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- Wu, Ping-Hsun, et al.
(author)
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The association between Single Nucleotide Polymorphisms of Klotho Gene and Mortality in Elderly Men: The MrOS Sweden Study
- 2020
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
- Westerberg, Per-Anton, 1967-
(author)
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Aspects of Fibroblast Growth Factor 23 in Mild to Moderate Renal Dysfunction
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Disturbances in mineral metabolism contribute to vascular calcification and mortality risk in chronic kidney disease (CKD). Serum levels of fibroblast growth factor (FGF)23, a bone derived, phosphaturic peptide, are associated with cardiovascular mortality in CKD. Membrane bound klotho(KL) is an obligate co receptor for FGF23 signaling in the kidney. To study aspects of FGF23 in mild to moderate impairment of renal function we have analyzed FGF23, estimated glomerular filtration rate (eGFR), parathyroid hormone(PTH), 1,25 (OH)2 vitamin D (1,25D), calcium and phosphate in one patient with a FGF23 producing tumor, before and after tumor removal (study 1), in 72 CKD patients with varying degree of renal dysfunction (study 2), in 9 healthy kidney donors, before and after nephrectomy (study 3). We also analyzed FGF23 (study 4), and performed genotyping of 27 single nucleotide polymorphisms (SNP) of the KL gene (study 5) in 2838 elderly Swedish men (MrOs study) and examined the association with mortality.FGF23 normalizes in 30-45 minutes after removal of a FGF23 producing tumor (study 1). 1,25D increases in hours and remains elevated months, even when the other parameters have normalized. FGF23 increase early in CKD, initially slowly, in correlation with PTH, but exponentially when hyperphosphatemia ensues (study 2). After unilateral nephrectomy (study 3) mineral homeostasis remain stable, initially due to a rise in PTH and later to an increase in FGF23.FGF23 levels are not correlated with mortality in elderly men after adjustment for eGFR, but with mortality due to cardiovascular disease, even in persons with normal eGFR (study 4). Polymorphism of the KL gene do not correlate with increased mortality risk in elderly men (study 5), but there is a modulating effect on FGF23 levels.FGF23 is of importance in maintaining phosphate homeostasis as renal function declines. It is co regulated with PTH until advanced renal dysfunction, and adjust the 1,25D to the actual GFR. FGF23 is associated with cardiovascular mortality. Further studies are needed to determine the mechanism, and if reduction of FGF23 by reducing phosphate intake may be beneficial even in persons with mild to moderate renal function.
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| 3. |
- Westerberg, Per-Anton, 1967-, et al.
(author)
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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
- 2018
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In: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 33:3, s. 466-471
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Journal article (peer-reviewed)abstract
- 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.
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| 4. |
- Westerberg, Per-Anton, 1967-, et al.
(author)
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Oncogenic osteomalacia illustrating the effects of fibroblast factor 23 on phospahte homeostasis
- 2012
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In: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 5:3, s. 240-243
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Journal article (peer-reviewed)abstract
- 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.
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| 5. |
- Wu, Ping-Hsun, 1982-, et al.
(author)
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The effect of fibroblast growth factor 23, vitamin D, and renal function on all-cause and cardiovascular mortality : The MrOS Sweden Study
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Other publication (other academic/artistic)abstract
- Background: Fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), estimated glomerular filtration rate (eGFR), and vitamin D have been linked to mortality and cardiovascular disease, but the limited data addressed the combined effect of these factors on mortality. We investigated these different aspects of mineral bone disease biomarkers that portray independent and prognostic information in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort.Methods: The baseline level of FGF23, PTH, vitamin D, and eGFR was categorized as a normal and abnormal group. The mortality risk of mineral bone markers was analyzed by Kaplan-Meier curve for group difference evaluation and restricted cubic regression spline curve for continuous values of markers. We compare the importance of markers by random forest. Cox proportional regression models were used to evaluate the mortality risk of abnormal mineral bone markers components and their independent effect.Results: The MrOS cohort included 2706 men whose mean aged 75.4±3.18 years, 9.4% had diabetes, and 36.3% had hypertension. During a mean follow-up of 4.48 years, 383 all-cause deaths and 144 cardiovascular deaths were recorded. A high intact FGF23 level, low eGFR, and vitamin D deficiency were associated with increased all-cause mortality. Participants with a combination of high FGF23 level, low eGFR, and vitamin D deficiency had a twofold increased all-cause and cardiovascular mortality risk compared to those without abnormalities after adjusting for confounders. FGF23 was the most important factor related to all-cause mortality in random forest analysis, but the association was attenuated after controlling eGFR in the Cox model. In contrast, a low vitamin D remained to predict all-cause mortality independently.Conclusions: A higher FGF23, lower renal function, and lower vitamin D level are associated with increased all-cause and cardiovascular mortality in elderly men. Renal dysfunction influenced the mortality prediction of FGF23 but not vitamin D.
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