Association between fibroblast growth factor 23 and functional capacity among independent elderly individuals

Lara Miguel Quirino Araújo; Patrícia Ferreira do Prado Moreira; Clineu de Mello Almada, Filho; Luciano Vieira de Araújo; Aline Granja Costa; Ricardo de Castro Cintra Sesso; John P Bilezikian; Marise Lazaretti-Castro; Maysa Seabra Cendoroglo

doi:10.31744/einstein_journal/2021AO5925

. 2021 Jul 22;19:eAO5925. doi: 10.31744/einstein_journal/2021AO5925

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Association between fibroblast growth factor 23 and functional capacity among independent elderly individuals

Lara Miguel Quirino Araújo ¹, Patrícia Ferreira do Prado Moreira ¹, Clineu de Mello Almada Filho ¹, Luciano Vieira de Araújo ², Aline Granja Costa ³, Ricardo de Castro Cintra Sesso ¹, John P Bilezikian ³, Marise Lazaretti-Castro ¹, Maysa Seabra Cendoroglo ¹

PMCID: PMC8302224 PMID: 34346986

ABSTRACT

Objective

To examine the association of between serum fibroblast growth factor 23 and the functional capacity among independent individuals, aged 80 or older.

Methods

The functional capacity of 144 elderly was assessed by Instrumental Activities of Daily Living, cognitive tests, handgrip strength and the timed ability to rise from a chair and sit down five times. Fibroblast growth factor 23 was measured using an ELISA assay.

Results

Participants in the lowest fibroblast growth factor 23 tertile had the highest mean±standard deviation estimated glomerular filtration rate, the highest mean hemoglobin level, the lowest average number of diseases and the lowest number of medications used. In participants with the estimated glomerular filtration rate >45mL/minute/1.73m², mean fibroblast growth factor 23 level was higher in those with 25(OH) vitamin D <20ng/mL than in those with 25(OH) vitamin D ≥20ng/mL (75.6RU/mL±42.8 versus 68.5RU/mL±41.7; p<0.001). There was an increase in the mean serum cystatin C (from 1.3mg/mL±0.3 to 1.5mg/mL±0.3 to 1.7mg/mL±0.4) as function of higher fibroblast growth factor 23 tertile (p<0.001). Fibroblast growth factor 23 levels were not significantly associated with capacity in physical or cognitive tests.

Conclusion

In independent community-dwelling elderly, aged ≥80 years, fibroblast growth factor 23 was associated with aged-related comorbidities and renal function but not with functional capacity.

Keywords: Fibroblast growth factors; Functional status; Cognitive aging; Aging; Aged, 80 and over; Kidney/physiology; Activities of daily living; Sarcopenia

INTRODUCTION

The identification of biomarkers of the aging process has the potential to promote the development of targets to prevent aging-associated syndromes. Fibroblast growth factor 23 (FGF23) is a candidate target because it is a key protein in aging-associated biochemical pathways. The FGF-Klotho endocrine axes plays a decisive role in aging-related diseases. Fibroblast growth factor 23 is an endocrine protein that enter in systemic circulation and the Klotho protein is the co-receptor to bind FGF23, with high affinity to fibroblast growth factor receptor (FGFR) in their target organs. The kidneys are the FGF23’s major target organ, where it induces phosphaturia by acting in the apical brush border membrane of proximal tubular cells. Moreover, FGF23, vitamin D, and parathyroid hormone (PTH) are in negative feedback loops to maintain phosphate homeostasis.⁽¹⁾

The lack of FGF23 or Klotho causes a premature aging phenotype, such as hypogonadism, premature thymic involution, ectopic calcification, dermal atrophy, pulmonary emphysema, neurodegeneration, hearing loss and vascular calcifications.^(2-5) There is some evidence to support this aging phenotype based on hyperphosphatemia.⁽⁶⁾ In chronic kidney disease (CKD) and in the aging kidney, FGF23 serum level rises to control hyperphosphatemia via the FGF23-Klotho-vitamin D-PTH axis. However, FGF23 fails to maintain phosphate balance, leading to hyperphosphatasemia, and the phosphate starts to exert its deleterious actions. On the other hand, an experiment with human muscle mesenchymal stem cells, important in the regeneration of muscle mass, showed that treatment with FGF23 promotes the aging phenotype independently of Klotho, through direct action in the regulation of cell cycle by p53 protein.⁽⁷⁾ Paradoxically, an experiment with physical exercise protocols in mice demonstrated an increase in serum FGF23 and longer-term exercise upregulated FGF23 mRNA and FGF23 in skeletal muscle. And the mice previously treated with FGF23 performed better in exercise, control of reactive oxidative species (ROS), and improved mitochondrial function in skeletal muscle. The mechanism for these actions is unknown.⁽⁸⁾ These studies suggest that the influence of FGF23 on muscle biology and physical performance depends on the context and different pathways. Deficit of FGF23 in serum causes premature aging by loosing of phosphate control and FGF23 overload can lead to cell senescence by p53. We could speculate that accelerated aging in CKD may be influenced by both mechanisms, depending on CDK stage. Conversely, serum FGF23 elevated by a healthy stimulus, such as physical exercise, could improve performance in physical exercise.

