الفهرس 
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Abstract
The incidence of cardiovascular disease (CVD) in End stage renal disease (ESRD) patients is about 10 to 20 fold higher than that in the general population, and it accounts for more than 50% of mortality rate. Traditional risk factors just as dyslipidemia, hypertension, diabetes mellitus and others, are involved in the pathogenesis of the vasculopathy among this category of patients.
Recently, cardiovascular calcification; which is a prominent feature in arterial disease in ESRD, has been proposed to contribute to this exceptionally increased risk of CVD. Vascular calcification is considered now as an independent important risk factor for cardiovascular events, as well as all-cause mortality in hemodialysis patients.
Hyperphosphatemia, hypercalcemia and hyperparathyroidism all coexist in ESRD patients, having a crucial role on activation the osteogenesis process in vascular smooth muscle cells, resulting in arteriosclerotic calcification.
On the other hand, vitamin D deficiency is also associated with severe vascular calcification in chronic kidney disease (CKD) patients. In CKD, glomerular filtration rate decline limits the delivery of 25(OH)D to the renal tubules. The decreased renal uptake of 25(OH)D limits the formation of the active form of vitamin D; calcitrol.
Furthermore, CKD also reduce the activity of 1-α-hydroxylase, 25-hydroxylase, and increase the activity of 24-hydroxylase, causing prominent reduction of endogenous 25(OH)D and 1,25(OH)2D product, along with increasing their decay.
There’s a growing evidence that extra-renal organs can possess an enzymatic machinery (through extra-renal 1-𝛼- hydroxylase activity) for converting 25(OH)D to active 1,25(OH)2D, which may play considerable biological roles beyond the traditional roles of vitamin D in ESRD patients.
Serum 25-hydroxyvitamin D (25(OH)D) values of <30 ng/mL are considered to be insufficient, while <20 ng/ml values are considered deficient. Experts consider a target of >30 ng/ml to be optimal.
This study aimed to evaluate the effect of cholecalciferol supplementation on 25(OH)D replenishment, and to detect its impact on markers of vascular calcification among hemodialysis patients.
This was a prospective, placebo-controlled, block randomized, single blinded study. The study was conducted in accordance with Good Clinical Practice guidelines, and the ethical principals in the Declaration of Helsinki (as revised in 2013). This study also applied CONSORT guidelines and ICMJE recommendations. All patients were requested to fill a written informed consent prior to their participation in the study. Intention to treat analysis was performed.
All hemodialysis patients in the unit were screened for eligibility. Sixty eligible patients have been randomized into two groups.
Drug group: 30 patients received 200.000 IU of cholecalciferol, orally, once monthly, in addition to their standard therapy, for a 3 months’ duration.
Placebo group: 30 patients received an oral placebo taken with the exact same regimen, for a 3 months’ duration.
At baseline, all patients were subjected to the following:
a. Patient data collection:
o Complete history of the patients was recorded at the initial visit.
o All patients were subjected to full clinical testing prior to participation.
o Patients’ demographics, baseline characteristics and laboratory data were collected at the recruitment time.
b. Laboratory data assessment:
o Primary outcome: increase in serum Fetuin-A level.
o Secondary outcomes: increase in serum 25-hydroxy vitamin D (25(OH)D) level, decrease in intact parathyroid hormone (iPTH) level, decrease in serum fibroblast growth factor-23 (FGF-23), decrease in serum osteoprotegerin (OPG), elevation of serum calcium level (Ca), elevation of serum phosphate level (PO4), or elevation in their product.
Follow up and patient evaluation after three months’ study period:
Follow up:
- Both groups were followed up for any adverse or side effects by the principal investigator on a weekly basis.
- The treatment intake was ensured by drug or placebo administration at the site; the hemodialysis unit, after patients have received their regular hemodialysis session.
- All patients received the same routine medications supplied by the unit. Therapies that may affect calcium or phosphate levels (phosphate chelators) were closely monitored.
Patient evaluation:
At the end of the three months’ period of either drug use or placebo use, the patients were subjected to full assessment and evaluation.
• Evaluation of cholecalciferol safety by assessing:
Serum Calcium
Serum Phosphate
Serum Calcium-Phosphate product
Serum Intact parathyroid hormone
• Evaluation of cholecalciferol effect on vascular calcification and vitamin D levels:
Serum 25(OH)D
Serum Fetuin-A
Serum FGF-23
Serum OPG
• Monitoring tolerability and adverse side effects
Patients Interviews: all patients were asked to report any undesirable or intolerable effects detected throughout the three months’ study period.
