The effect of high-dose vitamin D supplementation on hepcidin-25 and erythropoiesis in patients with chronic kidney disease.

BACKGROUND: Hepcidin is considered to play a central role in the pathophysiology of renal anemia. Recent studies in healthy individuals have demonstrated a suppressive effect of vitamin D (VD) on the expression of hepcidin. In this post-hoc analysis based on a randomized controlled study, we evaluated the effect of supplementing chronic kidney disease (CKD) patients (stage G3-G4) with a high daily dose of native VD on serum levels of hepcidin-25, the hepcidin/ferritin ratio, as well as on markers of erythropoiesis. METHODS: Patients with CKD stage G3-G4 included in a double blind, randomized, placebo (PBO) controlled study with available hepcidin measurements were analyzed. Study subjects received either 8000 international units (IU) of cholecalciferol daily or PBO for 12 weeks. We evaluated the change in markers of hepcidin expression, erythropoiesis, and iron status from baseline to week 12 and compared the change between the groups. RESULTS: Eighty five patients completed the study. Calcitriol, but not 25-hydroxyvitamin D (25(OH) D), was inversely correlated with serum levels of hepcidin-25 (rho = -0,38; p = < 0, 01 and rho = -0,02; p = 0, 89, respectively) at baseline. Supplementation with VD significantly raised the serum concentration of serum 25(OH)D in the treatment group (from 54 (39-71) to 156 (120-190) nmol/L; p = < 0, 01)) but had no effect on any of the markers of hepcidin, erythropoiesis, or iron status in the entire cohort. However, we did observe an increase in hemoglobin (HB) levels and transferrin saturation (TSAT) as compared to the PBO group in a subgroup of patients with low baseline 25(OH)D levels (< 56 nmol/L). In contrast, in patients with high baseline 25(OH)D values (≥ 56 nmol/L), VD supplementation associated with a decrease in HB levels and TSAT (p = 0,056) within the VD group in addition to a decrease in hepcidin levels as compared to the PBO group. CONCLUSION: High-dose VD supplementation had no discernible effect on markers of hepcidin or erythropoiesis in the entire study cohort. However, in patients with low baseline 25(OH)D levels, high-dose VD supplementation associated with beneficial effects on erythropoiesis and iron availability. In contrast, in patients with elevated baseline 25(OH)D levels, high-dose VD supplementation resulted in a decrease in hepcidin levels, most likely due to a deterioration in iron status.

The association between Single Nucleotide Polymorphisms of Klotho Gene and Mortality in Elderly Men: The MrOS Sweden Study.

The Klotho (KL) gene is involved in phosphate homeostasis. Polymorphisms in this gene have been reported to be associated with the risk of cardiovascular disease. Here we used computational tools to predict the damage-associated single nucleotide polymorphisms (SNPs) in the human KL gene. We further investigated the association of SNPs in the KL gene and mortality in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort. This study included 2921 men (aged 69-81 years) with mean 4.49 ± 1.03 years follow-up. 18 SNPs in the KL gene were genotyped using Sequenom. These SNPs were identified by in silico tools for the coding and noncoding genome to predict the damaging SNPs. After quality analyses, SNPs were analyzed for mortality risk using two steps approach on logistic regression model screening and then Cox regression model confirmation. Two non-synonymous SNPs rs9536314 and rs9527025 were found to be potentially damaging SNPs that affect KL protein stability and expression. However, these two SNPs were not statistically significantly associated with all-cause mortality (crude Hazard ratio [HR] 1.72, 95% confidence interval [CI] 0.96-3.07 in rs9536314; crude HR 1.82, 95% CI 0.998-3.33 in rs9527025) or cardiovascular mortality (crude HR 1.52, 95% CI 0.56-4.14 in rs9536314; crude HR 1.54, 95% CI 0.55-4.33 in rs9527025) in additive model using Cox regression analysis. In conclusion, these two potentially damaging SNPs (rs9536314 and rs9527025) in the KL gene were not associated with all-cause mortality or cardiovascular mortality in MrOs cohort. Larger scales studies and meta-analysis are needed to confirm the correlation between polymorphisms of the KL gene and mortality.

High doses of cholecalciferol alleviate the progression of hyperparathyroidism in patients with CKD Stages 3-4: results of a 12-week double-blind, randomized, controlled study.