The health of elderly individuals should be understood from a functional perspective (and not based on the disease), since healthy aging is “the process of developing and maintaining the functional ability that enables wellbeing in older age”. Functional capacity means “the health-related attributes that enable people to be and to do what they have reason to value”.⁽⁹⁾ Cognitive function and physical performance are pillars of these attributes and FGF23 may influence both. A sample from the Framingham Heart Study showed an association of serum FGF23 levels and incidence of dementia,⁽¹⁰⁾ and FGF23’s actions in muscle biology and premature aging may play a role in physical performance.

OBJECTIVE

To examine the association between serum fibroblast growth factor 23 and functional capacity among independent individuals aged 80 or over, as well as to investigated the association of fibroblast growth factor 23 with laboratory measurements of kidney-vitamin D-parathyroid hormone axis.

METHODS

Study participants

This is a cross sectional study of data from the first wave of the Longevity Project, a cohort of community-dwelling elderly aged 80 years or more, independent for activities of daily life,⁽¹¹⁾ and recruited by advertisement at local neighborhood newspapers, radio media and referral from other departments of the Universidade Federal de São Paulo (UNIFESP) to the Geriatrics Division, from 2010 to 2012. The inclusion criteria were to be able to walk without human support, to have all chronic disease under control at the time of the study, and no cognitive complains. The exclusion criteria were living in a nursing home, apparent cognitive impairment, end-stage disease, being unable to respond to the study tests, apparent infection, heart failure, liver cirrhosis, history of dialysis, immunosuppressive therapy in 6 months, previous chemotherapy for cancer, or HIV infection. All signed the Informed Consent Form, and the Research Ethics Committee of UNIFESP approved the study protocol 1532/09.

Measurements

Sociodemographic data and body mass index (BMI), clinical data, medication inventory and functional capacity domains were collected using a standard questionnaire administered by trained physicians.

Functional capacity

Depressive symptoms were obtained using the 15-item Geriatric Depression Scale.⁽¹²⁾ Cognitive function was assessed by the Mini-Mental State Examination (MMSE)⁽¹³⁾ and by category Verbal Fluency Test (VFT).⁽¹⁴⁾ The MMSE is a test of global cognition and the VFT tests language, executive functions and semantic memory. The self-reported ability to perform tasks for life in the community was assessed using Lawton’s scale of Instrumental Activities of Daily Living (IADL), scored from seven to 21 (the highest score means independence).⁽¹⁵⁾Physical performance was assessed by the timed ability to rise from a chair and sit down five times,⁽¹⁶⁾ and handgrip strength by the best result out of three attempts on a Jamar dynamometer.⁽¹⁷⁾

Laboratory measurements

Anthropometric and performance measurements were performed at the same time, and blood was collected in the following 4 months. The blood samples were drawn after a 12 hours fast, and creatinine, cystatine C, hemoglobin, albumin, serum 25(OH) vitamin D and intact PTH levels were measured. Serum FGF23 was analyzed by a second generation C-terminal FGF23 two-site Enzyme Linked Immunonosorbent Assay (ELISA; Immutopics, San Clemente, CA, USA). This assay detects two epitopes in the C-terminus of FGF23, and has a sensitivity of 1.5 relative units per mL (RU/mL), and inter- and intra-assay coefficients of variations of less than 5%. Serum creatinine was measured using a modified kinetic Jaffé colorimetric method on an autoanalyzer (AU 400, Beckman Coulter, CA. USA), which was calibrated to isotope dilution mass spectrometry, using a standard reference material (914a) traceable to the National Institutes of Standards and Technology (NIST). Plasma cystatin C levels were determined by an automated particle-enhanced immunoturbidimetric method using a Beckman AU 400 analyzer (Beckman Coulter), and reagents (code number LX002. s2361. X0973. X0974) obtained from DakoCytomation (Glostrup, Denmark), following the procedures recommended by the reagent producer. We estimated glomerular filtration rate (eGFR) by the CKD-EPI creatinine-cystatin C equation. All samples were frozen at −80°C.

