Reduced Hepatic Synthesis of Calcidiol in Uremia

Abstract

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D 3 C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P Ͻ 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D 3 or 1␣-hydroxyvitamin D 3 , respectively, suggesting impaired C-25-hydroxylation of vitamin D 3 . Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms. ] deficiency has also been demonstrated in patients with stages 3 and 4 chronic kidney disease (CKD) and in patients who are on dialysis. [1][2][3][4][5][6][7][8] In fact, low serum 25(OH)D 3 is so intimately associated with CRF that in one study, only 29 and 17% of patients with stages 3 and 4 CKD, respectively, had sufficient levels [defined as a serum 25(OH)D 3 concentrations Ͼ75 nmol/L or 30 ng/ml]. 2 A more recent study showed a prevalence of calcidiol insufficiency and deficiency as high as 98% in predialysis patients with a mean GFR of 18.3 ml/min. 4 Prevalence of low serum 25(OH)D 3 was 78 and 89% in two large cohorts of hemodialysis patients 9,10 and 87% in a large cohort of peritoneal dialysis patients. 11 The metabolic consequences of calcidiol defi-

Correction of vitamin D status by calcidiol: pharmacokinetic profile, safety, and biochemical effects on bone and mineral metabolism of daily and weekly dosage regimens

“…In the case of intestinal malabsorption, especially when associated with and steatorrhoea, calcidiol is better absorbed than cholecalciferol [31]. In addition, since a PTH-mediated inhibition of liver cytochrome isoforms has been shown in uremia, calcidiol utilization, instead of cholecalciferol, has been proposed for patients with chronic kidney disease [32].…”

Chronic Kidney Disease (Ckd)

“…41 As a compensatory mechanism Vitamin D catabolism is decreased in CKD pts and specially the patients on maintenance dialysis. 42 It is suggested that uraemic milieu causes a decrease in vitamin D synthesis secondary to PTH mediated fall in CYP450 isoforms 43 at the level of liver. It has been reported that muscular weakness and falls in patients on maintenance dialysis have been associated with vitamin D deficiency and it is a j curve with a maximal benefit is between 24 and 40 ng/ml of serum 25(OH)D levels.…”

Effect of nutritional vitamin D preparations on parathyroid hormone in patients with chronic kidney disease

“…Generally, patients with CKD are predisposed to low calcitriol (1,25(OH) 2 D) levels due to the progressive lack of kidney mass to perform 1a-hydroxylation, increasing age, reduced sun exposure and immobilization [20,21]. Uremia impairs the response to ultraviolet B rays [22] and, in animal models, reduces calcidiol synthesis secondary to PTH -mediated reduction in liver CYP450 isoforms [23]. Moreover, uremic plasma contains factors that inhibit nuclear uptake of calcitriol receptor and 1a -hydroxylase activity [24,25].…”

“…Blood levels of 25(OH)D reflect the total VitD derived from diet, sunlight exposure and adipose store [7]. Studies have reported varying prevalence rates of VitD deficiency in predialysis and dialysis patients ranging between 70 and 98% [23,27] and 51 and 100% [28,29], respectively. Patients with severe proteinuria have the lowest 25(OH)D levels (probably because of losses of protein-bound 25(OH)D) [30], while patients on PD have significantly lower levels of 25(OH)D compared to those on HD (probably because of increased 25(OH)D losses in the peritoneal effluent) [31].…”

“…Extensive published evidence [22,23,26,27,[32][33][34][35] demonstrates a modest decrease in PTH levels after calcidiol supplementation that does not, however, correct the PTH levels to normal. VitD supplementation is not accompanied by an increased risk of hypercalcemia and hyperphosphatemia.…”