Bone responsiveness to parathyroid hormone is negatively associated with parathyroid hormone-lowering drug use in patients undergoing hemodialysis: a cross-sectional study.

BACKGROUND: Parathyroid hormone (PTH) acts on bone to indirectly increase the number and activity of osteoclasts. Thus, PTH has a stimulatory effect on bone resorption and upregulates bone turnover. However, the responsiveness of bone to PTH varies widely among patients receiving dialysis. In fact, relative to the serum PTH level, the level of serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone resorption marker derived from osteoclasts, varies as well. This study aimed to examine factors related to bone responsiveness to PTH in patients undergoing chronic hemodialysis (HD). METHODS: This study included patients receiving chronic HD in Kawasaki Municipal Tama Hospital (Kanagawa, Japan) and Yonaha Medical Clinic (Okinawa, Japan) and excluded patients who received HD for less than 6 months, those who received a combination of HD and peritoneal dialysis, and those who had cancer bone metastases or myeloma. The TRACP-5b/intact PTH (iPTH) ratio was created as an index of bone responsiveness to PTH, categorized into tertiles (low, medium, and high), and a cross-sectional study was conducted. P < 0.05 indicated statistically significant differences. RESULTS: One hundred and six patients were analyzed. Age (P = 0.010), body mass index (BMI) (P = 0.003), use of calcium-sensing receptor (CaSR) agonists (P = 0.008), use of vitamin D receptor activators (VDRAs) (P = 0.012), plasma iPTH level (P < 0.001), serum 1,25(OH)2D level (P = 0.003), and serum TRACP-5b level (P < 0.001) were significantly different among the three categories. In the single linear regression analysis, age (P = 0.016), corrected serum calcium level (P = 0.007), and ln [1,25(OH)2D] (P = 0.044) showed a significant positive correlation with ln [TRACP-5b/iPTH], whereas BMI (P = 0.026), use of CaSR agonists (P = 0.001), use of VDRAs (P = 0.009), and serum phosphorus level (P = 0.018) showed a significant negative correlation. Upon conducting multiple linear regression analysis incorporating significant variables in the single linear regression analysis, a significant negative correlation was observed between the TRACP-5b/iPTH ratio and intravenous administration of a CaSR agonist (etelcalcetide) and/or a VDRA (calcitriol or maxacalcitol) in all the adjusted models. CONCLUSIONS: Bone responsiveness to PTH is negatively correlated with the intravenous administration of a CaSR agonist and/or a VDRA in patients undergoing chronic HD.

NUTRITIONAL OR ACTIVE VITAMIN D FOR THE CORRECTION OF MINERAL METABOLISM ABNORMALITIES IN NON-DIALYSIS CHRONIC KIDNEY DISEASE PATIENTS?

CONTEXT: Benefits of vitamin D therapies in chronic kidney disease (CKD) are debated. OBJECTIVE: To compare the effects of medium-term native (VitD) and active (VDRA) vitamin D on parameters of mineral metabolism and arterial function in non-dialysis CKD. DESIGN: Open-label, active comparator, randomized study. SUBJECTS AND METHODS: Forty-eight adult patients, vitamin D naïve, CKD stage 3 to 5 with increased parathyroid hormone (iPTH) were randomized to receive either oral cholecalciferol 1000UI/day (n=24) or paricalcitol 1mcg/day (n=24) for 6 months. Median changes at end of study vs. baseline in serum calcidiol, iPTH, total alkaline phosphatase (ALP), and cardio-ankle vascular index (CAVI) were the efficacy parameters. RESULTS: Higher increase in calcidiol (15.5 [95%CI 13.3; 17.2] vs. 0.4 [95%CI -6.1; 3.7]ng/mL, p<0.001) were found in VitD group. Conversely, the decline of iPTH (-35.2 [95%CI -83; 9] vs. 13.3 [95%CI -8.1; 35]pg/mL, p=0.008) and ALP (-34 [95%CI -58; -11] vs. -10 [95%CI -23; -2]U/L, p=0.02) were greater after paricalcitol. More subjects experienced iPTH decrease in VDRA group (71% vs. 39%, p=0.03). The variation in CAVI and the incidence of hypercalcemia and hyperphosphatemia were similar. CONCLUSIONS: It seems that secondary hyperparathyroidism was more efficiently treated by VDRA, whereas cholecalciferol better corrected the calcidiol deficiency in non-dialysis CKD.

Do the benefits of using calcitriol and other vitamin D receptor activators in patients with chronic kidney disease outweigh the harms?

The primary indication for administration of calcitriol or other vitamin D receptor activators (VDRA) in chronic kidney disease (CKD) is secondary hyperparathyroidism (SHPT). Prevention and treatment of SHPT appears important, as imbalances in mineral metabolism are associated with renal osteodystrophy, and higher parathyroid hormone (PTH) levels are associated with increased rates of mortality and morbidity in CKD patients. There is, however, a lack of controlled trial data that show lowering PTH with calcitriol/VDRA equates to improved clinical outcomes. Recent randomized controlled trials have concentrated on potential benefits of calcitriol/VDRA on cardiovascular outcomes and reduction of proteinuria and on possible differences between calcitriol and the various VDRA. Several systematic reviews and meta-analyses have also been published, evaluating the benefits and harms of calcitriol/VDRA. Concerns have been raised about the effectiveness of calcitriol/VDRA for suppression of SHPT in the CKD stages 3-5 population, as well as potential adverse outcomes such as hypercalcaemia and elevation in FGF23 levels, suggesting their routine use to treat SHPT in the pre-dialysis CKD population may not be favourable. Conversely, concerns still exist about the wide PTH range in advanced CKD, and that high values may negatively impact bone quality, result in the progression of parathyroid hyperplasia and decrease the effectiveness of treatments to reduce PTH. We discuss the current controversies relating to the challenges in the management of SHPT in patients with CKD stages 3-5 and the need for more evidence to determine the efficacy or harm of using calcitriol/VDRA in this population.

Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. METHODS: This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. RESULTS: In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84-1.51] and 1.02 [0.72-1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). CONCLUSIONS: Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients.

Strategies and limitations associated with in vitro characterization of vitamin D receptor activators.

In vitro cell-based assays are common screening tools used for the identification of new VDR ligands. For 25-hydroxyvitamin D3 [25(OH)D3] and 1α-hydroxyvitamin D3 [1α(OH)D3], protein expressions of CYP2R1 and CYP27B1, respectively, that form the active 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] ligand were detected in human embryonic kidney (HEK293) cells expressing the GAL4-hVDR, the human brain microvessel endothelial (hCMEC/D3) and adenocarcinoma colonic (Caco-2) cells. The impact of bioactivation enzymes was shown upon the addition of ketoconazole (10 µM KTZ), a pan-CYP inhibitor, which reduced the apparent potency of 25(OH)D3 and increased the EC50 from 272 to 608 nM in HEK293 cells. EIA assays verified that 1,25(OH)2D3 was formed and contributed to VDR activity independently of its precursors. In hCMEC/D3 cells where enzyme protein levels were lowest, changes in MDR1/P-gp expression with KTZ were minimal. In Caco-2 cells, the induction of TRPV6 (calcium channel), CYP24A1, CYP3A4, OATP1A2 and MDR1 mRNA expression was 1,25(OH)2D3 > 1α(OH)D3 > 25(OH)D3, with the magnitude of change being blunted by KTZ. Upon inclusion of KTZ in the cell-based assays, high transcriptional activities were observed for synthetic VDR activators from Teijin Pharma. Cyclopentanone derivatives: TPD-003, TPD-005, TPD-006, TPD-008 and TPD-009 (EC50s 0.06 to 67 nM, unchanged with KTZ) were found more potent over straight chain and lactone derivatives (antagonists). Most TPD compounds activated OATP1A2, CYP24A1, CYP3A4, and MDR1 (28-67%) and TRPV6 transcriptionally in Caco-2 cells. The results identified that cell-based assays with added KTZ could accurately identify new VDR activators, although these may be hypercalcemic with strong TRPV6 inducing properties.

Vitamin D in Chronic Kidney Disease and Dialysis Patients.

Vitamin D deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common among patients with chronic kidney disease (CKD) or undergoing dialysis. In addition to nutritional and sunlight exposure deficits, factors that affect vitamin D deficiency include race, sex, age, obesity and impaired vitamin D synthesis and metabolism. Serum 1,25(OH)2D levels also decrease progressively because of 25(OH)D deficiency, together with impaired availability of 25(OH)D by renal proximal tubular cells, high fibroblast growth factor (FGF)-23 and decreased functional renal tissue. As in the general population, this condition is associated with increased morbidity and poor outcomes. Together with the progressive decline of serum calcitriol, vitamin D deficiency leads to secondary hyperparathyroidism (SHPT) and its complications, tertiary hyperparathyroidism and hypercalcemia, which require surgical parathyroidectomy or calcimimetics. Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) experts have recognized that vitamin D insufficiency and deficiency should be avoided in CKD and dialysis patients by using supplementation to prevent SHPT. Many vitamin D supplementation regimens using either ergocalciferol or cholecalciferol daily, weekly or monthly have been reported. The benefit of native vitamin D supplementation remains debatable because observational studies suggest that vitamin D receptor activator (VDRA) use is associated with better outcomes and it is more efficient for decreasing the serum parathormone (PTH) levels. Vitamin D has pleiotropic effects on the immune, cardiovascular and neurological systems and on antineoplastic activity. Extra-renal organs possess the enzymatic capacity to convert 25(OH)D to 1,25(OH)2D. Despite many unanswered questions, much data support vitamin D use in renal patients. This article emphasizes the role of native vitamin D replacement during all-phases of CKD together with VDRA when SHPT persists.

Total Phosphate Elimination is Negatively Associated With Increased Serum Fibroblast Growth Factor 23 Levels in Patients who Undergo Peritoneal Dialysis.

As fibroblast growth factor 23 (FGF23) has been shown to induce cardiovascular disease directly in patients with chronic kidney disease, identification of factors and treatments that can modulate serum FGF23 (sFGF23) level is clinically important. This retrospective longitudinal study investigated factors that modulate sFGF23 in 49 patients who underwent peritoneal dialysis (PD). sFGF23 ratio (sFGF23 at 18 months/baseline sFGF23) was used as an indicator of changes in sFGF23 level. Total phosphate elimination was the sum of both renal phosphate excretion and dialysate phosphate elimination. In multivariate analysis, log sFGF23 ratio was associated negatively with total phosphate elimination and the use of cinacalcet at baseline, and positively with the use of vitamin D receptor activators at baseline, even after adjusting for potential confounding factors. Our study indicates that maintaining phosphate elimination can prevent increased sFGF23, thereby preventing cardiovascular events in patients who undergo PD.