Data analyses

The analyses were performed using the (SPSS) version 20.0. We categorized FGF23 levels into tertiles and examined the distribution of covariates in their categories. The functional capacity domains were presented as mean (±standard deviation – SD). We used the χ² test to examine the associations between the categorical variables; the analysis of variance (Anova) was used to compare the means of more than two groups; the Duncan test or the Dunnett’s C test we used for multiple comparisons; the Kolmogorov-Smirnov test and Levene test were used to verify the normality and homoscedasticity, respectively; the Brown-Forsythe correction was employed in case of mistakenly presuming homoscedasticity to correct the degrees of freedom of the F statistics; the Kruskal-Wallis was used in case of non-parametric distribution; and if the Kruskal-Wallis test was significant, the difference between groups was assessed using the Bonferroni-Dunn. In the multiple linear regression, clinical characteristics were independent variables and FGF23 was a dependent variable. Initially all variables were included in the model, then a non-significant 5% were excluded one by one in order of significance (backward method).

RESULTS

We studied 144 patients, with mean age of 85.4 years, 73.6% were women, with an average of four chronic diseases and regular use of six medications. Overall FGF23 was 91.05RU/mL±67.47. The eGFR less than 45mL/minute/1.73m²was noted in 33.3%, and 25(OH) vitamin D <20ng/mL was present in 59% of all participants. Table 1 shows all participants grouped by FGF23 tertiles to investigate demographic, clinical, laboratory and functional capacity differences.

Table 1. Demographic, clinical, and laboratory parameters of the study population by tertiles of fibroblast growth factor 23 levels.

Characteristics	All sample (n=144)	FGF23 (RU/mL)			p value
Characteristics	All sample (n=144)	1^st tertile <54.4 (n=47)	2^nd tertile 54.4-92.6 (n=48)	3^rd tertile ≥92.6 (n=49)	p value
Age, years	85.4±4.1	85.6±3.8	84.1±3.0^a	86.6±4.9^b	0.011
Gender					0.931
Male	38 (26.4)	13 (27.7)	13 (27.1)	12 (24.5)
Female	106 (73.6)	34 (72.3)	35 (72.9)	37 (75.5)
Race					0.069
White	96 (66.7)	26 (55.3)	32 (66.7)	38 (77.6)
Non-white	48 (33.3)	21 (44.7)	16 (33.3)	11 (22.4)
Number of chronic disease	4.4±1.9	3.9±1.9^a	4.5±1.6	4.9±2.0^b	0.018
Number of regular use medications	5.9±2.7	4.9±2.1^a	6.2±2.6^b	6.5±3.1^b	0.008
Vitamin D supplements	59 (41.3)	15 (31.9)	23 (47.9)	21 (43.8)	0.260
Weight, kg	70.7±78.9	65.1±12.5	82.4±135.6	64.7±13.8	0.687
Body mass index, kg/m²	26.8±4.3	27.4±4.0	26.5±4.1	26.5±4.9	0.562
25(OH)D, ng/mL	19.2±8.4	19.6±8.6	20.8±9.6	17.3±6.4	0.110
25(OH)D – category, ng/mL					0.183
<20ng/mL	85 (59.0)	26 (55.3)	25 (52.1)	34 (69.4)
≥20ng/mL	59 (41.0)	21 (44.7)	23 (47.9)	15 (30.6)
PTH, pg/mL	62.6±33.4	53.9±29.2	63.1±27.8	70.5±40.0	0.060*
Calcium, mg/dL	9.3±0.5	9.3±0.5	9.4±0.4	9.4±0.5	0.428
Phosphorus, mg/dL	3.4±1.1	3.2±0.5	3.3±0.4	3.7±1.8	0.091*
Hemoglobin, g/dL	13.4±1.3	13.9±1.2^b	13.3±1.3^a	13.1±1.3^a	0.012
Creatinine, mg/dL	0.96±0.28	0.87±0.19^a	0.97±0.24^b	1.04±0.35^b	0.007
Cystatin C, mg/L	1.50±0.37	1.32±0.28^c	1.49±0.29^a	1.69±0.43^b	<0.001
eGFR, mL/minute/1.73m²	51±14	58±12^b	50±12^a	45±14^a	<0.001
eGFR – category, mL/minute/1.73 m²					<0.001
<45mL/minute/1.73m²	48 (33.3)	6 (12.8)^a	17 (35.4)	25 (51.0)^b
≥45mL/minute/1.73m²	96 (66.7)	41 (87.2)	31 (64.6)	24 (49.0)
Functional capacity
Education, years	4.5±3.8	4.4±3.7	5.1±4.6	3.9±2.9	0.720*
GDS	3.9±2.7	3.4±2.2	3.9±2.9	4.4±2.8	0.259*
MMSE	24.2±3.4	23.7±3.2	24.5±3.6	24.5±3.3	0.466
VFT	12.9±3.5	12.5±3.4	12.9±3.6	13.3±3.7	0.562
IADL	18.8±2.5	19.0±2.6	19.3±2.1	18.2±2.8	0.156*
Handgrip strength, kgf^†
All	21.8±9.0	23.5±12.4	21.6±6.3	20.5±7.2	0.283
Male	30.2±11.4	35.0±17.1	27.5±5.7	28.0±6.2	0.130*
Female	18.8±5.4	18.9±5.6	19.3±5.0	18.1±5.6	0.612
Time to stand up and sit down, seconds^‡	20.3±8.4	22.1±10.4	19.2±7.6	19.6±6.7	0.451*

