Does this patient have Vitamin D deficiency?

Vitamin D deficiency (low levels of 25-hydroxyvitamin D) is common in patients with chronic kidney disease, including patients on dialysis. Etiology is likely multifactorial but may be related to diminished capacity of vitamin D production by skin, limited exposure to sunlight, reduced intake of foods rich in vitamin D, and older age. Recent evidence suggests that 25-hydroxyvitamin D may have important roles due to the ability of extrarenal tissues to convert 25-hydroxyvitamin D into the active form, or 1,25-dihydroxyvitamin D. However, the existing evidence is from observational and animal studies. Although repletion of vitamin D deficiency in ESRD appears to be safe in short-term studies, the benefits of repletion on hard clinical outcomes remain undetermined. Therefore, it is uncertain if levels should be measured in the clinical setting and how to manage deficiency if detected.

Key elements in the history

Usually detected when levels are checked
The number of 25-hydroxyvitamin D tests being performed has risen
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Key symptoms

Usually asymptomatic, though severe deficiency may be associated with muscle weakness, bone pain, fractures
In the dialysis population, low concentration of 25-hydroxyvitamin D may also contribute to erythropoetin resistance

Key signs and physical findings

Usually accompanies other abnormalities in the CKD-MBD syndrome, especially secondary hyperparathyroidism
Controversies in the differential diagnosis

Definitions for deficiency and sufficiency continue to be debated

Most commonly accepted thresholds are listed below

▪ Deficiency: 25-hydroxyvitamin D levels less than 10 ng/ml

▪ Insufficiency: 25-hydroxyvitamin D levels less than 30 ng/ml

▪ Sufficiency: level of 30 ng/ml and above is considered to be normal

What tests to perform?

Lab testing

Which tests should I order?

25-hydroxyvitamin D level
Many available tests, with accuracy varying by laboratory/test

How do I interpret test results?

Deficiency, insufficiency and sufficiency as defined above

How often should I order tests?

If sufficient, levels can be rechecked again …
If deficient or insufficient and treatment is instituted then levels could be checked again following repletion …

What are the next steps?

Consider 25-hydroxivitamin D levels along with other mineral metabolism laboratory values

Overall Interpretation of test results (diagnosis, prognosis)

Recognize that results may vary by assay method and laboratory used
If possible, use the same laboratory/assay over time
Consider seasonal variation
Consider 25-hydroxivitamin D levels along with other mineral metabolism lab values

Controversies in diagnostic testing

Definitions for deficiency and sufficiency continue to be debated
given paucity of evidence regarding outcomes following repletion in dialysis patients, it is not clear that levels should be measured in the clinical setting and how to manage deficiency if detected

How should patients with Vitamin D deficiency be managed?

Key treatment concepts

What to do first: REPLETION

the following regimens have been shown to be successful as repletion schedules:

Ergocalciferol 50,000 IU weekly for 24 weeks

Ergocalciferol 50,000 IU monthly for 6 months

Oral Cholecalciferol 100,000 IU monthly for 15 months

What to do next: MAINTENANCE:

at least 800 IU daily, more may be needed in colder climates and during winter season

Specific circumstances

if a patient is found to be vitamin D deficient and is already receiving active Vitamin D analogs, repletion with above regimen in addition to active vitamin D analogs, if undertaken, is likely safe but calcium and phosphorus levels should be monitored monthly

Controversies in patient management

Given paucity of data on patient level outcomes following repletion, it remains uncertain whether 25D levels should be checked in dialysis patients and if so how this should be managed
Those that recommend repletion are extrapolating from data in normal populations and few small studies in dialysis patients

What happens to patients with Vitamin D deficiency?

Natural history

Adequate levels depend on sufficient exposure to ultraviolet light and dietary sources
Dialysis patients are particularly at risk given limited exposure to sunlight, reduced intake of foods rich in vitamin D
Depleted stores may lead to insufficient substrate for conversion to the biologically active form

Epidemiology

In a cohort study of US incident dialysis patients, 78% were deficient (levels between <30 ng/ml) and 18% were severely deficient (levels <10 ng/ml)
Black race, female sex, winter season, and hypoalbuminemia were the strongest predictors of vitamin D deficiency

Anatomic and/or pathologic consequences

Fractures
Systemic consequences, as described below

Physiologic and/or pathophysiologic implications

Classic effects

Decreased levels of calcidiol in conjunction with decreased activity of 1-alpha-hydroxylase will lead to diminished production of the calcitriol

