Current and Future Status of Vitamin D Therapy in Hypertension and Kidney Disease

Michael W. Rich, MD

Review

Vaidya A, Forman JP. Vitamin D and vascular disease: the current and future status of vitamin D therapy

in hypertension and kidney disease. Curr Hypertens Rep. 2012;14:111-119.

I

n the past decade, numerous observational studies have implicated vitamin D insufficiency and deficiency as risk factors for hypertension, cardiovascular disease, and kidney disease. Yet prospective randomized trials reported to date have failed to provide convincing evidence that vitamin D supplementation has salutary effects on relevant clinical outcomes. Vaidya and Forman review the putative mechanisms underlying the potential vascular and renal effects of vitamin D; findings from observational studies examining the relationship between vitamin D, hypertension, and kidney disease; data from clinical trials; and future directions in vitamin D research and the role of vitamin D therapy in the prevention and treatment of cardiovascular and renal disease.1

Mechanisms

Based on multiple studies in both laboratory animals and humans, several plausible mechanisms have been proposed whereby low levels of vitamin D might contribute to elevated blood pressure and chronic kidney disease (CKD). By far the best studied and welldocumented effect is that low vitamin D levels are associated with increased activation of the renin-angiotensinsystem (RAS), including increased renin activation, increased circulating angiotensin II concentrations, and increased

RAS activity in cardiac and renal tissue. These effects contribute directly to elevations in blood pressure and left ventricular mass, as well as to renal injury. Conversely, these effects are attenuated by RAS inhibitors, vitamin D supplementation, or administration of vitamin D receptor (VDR) agonists.

Additional mechanisms that may contribute to the associations of vitamin D with vascular and renal pathology include vitamin D—mediated alterations in calcium flux in vascular smooth muscle cells, alterations in the effects of advanced glycation end products on endothelium, alterations in nitric oxide system activity, alterations in activity of inflammatory cytokines and other mediators of inflammation, and alterations in prostacyclin production. Studies in humans also indicate that higher vitamin D concentrations are associated with improved endothelial function, reduced oxidative stress, and increased circulating adipocytokine levels. Vitamin D may also inhibit renin gene expression, and there is evidence that VDR agonists inhibit transforming growth factor beta and extracellular signal-regulated protein kinase, implying anti-proliferative and/or anti-inflammatory renoprotective effects.

Studies

Cross-sectional and prospective observational studies examining the relationship between vitamin D and blood pressure have provided inconsistent findings. In several large prospective studies, including the Health Professionals’ Follow-up Study in men and both the Nurses’ Health Study and Michigan Bone Health and Metabolism

Study in women, lower vitamin D levels at baseline were associated with significantly higher rates of incident hypertension during follow-up periods ranging from 4 to 14 years.2-4 Conversely, the Tromso Study failed to find a significant relationship between baseline vitamin D levels and either blood pressure orincident hypertension during 14 years of follow-up.5

Observational studies evaluating the association between vitamin D and renal disease have also produced mixed results. In the Third National Health and Nutrition Examination Survey (NHANES III), a cross-sectional study of over 15,000 US adults, individuals in the lowest vitamin D quartile had a moderate but significantly higher prevalence of albuminuria than those in the highest quartile (odds ratio 1.37).6 Several small longitudinal studies have also shown an association between baseline

vitamin D levels and progression of kidney disease and proteinuria. Nonetheless, a meta-analysis of 22 studies of low to moderate quality, including 17 observational studies and 5 randomized trials, found no significant effect of vitamin D2 or D3 supplementation on either renal function or urinary albumin excretion.7

As previously reported by Vaidya and Forman and briefly summarized in the current review, there have been approximately 13 prospective randomized trials involving vitamin D therapy for which data on blood pressure are available.1,8 The largest of these studies, the Women’s Health Initiative, enrolled 36,252 subjects9; all other studies enrolled fewer than 500 subjects and more than half enrolled fewer than 100 subjects. The dose of vitamin D was highly variable and the followup duration ranged from 5 weeks to 7 years. Only 2 of the studies evaluated blood pressure as the primary end point in subjects free of antihypertensive therapy. Overall, 11 of the 13

studies found no effect of vitamin D therapy on blood pressure. Two studies reported a favorable effect, including 1 study in which blood pressure was the primary end point. In this study, 800 IU of vitamin D3 for 8 weeks was associated with a 7—mm Hg decline in systolic blood pressure compared with placebo among 148 older women with a mean baseline 25-(OH)-vitamin D level of 10 ng/mL.10 All studies reported to date are limited by small sample size, short follow-up, and/or insufficient dose of vitamin D to significantly affect serum levels.

