogenesis, increase apoptosis of osteoblast and increase osteoclastogenesis by increasing RNCKL/OPG ratio.
Calcinuron inhibitor associated with lower 25 OH Ddue to vitamin D resistance caused by down regulation of VDR and direct osteoclast activation.
Rabamycin does not have effect on vitamin D metabolism
**Discuss pros & cons of vitamin D therapy in KTRs.
Pros
Decrease PTH and improve BMD in KTR with osteoporosis and osteopenia
With Paricalcitol improve L3 and L4 BMD and decrease bone formation and reabsorption biomarker and not associated with higher level of hypercalcimia and decrease proteinuria
Cons
Hypercalcimia, not modify the progression of GFR, proteinuria, onset of interstitial fibrosis and tubular atrophy.
**Describe the different biological effects of different forms of vitamin D therapy.
The cholecalciferol and ergocalciferol both undergo 25 hydrxylation in the liver to 25 OH vitamin D 3 and 25 OH vitamin D 2 but cholecalciferol show superiority in elevation of 25 OH D level but causes increase levels of Ca and phosphorous level and decrease in PTH
Calcifedol a modefied release formulations increase 25 OH D in a dose dependant manner.
Selective vitamin D receptors activators VDRA causes regulation in PTH synthesis lower impact on ca phosphorous byproduct and lower procalcifying effects on arterial wall
**Analyze the evidence of antiproteinuric effect of VITDRA.
It is associated with significant reduction of about 16 % of proteinuria compared with the 6% among control with >100 fold reduction of proteinuria of >15 %.
**Criticize survival benefits of Vitamin D in CKD patients on dialysis.
The recent data show that low 25 OH D increase risk of hypertension and vitamin D s will decrease LV mass.
Mortality is high with those who have sever vitamin D deficiency of <30ng/ml and even associated with all causes mortality, include cardiac mortality risk and mortality risk for cancer.
Describe mechanisms of vitamin D activation:
· From skin as sunlight acts on 7-dehydrocholesterol and convert it vitD3, Vitamin D2 comes from plant source.
· 25-hydroxylation happen in the liver by CYP27A1 and CYP2R1 (from Cytochrome P450 family)
· it is transferred to the kidneys bound to vitamin D binding protein where further 1a-hydroxylation to active vitamin D happen in the kidneys through CYP27B1 enzyme
Describe mechanism of action and action of vitamin D:
· Active Vit D bind to a membrane receptor (VDR), the complex is internalized, and travel to nucleus to increase /Decrease gene transcription and translation of protein.
· Actions of active vit D includes PTH suppression , FGF23 production by osteocyte.
· it also has autocrine and paracrine functions like inhibition of cellular proliferation and stimulation of maturation in immune system , colon, breast and prostate.
Emphasize physiological regulation of vitamin D
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients: recommended to keep vitD > 30 (25-OH-VitD), stop giving if levels are >100. May induce Hypercalcemia in CKD ,deposited in soft tissues. Adynamic bone disease
Describe the different biological effects of different forms of vitamin D therapy.
· Vit D2 is derived from plants while vit D3 is of animal origin, there are two isoform of 1a-hydroxylase that work on vit D3, while vit D2 is is only acted on by one isoform. Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body so has more share of the actions
· Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.
· Supplemental Active vitamin D increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.
· Selective VDRA like paricalcitol suppresses PTH and 1a-hydroxylation but it causes less Ca and PO4 to be absorbed from intestine.
Analyze the evidence of antiproteinuric effect of VITDRA:
· There is evidence that cholecalciferol causes a mild but significant reduction of albuminuria among diabetic and non diabetic CKD. Other trials reported negative results.
· Recent meta-analysis by de Borst et al included 6 RCTs looking the effect of vitamin D on proteinuria, active vitamin D administration was associated with 16% reduction of proteinuria compared to 6% reduction among controls, the analysis not limited to diabetics but also include IgA Nephropathy
Criticize survival benefits of Vitamin D in CKD patients on dialysis:
· potential survival benefits of Vitamin D is conflicting and uncertain.
· no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescribe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle.
· Observational studies varies significantly on number of participants, time and duration of follow up
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
· weekly ingestion of 40,000 IU D3 for 8 weeks corrected hypovitaminosis D in CKD patients. However, they were not able to demonstrate any effects of vitamin D3 supplementation in HD patients (Marckmann et al.)
· cholecalciferol is effective in replenishing deficient hemodialysis patients without toxic effects.
· Mean serum 1,25(OH)2D increased significantly in the cholecalciferol-treated group, whereas it decreased in the placebo group (Armas et al).
· short-term, high-dose oral cholecalciferol treatment is effective in replenishing deficient hemodialysis patients without toxic effects (Wasse et al)
· cholecalciferol increased serum 25(OH)D levels and decreased PTH levels compared to controls without any observed toxicity (Delanaye et al.)
· cholecalciferol increased serum 25(OH)D and 1,25(OH)2D levels, but did not significantly modify serum levels of PTH, calcium, or PO4(Massart et al.)
· ergocalciferol increased 25(OH)D levels in incident HD patients without significant changes in blood calcium, phosphate, or PTH during a 12-week period (Bhan et al.)
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR:
· Vitamin D: CNIs lower levels of Vit D, mTOR-i do not have effects, and glucocorticoids increase PTH and FGF23
· Bone Health: Glucocorticoids Osteoclasts and inhibit Osteoblast thereby reducing bone density. mTORs-i enhance bone health by inhibiting osteoclast, and CNIs enhance osteoclast activities.
Discuss pros & cons of vitamin D therapy in KTRs.
· suppresses PTH,
· antifibrotic,
· antiproteinuric effects
but ..
Vit D3hyperphosphatemia
hypercalcemia
suppressing bone matrix mineralization .
Describe mechanisms of vitamin D activation.
The native form of vitamin D is produced endogenously from cholesterol as vitamin D3 (cholecalciferol). In skin, 7-dehydrocholesterol is converted to pre-vitamin D3 by a narrow band of solar ultraviolet (UV) radiation (290–315 nm) and thereafter it is isomerized by the body’s temperature to vitamin D3 .On the other hand, vitamin D2 (ergocalciferol) is derived from the sterol ergosterol of plants and the main intake is through diet. However, only less than one-third of the native form of vitamin D origi- nates from food as vitamin D2 or as vitamin D3 .Of note, very few foods contain vitamin D (e.g. fatty fish, fish liver oil, mushrooms and egg yolk) and vitamin D status is generally maintained by exposure to sunlight .
If sunlight exposure is adequate, dietary supplementation of vitamin D can be unnecessary.
Describe mechanism of action and action of vitamin D.
The dermal production of vitamin D is not an enzymatic process .The D2 and D3 differ only in their structure and the differences do not affect the activation process. Both forms function as prohormones and when activated exhibit identical biological responses .Conversely, the main steps in vitamin D metabolism, such as 25-hydroxy- lation, 1a-hydroxylation, and 24-hydroxylation are all enzymatic processes performed by cytochrome P450 mixed-function oxidases (CYPs). The liver is the major if not sole source of 25(OH)D production from native vitamin D. The native vitamin D2 and D3 are both 25-hydroxylated to 25(OH)D (calcidiol or calcifediol) by several 25-hy- droxlases, such as CYP27A1 and CYP2R1 .
The hepatic 25-hydroxylation is induced by the availability of the substrate D2 and D3 and is not inhibited by the concentrations of its product 25(OH)D. Thus regulation of vitamin D 25-hydroxylation is not a major concern, and circulating levels of 25(OH)D are commonly considered useful markers of vitamin D status. Nevertheless, the kidney is essential for maintaining adequate serum 25(OH)D levels by means of the megalin- mediated uptake of 25(OH)D from the glomerular ultrafiltrate and its recycling into to the circulation .
The 25(OH)D uptaken from the glomerular ultrafiltrate may also be 1-a-hydroxylated in the kidney to produce the fully active form 1,25(OH)2D (calcitriol). Unlike 25-hy- droxylation, there is only one enzyme recognized to have 1a-hydroxylase activity, i.e. CYP27B1.
Emphasize physiological regulation of vitamin D.
In the kidney the activity of CYP27B1 is primarily stimulated by parathyroid hormone (PTH) and suppressed by both fibroblast growth factor 23 (FGF23), and 1,25(OH)2D itself .
The renal CYP27B1 activity can be secondarily suppressed by calcium via PTH as well as by phosphate via FGF23, although a direct effect of these ions on renal 1a- hydroxylation cannot be excluded.
circulating 25(OH)D can also be 1-a-hydroxylated in extrarenal cells that express CYP27B1, such as keratinocytes and macrophages.
Regulation of extrarenal CYP27B1 differs from the renal one: it is site-dependent, and involves several hormones and inflammatory molecules .However the kidney is the major if not sole source of circulating 1,25(OH)2D and its extrarenal percentage is negligible.
Both calcidiol and calcitriol are transported in the blood by the vitamin D binding protein (DBP) and are catabolized through a 24-hydroxylation process involving the 24-hydroxylase CYP24A1 .