Decreased calcitriol levels will result in impaired gastrointestinal calcium absorption, negative calcium balance, secondary hyperparathyroidism, and bone disease
Other systemic effects

Increased infections

Anemia, erythropoetin resistance

Increased mortality

Pharmacologic considerations

Preparations

Plant derived – ergocalciferol – vitamin D2

Animal derived – cholecalciferol – vitamin D3

While cholecalciferol appears to be more effective in raising levels (possibly due to greater affinity to vitamin D binding protein and hence longer half-life), ergocalciferol remains the most commonly used form in practice.
Dose and duration of treatment

Several dosing regimens appear to be effective in raising 25-hydroxyvitamin D levels (with some studies also showing increased in 1,25-dihydroxyvitamin D levels and decreases in PTH levels) though data on patient level outcomes following treatment are missing

The following regimens have been shown to be successful in raising 25-hydroxyvitamin D levels:

Ergocalciferol 50,000 IU weekly for 24 weeks

Ergocalciferol 50,000 IU monthly for 6 months

Oral Cholecalciferol 100,000 IU monthly for 15 months

How to utilize team care?

Nurses may help track levels and repletion schedules.

Are there clinical practice guidelines to inform decision making?

Applications

Kidney Disease Outcomes Quality Initiative (KDOQI)

No recommendations regarding treatment due to insufficient evidence at the time
Kidney Disease: Improving Global Outcomes(KDIGO)

although randomized controlled trial (RCT) data are lacking, guidelines recommend managing deficiency in a manner similar to what is being done for the general population

Limitations

KDOQI published in 2003, prior to some of the recent emerging observational and experimental data

What is the evidence?

Bhan, I, Thadhani, R. “Dietary vitamin D intake in advanced CKD/ESRD”. Semin Dial. vol. 23. 2010. pp. 407-410. (This is a focused review of the available data on dietary vitamin D in chronic kidney disease.)

Rosen, CJ. “Vitamin D Insufficiency”. N Engl J Med. vol. 364. 2011. pp. 248-254. (This is a comprehensive review of the systemic effects of low vitamin D levels.)

Bhan, I, Burnett-Bowie, SA, Ye, J, Tonelli, M, Thadhani, R. “Clinical measures to identify vitamin D deficiency in dialysis”. CJASN. vol. 5. 2010. pp. 460-467. (This a report of a study performed in incident dialysis patients to identify predictive characteristics of hypovitaminosis D in this population.)

Wolf, M, Shah, A, Gutierrez, O, Ankers, E, Monroy, M, Tamez, H, Steele, D, Chang, Y, Camargo, CA, Tonelli, M, Thadhani, R. “Vitamin D levels and early mortality among incident hemodialysis patients”. Kid Int. vol. 72. 2010. pp. 1004-1013. (This is an observational study of incident dialysis patients that relates low vitamin D levels to poor clinical outcomes in dialysis patients.)

Jean, G, Souberbille, JC, Chazot, C. “Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation”. Nephrol Dial Transplant. vol. 24. 2009. pp. 3799-3805. (This is a pilot study that suggests that repletion of nutritional vitamin D may be effective in the dialysis setting.)

Moorthi, RN, Kandula, P, Moe, SM. “Optimal Vitamin D, Calcitriol, and vitamin D analog replacement in chronic kidney disease: to D or not to D: that is the question”. Curr Opin Nephrol Hypertens. vol. 20. 2011. pp. 354-9. (This is critical review of the recent evidence in support of vitamin D treatment in CKD.)

Bhan, I, Dobens, D, Tamez, H, Deferio, JJ, Li, YC, Warren, HS, Ankers, E, Wenger, J, Tucker, JK, Trottier, C, Pathan, F, Kalim, S, Nigwekar, SU, Thadhani, R. “Nutritional vitamin D supplementation in dialysis: a randomized trial”. Clin J Am Soc Nephrol. vol. 10. 2015. pp. 611-9. (This paper reports the results from a randomized, placebo-controlled, parallel-group multicenter trial compared two doses of ergocalciferol with placebo in 105 patients initiating hemodialysis. The study showed that repletion can be accomplished without significant changes in calcium or phosphate levels.)

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Nephrology Hypertension

Medical Management of the Dialysis Patient: Vitamin D Deficiency