Background: Calcidiol insufficiency may accelerate the development of secondary hyperparathyroidism (SHPT). We tested the effect of a substantial increase in calcidiol on mineral metabolism in patients with chronic kidney disease (CKD). Methods: Ninety-five patients with CKD Stages 3-4, parathyroid hormone (PTH) above 6.8 pmol/L and calcidiol below 75 nmol/L were randomized to receive either cholecalciferol 8000 IU/day or placebo for 12 weeks. The primary endpoint was difference in the mean change in iPTH after 12 weeks. The proportion of participants having a 30% reduction in PTH and the effect on hand grip strength, fatigue and different biochemical variables were also investigated. Results: Baseline calcidiol was 57.5 ± 22 and 56.8 ± 22 nmol/L in the cholecalciferol and placebo groups, respectively. The corresponding concentrations of PTH were 10.9 ± 5 and 13.1 ± 9 pmol/L. Calcidiol increased to 162 ± 49 nmol/L in patients receiving cholecalciferol, and PTH levels remained constant at 10.5 ± 5 pmol/L. In the placebo group, calcidiol remained stable and PTH increased to 15.2 ± 11 pmol/L. The mean change in PTH differed significantly between the two groups (P < 0.01). The proportion of subjects reaching a 30% decrease in PTH did not differ. No effect on grip strength, fatigue, phosphate or fibroblast growth factor 23 was observed. Cholecalciferol treatment resulted in stable calcium concentrations and a substantial increase in calcitriol. Conclusion: Treatment with high daily doses of cholecalciferol in patients with CKD Stages 3-4 halts the progression of SHPT and does not cause hypercalcaemia or other side effects.

Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs).

BACKGROUND: Fibroblast growth factor 23 (FGF23) is the earliest marker of disturbed mineral metabolism as renal function decreases. Its serum levels are associated with mortality in dialysis patients, persons with chronic kidney disease (CKD) and prevalent cardiovascular disease (CVD), and it is associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy in the general population. The primary aim of this study is to examine the association between FGF23 and mortality, in relation to renal function in the community. A secondary aim is to examine the association between FGF23 and CVD related death. METHODS: The population-based cohort of MrOS Sweden included 3014 men (age 69-81 years). At inclusion intact FGF23, intact parathyroid hormone (PTH), 25 hydroxyl vitamin D (25D), calcium and phosphate were measured. Mortality data were collected after an average of 4.5 years follow-up. 352 deaths occurred, 132 of CVD. Association between FGF23 and mortality was analyzed in quartiles of FGF23. Kaplan-Meier curves and Log-rank test were used to examine time to events. Cox proportional hazards regression was used to examine the association between FGF23, in quartiles and as a continuous variable, with mortality. The associations were also analyzed in the sub-cohort with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73 m(2). RESULTS: There was no association between FGF23 and all-cause mortality, Hazard ratio (HR) 95% confidence interval (CI): 1.02 (0.89-1.17). For CVD death the HR (95% CI) was 1.26 (0.99 - 1.59)/(1-SD) increase in log(10)FGF23 after adjustment for eGFR, and other confounders. In the sub-cohort with eGFR > 60 ml/min/1.73 m(2) the HR (95% CI) for CVD death was 55% (13-111)/(1-SD) increase in log(10)FGF23. CONCLUSIONS: FGF23 is not associated with mortality of all-cause in elderly community living men, but there is a weak association with CVD death, even after adjustment for eGFR and the other confounders. The association with CVD death is noticeable only in the sub-cohort with preserved renal function.

Oncogenic osteomalacia illustrating the effect of fibroblast growth factor 23 on phosphate homeostasis.

In oncogenic osteomalacia (OOM), fibroblast growth factor 23 (FGF23) induces renal phosphate wasting and inhibits the appropriate increase of calcitriol. A patient suffering from OOM is described. Serum calcium, phosphate, biointact parathyroid hormone and intact FGF23 as well as the calcitriol and 24,25-vitamin D levels were measured before and after tumour removal. The clinical approach to a patient with hypophosphataemia is discussed and the changes in mineral metabolism after removal of a FGF23-producing tumour are described.

Fibroblast growth factor-23 and mineral metabolism after unilateral nephrectomy.

