Does Treatment With Calciferol Have a Role in CKD Patients?

Vitamin D Metabolism 

“Vitamin D” refers to a group of fat-soluble prohormones. Vitamin D is produced endogenously in the skin, and is available in certain foods (either naturally or through fortification) or as a dietary supplement. Plant sources of vitamin D are in the form of ergocalciferol (D2), whereas animal sources are in the form of cholecalciferol (D3). Collectively, D2 and D3 are known as calciferol. Regardless of whether or not you receive vitamin D from food, dietary supplements, or the sun, these forms of vitamin D are inactive and require two hydroxylations. The first step occurs in the liver, to form 25 OHD (calcidiol), and the final step occurs with the addition of 1-α hydroxylase in the kidneys, to make 1,25 OHD or calcitriol, a potent hormone and the active form of vitamin D.1 Calcitriol produced from the kidneys is then released into circulation and has a systemic effect. Researchers have known for years the benefits of vitamin D, its role in bone mineral homeostasis, and the presence of vitamin D receptors throughout the body. The kidney was once believed to be the only location of 1-α hydroxylase activity. However, researchers are discovering that multiple tissues, including the colon, breast, prostate, and bone marrow, have 1-α hydroxylase enzymes that can convert circulating 25 OHD to active 1,25 OHD.2 Rather than exerting a systemic effect, calcitriol produced at the cellular level has more of a physiologic autocrine and paracrine function, acting through the vitamin D receptors of a particular cell.1, 2, 3, 4 This likely explains the correlation between low vitamin D levels and the risk for developing colon, breast, and other cancers.

Although recent studies indicate vitamin D deficiency in the general population, we have known for years that CKD patients are vitamin D-deficient. Calcitriol levels decrease as renal function declines, and after our patients reach CKD stage 5 (estimated glomerulofiltration rate<15mL/min), most are unable to make that final conversion of 25 OHD to 1,25 OHD.3 In dialysis, we primarily use parathyroid hormone (PTH) levels to initiate vitamin D analogs such as Hectorol or Zemplar. Wolf et al. studied a group of 825 incident hemodialysis patients, and found that 78% were vitamin D-deficient (<30 ng/mL).5 Of the study sample, women, blacks, and patients with diabetes were more likely to be vitamin D-deficient. Vitamin D deficiency correlated poorly with calcium, phosphorus, and PTH levels. In fact, nearly 80% of the patients with PTH levels <150pg/mL were vitamin D-deficient.5 These researchers also showed a correlation between low 25 OHD levels and an increased risk of mortality within 90 days of initiating dialysis.5

Until recently, many would have argued that little benefit accrued from giving D2 or D3 if patients were unable to covert them to calcitriol. However, as we learn more about the role of vitamin D at the cellular level and the possibility of providing some protection against certain cancers, heart disease, and autoimmune diseases, we may need to rethink this assumption.2, 6 As we look to supplementing vitamin D in the general population, we should consider the risks and benefits of supplementing vitamin D in the dialysis population. One concern involves the risk of increasing serum calcium and phosphorus levels when supplementing with D2 or D3. However, several studies that examined supplementing hemodialysis patients with either D2 or D3 showed improvements in vitamin D levels from baseline, with little to no effect on serum calcium and phosphorus.4, 7

Sources of Vitamin D 

Sources of vitamin D include sunlight, food sources, and dietary supplements. It is produced endogenously from 7-dehydrocholesterol when sunlight hits our skin. Although as few as 10 to 15minutes/day of sunlight are needed to prevent deficiencies, multiple factors may interfere with getting the full benefit of the sun, including the widespread use of sunscreen, the time of day, the time of year, the latitude in which you live, angle of the sun, skin pigmentation, and age. Table 1 lists food sources of vitamin D. It is often difficult to acquire enough vitamin D from food sources, which is a contributing factor to the widespread deficiency seen in the United States. For CKD patients, many of these foods may not be readily accessible or may be too high in phosphorus to allow them to reach an intake of 1000IU daily. Dietary supplements can provide a safe and cost-effective source of vitamin D. Table 2 list common vitamin D supplements. The type of vitamin D (D2 or D3) and how much is adequate remain unclear, both in the general population and CKD population. The vast majority of dietary supplements contain D3, which appears to be more shelf-stable and more effective at raising vitamin D levels.8, 11