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Results expressed are mean (± standard deviation), n (%).

Different letters have different means from multiple comparisons.

* p value: descriptive level of χ² test or Kruskal-Wallis/analysis of variance; ^† n=143 (male/female: 38/105); ^‡ n=136 (of 140 tested, 136 fulfilled the task).

FGF23: fibroblast growth factor 23; 25(OH) vit D: 25(OH) vitamin D; PTH: parathyroid hormone; eGFR: estimated glomerular filtration rate; GDS: Geriatric Depression Scale; MMSE: Mini-Mental State Examination; VFT: Verbal Fluency Test; IADL: Instrumental Activity Daily Living.

There was difference in age, number of chronic diseases and number of regular-use medications in the FGF23’s tertiles. The group with higher FGF23 was slightly older than that in the second tertile (p=0.011). Those with lower mean number of diseases and less use of medications were in the first tertile (p=0.018 and 0.008, respectively). Creatinine had the lowest mean value in the groups with lower FGF23 (p<0.007) and there was an increasing serum cystatin C as the FGF23 increased (p<0.001). The eGFR was higher in the first tertile (p<0.001). The distribution of participants with eGFR <45mL/minute/1.73m²was different in the FGF23 tertiles, with the highest proportion of participants in the third tertile and the lowest in the first tertile (p<0.001). Higher mean hemoglobin levels were found in the first tertile of FGF23.

Functional capacity showed no difference between FGF23 tertiles. Since there was a different performance by gender in handgrip strength (mean for male of 30.2kgf, SD ±11.4, and for female of 18.8kgf, SD ±5.4; p=0.0001), we assessed handgrip strength by gender in FGF23 tertiles and also there was no significant association.

According to table 2, in the group with high eGFR (≥45mL/minute/1.73m²), the mean FGF23 in the group with lower 25(OH) vitamin D level (<20ng/mL) was higher than the group with 25(OH) vitamin D above 20ng/mL. The multiple linear regression model was fitted to evaluate the simultaneous effects of age, color, number of diseases and medications, 25(OH) vitamin D, eGFR, hemoglobin, creatinine, cystatin C, PTH and phosphorus on FGF23. Considering there were indications of distinct FGF23 behaviors by levels of Vitamin D and eGFR (Table 2), we included the interaction between 25(OH) vitamin D and eGFR in the model. The results of the initial and final regression models are shown in table 3. Only the cystatin C remained significant in the final model (p=0.001). Thus, for an increase of 1mg/L cystatin C, on average, there is an increase of 83.71RU/mL in FGF23.

Table 2. Summarized measures of fibroblast growth factor 23 levels according to estimated glomerular filtration rate and 25 OH vitamin D.

	eGFR <45mL/minute/1.73m²		eGFR ≥45mL/minute/1.73m²		p value
	25(OH)D <20ng/mL	25(OH)D ≥20ng/mL	25(OH)D <20ng/mL	25(OH)D ≥20ng/mL	p value
FGF23 (RU/mL)					<0.001
Mean±SD	138.6±93.1	109.2±84.0	75.6±42.8^a	68.5±41.7^b
95%CI	104.4-172.7	66.00-152.4	63.9-87.3	55.5-81.5
n (%)	31 (21.5)	17 (11.8)	54 (37.5)	42 (29.2)

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p value: descriptive level of Kruskal-Wallis test. Kolmogorov-Smirnov test (p<0.001). Different letters have different means from multiple comparisons. eGFR: estimated glomerular filtration rate; 25(OH)D: 25(OH) vitamin D; FGF23: fibroblast growth factor 23; SD: standard deviation; 95%IC: 95% confidence interval.