Most 25(OH)D and 1,25(OH)2D circulates as bound to DBP , while less than 1 % circulates in its free form .
The circulating DBP-bound vitamin D reaches the liver, kidney and other cellular activation sites and is stored in the adipose tissue.
All genomic actions of biologically active vitamin D are mediated by the vitamin D receptor (VDR).
VDR activation leads to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption
Finally, the bioactive vitamin D fraction exerts its biological functions in target tissues and is catabolized by 24-hy- droxylase (CYP24A1) to inactive forms.
vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
the achievement of 25(OH)D levels [30 ng/ml seems a reasonable target for the prevention and treatment of secondary hyperparathyroidism in CKD patients.
Regardless of the preferred regime, in predialysis CKD patients treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in the presence of 25(OH)D levels [100 ng/ml and/or with persistent serum calcium levels [10.5 mg/dl in the absence of active vitamin D administration. Attention should be paid in the presence of potentially increased 1-a-hydroxylase activity, as in transplanted patients and in those affected by sarcoidosis or B cell lymphoma, where 25(OH)D levels even lower than 100 ng/ml may result toxic.
Current data suggest a mild impact of nutritional vitamin D on non-severe secondary hyperparathyroidism in pre-dialysis CKD patients ,with a moderately stronger effect when administered at high doses against its mild phenotype .An early replenishment of 25(OH)D levels could delay the onset and progression of secondary hyperparathyroidism .
Selective vitamin D receptor activators (VDRA) should favor a stronger down-
regulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
Significant improvement of osteitis fibrosa together with a low risk of adynamic bone disease was observed among pre-dialysis CKD patients receiving calcitriol or alfacalcidol .
Experimental data using paricalcitol showed better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol ,doxercalciferol and cinacalcet .
vitamin D has received growing interest as a treatment for several targets beyond PTH and bone health control, e.g. proteinuria, LVH and anemia.
Describe the different biological effects of different forms of vitamin D therapy.
Three nutritional forms are currently available for 25(OH)D replenishment: the two pro-drugs cholecalciferol and ergocalciferol (both requiring conversion by hepatic 25-a- hydroxylase to 25(OH)D3 or 25(OH)D2, respectively) and calcifediol (already available as 25(OH)D3). Many studies have indicated a potential superiority of cholecalciferol vs. ergocalciferol in increasing 25(OH)D levels .
calcifediol, in a modified-release formulation, resulted effective in increasing 25(OH)D levels in a dose-dependent manner among non-dialysis CKD patients compared to placebo.
treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in the presence of 25(OH)D levels [100 ng/ml and/or with per- sistent serum calcium levels [10.5 mg/dl in the absence of active vitamin D administration. Attention should be paid in the presence of potentially increased 1-a-hydroxylase activity, as in transplanted patients and in those affected by sarcoidosis or B cell lymphoma, where 25(OH)D levels even lower than 100 ng/ml may result toxic.
An early replenishment of 25(OH)D levels could delay the onset and progression of secondary hyperparathyroidism.
Selective vitamin D receptor activators (VDRA) should favor a stronger down-
regulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
vitamin D has received growing interest as a treatment for several targets beyond PTH and bone health control, e.g. proteinuria, LVH and anemia.
Analyze the evidence of antiproteinuric effect of VITDRA.
Proteinuria is an established biomarker of CKD severity as well as a strong direct pathogenetic factor of progression toward end-stage renal disease (ESRD), and
worse survival .Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and non diabetic patients ,although negative results were also reported .About the impact of nutritional vitamin D on proteinuria reduction and calcium-phosphate balance there is still not concordance between different studies .The recent meta- analysis by de Borst et al. included 6 RCTs investigating the effect of active vitamin D on proteinuria .Active vitamin D administration was associated with a significant 16 % reduction of proteinuria compared to 6 % reduction among controls with a more than 100-fold greater proba- bility to reach a proteinuria reduction >=15 % .The analysis was not limited to diabetics ,but it included patients with immunoglobulin (Ig)A nephropathy and patients with other renal disorders .Sensitivity analysis did not reveal differences between vitamin D compounds, paricalcitol doses, sample size and length of follow-up.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
• Low levels of 25(OH)D are very frequent in the dialysis population. Insufficiency or deficiency of 25(OH)D may affect survival by directly influencing mineral metabolism. Better survival of patients treated with native or nutritional or active vitamin D over and above the effects on mineral metabolism indicates that vitamin D possesses pleiotropic protective actions. For this reason many interventional studies have evaluated the effectiveness of 25(OH)D replenishment with cholecalciferol, ergocalciferol, or calcidiol in correcting deranged mineral metabolism as well as in improving survival.
• Most of the available data come from observational studies which are characterized by significant differences in number of enrolled patients, administered doses of vitamin D sterols, duration of treatment and assessed outcomes. Therefore strong evidence supporting an association between vitamin D sterols and survival is lacking. Large RCTs addressing this issue need to be performed.
• Active forms of vitamin D are more effective than other forms in correcting secondary hyperparathyroidism despite the fact that they are not able to increase and/ or normalize 25(OH)D levels. In contrast, native and nutritional vitamin D may increase 1,25(OH)2D levels and reduce PTH levels. This finding may support the therapeutic strategy of dual administration of active and native/nutritional vitamin D, taking into account that a potential interaction may not be excluded. Beneficial effects of dual supplementation on survival have not been assessed as yet.
• Almost all studies indicate that supplementation does not markedly affect levels of calcium or phosphorus and does not accelerate the vascular calcification process. However, markers of mineral metabolism should be monitored during long-term treatment according to the presence of comorbidities and half- life of supplemented vitamin D. These suggestions should be taken into account particularly in dialysis patients treated with active forms of vitamin D.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
There is an association between vitamin D supplementation and reduced LV mass as well as a positive effect of vitamin D supplementation on the immune system.
the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle.
an association between low serum levels with mortality.
a strong association was evident between severe vitamin D deficiency and short-term cardiovascular mortality while no significant association was found between non-cardiovascular mortality and vitamin D status.
Untreated deficient patients were at increased risk for early mortality compared to patients with the highest 25(OH)D or 1,25(OH)2D levels who received therapy with active vitamin D .
Low-dose oral alfacalcidol improved the survival rate in patients with and without 25(OH)D deficiency.
Cholecalciferol supplementation resulted safe and effective in correcting hypovitaminosis D with a significant reduction of CRP, IL-6 and LVH with minor changes of markers of mineral metabolism. These data suggest that cholecalciferol supplementation may have a prominent anti-inflammatory action with concomitant improvement of cardiac dysfunction.
Short-term, high-dose oral cholecalciferol treatment was effective in replenishing deficient/insufficient hemodialysis patients without toxic effects.
cholecalciferol (50,000 IU, once weekly for 8 weeks and then monthly for 4 months) increased serum 25(OH)D and 1,25(OH)2D levels but had no effect on muscle strength, functional capacity, pulse wave velocity or health-related quality of life (HRQOL), as shown by Hewitt et al. in 60 patients .
Higher serum 25(OH)D was associated with decreased risks of infectious events, cardiac events and all-cause deaths. In addition, high serum FGF23 levels were associated with infectious and cardiac events.
6 months of supplementation with ergocalciferol increased serum 25(OH)D levels in patients on hemodialysis with vitamin D insufficiency or deficiency, but it had no effect on epoetin utilization or secondary biochemical and clinical outcomes.
There was a significant improvement in 25(OH)D levels and reduction of PTH levels. PTH reduction was more evident in dialysis patients. Incidence of hypercalcemia and hyperphosphatemia was irrelevant with vitamin D supplementation.
Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
selective VDRA such as paricalcitol resulted associated with lower mortality compared to calcitriol in some but not all studies.
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR
Vitamin D
Immunosuppressive therapy may contribute to vitamin D derangement, although the scientific literature is still scanty in this regard. Steroids impair vitamin D metabolism activating the enzymes involved in vitamin D catabolism and increasing PTH and FGF23 levels .In contrast, steroid sparing/withdrawal improves vitamin D metabolism ,in particular, cumulative prednisone dose was found to be inversely associated with 1,25(OH)2D levels 2 years after transplantation and low 1,25(OH)2D levels were inversely associated with the higher FGF23 concentrations induced by steroid therapy .In agreement, Sanchez- Fructuoso et al. showed that high levels of FGF23 are associated with higher cumulative doses of steroids and low levels of 1,25(OH)2D. Several discrepancies have been observed between the effects of calcineurin and mam- malian target of rapamycin (mTOR) inhibitors on vitamin D metabolism. Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels .This finding is in agreement with experimental studies showing vitamin D resistance induced by CNI through VDR downregulation. The loss of VDR removes feedback inhibition of vitamin D on 1-a-hydroxylase and increases the 1,25(OH)2D level .Rapamycin does not have any effect on vitamin D metabolism .Substantial evidence has ascertained that the conversion of 25(OH)D to 1,25(OH)2D via 1-a-hydroxylase in osteoblasts, osteocytes and osteoclasts regulates processes such as cell proliferation, mineralization as well as bone resorption .
