Scientific Background
Patients with chronic kidney disease (CKD) may be more likely to die from
complications of their disease than to survive long enough to require
dialysis.1 Mortality in CKD patients is frequently linked to the
presence of cardiovascular disease (CVD). Data from the US Renal Data
System in 2006 indicate that mortality due to heart disease is
greater than 10 fold higher in patients with end stage renal disease
(ESRD) compared to the general population.2
The extent to which CVD may be attributed to disorders of vitamin D
metabolism, which develops as renal function declines, is the subject
of recent research interest.3,4 The concept that vitamin D receptors
(VDR), found in many cells and tissues, may play a role in
CVD in patients with CKD is relatively new.4 The current indication
for active vitamin D and its analogs is for the
treatment of secondary hyperparathyroidism (SHPT) associated with
CKD. Observational studies in ESRD patients have found: (1) distinct
differences in mortality between those who received vitamin D5,6
compared with no vitamin D and (2) a possible mortality benefit in CKD
patients receiving a selective VDR activator (VDRA) over a non-selective
VDRA.7,8 In addition, patients treated with a selective VDRA have
demonstrated improved hospitalization outcomes compared with patients treated
with a non-selective VDRA in real-world clinical settings.9
The emerging preclinical and clinical data supports a possible
effect of VDR activation in different tissues that regulate
inflammatory responses,10 vascular calcification,11,12,13 lipid metabolism,14
hypertension,15,16 cardiac hypertrophy,16,17,18,19 and tissue fibrosis.20 The
aforementioned possible effect appears to be independent of PTH,
serum calcium and phosphorus levels, suggesting that the
physiological effects of VDRA therapy may extend beyond bone and mineral
metabolism.4,21
There are several novel proposed mechanisms:
- Anti-inflammatory and antithrombotic effects via effects on PAI-1, MMP2 and 9 and CRP19,22
- Inhibition of vascular smooth muscle cell proliferation23
- Improving endothelial and vascular function by inhibiting the synthesis of
inducers of calcification (such as core binding factor alpha-1) and
modulating oxidative stress24
- Regression of left ventricular hypertrophy16,17,25
- Modulation of renin-angiotensin-aldosterone system (RAAS),15,16 which plays a key
role in hypertension, myocardial infarction and stroke
The hypothesized link of VDRA deficiency to increased cardiovascular risk
in CKD is particularly important, as CKD patients experience a
high rate of cardiovascular-related morbidity and
mortality. The primary objective of ExtenD is to advance the
current understanding surrounding the physiological effects of
selective vitamin D receptor activation in the following areas:
- Chronic kidney disease progression;
- Cardiovascular disease/heart failure;
- Cardiac and vascular function;
- Metabolic disorders (specifically diabetes mellitus) and
- Inflammation.
Proposals will be reviewed by the ExtenD committee, which consist of
internationally known experts in the fields of nephrology,
endocrinology, cardiology, basic science, and vascular biology.
Selection will be based on scientific merit, the novelty of the
proposal, the capability of the investigator's laboratory, and
the impact on the VDRA field.
1 U.S. Renal Data System. USRDS 2002 annual data report: atlas of end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2002.
2 United States Renal Data System. Annual Data Report. USRDS. Available at www.usrds.org.
3 Wu-Wong J, et al. Cardiovascular disease in chronic kidney failure: the role of VDR activators. Curr Opin Investig Drugs. 2006;7(3):206-213.
4 Levin A, Li Y. Vitamin D and its analogues: do they protect against cardiovascular disease in patients with chronic kidney disease? Kidney Int 2005;68(5):1973-1981.
5 Kalantar-Zadeh, et al. Survival predictability of time varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 2006;70(4):771-780.
6 Teng M, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005;16(4)1115-25.
7 Young E, et al. Vitamin D therapy and mortality in the dialysis outcomes and practice patterns study (DOPPS). (Poster) 2005 ASN. November 8-13, 2005, Philadelphia, PA.
8 Teng et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Eng J Med 2003;349(5): 446-456.
9 Dobrez DG, et al. Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol-treated patients in real-world clinical settings. Nephrol Dial Transplant 2004;19(5):1174-1181.
10 Mathieu and Adorini. The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 2002;8:174-179.
11 London, et al. Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia. Curr Opin Nephrol Hypertens 2005;14:525-531
12 Wu-Wong, et al. Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther 2006;318-:90-98.
13 Mizobuchi, et al. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. KI 2007;72:709-715.
14 Mak,. 1,25-dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. KI 1998;53:1353-1357.
15 Li, et al. 1-25-dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-238.
16 Xiang, et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab 2005;288:E125-132.
17 Bodyak, et al. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. PNAS 2007;104:16810-16815.
18 Aihara, et al. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Bio Chem 2004;279:35798-35802.
19 Wu-Wong, et al. Effects of Vtiamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 2006;186:20-28.
20 Tan, et al. Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 2006;17:3382-3393.
21 Thadhani R, Wolf M. Vitamin D in patients with kidney disease: cautiously optimistic. Adv Chronic Kidney Dis. 2007;14(1)22-26.
22 Wu-Wong JR, et al. Vitamin D analogs modulate the expression of plasminogen activator inhibitor-1,thrombospondin-1 and thrombomodulin in human aortic smooth muscle cells. J Vasc Res 2007;44:11-18
23 O'Connell, et al. 1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy. AJP 1997;272:1751-1758.
24 Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. KIT 2006;69:33-43.
25 Kim, et al. Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract 2006;102:c21-c29.
Articles of Interest