Table 3. Estimates of the coefficients and respective 95% confidence interval of the multiple linear regression models on fibroblast growth factor 23 levels.

	Initial model		Final model
	Coefficient (95%CI)	p value	Coefficient (95%CI)	p value
Age, years	-0.80 (-3.62-2.03)	0.578
Non-white	-10.66 (-34.03-12.72)	0.369
Number of chronic diseases	-0.25 (-7.04-6.54)	0.942
Number of regular-use medications	3.31 (-1.34-7.97)	0.161
25(OH)D <20ng/mL	6.49 (-20.14-33.12)	0.631
eGFR <45mL/minute/1.73m²	5.48 (-36.25-47.21)	0.795
25(OH)D*eGFR	7.76 (-39.2-54.73)	0.744
Hemoglobin, g/dL	-3.32 (-12.46-5.83)	0.474
Creatinine, mg/dL	-15.36 (-71.44-40.72)	0.589
Cystatin C, mg/L	71.06 (15.23-126.9)	0.013	84.19 (57.56-110.82)	<0.001
PTH, pg/mL	0.13 (-0.22-0.47)	0.477
Phosphorus	13.49 (-6.59-33.56)	0.186
R², %	28.8		21.6
n (%)	134		144

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Kolmogorov-Smirnov: initial (p<0.001) and final model (p<0.001). 25(OH)D*eGFR: interaction between 25(OH)D and eGFR in classes. 95%CI: 95% confidence interval; 25(OH)D: 25(OH) vitamin D; eGFR: estimated glomerular filtration rate; PTH: parathyroid hormone; R²: Coefficient of determination.

DISCUSSION

Serum FGF23 was associated with neither cognitive function nor physical performance in independent individuals aged 80 years or older. We found that those elderly with higher levels of FGF23 were older, had lower hemoglobin levels, more comorbidities, polypharmacy and greater impairment of renal function. These variables can estimate the general health status of the elderly and, thus, suggest that FGF23 may be a biomarker of aging, but FGF23 fails as a biomarker in the functional perspective of healthy aging.

A study of 2,977 elderly people, with an average age of 78 years,^(18,19) showed that serum levels of FGF23 were correlated with general health status as found in our study; in addition, the authors also showed the association of FGF23 with the frailty phenotype. However, when each component of frailty measured by physical performance was assessed individually, it was found that FGF23 duplication was associated with a 22% higher probability of slowness measured by the gait speed test, but no correlation with measured weakness by the grip strength in accordance with our result. This group of elderly people was younger and had a higher eTFG than ours, which reflects a lower serum level of FGF23 in this group. It is possible that there is a counterpoint between the increase in FGF23 due to the decline in renal function with aging or due to a healthy lifestyle, with a higher rate of physical activity.⁽⁸⁾ None of these analyses addressed possible endogenous stimuli, such as regular physical exercise.

Our population had a good cognitive performance and ability to perform daily tasks for community life (AIVD score). The homogeneity of voluntary participants made it difficult to show these associations with FGF23. However, physical performance was more diverse. Our population performed well on average in upper limbs, as clinically relevant weakness is the handgrip strength of less than 26kgf for men and 16kgf for women.⁽¹⁹⁾ But for the lower limbs, our patients performed poorly, on average, in the timed ability to rise from a chair, over 16.7 seconds.⁽¹⁶⁾ In both measures, there is a relevant intragroup heterogeneity.

In older community-dwelling adults, common aging features were associated with FGF23, such as reduced eGFR and CKD, left ventricular hypertrophy, cardiac insufficiency, cardiovascular disease, increased fat mass, dyslipidemia and increased mortality.^(20-24) In this study, patients with cardiovascular disease were excluded. Our results show that the serum FGF23 was related to renal function impairment. For example, among those with eGFR <45mL/minute/1.73m², FGF23 levels were significantly higher. It is in accordance with FGF23 as an early biomarker for kidney dysfunction.^(20,25) Another key index in renal function was the association between cystatin C and FGF23. For each 1mg/L increase in cystatin C, there was an increase of approximately 85 units of FGF23. This is in accordance with the idea that cystatin C is a better biomarker of renal function for octogenarians than creatinine because cystatin C is unaffected by muscle mass and dietary protein intake. As FGF23 participates in the regulation of phosphate and the vitamin D metabolism, we expected to find association with them. Among those with eGFR above 45mL/minute/1.73m², there was a correlation between lower levels of 25(OH) vitamin D and higher levels of serum FGF23.