Bone health
Various studies have shown that bone loss is considerable during the first year after transplantation, with a rate of 14.5 % in the first 6 months, followed by a mild improvement after the second year post-transplant ,and recovers within the pre-transplant range only 8 years after transplantation .Studies in late KTRs revealed a prevalence of osteoporosis ranging from 11 to 56 % and fractures ranging from 5 to 44 %; at any rate the risk of hip fracture, until 3 years after transplantation, is higher than in HD patients .A few studies have reported histological patterns of post-transplant bone disease, describing a considerable prevalence of adynamic bone disease and of high bone turnover .Immunosuppressive drugs elicit a deep impact on bone loss. Steroids directly worsen bone formation by inducing: derangement of vitamin D metabolism, impaired osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio .Both cyclosporin and tacrolimus similarly promote bone loss via a direct osteoclast activation .Conversely, sirolimus is taken as a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation.
Discuss pros & cons of vitamin D therapy in KTRs.
Pors
a significant improvement of PTH and calcium levels in KTRs receiving nutritional vitamin D.
calcitriol decreases PTH levels and improves BMD in KTRs with osteopenia or osteoporosis ,therefore becoming a well accepted preventive therapy against bone loss in KTRs .
greater PTH reduction and a lower prevalence of hyperparathyroidism (29–63 %) in KTRs receiving paricalcitol .
paricalcitol therapy was not associated with a higher risk of hypercalcemia.
Paricalcitol at low doses (3 lg/week) was ret- rospectively associated with a significant reduction of proteinuria at 24 months
Cons
cholecalciferol supplementation after kidney transplant did not modify the progres- sion of GFR, the onset of interstitial fibrosis, tubular atrophy and proteinuria .
cholecalciferol supplementation after kidney transplant did not modify the progres- sion of GFR, the onset of interstitial fibrosis, tubular atrophy and proteinuria .
1-Describe mechanisms of vitamin D activation.
VitD either D2 from plant sources or D3 from activation of sun rays through the skin is hydroxylated by 25 hydroxylases from the liver the activated the active form is 1,25 alpha-hydroxylaseby 1 alpha-hydroxylase from the kidney.
2-Describe mechanism of action and action of vitamin D.
The mechanism if action
active Vit D bind to a membrane receptor the complex is internalized, and travel to nucleus to increase /Decrease gene transcription and translation of protein.
Action of vit d regulation of bone mineral homeostasis with pth and lay major role for maintain ca po4 balance via activation of VDR leads to calcium and phosphate intestinal absorption
vitamin D activity regulate bone metabolism ,enhance bone resorption
suppress PTH secretion and enhance FGF23 production
vitamin D exert autocrine or paracrine function in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin ,the immune system and colonic ,breast and prostate cells.
3-Emphasize physiological regulation of vitamin D.
Activated by sunlight action on cholesterol in the dermis.
Stimulated by PTH at Liver and Kidneys
Supressed by FGF-23,Ca levels
and Phosphate levels
4-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
It is recommended to keep vitD > 30and stop giving if levels are >100.
This is limited by the fact that it may induce Hypercalcemia in CKD and +ve Calcium balance where Ca is deposited in soft tissues. Supplementation may also result in Adynamic bone disease especially with normal level of pth.
5-Describe the different biological effects of different forms of vitamin D therapy.
Naturally occurring Vit D2 and Vit D3 have the same biological actions and through the same VDR but vit D3 is more abundant in the body .
Supplemental 25-OH-Vitamin D have many pleotropic action, once activated to active vitamin D it increases PO4 and Ca reabsorption from intestine and suppresses PTH secretion and inhibit 1a-hydroxylase.
Recently selective VDRA like paricalcitol potant suppression of PTH and prevent ca absorption.
6-Analyze the evidence of antiproteinuric effect of VITDRA.
There is evidence that cholecalciferol causes a mild but significant reduction of albuminuria among diabetic and non diabetic CKD
Other trials reported negative results.
active vitamin D administration was associated with 16% reduction of proteinuria compared to 6% reduction among controls so still debay from study and no conclusive role of vit D and proteinuria.
7-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
There is no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescribe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle.
8-Enumerate reported benefits of
vitamin D therapy in CKD patients on dialysis.
Low vitD levels are associated with HTN, cardiovascular events, and reduced left ventricular mass.
VitD supplements are associated with an improved immune system.
VitD supplements improve renal anemia.
9-Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
The CNIs lower levels of Vit D, mTOR-i do not have effects, and glucocorticoids increase PTH and FGF23 and decrease Vit D
Bone Health: Glucocorticoids stimulate Osteoclasts and inhibit Osteoblast thereby reducing bone density. mTORs-i enhance bone health by inhibiting osteoclast, and CNIs enhance osteoclast activities.
10-Discuss pros & cons of vitamin D therapy in KTRs.
Pros Vit D3 suppresses PTH, is antifibrotic, and has antiproteinuric effect
Cons Vit D3hyperphosphatemia
hypercalcemia suppressing bone matrix mineralization .
***Describe mechanisms of vitamin D activation.
Native vitamin D produced endogenously from the conversion of 7 dehdrocholestrol in the skin to previtamin D after exposure to UVB light 290-315nm, then isomerized in the body to form cholecaciferol. While ergocalciferol formed from sterol ergosterol from plant food the vitamin D2 and D3 undergo 25 hydroxyl action in the liver by enzyme CYP2R1 and CYP27B1 then undergo 1 alfa hydrxylation in the kidney to active form calcitriol, which pass to circulation by vitamin D binding protein, it also catabolized by 24 hydrxylation to inactive form.
**Describe mechanism of action and action of vitamin D.
Active vitamin D bind to the VDR where it is activated by regulation of gene transcription and stimulation of intracellular signaling.
This lead to increase Ca and phosphorous intestinal absorption and renal tubular ca absorption. Also causes suppress PTH secretion by PT gland and increase FGF23 production by the osteocyte in addition to it’s paracrine and autocrine function it inhibit cellular proliferation and increase cell maturation in the skin, prostate, colon, breast and immune system.
***Emphasize physiological regulation of vitamin D.
Vitamin D after skin exposure to sunlight form cholecaciferol and from plant ergocalciferol activated in the liver by 25 hdroxylase enzy to 25 OH vitamin D which then undergo hydrxylation by kidney to active form which is bind to VDR once activated produce its action, then it catabolized by 24 hydrxylase enzyme to inactive form.
**Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The target above 30ng/ml and less than 100 ng/ml after which will causes hypercalcimia and xs suppression of PTH.
Describe mechanisms of vitamin D activation.
most vitamin D comes from skin as sunlight acts on 7-dehydrocholesterol and convert it vitD3, Vitamin D2 comes from plant source. 25-hydroxylation happen in the liver by CYP27A1 and CYP2R1 (from Cytochrome P450 family), it is transferred to the kidneys bound to vitamin D binding protein where further 1a-hydroxylation to active vitamin D happen in the kidneys through CYP27B1 enzyme
Describe mechanism of action and action of vitamin D
Like all Cholesterol derived hormones, active Vit D bind to a membrane receptor (VDR), the complex is internalized, and travel to nucleus to increase /Decrease gene transcription and translation of protein.
Actions of active vit D includes PTH suppression , FGF23 production by osteocyte.
it also has autocrine and paracrine functions like inhibition of cellular proliferation and stimulation of maturation in immune system , colon, breast and prostate.
Emphasize physiological regulation of vitamin D
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients
It is recommended to keep vitD > 30 (25-OH-VitD), and stop giving if levels are >100.
This is limited by the fact that it may induce Hypercalcemia in CKD and +ve Calcium balance where Ca is deposited in soft tissues. Supplementation may also result in Adynamic bone disease
Describe the different biological effects of different forms of vitamin D therapy.
· Vit D2 is derived from plants while vit D3 is of animal origin, there are two isoform of 1a-hydroxylase that work on vit D3, while vit D2 is is only acted on by one isoform.
Analyze the evidence of antiproteinuric effect of VITDRA.
There is evidence that cholecalciferol causes a mild but significant reduction of albuminuria among diabetic and non diabetic CKD
Other trials reported negative results.
the recent meta-analysis by de Borst et al included 6 RCTs looking the effect of vitamin D on proteinuria
active vitamin D administration was associated with 16% reduction of proteinuria compared to 6% reduction among controls
the analysis not limited to diabetics but also include IgA Nephropathy
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
potential survival benefits of Vitamin D is conflicting and uncertain. There is no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescribe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle. Observational studies varies significantly on number of participants, time and duration of follow up
– weekly ingestion of 40,000 IU D3 for 8 weeks corrected hypovitaminosis D in CKD patients. However, they were not able to demonstrate any effects of vitamin D3 supplementation in HD patients (Marckmann et al.)
– cholecalciferol is effective in replenishing deficient hemodialysis patients without toxic effects. Mean serum 1,25(OH)2D increased significantly in the cholecalciferol-treated group, whereas it decreased in the placebo group (Armas et al).
