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- Mirza, Majd A. I., 1982-
(författare)
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The role of fibroblast growth factor-23 in chronic kidney disease-mineral and bone disorder
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.
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| 2. |
- Mirza, Majd, 1982-, et al.
(författare)
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Serum Fibroblast Growth Factor-23 (FGF-23) and Fracture Risk in Elderly Men
- 2011
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 26:4, s. 857-864
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Tidskriftsartikel (refereegranskat)abstract
- A normal mineral metabolism is integral for skeletal development and preservation of bone integrity. Fibroblast growth factor 23 (FGF-23) is a bone-derived circulating factor that decreases serum concentrations of inorganic phosphorous (P-i) and 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]. Increased FGF-23 expression is a direct or indirect culprit in several skeletal disorders; however, the relation between FGF-23 and fracture risk remains undetermined. We evaluated the prospective relation between serum intact FGF-23 (measured by a two-site monoclonal antibody ELISA) and fracture risk employing the Swedish part of the population-based Osteoporotic Fractures in Men Study (MrOS; n = 2868; mean age 75.4 +/- 3.2 years; median follow-up period 3.35 years). The incidence of at least one validated fracture after baseline was 20.4 per 1000 person-years. FGF-23 was directly related to the overall fracture risk [age-adjusted hazard ratio (HR) per SD increase = 1.20, 95% confidence interval (CI) 1.03-1.40] and vertebral fracture risk (HR = 1.33, 95% CI 1.02-1.75). Spline models revealed a nonlinear relation between FGF-23 and fracture risk, with the strongest relation at FGF-23 levels above 55.7 pg/mL. FGF-23 levels above 55.7 pg/mL also were associated with an increased risk for hip and nonvertebral fractures (HR = 2.30, 95% CI 1.16-4.58, and HR = 1.63, 95% CI 1.01-2.63, respectively). These relations remained essentially unaltered after adjustment for bodymass index (BMI), bone mineral density (BMD), glomerular filtration rate, 25(OH)(2)D-3, parathyroid hormone (PTH), and other fracture risk factors. In conclusion, FGF-23 is a novel predictor of fracture risk in elderly men. (C) 2011 American Society for Bone and Mineral Research.
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