Our study participants are a homogeneous population with multiple comorbidities, but with a capacity for preserved self-care and only light self-reported dependency for tasks related to community life. Although we did not assess nutritional status in detail, BMI was in adequate condition. Their homogeneity could explain our difficulty to find associations between FGF23 and the physical and mental aspects investigated. On the other hand, our approach in assessing different domains of functional capacity pointed some divergence in intra-group physical capacity. The relatively small sample size may have limited the power of the study to detect such associations. In addition, sample size compromised our ability to perform some subgroup analyses (especially in men). It was also not possible to establish a cut-off point below which eGFR could predictably be associated with a rise in FGF23. Other factors, not addressed in this study, especially regular physical activity, may have influenced the results and should be investigated in further studies. Despite the difficulty in estimating GFR in the elderly, we have used the CKD EPI-creatinine-cystatin C equation previously validated in 95 individuals in this cohort.⁽²⁶⁾

CONCLUSION

Fibroblast growth factor 23 was not significantly associated with functional performance in community-dwelling independent elderly individuals aged 80 years or more; nonetheless fibroblast growth factor 23 was associated with age, comorbidities, medications and estimated glomerular filtration rate. To our knowledge, this was the first study to evaluate the association between fibroblast growth factor 23 and functional performance among independent elderly individuals.

ACKNOWLEDGEMENTS

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2011/12753-8). We thank the staff that carried out this study at Universidade Federal de São Paulo (UNIFESP) and at Endocrinology Division laboratories at Columbia University, and all volunteers for their dedication.

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Einstein (Sao Paulo). 2021 Jul 22;19:eAO5925. [Article in Portuguese]

Associação entre fator de crescimento de fibroblastos 23 e capacidade funcional em idosos independentes

RESUMO

Objetivo

Examinar a associação entre o fator de crescimento de fibroblastos 23 sérico e a capacidade funcional em indivíduos independentes, com 80 anos ou mais.

Métodos

A capacidade funcional de 144 idosos foi avaliada por meio de Atividades Instrumentais da Vida Diária, testes cognitivos, força de preensão manual e capacidade de levantar de uma cadeira e sentar cinco vezes. O fator de crescimento de fibroblastos 23 foi medido pelo teste ELISA.

Resultados

Os participantes no tercil mais baixo de fator de crescimento de fibroblastos 23 tiveram a maior média±desvio-padrão da taxa de filtração glomerular estimada, concentração média de hemoglobina mais alta, menor número médio de doenças e menor número de medicamentos utilizados. Em participantes com taxa de filtração glomerular estimada >45mL/minuto/1,73m², o nível médio do fator de crescimento de fibroblastos 23 foi maior naqueles com 25(OH) vitamina D <20ng/mL do que naqueles com 25(OH) vitamina D ≥20ng/mL (75,6RU/mL±42,8 versus 68,5RU/mL±41,7; p<0,001). Houve aumento na cistatina C sérica média (de 1,3mg/mL±0,3 a 1,5mg/mL±0,3 a 1,7mg/mL±0,4) em função do tercil de fator de crescimento 23 de fibroblastos mais alto (p<0,001). Os níveis de fator de crescimento de fibroblastos 23 não foram significativamente associados à capacidade em testes físicos ou cognitivos.

Conclusão

Em idosos independentes residentes na comunidade ≥80 anos, o fator de crescimento de fibroblastos 23 foi associado a comorbidades relacionadas à idade e à função renal, mas não à capacidade funcional.

Keywords: Fatores de crescimento de fibroblastos, Estado funcional, Envelhecimento cognitivo, Envelhecimento, Idoso de 80 anos ou mais, Rim/fisiologia, Atividades cotidianas, Sarcopenia

INTRODUÇÃO

A identificação de biomarcadores do processo de envelhecimento pode potencialmente promover o desenvolvimento de alvos para a prevenção de síndromes associadas ao envelhecimento. O fator de crescimento de fibroblastos 23 (FGF23) é um alvo candidato, porque é uma proteína-chave nas vias bioquímicas associadas ao envelhecimento. Os eixos endócrinos FGF-Klotho têm papel decisivo nas doenças relacionadas ao envelhecimento. O FGF23 é uma proteína endócrina que entra na circulação sistêmica, e a proteína Klotho é o correceptor para se ligar ao FGF23, com alta afinidade ao receptor do fator de crescimento de fibroblastos (FGFR) em seus órgãos-alvo. Os rins são o principal órgão-alvo do FGF23, no qual ocorre a indução à fosfatúria por ação na borda em escova da membrana apical das células tubulares proximais. Além disso, o FGF23, a vitamina D e o hormônio da paratireoide (PTH - parathyroid hormone) estão em ciclos de feedback negativo para manter a homeostase do fosfato.⁽¹⁾