– short-term, high-dose oral cholecalciferol treatment is effective in replenishing deficient hemodialysis patients without toxic effects (Wasse et al)
– cholecalciferol increased serum 25(OH)D levels and decreased PTH levels compared to controls without any observed toxicity (Delanaye et al.)
– cholecalciferol increased serum 25(OH)D and 1,25(OH)2D levels, but did not significantly modify serum levels of PTH, calcium, or PO4(Massart et al.)
– found that ergocalciferol increased 25(OH)D levels in incident HD patients without significant changes in blood calcium, phosphate, or PTH during a 12-week period (Bhan et al.)
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR
· Vitamin D: CNIs lower levels of Vit D, mTOR-i do not have effects, and glucocorticoids increase PTH and FGF23
· Bone Health: Glucocorticoids Osteoclasts and inhibit Osteoblast thereby reducing bone density. mTORs-i enhance bone health by inhibiting osteoclast, and CNIs enhance osteoclast activities.
Discuss pros & cons of vitamin D therapy in KTRs.
Pros
Vit D3 suppresses PTH, is antifibrotic, and has antiproteinuric effects (Debatable)
Cons
Vit D3hyperphosphatemia
hypercalcemia
suppressing bone matrix mineralization .
1- Vitamine D (either D2 or D3) is hydroxylated by 25 hydroxylases from the liver the activated (the active form is 1,25 alpha-hydroxylase) by 1 alpha-hydroxylase from the kidney.
2-Both
calcidiol and calcitriol are transported in the blood by vitamin-binding
protein. Alpha-hydroxylase of the kidney is stimulated by PTH and suppressed by
FGF-23 and itself. The active particle of active vitamin is deactivated by 24
alpha-hydroxylase to prevent toxicity. Vitamin D exerts its action by binding
to vitamin d receptors, which are activated by ligand binding via gene
transcription and regulation of intracellular signalling pathways.
Vitamin
suppresses PTH secretion by parathyroid glands and suppresses osteocyte release
of FGF-23.
3- vitamin D
is dependent mainly on its level evaluated as 25(OH) vitamin d. it increases
calcium absorption from the intestines
4- Normal
level of vitamin D differs among different guidelines (20-30 ng/ml) is enough.
In a normal population, less than 30 ng/ml is deficient. but in CKD patients 20
can be accepted. The early stages of CKD have compensator hyperparathyroidism
because of hypocalcemia and hyperphosphatemia. 3-5 times the normal PTH is
accepted.
5- Vitamin d can be administered in form of normal vitamin d (cholecalceferol, ergocalceferol or calcefediol), active vitamin d (calcitriol) or vitamin d receptor analogue (Paricaltol e.g). paricalcitol is said to have less hypercalcemia and hyperphosphatemia with a potent suppression effect on PTH release. The debate about this is still an issue.
6- In a metanalysis of 6 RCTs, Both in diabetics and non-diabetics, a 16% reduction of proteinuria was observed (controls %6).
7- vitamin d has many benefits and pleiotropic effects in both normal persons as well as CKD patients including those on dialysis. In ESRD , activation of vitamin D is a problem so, calcitroil od . normal vitamin D, though, may increase 1-25 OH vitamin d and suppress PTH
8- vitamin d deficiency or insufficiency is common in Kidney transplant recipients. CNIs have been recently associated with lower vitamin d levels. Experimental studies showed resistance to vitamin D in CNI users by VDR downregulation. The level of 1,25 OH vitamin d is increased because of the absence of a decrease in VDR (downregulated). Rapamycin was found to have no effect on vitamin D metabolism. . Steroids directly worsen bone formation by inducing derangement of vitamin D metabolism and impair osteogenesis through an increased receptor activator of nuclear factor kappa (RANKL)/OPG (osteopetrogerin) ratio. Both tacrolimus and cyclosporin promote bone loss via direct osteoclast activation. Sirolimus is thought of as bone-sparing immunosuppressive. It has the ability to inhibit osteoclast generation.
9-
Vitamin D replacement may have the advantage of protecting bone and increasing calcium absorption. It may have a useful effect on blood pressure and cardiac function, but translation into graft survival is not known. It may have a risk of hypercalcemia and calcium overload. The optimal dose needs to be reevaluated.
we have prohormones D2and D3 from skin (sun exposure by UV rays )and diet
which activated by 25 hydroxylation in the liver to 25 (OH )D3 calcidiol
then 1 alfa hydroxylation on the kidney to active calcitriol 1,25 (OH )2D3
the genomic actions of active vitamin D are mediated by the vitamin D receptors (the VDR)
VDR produce extensive biological response when activated by ligand binding via regulation of gene transcription and stimulation of intracellular signaling pathways .
the major endocrine action of VDR IS TO REGULATE MINERAL AND BONE HEMOSTASIS IN INTESTINAL ,RENAL AND BONE
activation of VDR leads to calcium and phosphate intestinal absorption
vitamin D activity regulate bone metabolism ,enhance bone resorption
suppress PTH secretion and enhance FGF23 production
vitamin D exert autocrine or paracrine function in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin ,the immune system and colonic ,breast and prostate cells.
therapy with nutritional and active vitamin D in predialysis patients depend on :
1-how to deal with 25(OH)D deficiency 2-how and when to treat SHPT and CKD -MBD3- potential efficacy of different formulation of vitamin D on proteinuria ,LVH and anaemia ,
the optimal target of 25(OH)D and the best approach to obtain adequate vitamin D remain unknown .
different guidelines have heterogenous defintions of 25(OH)d DEFICIENCY AND THEY SUGGEST DIFFERENT THERAPEUTIC STRATEGIES FOR TREATMENT
KDOQI and ERBP >>TARGET 25(oh)D IS >30 ng/ml
NICE >>> target >20 ng/ml
=====================
cholecalciferol induceed a mild but significant reduction of albuminuria among diabetics and non diabetics
although negative results were also reported ,
about the impact of nutritional vitamin D on proteinuria reduction and calcium -phosphate balance
the recent meta analysis iby de Borst et al included 6 RCTs investigating the effect of vitamin D on proteinuria
active vitamin D administration was associated with asignificant 16% reduction of proteinuria compared to 6% reduction among controls
the analysis not limited to diabetics but also include IGAN
STEROID >directly worsen bone formation by inducing bone derangement of vitamin D METABOLISM
CNI >promote bone loss by direct osteoclast activation
SIROLIMUS >.inhibit osteoclast generation
================
mTORi>no effect on vitamin D metabolism
CNI >>lower 25(OH)d
according to KDIGO vitamin D deficiency and insufficiency should be corrected
PRO
1-significant improvement of PTH and calcium levels
2-calcitriol decrease PTH levels and improve BMD in KTRs with osteopenia or osteoprosis 3-paricalcitol improve L3-L4 vertebral BMD without risk of hypercalcemia.
CONS
risk of hypercalcemia
7 Dehydrocholesterol is transformed to cholecalciferol via UV Light.
25 Hydroxycholecalciferol ist made by liver from cholecalciferol or ergocalciferol without a feedback mechanism.
Vitamin D ist converted in Kidney from 25- Hydroxycholecalciferol to 1,25 Hydroxcholecalciferol . The responsable Enzyme is 1alpha hydroxylase in renal tubule.
24hydroxylase from kidney deactivate 25 OH Vitamin D
The 1,25Vitamin D3 level have a inhibitory effect on 1alpha hydroxylase.
PTH stimulate 1 alpha hydroxylase
FGF23 inhibit 1 apha hydroxylase
-All Genomic actions of biologically active Vitamin D are mediated with VDR.
VDR regulate gene transcription and stimulate intracellular signaling pathway.
-The Major sites of VDR are in bones , intestine and Kidney.
VDR Activation lead to phosphate and calcium intestinal absorption as well as to renal calcium tubular reabsorption.
*In Bones the effect is dependent on calcium. When calcium is insufficient acquired , it enhance calcium resorption from bone and supress bone matrix mineralization.
if calcium is sufficient, it induce bone mineralisation.
-VDR suppress PTH Secretion , VDR activation enhance FGF23 production by osteocyte.Other new function: Paracrine and autocrine activity of VDR, inhibition of cellular proliferation and stimulation of maturation in immune system , colon, breat and prostate.
Active vitamin D suppress PTH
Active Vitamin D stimulate FGF23
PTH stimulate 1 alpha hydroxylase
FGF23 inhibit 1 alpha hydroxylase
High level of 1,25 OHVitaminD3 inhibit 1 alpha hydroxylase( Negative Feed back mechanism)
24alpha hydroxylase deactivate the 25OHVitaminD3.
Low calcium can stimulate PTH Secretion. (So effect of Ca threw PTH)
High calcium can inhibit PTH
Low Phosphate can inhibit PTH and FGF23
High Phosphate can stimulate both PTH and FGF23 affecting indirectly Vitamin D activation.
Approximatly 90% of Vitamin D is binded to Vitamin D Binding Proteind(DBP). it is secreted by liver.
