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.

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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.


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