A falta de FGF23 ou Klotho causa um fenótipo de envelhecimento prematuro, como hipogonadismo, involução tímica prematura, calcificação ectópica, atrofia dérmica, enfisema pulmonar, neurodegeneração, perda auditiva e calcificações vasculares.^(2-5) Existem algumas evidências para apoiar esse fenótipo de envelhecimento, com base na hiperfosfatemia.⁽⁶⁾ Na doença renal crônica (DRC) e no rim envelhecido, o nível sérico de FGF23 aumenta, para controlar a hiperfosfatemia por meio do eixo FGF23-Klotho-vitamina D-PTH. No entanto, o FGF23 não consegue manter o equilíbrio do fosfato, o que resulta em hiperfosfatasemia, e o fosfato passa a exercer suas ações deletérias. Por outro lado, um experimento com células-tronco mesenquimais de músculo humano, importante na regeneração da massa muscular, mostrou que o tratamento com FGF23 promove o fenótipo de envelhecimento independente do Klotho, por meio de ação direta na regulação do ciclo celular pela proteína p53.⁽⁷⁾ Paradoxalmente, um experimento com protocolos de exercício físico em camundongos demonstrou aumento no FGF23 sérico e no mRNA de FGF23 regulado positivamente para exercícios de longo prazo e FGF23 no músculo esquelético. Os camundongos previamente tratados com FGF23 tiveram melhor desempenho em exercícios, controle de espécies reativas de oxigênio (ROS) e melhora da função mitocondrial no músculo esquelético. O mecanismo dessas ações é desconhecido.⁽⁸⁾ Esses estudos sugerem que a influência do FGF23 na biologia muscular e no desempenho físico depende do contexto e das diferentes vias. O deficit de FGF23 no soro causa envelhecimento prematuro pela perda do controle do fosfato, e a sobrecarga de FGF23 pode levar à senescência celular por p53. Seria possível especular que o envelhecimento acelerado na DRC pode ser influenciado por ambos os mecanismos, dependendo do estágio da DRC. Por outro lado, o FGF23 sérico elevado por um estímulo saudável, como o exercício físico, pode melhorar o desempenho no exercício físico.

A saúde do idoso deve ser entendida a partir de uma perspectiva funcional (e não baseada na doença), uma vez que o envelhecimento saudável é “o processo de desenvolvimento e manutenção da capacidade funcional que permite o bem-estar na idade avançada”. A capacidade funcional significa “os atributos relacionados à saúde que permitem que as pessoas sejam ou façam aquilo que valorizam”.⁽⁹⁾ A função cognitiva e o desempenho físico são os pilares desses atributos, e o FGF23 pode influenciar em ambos. Uma amostra do Framingham Heart Study mostrou haver associação entre os níveis séricos de FGF23 e a incidência de demência,⁽¹⁰⁾ e que as ações do FGF23 na biologia muscular e no envelhecimento prematuro podem desempenhar papel no desempenho físico.

OBJETIVO

Examinar a associação entre fator de crescimento de fibroblastos 23 sérico e capacidade funcional em indivíduos independentes com 80 anos ou mais, além de verificar a associação do fator de crescimento de fibroblastos 23 com medições laboratoriais do eixo rim-vitamina D-hormônio da paratireoide.

MÉTODOS

Participantes do estudo

Este é um estudo transversal de dados da primeira onda do Projeto Longevidade e incluiu uma coorte de idosos residentes na comunidade com 80 anos ou mais, independentes para Atividades da Vida Diária⁽¹¹⁾ e recrutados por meio de anúncio em jornais de bairro, rádios ou encaminhamento de outros departamentos da Universidade Federal de São Paulo (UNIFESP) para a Divisão de Geriatria, no período de 2010 a 2012. Os critérios de inclusão foram ser capaz de andar sem apoio humano, ter todas as doenças crônicas sob controle no momento do estudo e não ter queixa cognitiva. Os critérios de exclusão foram morar em casa de repouso; apresentar deficiência cognitiva aparente; ter doença terminal; ser incapaz de responder aos testes do estudo; ter infecção aparente, insuficiência cardíaca, cirrose hepática ou história de diálise; ter passado por terapia imunossupressora nos 6 meses anteriores ou ter se submetido a quimioterapia para câncer, ou ter infecção por HIV. Todos assinaram o Termo de Consentimento Livre e Esclarecido, e o Comitê de Ética em Pesquisa da UNIFESP aprovou o protocolo de estudo 1532/09.