Vitamin D is measured through the level of 25OHVitaminD (As standard)
Sufficient is above 30 ng/mL.
Limiting factor for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD Patient are :
-Hypercalcemia and Hyperphosphatemia in patients.
-Attention should be paid in the presence of potentially increased 1 alpha hydroxylase activity like in B Cell lymphoma and sarcoidosis.
-Cost of some active form of Vitamin D like Paricalcitol.
-limited Sunexposure, seasonal variation should be taken in cosideration and measurement should be done in late winter and late summer.
There is not difference between Vit D2 (from vegetable) and Vitamin D3 (from meat)
The ergocalciferol , Cholecalciferol and calcidiol (So not active) exercice pleiotropic effect more (e.g. antineoplastic, antiinflammatory, regulating immune system, preventing depression,gestational diabetes and preeclampsia, low vitamin D assosiated with incread risk of cardiovascular death.)
Calcitriol has low pleiotropic effect and because is more selective.
Paricalcitol is the most selective , it lower PTH level the most without inducing hypercalcemia or hyperphosphatemia in low-moderate dosage.
Examples:
Encouraging data about paricalcitol, ergocalciferol and calcitriol suggesting adjuvant affect against renal anemia.
Cholecalciferol was more effective than ergocalciferol in providing 25OH Vit D replenishment (Daroux) but other studies did not confirm that.
Cholecalciferol reduced IL6, CRP and LVH (Bucharles et al.)
Recent metaanalysis by de Borst et al. included 6 RCTs investigating the effect of active vitamin D on protienuria. it was associated with a significant 16% reduction of protienuria compared to 6% reduction among controls with more than 100 fold greater probabiltiy to reach a proteinuria reduction >15%. The analysis included diabetics and Ig A Nephropathy patient and other renal disorders
-In KTR the evidence look more promising: Paricalcitol at low doses (3µg/week) was retrospectively associated with a significant reduction of proteinuria at 24 months
-Trillini et al. performed a randomized , crosssectional study and showed a significant decrease in proteinuria on paricalcitol by KTR.
Amr et al. showed decreased intersitial fibrosis in KTR on paricalcitol.
these studies was not designed to investigate the proteinuria as a primary outcome.
The current evidence on the potential survival benefits of Vitamin D is conflicting and uncertain. There is no consensus on the optimal timing to start treatment , the appropriate form of vitamin D to prescirbe, the ideal dosage or the preferred administration route. Additionally , since most Vit D is obtained from sun exposure , confounding factors may impact the results of observational studies in this population, and the association between 25(OH) levels and improved outcomes may by influenced by patients lifestyle. Observational studies varies significantly on number of participants, time and duration of follow up .
-Marckmann et al. found that weekly ingestion of 40,000 IU D3 for 8 weeks corrected hypovitaminosis D in CKD patients. However, they were not able to demonstrate any effects of vitamin D3 supplementation in HD patients (except for a rise of FGF23).
-Armas et al. supplemented patients with cholecalciferol and found that it was effective in replenishing deficient/insufficient hemodialysis patients without toxic effects. Mean serum 1,25(OH)2D increased significantly in the cholecalciferol-treated group, whereas it decreased in the placebo group.
-Wasse et al. found that short-term, high-dose oral cholecalciferol treatment was effective in replenishing deficient/insufficient hemodialysis patients without toxic effects.
-Delanaye et al. found that cholecalciferol supplementation increased serum 25(OH)D levels and decreased PTH levels compared to controls without any observed toxicity.
Hewitt et al. found that cholecalciferol therapy had no effect on muscle strength, functional capacity, pulse wave velocity, or health-related quality of life (HRQOL).
-Massart et al. reported that supplementation with cholecalciferol increased serum 25(OH)D and 1,25(OH)2D levels, but did not significantly modify serum levels of PTH, calcium, or phosphorus.
-Bhan et al. found that ergocalciferol increased 25(OH)D levels in incident HD patients without significant changes in blood calcium, phosphate, or PTH during a 12-week period. When the two ergocalciferol arms were combined, the authors noted a trend toward reduction in all-cause mortality among ergocalciferol-treated participants compared to placebo-treated participant
Vitamin D Level
-25 OH D Deficiency and insufficiency are common in KTRs with prevalence of 30% and 81% respectively
-1,25(OH)2D reach normal level within 3 to 6 month after transplantation
-High FGF23 levels inhibit 1-a-Hydroxylase and enhance 24 alpha hydroxylase, leading to reduced 1,25ohD and 25ohD initialy in KTR.
-Steroids impair vitamin D metabolism by activating the enzyme involved in Vitamin D Catabolism and increasing PTH and FGF23.
-Calcineurin inhibitor(CNI) suggest that vitamin D resistance induced by CNI through VDR Downregulation (Low 25 OH VitaminD).
-Rapamycin does not have any effect on vitamin D metabolism
Bone Health
Bone loss is considerable during the first year after transplantation, with a rate of 14,5% in the first 6 months followed by a mild improvement after the second year post transplant.
-The risk of hip fracture, until 3 years after transplantation is higher than in HD patients.
-Steroids directly worsen bone formation by inducing derangement of VitD metabolism, impaired osteoblastogenesis , increased apoptosis of osteoblasts, and enhanced osteoclastogeneisis through increased RANKL/OPG ratio.
-Both Cyclosporin and tacrolimus similarly promote bone loss via a direct osteoclast activation
-Sirolimus is a bone sparing immunosuppresive to to its capability to inhibit osteoclast activity.
Pros:
reduced risk of bone loss , Vitamin D can help prevent osteoporosis and bone loss which are common in KTR due to use of immunosuppressant. There is improvement in Bone mineral density and reduce risk of fracture
There is reduced PTH level under Vitamin D therapy by KTR.
There is some studies that suggest that Vitamin D especially paricalcitol reduce proteinuria waht ca improve long term graft survival.
There is a potential CV benefits .
Cons:
Risk of Hypercalcemia
Drug interaction and increased adverse effect.
Lack of evidence of benefits. Most evidence are conflicting and more research is needed to determine optimal dosing, duration, timing of vitamin D.
thanks doctor Nour for your excellent answers.
just few notions to remind
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
2-Describe the different biological effects of different forms of vitamin D therapy.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with KD not yet on dialysis, regression of osteitis fibrosa WITH limited Increase in the hazard of tr adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. Notably, experimental studies also suggested that the use of paricalcitol was assoiated with better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol, doxercalciferol and cinacalcet.
● Zheng et al. performed a meta-analysis from 20 studies that compared several forms of vitamin D. Participants that received calcitriol \and paricalcitol had a lower cardiovascular mortality.
3-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Mechanism of viD activation
Physiological regulation of vitD
Mechanism of action
VitD target level in CKD
2. Although recommended to treat the VitD deficiency, the optimum target level is not clear till now.
3. Different definitions with different therapeutic recommendations by several studies.
4. KDOGI 2003; for treatment of CKD3-5, target vitD > 30 with PTH above the target range.
5. KDIGO 2009; CKD3-5, as suggested for the general population.
6. KDIGO 2012; do not assess routinely, not to be subscribed in the absence of deficiency.
7. ERBP 2010, at least once in CKD 3-4, target vitD>30, replenish if <12.5.
8. NICE 2014, In all patients with CKD 4-5, target >20.
Evidence of the antiproteinuric effect of vitD
Survival benefit and reported benefit of vitD on CKD patients on dialysis
Effect of different immunosuppressive therapy on vitD level and bone health.
VitD pros and cons;
Prons
Cons
Thanks dr Kamal for comprehensive answers, just few notions
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
2-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Crucially, in patients with relatively high 1-a-hydroxylase activity, as transplanted patients and in those with sarcoidosis or B cell lymphoma, are more prone to toxicity therefore, lower targets of 25(OH)D levels are recommend.
The amount of 7-dehydrocholesterol that is changed into pre-vitamin D3 in the skin as a result of exposure to the sun’s ultraviolet B rays is highest at levels of sun exposure that do not cause the skin to burn. After that, it undergoes an isomerization process in which the warmth of the body converts it to vitamin D3.
Vitamin D2 (also known as ergocalciferol) comes from the plant sterol known as ergosterol, and the main way that people get it is through their food. However
Within the organ of the liver Both vitamin D2 and vitamin D3 are converted to 25-OHD, also known as calcidiol or calcifediol when they are exposed to the 25-hydroxylases CYP27A1 and CYP2R1.
The kidney is absolutely necessary for the maintenance of sufficient blood 25(OH)D levels because of the megalin-mediated absorption of 25(OH)D from the glomerular ultrafiltrate and its recycling back into circulation. This process takes place in the kidney.
The 25(OH)D that is created by the liver must go through a process called 1-a-hydroxylation in the kidney before it can be converted into the fully active form 1,25(OH)2D. (calcitriol).
The further metabolism of vitamin D to its major circulating form also takes place in other tissues where the 1,25(OH)2D that is produced serves a paracrine or autocrine function. Some examples of these tissues include the skin, cells of the immune system, the parathyroid gland, the intestinal epithelium, the prostate, and the breast.
