Intravenous Calcitriol Therapy Increases Serum Concentrations of Fibroblast Growth Factor-23 in Dialysis Patients with Secondary Hyperparathyroidism

Nishi, Hiroshi; Nii-Kono, Tomoko; Nakanishi, Shohei; Yamazaki, Y.; Yamashita, Takefumi; Fukumoto, Seiji; Ikeda, Keisuke; Fujimori, A.; Fukagawa, Masafumi

doi:10.1159/000086347

Cited by 111 publications

(74 citation statements)

References 36 publications

(32 reference statements)

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“…In patients with ESRD, treatment with low-dose calcitriol analogs resulted in an increased trend of FGF-23 levels and a decrease in PTH levels (32). In patients on dialysis, active vitamin D therapy was shown to increase serum FGF-23 levels in patients with secondary hyperparathyroidism and to decrease significantly serum intact PTH levels (33). In our patients, the mean 25OH vitamin D was at the upper end of the range of insufficiency, implying that ϳ50% of the patients were at least vitamin D deficient.…”

Section: Discussionmentioning

confidence: 49%

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

Kanaan¹,

Claes²,

Devogelaer

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Among the multiple factors contributing to bone mineral density (BMD) loss after renal transplantation, hypophosphatemia is increasingly recognized to play an important role. Hypophosphatemia occurs in up to 90% of the renal transplant recipients in the early post-transplant period and is caused by renal phosphate wasting. We hypothesized that a high pretransplant level of the recently described phosphaturic hormone fibroblast growth factor 23 (FGF-23) is a risk factor for accelerated BMD loss occurring within the first post-transplant year.Design, setting, participants, & measurements: We performed a two-center observational retrospective cohort study in 127 incident renal transplant recipients. Serum full-length FGF-23, parathyroid hormone (PTH), and parameters of mineral metabolism were determined at the time of transplantation. BMD was assessed by osteodensitometry at the time of transplantation and 1 year later.Results: A moderate decrease of BMD was observed during the first post-transplant year. High FGF-23 levels were associated with BMD loss at the lumbar spine and total hip region, whereas low PTH levels were associated with BMD loss at all three regions. Cumulative doses of prednisone and post-transplant serum phosphate level were not correlated with BMD changes.Conclusion: Our data indicate that patients with a high serum FGF-23 level and/or a low PTH level at the time of transplantation are at risk for increased BMD loss during the first post-transplant year.

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Section: Discussionmentioning

confidence: 49%

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

Kanaan¹,

Claes²,

Devogelaer

et al. 2010

Clinical Journal of the American Society of Nephrology

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“…In some, but not all, clinical studies, FGF23 levels have been strongly and independently correlated with levels of P (16,17), calcium (Ca) ϫ P product (17), and parathyroid hormone (PTH) (16,17), suggesting the possibility that SHPT treatments that alter circulating levels of Ca, P, and PTH may affect FGF23 levels. Additionally, use of calcitriol analogs is associated with increased FGF23 levels in humans with ESRD (10,18), consistent with observations that calcitriol increases FGF23 gene transcription (8). Cinacalcet, an allosteric modulator of the calcium sensing receptor (19), was introduced several years ago as a calcitriol analog-sparing therapy for SHPT (20 -24).…”

mentioning

confidence: 53%

“…Nonetheless, given the current knowledge of the regulation of FGF23 expression, there are several potential explanations for our findings. Because calcitriol is known to stimulate FGF23 production in osteoblasts (8) and calcitriol administration increases FGF23 levels in hemodialysis patients (18), the lower overall exposure to calcitriol analog dose in the Cinacalcet-D group (amounting to about one half compared with the Flex-D group) might account for the observed behavior of FGF23. In addition, the reduction in FGF23 after discontinuation of calcitriol analog therapy during the washout supports an important role of calcitriol in regulating FGF23.…”

