Vitamin D deficiency is common in CKD patients and linked to increased cardiovascular disease risk. This study found that cholecalciferol supplementation in nondiabetic CKD patients with vitamin D deficiency significantly improved brachial artery flow-mediated dilation and pulse wave velocity, markers of endothelial function and arterial stiffness respectively, over 16 weeks. Biomarkers of endothelial function, inflammation, and vascular calcification also improved. These results provide evidence that correcting vitamin D deficiency reduces cardiovascular risk in CKD patients.

1. Moh’d Sharshir, MD
Nephrology Fellow

2. INTRODUCTION:
• Because most patients with early CKD die of cardiovascular disease (CVD)
before developing advanced kidney failure, CVD risk reduction is an important
management goal in CKD.

3. INTRODUCTION:
• The widespread recognition of vitamin D deficiency, and the strong epidemiologic
data linking vitamin D deficiency to cardiovascular mortality in the general
population and patients with CKD, has interest in examination of vitamin D
deficiency as a potentially modifiable CVD risk factor.
Pilz S, Tomaschitz A, Drechsler C, de Boer RA: Vitamin D deficiency and heart disease. Kidney Int Suppl 1: 111–115, 2011

4. INTRODUCTION:
Pilz S, Tomaschitz A, Drechsler C, de Boer RA: Vitamin D deficiency and heart disease. Kidney Int Suppl 1: 111–115, 2011

5. INTRODUCTION:
• In a meta-analysis, each 10 ng/ml reduction in vitamin D increased the risk of all-
cause mortality by 14% in patients with CKD.
Melamed ML, Michos ED, Post W, Astor B: 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008; 168: 1629–1630.

6. INTRODUCTION:
• Another meta-analysis showed a 37% reduction of cardiovascular mortality with
active vitamin D therapy in patients with CKD.
Duranton F, Rodriguez-Ortiz ME, Duny Y, Rodriguez M, Daurès JP, Argilés A: Vitamin D treatment and mortality in chronic kidney disease: A systematic review and meta-analysis. Am J Nephrol 37: 239–248, 2013

7. INTRODUCTION:
• Endothelial dysfunction sets in early in patients with CKD and correlates with future CVD.
• Vitamin D induces concentration dependent increase in endothelial nitric oxide production.
Molinari C, Uberti F, Grossini E, VaccaG, Carda S, InvernizziM, Cisari C: 1a,25-dihydroxycholecalciferol induces nitric oxide production in cultured endothelial cells. Cell Physiol Biochem 27: 661–668, 2011

8. INTRODUCTION:
• Low serum 25-hydroxy vitamin D [25(OH)D] has been shown to be an
independent predictor of impaired endothelial function in CKD.
• Small observational and case control studies have shown improvement in
endothelial function with vitamin D supplementation.
Chitalia N, Ismail T, Tooth L, Boa F, HampsonG, Goldsmith D, Kaski JC, Banerjee D: Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PLoS One 9: e91363, 2014

9. INTRODUCTION:
• Vitamin D repletion strategies in CKD have largely involved use of activated
vitamin D because of the belief that vitamin D activation will be hampered in
patients with CKD, and the greater affinity of vitamin D receptor (VDR) for
activated forms.

10. INTRODUCTION:
• Flow-mediated dilation (FMD), a well established technique for assessing
endothelial function, predicts CVD events in patients with CKD.
• CVD risk factor modification improves FMD, making it a relevant and accepted
surrogate for CVD events.
Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Lüscher TF, Shechter M, Taddei S, Vita JA, Lerman A: The assessment of endothelial function: From research into clinical practice. Circulation 126: 753–767, 2012.

11. AIM OF STUDY:
• They investigated whether supplementation with Cholecalciferol would improve
brachial artery Flow-mediated dilation (FMD) in nondiabetic patients with CKD
and vitamin D deficiency.
• Also evaluated changes in pulse wave velocity (PWV; a marker of vascular
stiffness) and biomarkers of endothelial function (E-selectin and vWF) and
inflammation (high-sensitivity C-reactive protein [hs-CRP] and IL-6).