Parathyroid hormone, FGF23, calcium, and phosphate are the primary regulators of the renal 1-hydroxylase (CYP27B1, the enzyme responsible for the production of 1,25(OH)2D); the regulation of the extrarenal 1-hydroxylase is different from that of the kidney and includes cytokines.
The 24-hydroxylase is the primary enzyme that is responsible for catabolizing 25(OH)D and 1,25(OH)2D. Similar to the 1-hydroxylase, it is tightly controlled in the kidney in a manner that is diametrically opposed to that of the 1-hydroxylase. However, similar to the 1-hydroxylase, it is widespread in other tissues where its regulation is distinct from that of the kidney.
Emphasize physiological regulation of vitamin D.
The primary mechanism by which 1,25(OH)2D lowers the levels of 1,25(OH)2D in cells is by increasing its catabolism via the activation of CYP24A1.
This enzyme hydroxylates 5- 25OHD and 1,25(OH)2D at the 24 position, resulting in the formation of 24,25(OH)2D and 1,24,25(OH)3D.
In individuals with CKD, it is possible that a goal of achieving 25(OH)D levels of more than 30 ng/ml is an appropriate aim for the prevention and treatment of secondary hyperparathyroidism.
Reaching 25(OH)D levels of [30 ng/ml appears to be a reasonable first-step intervention to avoid vitamin D deficiency and/or treat secondary hyperparathyroidism in CKD stages 3–5. Optimal 25(OH)D levels are still not well defined; however, achieving these levels seems like a reasonable first-step intervention.
Supplementation looks beneficial. Untreated deficient individuals had a higher risk of early death than those with the highest 25(OH)D or 1,25(OH)2D levels who received active vitamins. Intriguingly, even inactive vitamin D improved mortality. Low-dose oral alfacalcidol enhanced survival in 25-OHD-deficient and non-deficient patients. In Bucharles et al.’s trial, 30 patients received oral cholecalciferol once a week (50,000 IU) for the first 12 weeks and 20,000 IU for the remaining 12 weeks. Inflammation indicators included high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, and serum albumin.
Serum 25(OH)D and calcitriol analog treatment determined a 42-month survival study. After adjusting for age, gender, dialysis vintage, calcemia, phosphatemia, CVD, and diabetes, 25(OH)D levels above the median (18 ng/ml) were related with decreased all-cause mortality (HR, 0.73 [0.5–0.96], p = 0.02). Krause et alretrospective .’s investigation found a link between low vitamin D and mortality. 6518 German Renal Registry patients matched with 73,919 25(OH)D readings. Vitamin D deficiency increases all-cause mortality. Vitamin D insufficiency—25(OH)D levels ranging from 20 to ±30 ng/ml—increased risk somewhat; vitamin D deficiency—25(OH)D ranging from 12.5 to ±20 ng/ml—increased risk significantly; and severe vitamin D deficiency—25(OH)D <12.5 ng/ml—doubled mortality risk. Vitamin D deficiency increased all-cause death, cardiac mortality, and cancer mortality.
Ergocalciferol and cholecalciferol were supplemented in patients with non-dialysis-dependent CKD, dialysis-dependent CKD, and renal transplant recipients. Serum 25(OH)D, intact PTH, 1,25(OH)2D, calcium, and phosphorus were biochemical objectives. Clinical objectives included cardiovascular events, bone disease, and all-cause death. 25(OH)D and PTH improved significantly. Dialysis patients reduced their PTH more.
Steroids activate vitamin D catabolism enzymes and raise PTH and FGF23 [149]. Steroid sparing/withdrawal increases vitamin D metabolism [139]: cumulative prednisone dosage was inversely linked with 1,25(OH)2D levels 2 years after transplantation, and low 1,25(OH)2D levels were inversely associated with greater FGF23 concentrations caused by steroid treatment.
Calcineurin inhibitors (CNI) have been recently associated with lower 25(OH)D levels.
Pros;
Reduced PTH levels result in an improvement in BMD.
This may lead to an increase in allograft survival(scanty data)
Anti-proteinuric action
Anti-fibrotic
Cons:
Stavroulopoulos et al. found that hypercalcemia after kidney transplantation ranges from 11–66%, depending on time post-transplantation. Vitamin D medication may aggravate hypercalcemia, which may limit patient eligibility.
THANKS dr Weam for your effort, just few notions
1-Describe mechanism of action and action of vitamin D.
I- Mechanism of Action
All genomic actions of biologically active vitamin D are mediated by the vitamin D receptor (VDR). This occurs via ligand binding to VDR leading to modification of gene transcription and activation of intracellular signaling pathways.
II- Action
Principally, vitamin D main action is regulation of mineral and bone homeostasis in intestinal, renal and bone tissues. This is mainly achieved by VDR activation leading to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption. On the other hand, its effect on bone health is dependent on level of calcium. In case of calcium deficiency, VDR activation leads to bone resorption and suppressing bone matrix mineralization. In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes.
2-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Crucially, in patients with relatively high 1-a-hydroxylase activity, as transplanted patients and in those with sarcoidosis or B cell lymphoma, are more prone to toxicity therefore, lower targets of 25(OH)D levels are recommend.
3-Describe the different biological effects of different forms of vitamin D therapy.
Describe the different biological effects of different forms of vitamin D therapy.
● The positive effects of cholecalciferol seem to be limited to replenishment of deficiency/insufficiency of 25(OH)D.
.
● Selective vitamin D receptor activators (VDRA) should favor a stronger downregulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
● The positive effects of cholecalciferol seem to be limited to replenishment of deficiency/insufficiency of 25(OH)D.
.
● Selective vitamin D receptor activators (VDRA) should favor a stronger downregulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with cKD not yet on dialysis, regression of osteitis fibrosa with limited Increase in the hazard of adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. .
4-Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
● An association between vitamin D supplementation and reduced LV mass as well as a positive effect of vitamin D supplementation on the immune system has been reported in patients with ESRD
● There was a significant improvement in 25(OH)D levels and reduction of PTH levels. PTH reduction was more evident in dialysis patients.
● The active forms of vitamin D have been successfully used for a long time to treat secondary hyperparathyroidism in dialysis patients. The main characteristics of selective VDRA are their stronger effect in reducing serum concentration of PTH, lower impact on concentrations of calcium and phosphate, and reduced toxicity.
● Supplementation therapy appears to offer controversial survival advantages.
The kidney will do the second hydroxylation to 1,25 HO (calcitriol).
PTH , FGF23,Ca and po4 is the main regulator for 1, hydroxylation.
Emphasise physiological regulation of vitamin D.
PTH controls the kidney’s production of 1,25 VIT D Calcitrole and is inhibited by Ca ,po4 and FGF23.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The optimal level for Vit D level in CKD patients is >then 30 and less than 100
30 is a good level to treat and prevent SHPTH.
iT was advised to discontinue the Vit D in the. Following conditions:
hyper Ca
high and high trends for PTH
Describe the different biological effects of different forms of vitamin D therapy.
The two confusing forms of Vit D needs liver hydroxylation to be active :
Ergocalciferol is Vit D from the plant D2, and Cholecalciferol D3 is vit D from animal sources, both of them will be hydroxylated in the liver to 25(OH) D3 and 25(oh) D2, respectively.The third form is the calcifediol, which is the 25 (OH) D3 THE SYNTHETIC .1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR).
The major function of 1,25(OH)2D is to regulate calcium homeostasis
other biological activities include the regulation of proliferation and differentiation of several cell lines, including keratinocytes, endothelial cells, osteoblasts, and lymphocytes. Most of these biological functions are mediated via the vitamin D nuclear receptor (VDR), which acts as a transcription factor regulating the transcription of target genes.
Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.
the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle. available studies are certainly interesting but still they do not offer us solid certainties on the use of vitamin D in patients on dialysis.
Observational studies show great differences in duration of follow-up and number of enrolled patients; indeed, observation time varies from 90 days to 3 years and the number patients varies from a few tens to thousands. Further differences between studies are the aims to be assessed. They do not give specific algorithms or guidelines for practice
thanks dr Rihab for your effort, just few notions:
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D
2-Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Crucially, in patients with relatively high 1-a-hydroxylase activity, as transplanted patients and in those with sarcoidosis or B cell lymphoma, are more prone to toxicity therefore, lower targets of 25(OH)D levels are recommend.
3-Describe the different biological effects of different forms of vitamin D therapy.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with KD not yet on dialysis, regression of osteitis fibrosa WITH limited Increase in the hazard of tr adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. Notably, experimental studies also suggested that the use of paricalcitol was assoiated with better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol, doxercalciferol and cinacalcet.
Analyze the evidence of antiproteinuric effect of VITDRA.
Evidence of antiproteinuric effect of VITDRA is ontroversial
● Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and non-diabetic patients, although negative results were also reported.
· Describe mechanisms of vitamin D activation.