As noted previously, a meta-analysis that included 5 low- to moderate-quality randomized trials failed to show a beneficial effect of vitamin D therapy on renal outcomes. On the other hand, 5 trials evaluating the effect of a VDR agonist (paricalcitol or calcitriol) on proteinuria consistently demonstrated a salubrious effect. These studies ranged in size from 10 to 281 subjects, and follow-up ranged from 1 month to 6 months; all subjects had baseline CKD stages 2 to 4. In the largest and most

recent study, paricalcitol 2 mcg/d for 6 months was associated with an 18% to 28% reduction in the urinary albuminto-creatinine ratio relative to placebo.11 A limitation of these studies, apart from small sample size and short duration, is that none evaluated renal function per se as the primary outcome.

Conclusion

Mechanistic studies in laboratory animals and humans provide strong support for a role for vitamin D in the regulation of vascular and renal function, as well as a clear basis for an association between vitamin D insufficiency and deficiency and hypertension, vascular disease, and kidney disease. However, observational studies and clinical trials in humans have been inconclusive. It is important to note that all randomized trials to date are beset with major limitations. It is therefore evident that additional mechanistic and clinical studies are essential in order to elucidate the role of vitamin D replacement therapy, VDR agonists, and increased sun exposure in the prevention and treatment of hypertension and kidney disease. In this regard, the ongoing Vitamin D and Omega-3 (VITAL) study, which is randomizing 20,000 US subjects to vitamin D3 2000 IU daily or placebo and to omega-3 fatty acids or placebo, should provide valuable insights.12

References

1. Vaidya A, Forman JP. Vitamin D and vascular disease: the current and future status of vitamin D therapy in hypertension and kidney disease. Curr Hypertens Rep. 2012;14:111-119.

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

3. Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension among young women. Hypertension. 2008;52:828-832.

4. Griffin FC, Gadegbeku CA, Sowers MR. Vitamin D and subsequent systolic hypertension among women. Am J Hypertens. 2010;24:316-321.

5. Jorde R, Figenschau Y, Emaus N, Hutchinson M, Grimnes G. Serum 25-hydroxyvitamin D levels are strongly related to systolic blood pressure but do not predict future hypertension. Hypertension. 2010;55:792-798.

6. deBoer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination

Survey (NHANES III). Am J Kidney Dis. 2007;50:69-77.

7. Kandula P, Dobre M, Schold JD, Schreiber Jr MJ, Mehrotra R, Navaneethan SD. Vitamin D supplementation in chronic kidney disease: a systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol. 2011;6:50-62.

8. Vaidya A, Forman JP. Vitamin D and hypertension. Current evidence and future directions. Hypertension. 2010;56:774-779.

9. Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: the Women’s Health Initiative Randomized Trial. Hypertension. 2008;52:847-855.

10. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen D. Effects of a shortterm vitamin D(3) and calcium supplementation on blood pressure and parathyroid

hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86:1633-1637.

11. De Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL

study): a randomised controlled trial. Lancet. 2010;376:1543-1551.

12. Clinicaltrials.gov. Vitamin D and Omega-3 Trial (VITAL). http://clinicaltrials.gov/ct2/show/NCT01169259. Accessed April 9, 2012.

13. McGreevy C, Williams D. New insights about vitamin D and cardiovascular disease: a narrative review. Ann Intern Med. 2011;155:820-826.

14. Qaseem A, Snow V, Shekelle P, Hopkins R Jr, Forciea MA, Owens DK. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149:404-415.

15. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and metaanalysis. BMJ. 2011;342:d2040.

