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Aspects of Fibroblast Growth Factor 23 in Mild to Moderate Renal Dysfunction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 852
Keyword [en]
FGF23, phosphate, mineral metabolism, elderly, mortality
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-188233ISBN: 978-91-554-8564-1 (print)OAI: oai:DiVA.org:uu-188233DiVA: diva2:576912
Public defence
2013-02-08, Enghoffsalen, Akademiska Sjukhuset , ingång 50, plan1, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2013-01-17 Created: 2012-12-14 Last updated: 2013-04-02Bibliographically approved
List of papers
1. Oncogenic osteomalacia illustrating the effects of fibroblast factor 23 on phospahte homeostasis
Open this publication in new window or tab >>Oncogenic osteomalacia illustrating the effects of fibroblast factor 23 on phospahte homeostasis
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2012 (English)In: Clinical Kidney Journal, ISSN 2048-8505, Vol. 5, no 3, 240-243 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-188144 (URN)10.1093/ckj/sfs031 (DOI)
Note

Clinical report

Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2013-02-21Bibliographically approved
2. Regulation of fibroblast growth factor-23 in chronic kidney disease
Open this publication in new window or tab >>Regulation of fibroblast growth factor-23 in chronic kidney disease
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2007 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 22, no 11, 3202-3207 p.Article in journal (Refereed) Published
Abstract [en]

Background

Fibroblast 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).

Methods

Intact 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.

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 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.

Conclusions

We 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.

Keyword
chronic kidney disease, fibroblast growth factor-23(FGF23), hyperphosphataemia, parathyroid hormone, phosphate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-13187 (URN)10.1093/ndt/gfm347 (DOI)000250683900019 ()17567652 (PubMedID)
Available from: 2008-03-25 Created: 2008-03-25 Last updated: 2017-12-11
3. Fibroblast growth factor-23 and mineral metabolism after unilateral nephrectomy
Open this publication in new window or tab >>Fibroblast growth factor-23 and mineral metabolism after unilateral nephrectomy
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2010 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 25, no 12, 4068-4071 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
FGF23, FGF-23, mineral metabolism, nephrectomy, phosphate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-139260 (URN)10.1093/ndt/gfq288 (DOI)000284640400041 ()
Available from: 2010-12-22 Created: 2010-12-22 Last updated: 2017-12-11Bibliographically approved
4. Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs)
Open this publication in new window or tab >>Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs)
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2013 (English)In: BMC Nephrology, ISSN 1471-2369, E-ISSN 1471-2369, Vol. 14, 85- p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
FGF23, mortality, mineral metabolism
National Category
Urology and Nephrology
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-188146 (URN)10.1186/1471-2369-14-85 (DOI)000318618700001 ()
Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2017-12-07Bibliographically approved
5. Klotho polymorphisms, FGF23 and mortality among elderly men (Swedish MrOs).
Open this publication in new window or tab >>Klotho polymorphisms, FGF23 and mortality among elderly men (Swedish MrOs).
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

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.

Keyword
Klotho, FGF23, mineral metabolism, phosphatonin, mortality, elderly
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-188225 (URN)
Available from: 2012-12-14 Created: 2012-12-14 Last updated: 2013-02-11

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