1- In skin 7-dehydrocholesterol is converted to pre-vitamin D3 under the influence of sunlight (UVB) is maximized at levels of sunlight exposure that do not burn the skin. and thereafter it is isomerized by the body’s temperature to vitamin D3
2- Vitamin D2 (ergocalciferol) is derived from the sterol ergosterol of plants and the main intake is through diet. However
3- In the liver The native vitamin D2 and D3 are both 25-hydroxylated to 25(OH)D (calcidiol or calcifediol) by 25-hydroxlases,CYP27A1 and CYP2R1
4- the kidney is essential for maintaining adequate serum 25(OH)D levels by means of the megalin mediated uptake of 25(OH)D from the glomerular ultrafiltrate and its recycling into to the circulation,
5- The 25(OH)D produced by liver be 1-a-hydroxylated in the kidney to produce the fully active form 1,25(OH)2D (calcitriol).
6- Further metabolism of vitamin D to its major circulating form takes place also in other tissues where the 1,25(OH)2D produced serves a paracrine/autocrine function: examples include the skin, cells of the immune system, parathyroid gland, intestinal epithelium, prostate, and breast.
7- Parathyroid hormone, FGF23, calcium and phosphate are the major regulators of the renal 1-hydroxylase (CYP27B1, the enzyme producing 1,25(OH)2D); regulation of the extra renal 1-hydroxylase differs from that in the kidney and involves cytokines.
8- The major enzyme that catabolizes 25(OH)D and 1,25(OH)2D is the 24-hydroxylase; like the 1-hydroxylase it is tightly controlled in the kidney in a manner opposite to that of the 1-hydroxylase, but like the 1-hydroxylase it is widespread in other tissues where its regulation is different from that of the kidney.
· Emphasize physiological regulation of vitamin D.
1- The production of 1,25(OH)2D in the kidney being stimulated by parathyroid hormone (PTH),
2- The production of 1,25(OH)2D inhibited by calcium, phosphate and FGF23.
3- Extra renal production of 1,25(OH)2D as in keratinocytes and macrophages is under different control, being stimulated primarily by cytokines such as tumor necrosis factor alfa (TNFα) and interferon gamma (IFNg).
4- 1,25(OH)2D reduces 1,25(OH)2D levels in cells primarily by stimulating its catabolism through the induction of CYP24A1(24-hydroxylase).
5- 25OHD and 1,25(OH)2D are hydroxylated in the 24 position by this enzyme to form 24,25(OH)2D and 1,24,25(OH)3D, respectively.
6- This 24-hydroxylation is generally the first step in the catabolism of these active metabolites to the final end product of calcitroic acid, although 24,25(OH)2D and 1,24,25(OH)3D have their own biologic activities.
7- CYP24A1 also has 23-hydroxylase activity that leads to a different end product.
· Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
The optimal targets of 25(OH)D circulating levels and the best approach to obtain vitamin D replenishment remain unknown.,
1- 30 ng/ml seems a reasonable target for the prevention and treatment of secondary hyperparathyroidism in CKD patients.
discontinue vit D when
Describe the different biological effects of different forms of vitamin D therapy.
Two pro-drugs cholecalciferol and ergocalciferol (both requiring conversion by hepatic 25-ahydroxylase to 25(OH)D3 or 25(OH)D2, respectively) and calcifediol (already available as 25(OH)D3). Many studies have indicated a potential superiority of cholecalciferol vs. ergocalciferol in increasing 25(OH)D levels.
The levels of 25(OH)D are not always completely corrected; therefore alternative regimens with cholecalciferol and ergocalciferol supplementation have been proposed to reach the therapeutic levels of 25(OH)D as suggested by the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines a modified-release calcifediol formulation, resulted in effective increasing 25(OH)D levels in a dose dependent manner among non-dialysis CKD patients compared to placebo
Regardless of the preferred regime, in predialysis CKD patients treatment with cholecalciferol, ergocalciferol and calcifediol should be discontinued in the presence of 25(OH)D levels[100 ng/ml and/or with persistent serum calcium levels 10.5 mg/dl in the absence of active vitamin D administration. Attention should be paid in the presence of potentially increased 1-a-hydroxylase
A potential superiority of selective VDRA, e.g. paricalcitol, with respect to non-selective VDRA such as calcitriol, alfacalcidol or doxercalciferol is still the subject of debate. Despite encouraging experimental data, not all the available active vitamin D formulations have been tested in head-to-head RCTs on hard endpoints, PTH control, bone histology and vascular aging.
Describe how control of cardiovascular risk factors is different in patients with CKD in comparison to the general population?
1- CKD mainly medial layer which is affected in the vessel wall(arteriosclerosis) previously called Mönckeberg’s arteriosclerosis calcification
2- in general population where intima mainly affected with atherosclerotic plaque.
3- Control of traditional cardiovascular risk have limited success in patients with CKD.
4- cholesterol control has not been conclusively proven to be of benefit in patients with advanced CKD.
5- Trials that target CKD-specific; nontraditional risk factors have failed to show benefit.
Using vitamin D in general population is associated with improvement in cardiovascular outcome and mortality. Analyze the evidence supporting vitamin D use in general population.
1- there is relationship of vitamin D deficiency with cardiovascular disease, including
A) carotid intima-media thickness,
B) peripheral vascular disease, and
c) cardiovascular death.
2- Vitamin D supplementation improves BP and endothelial function and reduces levels of inflammatory markers and lipids (particularly triglycerides) in the general population with or without vitamin D deficiency.
3- a prospective, randomized trial Vitamin D supplementation did not improve incident cardiovascular disease and death, or myocardial infarction, angina, heart failure, and arrhythmia.
4- More recently, in 25,871 patients with baseline vitamin D concentration of 77 nmol/L, use of 2000 IU/daily of cholecalciferol did not improve cardiovascular outcomes
Criticize the cardiovascular benefits of using vitamin D supplement in patients with CKD.
No adequately powered, randomized, controlled trials have not been conducted. Hence, the impact of vitamin D therapy on cardiovascular health in patients with CKD is unknown 1- Vitamin D deficiency associated with all-cause and cardiovascular mortality in patients with CKD, 2- improvement of cardiovascular and all-cause mortality after treatment with vitamin D and its analogs in patients with CKD.
Impact of Vitamin D on Vascular Function in CKD
1- vitamin D supplementation improve on brachial artery flow-mediated dilatation,
2- reduce markers of inflammation,
3- effect on arterial stiffness,
4- decrease parathyroid hormone,
5- Modulate intracellular cell adhesion molecule, vascular cell adhesion molecule.
6- In CKD eGFR of 15–45 ml/min per 1.73 m2 pulse wave velocity improved after 6-month supplementation with 25-hydroxy vitamin D
7- and brachial artery flow-mediated dilatation improved with 12-week paricalcitol therapy in patients with CKD stages 3 and 4.
8- On the other hand, two studies failed to find any change in flow-mediated dilatation and pulse wave velocity, respectively. Although the effects are inconsistent,
9- a recent meta-analysis showed that vitamin D treatment led to an improvement of endothelial function.
Impact of Vitamin D on Cardiac Structure and Function.
1-year active vitamin D supplementation failed to improve cardiac structure and function in patients with CKD.
2- there is improvement of left atrial volume, diastolic function, and significant improvement in the number of hospitalizations due cardiovascular events.
3- Epidemiology suggests a link between of vitamin D deficiency with cardiovascular events in patients with CKD.
4- Observational cohorts and small, randomized, placebo controlled trials have shown some benefits with supplementation.
5- There is no randomized trial evidence to justify supplementation in patients with CKD patients to improve cardiovascular function in regular clinical care and there is lack of strong evidence for vitamin D therapy to prevent cardiovascular disease in CKD.
· Analyze the evidence of antiproteinuric effect of VITDRA.
1- vitamin D has received growing interest as a treatment for several targets beyond PTH and bone health control, e.g. proteinuria, LVH and anemia.
2- Cholecalciferol at different dosages induced a mild but significant reduction of albuminuria among diabetic and nondiabetic patients, although negative results were also reported
3- meta analysis concluded that Active vitamin D administration was associated with a significant 16 % reduction of proteinuria compared to 6 % reduction among controls with a more than 100-fold greater probability to reach a proteinuria reduction C15 %
4- The analysis was not limited to diabetics but it included patients with immunoglobulin (Ig)A nephropathy and patients with other renal disorders.
· Criticize survival benefits of Vitamin D in CKD patients on dialysis.
available data ABOUT survival benefits of Vitamin D in CKD patients on dialysis are conflicting and, uncertain. Not known when to start treatment, on which vitamin D to prescribe, on dose to administer and on the route to prefer
because most vitamin D comes from the sun and healthier people have more opportunities to spend time outdoors, studies in patients are particularly susceptible to confounding. Therefore, the association between 25(OH)D levels with better outcome could be simply due to patients’ lifestyle. available studies are certainly interesting but still they do not offer us solid certainties on the use of vitamin D in patients on dialysis.
Observational studies show great differences in duration of follow-up and number of enrolled patients; indeed, observation time varies from 90 days to 3 years and the number patients varies from a few tens to thousands. Further differences between studies are the aims to be assessed. They do not give specific algorithms or guidelines for practice
· Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
1- Decrease PTH level .