12. METHODS:
• Study Design:
 The study was a single center, parallel arm, randomized, double-blind, placebo-controlled trial.
 Performed at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

13. METHODS:
• Study Population: Stable patients with CKD attending the Renal Clinic at PGIMER and having an eGFR
between 15 and 60 ml/min per 1.73 m2 (using the four-variable Modification of Diet in Renal Disease equation).
• Inclusion criteria:
 Age 18–70 years.
 Vitamin D deficiency [serum 25(OH)D levels </=20ng/ml].
 Absence of diabetes mellitus.
• Exclusion criteria:
 Heart failure.
 Present or past malignancy, pregnancy, or vitamin D (ergocalciferol or cholecalciferol) supplementation within the past
30 days.

14. METHODS:
• Randomization and Blinding: Patients were randomized in a 1:1 allocation ratio, and entered a
2 week run-in period, during which usual treatment was verified and continued.
• Intervention and Follow-Up Upon completion of the run-in period, patients received their
assigned interventions: two oral doses of either 300,000 IU of Cholecalciferol or
matching placebo at baseline and 8 weeks later.
• Follow-up visits were done at 8 and 16 weeks
• FMD and endothelium-independent NMD were measured at baseline and 16 week.

15. METHODS:
• Outcomes:
• The primary out come: was change in brachial artery FMD at 16 weeks.
• Secondary outcome: measures were changes in PWV and levels of serum
1,25(OH)2D, serum iPTH, serum FGF-23, serum E-selectin, serum hs-CRP,
serum IL-6, and plasma vWF.

17. BASELINE CHARACTERISTICS:

19. CHANGE IN SERUM 25(OH)D LEVELS:

21. CHANGES IN VASCULAR FUNCTION:

23. CHANGES IN VASCULAR FUNCTION:
• Change in FMD remained significant in all prespecified subgroups (P< 0.001) with potential
heterogeneity by sex and age.

24. CHANGES IN VASCULAR FUNCTION:
• Figure shows change in FMD and NMD for
individual patients in the two groups.

25. CHANGES IN VASCULAR FUNCTION:
• Antihypertensive drug doses remained unaltered, and there was no change in
systolic or diastolic BPs in either group over the study period.

26. CHANGE IN BIOCHEMICAL PARAMETERS AND CIRCULATING BIOMARKERS:
• Serum calcium levels increased whereas alkaline
phosphatase levels decreased in the cholecalciferol group
(between-group difference in mean change: 0.69 mg/dl [95%
CI, 0.31 to 1.06; P=0.001] and 220.25 U/L [95% CI, 235.14
to 25.38; P< 0.01] for serum calcium and alkaline
phosphatase, respectively).

27. CHANGE IN BIOCHEMICAL PARAMETERS AND CIRCULATING BIOMARKERS:
• Serum inorganic phosphorus, serum FGF-23, serum
creatinine, eGFR, and blood hemoglobin levels did not
change in either group.

28. CHANGE IN BIOCHEMICAL PARAMETERS AND CIRCULATING
BIOMARKERS:
• There was no change in the proportion of patients with dipstick-positive
proteinuria in intervention (53% versus 50%; P=0.71) or control (51% versus
51%; P.0.99) groups.

29. CHANGE IN BIOCHEMICAL PARAMETERS AND CIRCULATING
BIOMARKERS:
• Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels
increased.
• Intact parathyroid hormone (iPTH) and IL-6 levels
decreased in the cholecalciferol group.

30. ADVERSE EVENTS:
• There were no hospitalizations or serious adverse events.
• One patient complained of mild headache and dizziness after NMD testing, which
improved with 15 minutes of rest.

31. DISCUSSION
• This randomized placebo-controlled trial provides the strongest evidence so far that
correction of vitamin D deficiency by cholecalciferol supplementation improves FMD
and PWV in predialysis patients with CKD, both of which are predictors of future CVD
risk.
• Change in serum 25(OH)D level significantly correlated with change in FMD, lending
further support to vitamin D deficiency as a potentially modifiable CVD risk factor in
patients with CKD.

32. CONCLUSION:
• Correction of vitamin D deficiency by cholecalciferol supplementation improves
CVD risk factor profile through positive effect on vascular function in nondiabetic
patients with early CKD, likely due to improvement in both endothelial and
vascular smooth muscle cell functions.

33. CONCLUSION:
• Strong evidence that cholecalciferol supplementation is safe and could be used
for CV risk reduction in patients with CKD and vitamin D deficiency.