Section: Discussionmentioning

confidence: 99%

Effects of Cinacalcet and Concurrent Low-Dose Vitamin D on FGF23 Levels in ESRD

Wetmore¹,

Liu²,

Krebill

et al. 2010

Clinical Journal of the American Society of Nephrology

140

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Background and objectives: Fibroblast growth factor-23 (FGF23) levels are elevated in ESRD and have been associated with adverse outcomes. The effects of various treatments for secondary hyperparathyroidism on FGF23 levels in ESRD have not been examined in a clinical trial.Design, setting, participants, & measurements: We assessed intact FGF23 levels in 91 subjects over the course of the ACHIEVE trial, which was designed to compare escalating doses of Cinacalcet plus fixed low-dose calcitriol analogs (Cinaclcet-D) with titration of calcitriol analogs alone (Flex-D) to suppress parathyroid hormone. Between-group and withingroup changes in log-transformed FGF23 levels were analyzed. Factors associated with change in FGF23 were assessed using a multiple regression model.Results: Intact FGF23 levels were markedly elevated in subjects at baseline. A statistically significant difference in percent change in log FGF23 levels was observed between treatment groups (P < 0.002). The Cinacalcet-D group had a significant decrease in percent change in log FGF23 levels (corrected P ‫؍‬ 0.021), whereas FGF23 levels trended toward an increase in the Flex-D group. Change in FGF23 level was significantly associated with changes in levels of phosphate (P < 0.0001) and calcium (P ‫؍‬ 0.0002) but not parathyroid hormone.Conclusions: Treatment with Cinacalcet plus low-dose calcitriol analogs results in lower FGF23 levels compared with a treatment regimen using calcitriol analogs alone in ESRD. The mechanisms underlying the differential effects of these treatment regimens on FGF23 levels and the clinical impact of these changes on FGF23 remain to be defined.

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“…If a markedly elevated FGF23 level is directly toxic, then reducing the level or blocking its effect would emerge as a novel therapeutic target in CKD. Shortterm studies of dialysis patients demonstrated a modest reduction in FGF23 levels in response to cinacalcet and a modest increase in levels after treatment with active vitamin D. 80,81 Whether these effects prove to be clinically relevant when considered against the background of massive elevations in levels of FGF23 in dialysis patients is unclear. Administering a more targeted mAb that neutralizes FGF23 is theoretically attractive (but not yet available) for dialysis patients who do not depend on native renal clearance of phosphorus.…”

Section: How Do Fgf23 Levels Differ In Specific Ckd Subpopulations?mentioning

confidence: 99%

Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease

Wolf

2010

Journal of the American Society of Nephrology

273

219

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In only a few years, the discovery and characterization of fibroblast growth factor 23 (FGF23) is drastically changing our understanding of disordered mineral metabolism in chronic kidney disease (CKD). The journey of FGF23 from anonymity to center stage began with studies of a family of rare diseases that share a common phenotype, including hypophosphatemia, isolated urinary phosphate wasting, rickets or osteomalacia, and insufficient calcitriol production for the degree of hypophosphatemia. The main diseases in the group are X-linked hypophosphatemia (the most common), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia (TIO; a sporadic form). 1,2 With no known cause for the diseases, overexpression of one or more circulating phosphaturic factors, termed "phosphatonins" was hypothesized.Genetic studies provided the breakthrough. Positional cloning revealed missense mutations in the gene encoding FGF23 on chromosome 12 in each of four families with autosomal dominant hypophosphatemic rickets, encompassing 26 affected individuals. 3 These mutations were later shown to protect FGF23 from proteolytic cleavage. 4,5 Confirmation of the causal role of FGF23 in the hypophosphatemic disorders came in 2001, when high expression of FGF23 was isolated from tumor cells from patients with TIO. 6 The development of high-precision assays for measuring FGF23 confirmed elevated circulating levels in patients with TIO, X-linked hypophosphatemia, and ESRD compared with healthy individuals (Figure 1) 7,8 and opened the door to a new era of human physiologic research on FGF23. NORMAL FGF23 PHYSIOLOGYFGF23 is primarily secreted by osteocytes 9 and has several endocrine effects on mineral metabolism (Figure 2): FGF23 induces phosphaturia by decreasing phosphate reabsorption in the proximal tubule through downregulation of luminal sodium-phosphate co-transporters 10,11 ; FGF23 reduces circulating levels of calcitriol by inhibiting renal 1-␣ hydroxylase 10,11 and stimulating 24-hydroxylase, 11 which catalyzes the initial step in vitamin D degradation; and FGF23 inhibits secretion of parathyroid hormone (PTH). 12 These effects are dependent on the presence of klotho, which is highly expressed in the kidney and the parathyroid glands and acts as a co-receptor for FGF23 by markedly increasing the affinity of FGF23 for ubiquitous FGF receptors. 13,14 These aspects of FGF23 physiology were demonstrated in studies of animals that were administered FGF23, 4,10,12,15 transgenic mice that overexpress FGF23, 16 -19 and klotho 20 and FGF23 null mice. 21 Physiologic studies of normal humans were confirmatory, 22-24 as were observations from patients with ABSTRACTThe discovery of fibroblast growth factor 23 (FGF23) as the causal factor in the pathogenesis of rare forms of hypophosphatemic rickets is rapidly reshaping our understanding of disordered mineral metabolism in chronic kidney disease (CKD). Excessive production of FGF23 by osteocytes is an appropriat...

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Intravenous Calcitriol Therapy Increases Serum Concentrations of Fibroblast Growth Factor-23 in Dialysis Patients with Secondary Hyperparathyroidism

Cited by 111 publications

References 36 publications

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

Effects of Cinacalcet and Concurrent Low-Dose Vitamin D on FGF23 Levels in ESRD

Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease

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