Calcitriol Accelerates Vascular Calcification Irrespective of Vitamin K Status in a Rat Model of Chronic Kidney Disease with Hyperphosphatemia and Secondary Hyperparathyroidism

Abstract

Patients with chronic kidney disease (CKD) have a markedly increased risk for developing cardiovascular disease. Nontraditional risk factors, such as increased phosphate retention, increased serum fibroblast growth factor 23 (FGF-23), and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol [1,25-(OH)-D] is a key transcriptional regulator of matrix Gla protein, a vitamin K-dependent protein that inhibits vascular calcification. We hypothesized that calcitriol treatment would inhibit the development of vascular calcification and this inhibition would be dependent on vitamin K status in a rat model of CKD. Rats were treated with dietary adenine (0.25%) to induce CKD, with either 0, 20, or 80 ng/kg of calcitriol with low or high dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at both lower (20 ng/kg) and moderate (80 ng/kg) doses increased the severity of vascular calcification, and contrary to our hypothesis this was not significantly improved by high dietary vitamin K1. Calcitriol had a dose-dependent effect on: 1) lowering serum parathyroid hormone, 2) increasing serum calcium, and 3) increasing serum FGF-23. Calcitriol treatment significantly increased aortic expression of the calcification genes and These data also implicate impaired vitamin D catabolism in CKD, which may contribute to the development of calcitriol toxicity and increased vascular calcification. The present findings demonstrate that in an adenine-induced rat model of CKD calcitriol treatment at doses as low as 20 ng/kg can increase the severity of vascular calcification regardless of vitamin K status.

Pathogenesis and management of vascular calcification in CKD and dialysis patients

“…Also, mortality was higher in the vitamin D analog group compared to the other groups . This finding was also demonstrated in several other experimental studies …”

“…63 This finding was also demonstrated in several other experimental studies. [65][66][67]69 Earlier, in well performed human RCTs of calcitriol and vitamin D analogs vs placebo in patients with mild to moderate CKD, PTH levels decreased with the combination as expected along with significantly improved bone histomorphometry parameters, likely related to the drop in PTH levels. 70,71 However, there is evidence of a significant risk of hypercalcemia in patients treated with vitamin D analogs.…”

PTH suppression by calcitriol does not predict off‐target actions in experimental CKD

“…Furthermore, calcitriol upregulates several pro‐calcification genes in vasculature and can cause iatrogenic PTH over‐suppression leading to adynamic bone disease. Together, these observations provide some indirect evidence for the link between calcitriol treatments and the development of calcification that has been reported in experimental models 12,14–16 . It is noteworthy that pre‐clinical studies report discordant effects of calcitriol on VC that appear to be linked to dose.…”

“…It is noteworthy that pre‐clinical studies report discordant effects of calcitriol on VC that appear to be linked to dose. That is, low doses of calcitriol (eg, 20 ng/d) have been shown to inhibit VC progression in murine models while higher doses promote VC in rats with CKD 6,8–10,12,15–20 …”

Vitamin D niemals ohne Vitamin K2 – Imperativ oder Konjunktiv?

“…In zahlreichen Publikationen zu Vitamin D wurde über die unzähligen positiven Effekte des Sonnenhormons in der Prävention und Therapie berichtet [1] [2] [3][4] [5]. Allerdings wurde die anfängliche Euphorie zu Vitamin D ein wenig getrübt als die ersten Stimmen laut wurden, die darlegten, man dürfe Vitamin D nur zusammen mit Vitamin K2 supplementieren [6] [7] [8] [9]. In Bezug auf die Grundlagen zu Vitamin K, die verschiedenen K2-Formen und deren unterschiedliche Bioverfügbarkeit verweisen wir auf unseren Beitrag [10].…”