Examining the effects of uric acid-lowering on markers vascular of calcification and CKD-MBD; A post-hoc analysis of a randomized clinical trial

Abstract

BackgroundChronic kidney disease (CKD)-mineral and bone disorder (MBD) is a systemic disorder that leads to vascular calcification and accelerated atherosclerosis. Uric acid has been shown to associate with vascular calcification and with carotid intima-media thickness (CIMT) and to suppress the 1 α-hydroxylase enzyme leading to lower 1,25-dihydroxyvitamin D (1,25(OH)2D) and higher intact parathyroid hormone (iPTH) levels. We hypothesized that lowering serum uric acid would reduce CIMT, calcification propensity, and circulating markers of CKD-MBD in CKD.MethodsThis is a post-hoc analysis of a randomized, double-blind study of 80 patients with stage 3 CKD and hyperuricemia who received allopurinol or placebo for 12 weeks. CIMT and T50 were measured as markers of vascular disease and serum calcification propensity, respectively. The following markers of CKD-MBD were measured: serum calcium, phosphorus, vitamin D metabolites, iPTH, and fibroblast growth factor-23 (FGF-23). Expression of extra-renal 1α-hydroxylase was evaluated in endothelial cells of study participants.FindingsAllopurinol successfully lowered serum uric acid levels compared to placebo with an estimate of -3.3 mg/dL (95% C.I. -4.1,-2.5; p < 0.0001). After 12 weeks, however, we found no significant change in CIMT or serum T50. There was not a significant change in vitamin D metabolites, iPTH, FGF-23, or the expression of endothelial 1α-hydroxylase.ConclusionThese data suggest that factors other than uric acid may play a more important role in the regulation of CKD- MBD including vascular calcification and vitamin D metabolism in patients with CKD.

Harnessing hyperuricemia to atherosclerosis and understanding its mechanistic dependence

“…Hence, researchers worked on hypothesizing that reducing the UA levels would benefit carotid intima‐media thickness reduction, lowering calcification, and reducing the other markers associated with CKD and mineral and bone disorder. The results evidence UA plays a key role in the mitigation of vascular calcification and improved the condition of patients with CKD 53 …”

New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease

“…However, the existence of a causal link between hyperuricemia-induced CVC and UA-induced M1 polarization of monocytes/macrophages has not yet been investigated. In this context, it should be borne in mind that in stage 3 CKD patients with hyperuricemia, an allopurinol-induced lowering of UA levels did not modulate carotid intima-media thickness [169], suggesting that factors other than UA may play a more important role in the regulation of CVC development. Well-designed, prospective, randomized, controlled trials including a larger cohort of patients might help to firmly conclude the effect of UA on CVC in this setting.…”

Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall

“…This study outlines the integral role that UA plays in vascular inflammation, even though the exact causal link is yet to be determined. One key finding from Andrews and colleagues shows that UA may have an even more significant role in VC progression as the administration of allopurinol among stage 3 CKD patients did not impact the carotid-intima media thickness [ 82 ]. Among the many roles monocytes and macrophages are involved in, the complex array of phenotypes these cells exhibit is remarkable, especially in the development of VC in the context of CKD.…”