Is activated vitamin D supplementation renoprotective?

If activated vitamin D supplementation is renoprotective, is it because of suppression of the parathyroid hormone (PTH) or selective vitamin D receptor activation? In the present issue of Hypertension, Alborzi et al1 present the results of a well-done prospective clinical trial to evaluate the effects of short-term (1-month) treatment with activated vitamin D (paricalcitol) on blood pressure, biomeasures of inflammation, endothelial function, and measures of urinary protein excretion. The results are fascinating. As others have noted previously,2 there is an unmistakable effect in reducing urinary protein excretion and also on C-reactive protein levels. Yet, intriguingly, there is no apparent effect on blood pressure, measured either in the office or with 24-hour ambulatory blood pressure monitoring, nor was there an effect on renal hemodynamics, vascular function, or PTH levels. The combination of persistently high PTH levels and low 1,25-dihydroxyvitamin D levels has been reported to be associated with bone loss, cardiovascular disease, immunosuppression, and increased mortality in patients with endstage kidney disease.3,4 Recent studies in patients with chronic kidney disease (CKD) or end-stage kidney disease have suggested that paricalcitol (a selective activator of the vitamin D receptor) is associated with improved mortality.5 The explanation for this potential benefit is elusive. Some have suggested that vitamin D receptor activation may mitigate the effects of arterial calcification and possibly even prevent or ameliorate factors leading to atherosclerosis.3 The later benefits may be related to suppression of inflammation, inhibition of bone loss, or possibly attenuation of the activity of the renin-angiotensin system and transforming growth factor (TGF)axis. The cardiovascular disease associated with CKD is, in large part, related to the associated classic Framingham Heart Study risk factors. However, many have suspected that other factors may play a role, and, in particular, levels of PTH and vitamin D may be important. We know that treatment of patients with activated vitamin D analogs suppresses PTH levels. However, is it too much of 1 (PTH) and too little of the other (1,25-dihydroxyvitamin D) that increases the risk for cardiovascular disease? How can we explain the biological benefit of vitamin D receptor activation? A number of interesting reports suggest that there may be a relationship between 25-hydroxyvitamin D levels and the risk for kidney disease progression. In one study, investigators noted a stepwise increase in the prevalence of albuminuria in patients from the Third National Health and Nutrition Examination Survey with decreased 25-hydroxyvitamin D levels.6 However, the cross-sectional design of the study did not allow demonstration of temporal or causal relationships between levels of vitamin D and albuminuria. Another study noted that treatment with the activated vitamin D analog calcitriol was associated with significantly greater survival in patients with CKD.7 However, the retrospective treatment association, although of interest, begs for a prospective clinical trial to test the causality of these associations. Experimental studies have demonstrated that inadequate vitamin D receptor activation worsens diabetic nephropathy.8 Zhang et al8 noted that more fibronectin and less nephrin were expressed in vitamin D receptor knockout diabetic mice compared with diabetic wild-type mice. They also noted that increased measures of the renin-angiotensin system activation and TGFlevels accompany more severe renal injury in this model. In this same in vitro model, 1,25-dihydroxyvitamin D 3 inhibited high glucose-induced fibronectin production and increased nephrin expression in cultured podocytes. Vitamin D analogs also suppressed high glucose-induced activation of the renin-angiotensin system and TGF in both mesangial and juxtaglomerular cells.8 Other investigators have noted that combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses progression of renal insufficiency in uremic rats likely through suppression of TGFsignaling pathways.9 Paricalcitol has also been demonstrated in experimental models of obstructive nephropathy to inhibit renal interstitial fibrosis possibly by suppressing TGF1–mediated E-cadherin suppression of smooth muscle actin and fibronectin induction in renal tubular epithelial cells.10 As a result of this effect, there was limited epithelial-to-mesenchymal transition. Thus, there is consistent experimental evidence indicating that are there unique cellular benefits of activated vitamin D. Consequently, there is a rationale to explore the biological consequence of vitamin D supplementation in humans, particularly in those with CKD. In clinical studies of vitamin D supplementation, Agarwal et al2 have noted that paricalcitol reduced proteinuria in patients with CKD. More recently, Szeto et al11 demonstrated that calcitriol had modest antiproteinuric effects in patients with nephropathy and persistent proteinuria despite renin-angiotensin system blockade. Not yet answered in these studies is whether this is an effect related to suppression of PTH, vitamin D receptor activation, or both. The small but well done study by Alborzi et al1 helps answer some of these questions. They demonstrate that there The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Nephrology, University of Maryland Medical Systems, Baltimore. Correspondence to Matthew R. Weir, Division of Nephrology, University of Maryland Medical Systems, 22 S Greene St, Rm N3W143, Baltimore, MD 21201. E-mail [email protected] (Hypertension. 2008;52:211-212.) © 2008 American Heart Association, Inc.