Table 1. Dietary Sources of Vitamin D12

	Food	Amount	Vitamin D Content	Phosphorus Content
	Bluefish	3 ounces	415IU	247mg
	Catfish	3 ounces	425IU	208mg
	Cod liver oil	1 teaspoon	450IU	0mg
	Egg yolk	1 whole	25IU	66mg
	Mackerel	3 ounces	395IU	236mg
	Milk, vitamin D-fortified	1 cup	100IU	248mg
	Mushrooms, shitake	4 mushrooms	55IU	22mg
	Oysters	3 ounces	545IU	79mg
	Salmon, farmed	3 ounces	275IU	218mg
	Salmon, wild	3 ounces	1000IU	274mg
	Sardines, canned in oil	1.75 ounces	230IU	209mg
	Shrimp	3 ounces	120IU	174mg
	Tuna, blue-fin	3 ounces	170IU	216mg
	Tuna, canned in water	3 ounces	135IU	139mg

Table 2. Vitamin D Supplements

	Product	Description	Vitamin/Serving	Elemental Calcium	Phosphorus	Cost/quantity	Contact Information
	Drisdol	By prescription; vitamin D (weekly or monthly dosing)	50,000IU D2/soft gel	None	None	Medicaid-reimbursed in many states; out-of-pocket cost, $3 to $4/soft gel	Sanofi-Aventis U.S., LLC, Bridgewater, NJ 08807
	Caltrate	Calcium and vitamin D supplement	400IU D3/tablet	240mg	Unknown	$12.99/120 tablets	Wyeth Consumer Healthcare, P.O. Box 26609, Richmond, VA 23261-6609
	Carlson	Vitamin D supplement	2000IU D3/soft gel	none	none	$8.80/120 soft gels	Carlson Laboratories, 15 College Dr., Arlington Heights, IL 60004-1985; website: www.vitacost.com
	CVS vitamin D	Vitamin D supplement	1000IU D3/tablet	60mg	Unknown; contains dicalcium phosphate	$5.49/100 tablets	Telephone: 888-607-4287; e-mail: customercare@cvs.com
	GNC	Vitamin D	400IU D3/tablet	None	Unknown; contains dicalcium phosphate	$3 to $4/120 tablets	Website: www.GNC.com
	Life Fitness	Vitamin D	1000IU D3/tablet	60mg	Unknown; contains dicalcium phosphate	$6.99/100 tablets	Life Fitness, 5100N. River Road, Schiller Park, IL 60176
	Little Critters Calcium Gummy With D	Calcium and vitamin D supplement	200IU D2/two gummy bears	76mg	100mg tricalcium phosphate	$5.44/60 gummy bears	Northwest Natural Products; telephone: 1-800-661-2736
	Little Critters Vitamin D	Vitamin D	800IU D2/two gummy bears	None	None	$5.49/60 gummy bears	Northwest Natural Products; telephone: 1-800-661-2736
	Maximum D3	Vitamin D (weekly dosing)	10,000IU D3/gel cap	None	None	5 gel caps (5 weeks)=$6.40 + $4.90 shipping and handling	BTR Group, Inc., P.O. Box 501, Pittsfield, IL 62363-0501; telephone: 217-320-1597
	Nature's Bounty	Vitamin D	400IU D3/tablet	None	Unknown; contains dicalcium phosphate	$4.99/100 tablets	Nature's Bounty Consumer Affairs, 110 Orville Drive, Bohemia, NY 11716; telephone: 1-800-433-2990
	Nature Made	Vitamin D	1000IU D3/tablet	Unknown; contains calcium carbonate	None	$9.69/100 tablets	Nature Made, P.O. Box 9606, Mission Hills, CA 91346-9606; telephone: 1-800-276-2878
	Nature Made Calcium With D	Calcium and vitamin D	200IU D3/tablet	200mg	None	$8.29/130 tablets	Nature Made, P.O. Box 9606, Mission Hills, CA 91346-9606; telephone: 1-800-276-2878
	Nature's Plus	Vitamin D	1000IU D3/soft gel	None	None	$9.29/180 soft gels	Telephone: 1-800-645-9500
	Oscal 500+D	Calcium and vitamin D supplement	400IU D3/caplet	200mg	None	$15.99/120 caplets	Telephone: 1-800-245-1040
	Puritan's Pride	Vitamin D3 with calcium	1000IU D3/tablet	48mg	Unknown; contains dicalcium phosphate	$5.99/100 tablets	Puritan's Pride, 1233 Montauk Highway, P.O. Box 9001, Oakdale, NY 11769-9001; website: www.purtitan.com
	Vital D Rx	Renal vitamin (B complex with D3)	1750IU cholecalciferol	None	None	Medicaid-reimbursable in some states; out-of-pocket cost, $11 to $14/month	Nephro-Tech, Inc., Shawnee, KS 66203; telephone: 1-800-879-4755
	Vitamin Shoppe	D3	1000IU D3	None	None	$7.99/200 soft gels	Customer Care Department, The Vitamin Shoppe, 2101 91st Street, North Bergen, NJ 07047
	Vitamin World Calcium and D	Calcium and Vitamin D	250IU/two caplets	480mg	None	$7.99/250 caplets	VitaminWorld.com, 105 Orville Drive, Bohemia, NY 11716-2599; telephone: 1-866-667-8977

