Evaluating hormonal mechanisms of vitamin D receptor agonist therapy in diabetic kidney disease: the VALIDATE-D study

Abstract

Background: Insufficient vitamin D status and increased renin-angiotensin system (RAS) activity have been associated with renal-vascular disease and nephropathy in diabetes. Accumulating evidence indicates that vitamin D receptor (VDR) activation lowers unfavorable RAS activity; however, more human intervention studies evaluating whether this mechanism could influence diabetic kidney disease are needed. We previously reported that both vitamin D levels and genetic variation at the VDR predict human RAS activity, and that vitamin D therapy can lower RAS activity in non-diabetics. The VALIDATE-D study is a randomized, placebo-controlled, intervention study designed to extend these findings by evaluating whether direct VDR activation in diabetes lowers circulating and local renal-vascular tissue RAS activity (Aims 1 and 2) in a manner similar to the action of ACE inhibitors (Aim 3).

Methods/design: Forty subjects with type 2 diabetes, microalbuminuria, and without chronic kidney disease will be recruited to undergo detailed assessment of the RAS before and after randomization to calcitriol 0.75 mcg/day or placebo. Primary analyses will evaluate whether calcitriol therapy reduces circulating and renal-vascular tissue-RAS activity in comparison to placebo. All subjects will thereafter be treated with lisinopril and followed for 3.5 months to evaluate whether combination therapy (calcitriol + lisinopril vs. placebo + lisinopril) additively or synergistically improves renal-vascular function, and lowers proteinuria.

Discussion: The VALIDATE-D study is the first human intervention study to evaluate whether direct VDR activation can lower the human RAS in diabetes, compared to the effect of an ACE inhibitor, and whether this mechanism can translate to clinically relevant endpoints for diabetic kidney disease. The outcomes of VALIDATE-D will have major implications for the recommendation of vitamin D supplementation for the primary prevention of kidney complications in diabetes.

Trial registration: ClinicalTrials.gov, NCT01635062.

Figures

Figure 1

The proposed interaction between vitamin D and RAS metabolism. Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is further converted to the vasoactive peptide angiotensin II. Angiotensin II is a direct vasoconstricter, and can also ilicit aldosterone secretion from the adrenal cortex. Under physiologic situations, activation of the RAS in response to renal-vascular hypo-perfusion serves to increase blood pressure and renal salt retention. However, in pathologic states (such as in diabetes and obesity), inappropriately high RAS activity contributes to vascular and kidney diseases. Vitamin D3 is largely produced in the skin with exposure to ultraviolet radiation, but may also be ingested orally. This precursor is hydroxylated to 25-hydroxyvitamin D (25[OH]D) and 25(OH)D serves as the stable barometer of clinical “vitamin D status.” Under the control of parathyroid hormone and calcium status, 25(OH)D can be hydroxylated to form the active vitamin D receptor (VDR) agonist 1,25-dihydroxyvitamin D (1,25[OH]2D). Activation of the VDR by 1,25(OH)2D is known to influence the regulation and expression of a myriad of genes, including renin.

Figure 2

VALIDATE-D study schema: subjects will be screened and then may undergo a medication washout to withdraw interfering anti-hypertensive medications (when applicable). Aim 1: The circulating RAS will be assessed on LS diet before and after randomization to calcitriol/placebo (visits 2 & 5). Aim 2: The renal-vascular tissue-RAS will be assessed on HS diet before and after calcitriol/placebo (visits 3 & 6). Aim 3: All subjects will then receive lisinopril 5 mg/d in addition to calcitriol/placebo to assess the impact of combination therapy (calcitriol + lisinopril vs. placebo + lisinopril) on the renal-vascular tissue-RAS (visits 6 & 8) and proteinuria (visits 6, 8, 13). Serum calcium and phosphate will be monitored weekly throughout the study for safety, at each visit and at designated safety checks (visits 4, 7, 9–12).

Figure 3

Reciprocal relationship between renal-vascular tissue-RAS activity and the renal-vascular response to angiotensin II. A blunted response to angiotensin II reflects a high level of local, endogenous, renal-vascular tissue-RAS activity (the smaller the decline in renal plasma flow in response to an infusion of angiotensin II, the greater the activity of the local renal-vascular tissue-RAS). Conversely, a robust response to angiotensin II is observed when tissue-RAS activity is low.