| 1. |
- Westerberg, Per-Anton, et al.
(författare)
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Variation in the klotho gene is not associated with mortality risk among elderly men in MR OS Sweden
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:Suppl 1, s. S103-S104
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Polymorphisms in the Klotho (Kl) gene, which is central for vitamin D regulation by fibroblast growth factor 23 (FGF23), have been associated with longevity, coronary disease and stroke. The CC genotype of the single nucleotide polymorphism (SNP) rs577912 in the Kl-gene is associated with decreased Kl expression, as well as increased mortality in end stage renal disease. We examined if SNP in the Kl-gene was associated with mortality in the community derived cohort of 70 to 80 year old males of MrOS Sweden (N = 3014).High throughput genotyping of the KLOTHO SNPs was achieved by use of SequenomR MassEXTEND/Mass/ARRAY technology. 2738 subjects had a valid result for rs577912: CC 73.1% and CA + AA 26.9%. There were no differences in the serum levels of FGF23, phosphate, parathyroid hormone or renal function between genotypes CC and CA + AA. During a follow-up of a median of 4.5 years there were 337 deaths, 253 (12.6%) in the CC group and 84 (11.4%) in the CA + AA group. With log rank analysis there were no differences in mortality between the genotypes for all cause mortality (P = 0.39) or cardiovascular mortality (P = 0.60). None of the other SNPs in the Kl gene was associated with mortality in this cohort either.Conclusion:There is no association between the SNP rs577912 in the Kl-gene and mortality among elderly men.
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| 2. |
- Westerberg, Per-Anton, 1967-
(författare)
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Aspects of Fibroblast Growth Factor 23 in Mild to Moderate Renal Dysfunction
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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, et al.
(författare)
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Fibroblast growth factor-23 and mineral metabolism after unilateral nephrectomy
- 2010
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 25:12, s. 4068-4071
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Westerberg, Per-Anton, et al.
(författare)
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Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs).
- 2013
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Ingår i: BMC nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- 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 m2. 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 m2 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.
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| 5. |
- Westerberg, Per-Anton, 1967-, et al.
(författare)
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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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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 33:3, s. 466-471
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Westerberg, Per-Anton, et al.
(författare)
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Klotho polymorphisms, FGF23 and mortality among elderly men (Swedish MrOs).
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Westerberg, P-A and Kindmark, A contributed equally in preparation of the manuscript.Introduction. α-Klotho is the co receptor for Fibroblast growth factor(FGF)23and crucial for phosphate and vitamin D metabolism. Variants in the KLOTHO (KL) gene are associated with longevity and cardiovascular morbidities. Primary aim of this study is to examine if variations in KL affect mortality risk in a cohort of elderly men. Secondary aims are to examine associations with serum levels of FGF23, phosphate and renal function.Methods and results. 27 single nucleotide polymorphisms (SNP) in KLOTHO were genotyped using single base primer extension mass array technique on samples from 2924 men, aged 69 to 81 years, included in Swedish MrOs. After in average 6.1 years of follow up 584 had died, 214 of cardiovascular cause. After quality analyses and tagging of haplotypes 11 SNPs were analyzed for variation in mortality risk, serum levels of FGF23, phosphate, calcium and renal function. There were no associations with mortality of all cause. One SNP, (rs398655), in proximity to the promoter, demonstrated an increased Hazard ratio (95% Confidence interval(CI)) of 53% (95% CI, 8-118%) for death due to CVD in heterozygotes compared to homozygotes. Analysis using a dominant model showed an association between SNPs in the 5’ end of the gene and eGFR, phosphate level and logFGF23 (P=0.01).Conclusion. KL polymorphisms are associated with variation in FGF23 and phosphate.
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| 7. |
- Westerberg, Per-Anton, 1967-, et al.
(författare)
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Oncogenic osteomalacia illustrating the effects of fibroblast factor 23 on phospahte homeostasis
- 2012
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Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 5:3, s. 240-243
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Westerberg, Per-Anton, et al.
(författare)
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Osteomalaci på grund av tumörorsakad fosfatbrist : Fokus på FGF23 i fysiologi och klinik
- 2012
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 109:32-33, s. 1414-1416
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Oncogenic osteomalacia is a rare syndrome caused by a small tumor, of mesenchymal origin, that produces FGF23. FGF23 is a recently described bone derived factor closely regulated by calcitriol and phosphate load. In a feedback loop it increases renal phosphate loss and decreases calcitriol activation. Unregulated production of FGF23 by a tumor causes negative phosphate balance and deficient mineralization of the skeleton, with pain and fractures as a consequence. We have used determination of a venous gradient of FGF23 as an aid in localizing FGF23 producing tumors in 10 cases. In eight cases the tumor has been removed, one patient awaits further examination and in one case it has not been possible to localize the tumor.
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| 9. |
- Westerberg, Per-Anton, et al.
(författare)
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Preoperative tumor localization by means of venous sampling for fibroblast growth factor-23 in a patient with tumor-induced osteomalacia
- 2008
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Ingår i: Endocrine Practice. - 1530-891X .- 1934-2403. ; 14:3, s. 362-7
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Westerberg, Per-Anton, et al.
(författare)
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Regulation of fibroblast growth factor-23 in chronic kidney disease
- 2007
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 22:11, s. 3202-3207
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFibroblast growth factor-23 (FGF23) is a circulatingfactor that regulates the renal reabsorption of inorganic phosphate(Pi) and is increased in chronic kidney disease (CKD). The aimof the current investigation was to study the regulation ofFGF23 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)2vitamin D3(1,25(OH)2D3) and estimated glomerular filtrationrate (eGFR).MethodsIntact FGF23 and other biochemical variables were analysedin 72 consecutive adult out-patients with various stages ofCKD (eGFR ranging from 4–96 ml/min.) Association studieswere performed using linear univariate and multivariate analysis.ResultsFGF23 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 FGF23and 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 logPTH (P < 0.05) was the only independent predictor of logFGF23 in multivariate analysis. In CKD 1–5, Pi (P <0.00001) and log PTH (P < 0.01) were explanatory variablesfor log FGF23 in multivariate analysis.ConclusionsWe conclude that serum FGF23 increases in CKD 4–5,in parallel with the emerging hyperphosphataemia. Serum Pi isthe most important predictor of FGF23 when GFR is less than30 ml/min. In contrast, our data suggest that Pi may not bean important determinant of FGF23 in normophosphataemic CKDsubjects. Finally, the association between FGF23 and PTH inCKD may suggest a co-regulation that remains to be further elucidated.
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