Vitamin D and Outcomes: Albuminuria and LVH
Vitamin D therapy, both in CKD and in the general population, has been hypothesized to have multiple health benefits outside of bone health including effects on albuminuria, left ventricular size and function, and kidney disease progression. There are current on-going clinical trials in both CKD, ESRD, and in the general population to try to clarify whether these effects exist.
A recent clinical trial (the VITAL study) showed that paricalcitol has beneficial extra-skeletal effects. This trial was a multicenter, multinational study of 281 patients with albuminuria and on an ACE inhibitor or angiotensin receptor blocker at baseline. The study revealed a significant reduction in the urinary albumin/creatinine ratio in participants on the 2 microgram dose of paricalcitol compared with placebo.
This was associated with a lowering of estimated glomerular filtration rate (GFR) that was significant also at the 1 microgram dose. This was a well-designed study evaluating effects on albuminuria, but it did not examine the more important question of whether this decrease in albuminuria translates to better clinical outcomes, such as less rapid progression to dialysis.
An association between low vitamin D levels and left ventricular hypertrophy (LVH) is clear in animal models, but, based on recent data, not as clear in humans. The vitamin D receptor knock-out mouse develops LVH, and 1,25-dihydroxyvitamin D has been shown to regulate myocyte proliferation.10
In humans, treatment with paricalcitol for 48 weeks in 227 patients with CKD did not change left ventricular myocardial index as shown by the recent PRIMO study.11 In a post hoc analysis, paricalcitol treatment did decrease left atrial volume index.12 It is unclear at this point why paricalcitol did not decrease LVH in the PRIMO trial as it did in animal models.
Side effects of Vitamin D therapy?
Observational studies suggest that treatment with vitamin D may affect survival of dialysis patients. Several recent trials have used low-dose nutritional vitamin D in addition to an active agent (such as activated vitamin D or cinacalcet). The question then becomes, can patients with CKD or on dialysis get too much vitamin D? There is potentially an important difference in vitamin D’s action depending on the dose of a vitamin D analog. For example, in a mouse model of kidney disease, low levels of vitamin D (paricalcitol or calcitriol) were protective against vascular calcification while higher doses were associated with more calcification.13
Potentially, both lack of and too much vitamin D may lead to vascular calcification. In addition, in post-menopausal women, even a low dose of vitamin D (cholecalciferol 400 IU combined with calcium treatment) was associated with a greater risk of kidney stones compared to placebo treatment.14
Thus, vitamin D in both nutritional and activated forms may have side effects that are as yet under-appreciated. More research is needed in this area.
Michal L. Melamed, MD, MHS, is an associate professor in the Department of Medicine and the Department of Epidemiology and Population Health, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, N.Y.
- Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007;72:1004-1013.
- Bhan I, Burnett-Bowie SA, Ye J, et al. Clinical measures identify vitamin D deficiency in dialysis. Clin J Am Soc Nephrol2010;5:460-467.
- Ravani P, Malberti F, Tripepi G, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 2009;75:88-95.
- Drechsler C, Pilz S, Obermayer-Pietsch B, et al. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J2010;31:2253-2261.
- Drechsler C, Verduijn M, Pilz S, et al. Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. Nephrol Dial Transplant 2011;26:1024-1032.
- Kalantar-Zadeh K, Kovesdy CP. Clinical outcomes with active versus nutritional vitamin D compounds in chronic kidney disease. Clin J Am Soc Nephrol 2009;4:1529-1539.
- Melamed ML, Thadhani RI. Vitamin D therapy in chronic kidney disease and end stage renal disease. Clin J Am Soc Nephrol 2012;7:358-365.
- Palmer SC, McGregor DO, Macaskill P, et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med 2007;147:840-853.
- Kandula P, Dobre M, Schold JD, et al. 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.
- Xiang W, Kong J, Chen S, 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.
- Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA 2012;307:674-684.
- Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J 2012;164:902-9 e2.
- Mathew S, Lund RJ, Chaudhary LR, et al. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol 2008;19:1509-1519.
- Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.