2- increase-Serum 1,25(OH)2D level
3- Endothelial cardiovascular markers improvement .
4- decrease Inflammation markers
5- Reduced proteinuria ,
there is an association between 25(OH)D low serum levels and mortality.
Mortality was higher in severely vitamin D deficient patients compared to the other groups.
while no significant association was found between non-cardiovascular mortality and vitamin D.
Patients (n = 6518) from the German Renal Registry were matched with 73,919 recorded 25(OH)D measurements. All-cause mortality risk increased with decreasing vitamin D levels,
1- for vitamin D insufficiency—25(OH)D levels ranging from 20 to\30 ng/ml—a moderate increase in risk was observed;
2- for vitamin D deficiency—25(OH)D ranging from 12.5 to\20 ng/ml—the risk was much more pronounced;
3- for severe vitamin D deficiency—25(OH)D\12.5 ng/ml—mortality risk was more than doubled.
· Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
1- the impairment of vitamin D metabolism reflects allograft function, FGF23 and PTH levels, immunosuppressive therapy and environmental factors (nutritional deficiency, decreased sun exposure)
Vitamin D level
bone level
· Discuss pros & cons of vitamin D therapy in KTRs.
· the effects of ergocalciferol and cholecalciferol and calcifediol on BMD remains controversial
· No specific guidelines have been released to orient nutritional vitamin D replenishment in KTRs,
· Although several authors reported a significant improvement of PTH and calcium levels in KTRs receiving nutritional vitamin D,
· cholecalciferol supplementation after kidney transplant did not modify the progression of GFR, the onset of interstitial fibrosis, tubular atrophy and proteinuria
· Pros
B.Cons
hyperphosphatemia
hypercalcemia
suppressing bone matrix mineralization .
thanks dr Ahmed for your comprehensive answers just few notions
1-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
2-Describe the different biological effects of different forms of vitamin D therapy.
● Selective vitamin D receptor activators (VDRA) should favor a stronger downregulation of PTH synthesis with a lower impact on positive calcium-phosphate balance and a lower pro-calcifying effect on arterial walls.
● Effects of different active vitamin D compounds on bone histology and risk of fractures has not been tested in head-to-head RCTs. In patients with KD not yet on dialysis, regression of osteitis fibrosa WITH limited Increase in the hazard of tr adynamic bone disease was observed after treatment with calcitriol or alfacalcidol. Notably, experimental studies also suggested that the use of paricalcitol was assoiated with better protective effects on bone health and a lower risk of adynamic bone disease than calcitriol, doxercalciferol and cinacalcet.
3-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Finally, considering the inherent limitations of retrospective analyses characterized by significant differences in number of enrolled patients, administered doses of vitamin D sterols, duration of treatment and assessed outcomes, the benefit of VDRA treatment on survival in hemodialysis patients still remains to be confirmed by prospective RCTs.
Describe mechanisms of vitamin D activation.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients
30 ng/ml is the minimum level of 25(OH)D .
discontinue vit D when
Describe the different biological effects of different forms of vitamin D therapy.
The two forms of vitamin D differ depending on their food sources. Vitamin D3 is only found in animal-sourced foods, whereas D2 mainly comes from plant sources and fortified foods.
1,25(OH)2D, the biologically active form of vitamin D, exerts most of its functions through the almost universally distributed nuclear vitamin D receptor (VDR). Upon stimulation by 1,25(OH)2D, VDR forms a heterodimer with the retinoid X receptor (RXR).
The major function of 1,25(OH)2D is to regulate calcium homeostasis
other biological activities include regulation of proliferation and differentiation of several cell lines including keratinocytes, endothelial cells, osteoblasts, and lymphocytes. Most of these biological functions are mediated via the vitamin D nuclear receptor (VDR) which acts as a transcription factor regulating transcription of target genes .
Analyze the evidence of antiproteinuric effect of VITDRA.
antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis.
The information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis.
Serum PTH level decrease .
increase-Serum 1,25(OH)2D level
Endothelial cardiovascular markers improvement .
decrease Inflammation markers
Reduced proteinuria ,
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
Vitamin D level
bone level
Discuss pros & cons of vitamin D therapy in KTRs.
.Pros
B.Cons
hyperphosphatemia
hypercalcemia
suppressing bone matrix mineralization .
thanks dr Ashraf for your effort, just few notions:
1-Describe mechanism of action and action of vitamin D.
II- Action
Principally, vitamin D main action is regulation of mineral and bone homeostasis in intestinal, renal and bone tissues. This is mainly achieved by VDR activation leading to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption. On the other hand, its effect on bone health is dependent on level of calcium. In case of calcium deficiency, VDR activation leads to bone resorption and suppressing bone matrix mineralization. In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes. More recently, vitamin D has been shown to exert autocrine or paracrine activities in multiple cell functions including inhibition of cellular proliferation and stimulation of cell maturation which may involve skin, the immune system and colonic, breast and prostate cells.
2-Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Finally, considering the inherent limitations of retrospective analyses characterized by significant differences in number of enrolled patients, administered doses of vitamin D sterols, duration of treatment and assessed outcomes, the benefit of VDRA treatment on survival in hemodialysis patients still remains to be confirmed by prospective RCTs.
3-Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
II- bone health
Immunosuppressive drugs elicit a deep impact on bone loss.
● Steroids may harm the bone health by direct suppression of bone formation through impairment of vitamin D metabolism, inhibited osteoblastogenesis, increased apoptosis of osteoblasts and enhanced osteoclastogenesis through an increased receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio.
● Both cyclosporine and tacrolimus may indue bone loss via a direct osteoclast activation.
● Conversely, sirolimus is a bone-sparing immunosuppressive agent, due to its capability to inhibit osteoclast generation.
Describe mechanisms of vitamin D activation.
Describe mechanism of action and action of vitamin D.
Emphasize physiological regulation of vitamin D.
Mention the recommended target vitamin D level and limiting factors for vitamin D treatment for prevention and treatment of secondary hyperparathyroidism in CKD patients.
Describe the different biological effects of different forms of vitamin D therapy.
Analyze the evidence of antiproteinuric effect of VITDRA.
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
Enumerate reported benefits of vitamin D therapy in CKD patients on dialysis
Describe the effects of different immunosuppressives on both vitamin D level and bone health in KTR.
A.Vitamin D level
B.Bone health
Discuss pros & cons of vitamin D therapy in KTRs.
A.Pros
B.Cons
thanks dr Ben Lomatayo for your effort, just few notions
1-Describe mechanisms of vitamin D activation.
A- Hepatic hydroxylation
Mechanism: The liver is the major if not sole source of 25 (OH) D productions from native vitamin D. The native vitamin D2 and D3 are both 25-hydroxylated to 25(OH)D (calcidiol or calcifediol) by several 25-hydroxlases, such as CYP27A1 and CYP2R1.
C- Extrarenal extrahepatic
Mechanism: circulating 25(OH)D can also be 1-a-hydroxylated in extrarenal cells that express CYP27B1, such as keratinocytes and macrophages.
2-Describe mechanism of action and action of vitamin D.
Principally, vitamin D main action is regulation of mineral and bone homeostasis in intestinal, renal and bone tissues. This is mainly achieved by VDR activation leading to calcium and phosphate intestinal absorption as well as to renal calcium tubular reabsorption. On the other hand, its effect on bone health is dependent on level of calcium. In case of calcium deficiency, VDR activation leads to bone resorption and suppressing bone matrix mineralization. In addition, VDR activation suppresses PTH secretion by parathyroid glands and enhances FGF23 production by osteocytes
3-Emphasize physiological regulation of vitamin D.
After execution of the physiological role of bioactive vitamin D, it is catabolized by 24-hydroxylase (CYP24A1) to inactive forms. The ubiquitous CYP24A1 represents a powerful catabolic enzyme provided with both 24-hydroxylase and 23-hydroxylase activities, therefore it can stop buildup of toxic levels of 1,25(OH)2D and 25(OH)D.
4-
Criticize survival benefits of Vitamin D in CKD patients on dialysis.
With
● Former studies reported that non-active forms of vitamin D showed significant positive effects on mortality.
● Zheng et al. performed a meta-analysis from 20 studies including several forms of vitamin D. In aggregate, participants receiving vitamin D had lower mortality compared to those with no treatment with participants that received calcitriol and paricalcitol had a lower cardiovascular mortality.
● Other Observational studies report improved cardiovascular and all-cause survival in hemodialysis patients receiving VDRA therapy compared to non-VDRA-treated patients.
Against
● The DOPPS cohort reported that VDRA administration was not associated with improved survival in models that were more independent of unmeasured confounders as comorbidities
● Miskulin et al. tested the efficacy of 6 months ergocalciferol versus placebo on epoetin utilization and other secondary outcomes. Rates of all-cause and cardiovascular mortality as well as of infection-related hospitalizations did not differ between study arms.
Thanks
Brilliant article and good review to have
Thank you for your comment and please answer the questions.