At baseline, the current study has showed the following:
• At baseline, there was no significant difference between both study groups in terms of patients’ demographics, clinical characteristics, and baseline laboratory parameters.
• The preliminary observation started with a total of 88% vitamin D deficient patients, while the rest 22% were vitamin D insufficient.
• An increase in serum FGF-23 levels was noticed in the current study when measured at baseline in both drug and placebo groups, but no significant difference was noticed between drug group and placebo group.
• An increase in serum OPG levels was noticed in the current study when measured at baseline in both drug and placebo groups, but no significant difference was noticed between drug group and placebo group.
• A decrease in fetuin-A level was noticed in the current study when measured at baseline in both drug and placebo groups, but no significant difference was noticed between drug group and placebo group.
After 3 months of either cholecalciferol supplementation or placebo, the current study has showed the following:
• Patients on drug group have experienced a dramatic increase in serum level of 25(OH)D. Cholecalciferol succeeded to replenish 25(OH)D levels to end with a 0% deficient patients; (25(OH)D <20ng/ml), while only 24% of the patients remained insufficient; (25(OH)D <30ng/ml). Meanwhile, no cases of hyper-vitaminosis-D or vitamin D toxicity; (>100 ng/ml) were reported.
• Placebo group started with 66% vitamin D deficient patients, and ended up with 83% deficient patients.
• Serum fetuin-A level in drug group has significantly increased during the three months’ study period in only drug group.
• A significant decrease in iPTH level (a within subject statistical significance, p-value <0.001) throughout the study duration in drug group. When it comes to the change in iPTH level (ΔiPTH), also a statistical significant difference was found between the two study groups. This support that cholecalciferol supplementation may have a role in controlling secondary hyperparathyroidism in hemodialysis patients.
• Both serum FGF-23 and serum OPG haven’t shown to be changed throughout the study in both groups.
• After comparing the two study groups at the end, there was a significant difference in serum levels of 25(OH)D levels and fetuin-A. This may reflect beneficial effect of cholecalciferol supplementation on 25(OH)D level replenishment, along with a modulatory effect on vascular calcification markers.
• Levels of calcium, phosphate or calcium-phosphate product didn’t change either throughout, or at the end of study, in the two study groups. This indicate that cholecalciferol may have no safety issues regarding hypercalcemia or hyperphosphatemia.
• No dose modification was required all through the 3 months’ study period.
• Oral cholecalciferol 200.000 IU was well-tolerated without any reported adverse or undesirable side effects.
• A significant positive correlation was noticed between 25(OH)D level and fetuin-A, FGF-23 and OPG.
Conclusion
from the results obtained in this study, the following be concluded:
The administration of cholecalciferol, orally, once monthly for adult patients on regular hemodialysis has showed:
An increase in serum vitamin D level.
An increase in serum fetuin-A level.
A decrease in serum intact parathyroid hormone level.
Absence of any significant elevation in serum levels of calcium, phosphate or their product.
No change in serum levels of fibroblast growth factor-23 or osteoprotegerin.
Absence of any mild or serious side effects or adverse events.
No cases of toxicity or hyper-vitaminosis-D.
Cholecalciferol was shown to be an effective, tolerable, inexpensive pharmacotherapeutic option to overcome vitamin D deficiency, with a modulatory effect on vascular calcification regulator, among hemodialysis patients. This beneficial role came with no negative effects on calcium or phosphate levels, nor with adverse effects reported.
Limitations
1. Single-center trial.
2. Short duration of the study period.
3. Need of follow up after drug discontinuation.
4. Lack of facilitations like portable Doppler device.
5. Lack of imaging techniques for better evaluation of vascular calcification.
Additional large scale, multicenter, randomized, double-blinded placebo controlled trials for longer duration are warranted to further assess the following;
• The safety profile of cholecalciferol when used in higher frequencies and dosing.
• Pharmacokinetics studies to evaluate and establish the appropriate dosage and drug disposition.
• Assessment of cholecalciferol effect in other CKD population (patients on peritoneal dialysis, stage 2 and 3 CKD patients).
• Involve imaging techniques for better evaluation of vascular calcification