How to Manage Vitamin D Deficiency

How to Manage Vitamin D Deficiency
October 23, 2007

The problem is so prevalent in CKD and dialysis patients that most will require supplementation

BY DANIEL W. COYNE, MD

THE ACTIVE forms of vitamin D—calcitriol, paricalcitol, and doxercalciferol—which also are known as vitamin D receptor activators (VDRAs), have been largely used in nephrology only as a treatment for secondary hyperparathyroidism, an elevation in parathyroid hormone (PTH) due to renal failure. Serum levels of calcitriol, the native form of active vitamin D, decline as renal function worsens, and calcitriol deficiency is almost universal among untreated patients on dialysis.1,2 Simultaneously, CVD and death risk rise dramatically as renal failure progresses. Emerging data suggest calcitriol deficiency and nutritional vitamin D deficiency contribute to the cardiovascular burden independent of changes in PTH.3

Patients with kidney disease have a high incidence of deficiency of nutritional vitamin D, which is hydroxylated by the liver to 25(OH)D, the substrate for the formation of calcitriol. Hormonal, or circulating, calcitriol (1,25-dihydroxyvitamin D) is produced by a 1α-hydroxylase in the kidney, and less calcitriol is produced in CKD patients. Multiple other tissues, such as the vasculature, prostate, breast, and immune cells also have the 1α-hydroxylase enzyme. These tissues are believed to produce high levels of local calcitriol to serve as crucial autocrine and paracrine factors acting through the vitamin D receptor (VDR) present in a wide range of tissues, including heart and vascular smooth muscle and immune cells.

Nutritional vitamin D deficiency can limit the available substrate for calcitriol production by the kidney and in all other tissues expressing 1α -hydroxylase. Additionally, 25(OH)D may have independent activity in the body. Use of VDRAs treats hormonal calcitriol deficiency, but nutritional vitamin D deficiency still can limit local calcitriol production. Consequently, repletion of vitamin D stores appears reasonable even if VDRA therapy is being administered.

Hence, the role of vitamin D and calcitriol have shifted from solely involved with enhancing calcium absorption and suppressing PTH, to crucial agents maintaining the health of the vasculature, immune system, and other tissues by activating the VDR.4

Deficiency in calcitriol, and the resultant decreased activation of the VDR, may contribute to vascular smooth muscle proliferation and cardiac hypertrophy, endothelial dysfunction, thrombosis, and other abnormalities which cumulatively increase the risk of mortality.

Deficiencies common

The recently published SEEK Study1 examined nutritional vitamin D levels (25(OH)D) and calcitriol levels in 1,814 CKD patients. Approximately half of Stage 2 and 3 CKD patients were nutritionally vitamin D deficient (25(OH)D less than 30 ng/mL), and this deficiency was even more common among stage 4 CKD patients. Additionally, calcitriol levels were overtly low (less than 22 pg/mL) in 13% of patients with an estimated glomerular filtration rate (GFR) greater than 80 mL/min per 1.73 m2 and greater than 60% when GFR was below 30 mL/min per 1.73 m2. Similarly, a study of incident dialysis patients found the vast majority were deficient in nutritional vitamin D and had low calcitriol levels.2

Vitamin D and calcitriol deficiency generally have been viewed in nephrology as a problem only if hyperparathyroidism was present. Consequently, guidelines written by the National Kidney Foundation's Kidney Diseases Outcomes Quality Initiative (KDOQI) in 2003 recommended evaluation and treatment for nutritional vitamin D deficiency only if PTH is elevated, and then restricted that recommendation to non-dialysis patients. Yet, SEEK data showed that only 35% of CKD patients deficient in nutritional vitamin D had elevated PTH, and dialysis patients exhibit a poor correlation between vitamin D deficiency and hyperparathyroidism.

Use of the VDRAs calcitriol, paricalcitol, and doxercalciferol was recommended by KDOQI guidelines only if PTH was elevated based on CKD stage-specific targets. Use of a VDRA was discouraged if serum phosphorus exceeded 5.5 mg/dL or serum calcium exceeded 9.5 mg/dL. Yet, only 49% of stage 3 and 4 CKD patients with calcitriol deficiency had an elevated PTH,1 and incident dialysis patients exhibit a poor correlation between calcitriol levels and PTH.2 These data indicate an elevated PTH is a poor indicator of deficiencies of nutritional vitamin D and calcitriol in CKD patients.

Nutritional vitamin D deficiency is now believed to have diverse adverse effects well beyond PTH and its re-lated bone disease. Large observational studies have recently found nutritional D deficiency is associated with greater insulin resistance among CKD patients,5 and an increased likelihood of having diabetes, elevated triglycerides, or hypertension.6 In the general population, nutritional vitamin D deficiency is associated with subsequently developing hypertension.7

Vitamin D deficiency at initiation of dialysis strongly correlates with the risk of death in the subsequent 90 days.2 Additionally, supplementation with ergocalciferol in CKD and dialysis patients has not been noted to have any adverse effects, does lower PTH in CKD patients, and is associated with significant reductions in epoetin requirements in dialysis patients.8, 9 Lastly, treatment of vitamin D deficiency prevents osteomalacia, a serious bone disorder that causes bone pain, deformity, and fractures.