Evaluating Vitamin D Levels 

When assessing vitamin D levels, 25 OHD (calcidiol) is the best marker for concentrations of vitamin D status.1 Its concentration in the serum is about 1000-fold higher than that of calcitriol, and it has a much longer half-life of 15 days, compared with only 15hours for calcitriol.2, 5 Although the vast majority of dialysis patients are vitamin D-deficient, it remains unclear as to which patients should have their Vitamin D levels tested and whether they should be treated if levels are low. Target groups to consider evaluating are those patients with other co-morbidities such as cancer or autoimmune disorders or those who may not have been treated with Vitamin D analogs. Also unclear is the optimal level of vitamin D for overall health and well-being, as well as the level that might be considered toxic. Severe deficiency is defined as levels <25 nmol/L, while optimal levels are set at >75 nmol/L; levels >250 nmol/L are considered toxic.1, 6, 9, 10

Addressing Low Vitamin D Levels 

In the general population, adequate intake levels are recommendations by the United States Institute of Medicine of the National Academy of Sciences, in an effort to prevent deficiencies.

According to current research, the recommendation of 400 to 600IU per day appears insufficient to prevent deficiencies in many people, and for those who are vitamin D-deficient, 400IU of vitamin D will not be enough to raise 25 OHD levels to >75 to 80 nmol/L.6 If vitamin D levels are reported low, most practitioners treat with 50,000IU of vitamin D once a week for 6 to 12 weeks. This amount may vary, based on degree of deficiency and the physician's protocol. After the initial or loading course is completed, levels need to be rechecked. After optimal levels are achieved, they can be maintained through diet and a vitamin D supplement. Maintenance vitamin D supplementation can be given as daily dosing or monthly dosing. Because further research has shown the benefits of vitamin D, researchers are asking for increased recommendations for vitamin D of at least 1000IU daily.2, 9 Up to 10,000IU daily was shown to constitute a safe upper limit in the general population.2, 6 More research needs to be performed regarding safe levels in the CKD population.

Conclusions 

Patients with CKD are low in vitamin D, especially as they approach CKD stage 5D. We have been using vitamin D analogs to treat secondary hyperparathyroidism for years, and there appears to be a role for supplementing 25 OHD in our CKD population. With limited exposure to sunlight, and food sources that are high in phosphorus, dietary supplements are the best bet for ensuring an adequate intake of vitamin D. If you choose to recommend a vitamin D supplement, be aware that many come as vitamin D alone, some are added to multivitamins, and some are supplemented with calcium. Read the labels carefully, in an effort to make the best choice for your patient.