Commentary

Current and Future Status of Vitamin D Therapy

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ardly a week goes by without a new article in a major medical journal expounding on the dangers of vitamin D deficiency or extolling the virtues of vitamin D supplementation. Indeed, vitamin D deficiency has been linked not only to hypertension and cardiovascular disease, but also to diabetes, stroke, kidney disease, various forms of cancer, multiple sclerosis, dementia, pre-eclampsia, and even statin myopathy (not to mention the more prosaic disorders, osteoporosis and fractures). Conversely, vitamin D supplementation, usually in mega-dosages, is proposed as a potential panacea for all of these ills. But where is the evidence? Is this the vitamin

E, vitamin C, homocysteine, and hormone replacementtherapy story all over again?

One thing is clear: vitamin D insufficiency and deficiency are very common among American adults, affecting up to 75% of individuals.8 But is there even consensus on what constitutes insufficiency or deficiency? Not really, as insufficiency has been variously defined as <40 ng/ mL, <30 ng/mL, or <25 ng/mL, and deficiency has been defined as <20 ng/mL, <15 ng/mL, or <10 ng/mL. Given how arbitrary these definitions appear to be, it seems that some degree of skepticism is appropriate before accepting the claim that 75% of Americans are afflicted with hypovitaminosis D.

Fortunately, reviews like the one published in Current Hypertension Reports and another similar review by Mc-Greevy and Williams in the Annals of Internal Medicine

provide a more balanced view.1,13 Yes, there is good evidence that vitamin D plays a role in regulating the RAS and vascular function. And, yes, there is reasonable evidence that low vitamin D levels (however defined) may be associated with higher blood pressure and increased risk for vascular disease, kidney disease, and possibly other disorders. But there is no convincing evidence at this time that vitamin D replacement has a beneficial effect on any conditions other than rickets and osteoporosis (including prevention of hip fractures).

So how should the clinician translate current data on vitamin D into routine patient care? Should 25-(OH)-vitamin D levels be incorporated into patients’ cardiovascular risk profiles and assessed as part of standard chemistry batteries at regular intervals? Certainly not. However, it is reasonable and appropriate to check vitamin

D and possibly parathyroid hormone (PTH) levels in individuals at increased risk for osteoporosis, falls, and fractures, and to advocate supplemental vitamin D and calcium in accordance with current guidelines.14 Absent a routine vitamin D level, should all patients be advised to take vitamin D supplements (given that most

are likely to have “low” levels), and if so, how much? This is a difficult question. All patients should be encouraged to eat a balanced diet that contains sufficient

amounts of vitamin D from natural sources to meet or exceed the recommended daily allowance. Regular exercise and adequate sun exposure are also appropriate. But

based on the current lack of evidence to support vitamin D supplementation for the prevention or treatment of hypertension, cardiovascular disease, or kidney disease, routine vitamin D supplementation does not seem warranted. Indeed, there is evidence to suggest that vitamin D taken in conjunction with calcium may actually promote accelerated atherosclerosis.15

What do I tell my patients who ask if they should take vitamin D? For individuals with or at risk for osteoporosis, the answer is “yes,” and I usually recommend a minimum of 2000 IU daily along with calcium and close follow-up by their primary care physician. For those not at risk for osteoporosis, I usually explain that there is no evidence that taking vitamin D is beneficial, but also that it’s probably not harmful at modest dosages, such as 1000 to 2000 IU per day, and that it is therefore OK to take it, if desired.

In conclusion, I completely concur with Vaidya and Forman’s call for additional research on vitamin D, and eagerly await the results of the VITAL study (unfortunately, probably some 5 years away), which will hopefully answer key questions not only about vitamin D, but also about omega-3 fatty acid supplementation.

About the Author

Michael W. Rich, MD, is professor of medicine in the Cardiovascular Division of the Washington University School of Medicine in St. Louis, MO. He is also director of the Cardiac Rapid Evaluation Unit at Barnes- Jewish Hospital in St. Louis. He received his MD from the University of Illinois College of Medicine in Chicago, and did his internship, residency, and cardiology fellowship at the Jewish Hospital of St. Louis. Dr Rich’s main areas of interest are cardiovascular aging and cardiovascular disease in the elderly. He has published many papers, reviews, and book chapters related to heart failure and atrial fibrillation.