Similar to nutritional vitamin D deficiency, calcitriol deficiency has been associated with an increased risk of death in the first 90 days on dialysis.2 Low calcitriol levels in dialysis patients correlate with increased aortic pulse wave velocity and de-creased arterial distensibility, indicating impaired arterial function. 10 Large observational studies have found use of calcitriol or other VDRA is associated with a significant improvement in survival in dialysis.11-13

The putative survival benefit from use of VDRA is unlikely to be mediated through changes in PTH alone. Rather, the diverse actions of VDRAs likely provide cardiovascular and immunologic benefits observed in various recent preclinical studies.4

Randomized, placebo controlled trials have found treatment with vitamin D supplements provides benefits and is safe. Ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) can be used to treat nutritional vitamin D deficiency. In randomized trials, ergocalciferol significantly improved neuromuscular performance and balance among elderly with a history of falls,14 and in a second study reversed muscular atrophy and reduced falls and hip fractures.15 A recent meta-analysis of trials supports the view that treatment of vitamin D deficiency reduces falls in the elderly by more than 20%.16 A double blind trial of cholecalciferol in heart failure patients showed vitamin D lowered PTH, and increased the anti-inflammatory cytokine interleukin-10 while preventing an increase in the pro-inflammatory cytokine TNF-α .17

While these studies and analyses have shown the benefits of treating vitamin D deficiency, others have not, and larger studies are warranted. Nevertheless, treatment with vitamin D has been shown to decrease vertebral fractures in women, and lower PTH in patients with stage 3 CKD. Moreover, data suggest there is virtually no risk associated with vitamin D supplementation, so the broad use of vitamin D supplements among CKD patients appears reasonable.

The risk-benefit ratio for use of calcitriol and other VDRAs is not as broad as nutritional vitamin D. Calcitriol appears to have the narrowest therapeutic index, resulting in a high incidence of hypercalcemia and hyperphosphatemia as the dose is increased. However, even small doses of calcitriol may provide benefits.11,13 Paricalcitol has the widest therapeutic window, and is also associated with a greater survival benefit compared to calcitriol.18 Consistent with the view that VDRAs have non-PTH mediated benefits, a post hoc analysis of a placebo controlled trial in CKD patients found paricalcitol reduced proteinuria, an effect difficult to ascribe to PTH reduction.19

Management

Given the high prevalence of vitamin D deficiency in CKD and dialysis patients, limiting screening and treatment of vitamin D deficiency to only those with hyperparathyroidism is not appropriate. Additionally, screening for vitamin D deficiency in CKD and dialysis patients by measuring 25(OH)D levels is expensive and is probably unnecessary as treatment can be provided safely to virtually all patients.8,9 The very high prevalence of vitamin D deficiency in both CKD and dialysis populations means most patients will require supplementation.

Typical supplemental doses of vitamin D can replete vitamin D deficient patients while presenting no risk to patients with adequate vitamin D stores. Using just such a global treatment strategy in our dialysis center, our group has found a single monthly 50,000 IU ergocalciferol capsule repleted virtually all vitamin D deficient patients within six months and resulted in no dangerously high vitamin D levels.8 After two years of continued monthly supplementation, 25(OH)D levels remain in a safe and satisfactory range without apparent adverse effects.

Hyperparathyroidism is a clear indication for use of VDRAs in CKD and dialysis patients, and provides the opportunity for clinicians to treat calcitriol deficiency. Serum calcium and phosphorus should be monitored, and the VDRA dose adjusted or VDRAs with wider therapeutic windows used to avoid hypercalcemia and minimize increases in serum phosphorus. Hypocalcemia is another opportunity to use VDRAs. Claims that VDRA-induced changes in calcium and phosphorus increase mortality are speculative at best, and inconsistent with available observational data. These claims also have at their core the belief that a deficiency in the calcitriol hormone is good for patients. Although use of VDRAs when hyperparathyroidism is not present appears to provide a survival benefit in observational studies, randomized controlled trials in CKD and dialysis patients with low or normal PTH are needed to confirm that such therapy provides benefits that outweigh potential harm.

References

1. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71(1):31-38.

2. Wolfe M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;Advance online publication, 8 August 2007; doi:10.1038/sj.ki.5002451.

3. Wu-Wong JR. The potential for vitamin D receptor activation in cardiovascular research. Expert Opin Investig Drugs. 2007;16:407-411.

4. Wu-Wong JR. Vitamin D receptor: a highly versatile nuclear receptor. Kidney Int. 2007;72(3):237-239.

5. Chonchol M, Scragg R. 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney Int. 2007;71:134-139.

6. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2007;167:1159-1165.

7. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. 2007;49:1063-1069.

8. Saab G, Young DO, Gincherman Y, et al. Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract. 2007;105:c132-c138.

9. Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease. Am J Nephrol. 2007; 27:36-43.

10. London GM, Guerin AP, Verbeke FH, et al. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007;18:613-620.

11. Teng M, Wolf M, OfsthunMN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115-1125.

12. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70:771-780.

13. Tentori F, Hunt WC, StidleyCA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 2006;70:1858-1865.

14. Dhesi JK, Jackson SH, Bearne LM, et al. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing. 2004;33:589-595.

15. Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis. 2005;20:187-192.

16. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293:2257-2264.

17. Schleithoff SS, Zittermann A, Tenderich G, et al. Vitamin D supplementation im-

proves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006;83:754-759.

18. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446-456.

19. Agarwal R, Acharya M, Tian J, et al. Antiproteinuric effect of oral paricalcitol

in chronic kidney disease. Kidney Int. 2005;68:2823-2828.

Dr. Coyne is professor of medicine at the Washington University School of Medicine in St. Louis, Mo.

Conflicts of Interest: Consultant to Abbott, Watson, INEOS; Speaker for Abbott, Amgen, Watson; Research support from Abbott, Amgen, Genentech, Roche, and Watson.
From the October 2007 Issue of Renal And Urology News

http://www.renalandurologynews.com/How-to-Manage-Vitamin-D-Deficiency/article/58154/