BACKGROUND: Fibroblast growth factor -23 (FGF-23) is a key regulator of mineral metabolism. It regulates renal phosphate (Pi) reabsorption and calcitriol synthesis, and has an inhibitory effect on parathyroid hormone (PTH) secretion. FGF-23 increases early in chronic kidney disease (CKD), but the regulation of FGF-23 in mild -to -moderate renal dysfunction is not fully understood. METHODS: Nine healthy kidney donors underwent unilateral nephrectomy. Estimated glomerular filtration rate (eGFR) calculated from cystatin C and parameters of mineral metabolism: (Pi, ionized calcium, biointact PTH, intact FGF-23, calcitriol, and urinary excretion of calcium and Pi) were analysed before surgery, and one day, one week and three to six months after surgery. RESULTS: On the first post-operative day, PTH increased due to a decrease in the calcium level. One week after nephrectomy, the FGF-23 level increased from 31.8 ± 12.3 pg/mL to 55.8 ± 15.1 pg/mL, while PTH, Pi and calcium levels were unchanged compared towith baseline. On follow-up, eGFR improved compared with its one-week value, and PTH and FGF-23 were unchanged compared towith baseline. The calcitriol level decreased but was in the normal range at all points in time. The total amount of Pi in urine did not change, while the calcium excretion decreased significantly. CONCLUSIONS: Pi homeostasis after nephrectomy is maintained by PTH on the first day. When serum calcium is stabilized and food intake resumed, FGF-23 rises, possibly in response to the Pi- load in relation to GFR.

Preoperative tumor localization by means of venous sampling for fibroblast growth factor-23 in a patient with tumor-induced osteomalacia.

OBJECTIVE: To report on a novel strategy for tumor localization in a 62-year-old man with hypophosphatemic tumor-induced osteomalacia (TIO). METHODS: Repeated computed tomographic and magnetic resonance imaging scans failed to localize any tumor in a patient with adult-onset hypophosphatemic osteomalacia. Therefore, venous sampling for fibroblast growth factor-23 (FGF23)--a circulating hormone that has been identified as a causative factor for TIO--in major veins was conducted. Serum FGF23 was measured from collected samples by an intact FGF23 enzyme-linked immunosorbent assay. RESULTS: Venous sampling suggested a local increase in serum FGF23 in the left femoral vein; this finding prompted performance of octreotide scintigraphy restricted to the left leg. A tumor was located at the lateral condyle of the left femur, which was also confirmed by magnetic resonance imaging. Surgical resection of the tumor normalized the serum phosphorus and 1,25-dihydroxyvitamin D3 levels within 5 to 10 days, and FGF23 declined to normal levels within 24 hours. Histologic analysis supported the diagnosis of a soft-tissue giant cell tumor. CONCLUSION: Our study case demonstrates the diagnostic complexity and difficulties in localizing a small tumor in a patient with TIO. Venous sampling for FGF23 may be helpful in tumor localization in sporadic cases of hypophosphatemic osteomalacia, especially when noninvasive diagnostic techniques prove insufficient.

Regulation of fibroblast growth factor-23 in chronic kidney disease.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a circulating factor that regulates the renal reabsorption of inorganic phosphate (Pi) and is increased in chronic kidney disease (CKD). The aim of the current investigation was to study the regulation of FGF23 in CKD subjects with various degree of renal function. As such, we analysed the relationship between FGF23, Pi, calcium, parathyriod hormone (PTH), 25(OH) vitamin D3(25(OH)D3), 1,25(OH)2 vitamin D3(1,25(OH)2D3) and estimated glomerular filtration rate (eGFR). METHODS: Intact FGF23 and other biochemical variables were analysed in 72 consecutive adult out-patients with various stages of CKD (eGFR ranging from 4-96 ml/min.) Association studies were performed using linear univariate and multivariate analysis. RESULTS: FGF23 was significantly elevated at CKD stage 4 (266 +/- 315 pg/ml, P < 0.001) and 5 (702 +/- 489 pg/ml, P < 0.001) compared with CKD 1-2 (46 +/- 43 pg/ml). In CKD 4-5 an independent association between log FGF23 and Pi (P < 0.001), 25(OH)D3 (P < 0.05) as well as eGFR (P < 0.01) was observed. In contrast, in CKD 1-3 log PTH (P < 0.05) was the only independent predictor of log FGF23 in multivariate analysis. In CKD 1-5, Pi (P < 0.00001) and log PTH (P < 0.01) were explanatory variables for log FGF23 in multivariate analysis. CONCLUSIONS: We conclude that serum FGF23 increases in CKD 4-5, in parallel with the emerging hyperphosphataemia. Serum Pi is the most important predictor of FGF23 when GFR is less than 30 ml/min. In contrast, our data suggest that Pi may not be an important determinant of FGF23 in normophosphataemic CKD subjects. Finally, the association between FGF23 and PTH in CKD may suggest a co-regulation that remains to be further elucidated.