Medidas

Foram coletados dados sociodemográficos e índice de massa corporal (IMC), dados clínicos, lista de medicamentos e domínios da capacidade funcional por meio de um questionário padrão administrado por médicos treinados.

Capacidade funcional

Os sintomas depressivos foram obtidos por meio da Escala de Depressão Geriátrica de 15 itens.⁽¹²⁾ A função cognitiva foi avaliada pelo Miniexame do Estado Mental (MEEM)⁽¹³⁾ e pelo Teste de Fluência Verbal (TFV) de categorias.⁽¹⁴⁾ O MEEM é um teste de cognição global, e o TFV verifica a linguagem, as funções executivas e a memória semântica. A capacidade autorrelatada de realizar tarefas para a vida na comunidade foi avaliada por meio da escala de Atividades Instrumentais de Vida Diária (AIVD) de Lawton, com pontuação de sete a 21 (a pontuação mais alta significa independência).⁽¹⁵⁾O desempenho físico foi avaliado pela habilidade cronometrada para se levantar de uma cadeira e se sentar cinco vezes,⁽¹⁶⁾ bem como pela força de preensão pelo melhor resultado em três tentativas usando um dinamômetro Jamar.⁽¹⁷⁾

Medidas laboratoriais

As medidas antropométricas e de desempenho foram realizadas ao mesmo tempo, e a coleta de sangue foi feita nos 4 meses subsequentes. As amostras de sangue foram coletadas após jejum de 12 horas, sendo medidos os níveis de creatinina, cistatina C, hemoglobina, albumina, 25(OH) vitamina D sérica e PTH intacto. O FGF23 sérico foi analisado por um kit de segunda geração do Enzyme Linked Immunonosorbent Assay (ELISA) de dois locais para terminal C de FGF23 (Immutopics, San Clemente, CA, Estados Unidos). Esse teste detecta dois epítopos no terminal C de FGF23 e tem sensibilidade de 1,5 unidade relativas por mL (RU/mL) e coeficientes de variação inter- e intraensaio de menos de 5%. A creatinina sérica foi medida usando um método colorimétrico de Jaffé cinético modificado em um analisador automático (AU 400, Beckman Coulter, CA, Estados Unidos), que foi calibrado para espectrometria de massa de diluição isotópica, usando material de referência padrão (914a) rastreável para o National Institutes of Standards and Technology (NIST). Os níveis plasmáticos de cistatina C foram determinados por método imunoturbidimétrico intensificado por partículas automatizado usando um analisador Beckman AU 400 (Beckman Coulter) e reagentes (códigos LX002. s2361. X0973. X0974) obtidos de DakoCytomation (Glostrup, Dinamarca), seguindo os procedimentos recomendados pelo fabricante dos reagentes. Calculou-se a estimativa da taxa de filtração glomerular (eTFG) pela equação CKD-EPI creatinina-cistatina C. Todas as amostras foram congeladas a -80° C.

Análise dos dados

As análises foram realizadas no (SPSS) versão 20.0. Os níveis de FGF23 foram categorizados em tercis e examinou-se a distribuição das covariáveis em suas categorias. Os domínios da capacidade funcional foram apresentados como média (± desvio-padrão – DP). O teste do χ² foi usados para examinar as associações entre as variáveis categóricas; a análise de variância (Anova) foi usada para comparar as médias de mais de dois grupos; o teste de Duncan ou o teste C de Dunnett foi utilizado para comparações múltiplas; o teste de Kolmogorov-Smirnov e o teste de Levene foram utilizados para verificar a normalidade e a homoscedasticidade, respectivamente; a correção de Brown-Forsythe foi empregada no caso de presunção errônea de homoscedasticidade para corrigir os graus de liberdade da estatística F; o teste de Kruskal-Wallis foi utilizado nos casos de distribuição não paramétrica; e, caso o teste de Kruskal-Wallis fosse significativo, a diferença entre os grupos foi avaliada pelo teste de Bonferroni-Dunn. Na regressão linear múltipla, as características clínicas foram variáveis independentes, e o FGF23 foi uma variável dependente. Inicialmente todas as variáveis foram incluídas no modelo e, em seguida, os 5% não significativos foram excluídos um a um, em ordem de significância (método backward).

RESULTADOS

Foram estudados 144 pacientes, com média de idade de 85,4 anos, 73,6% eram mulheres, com média de quatro doenças crônicas e uso regular de seis medicamentos. O FGF23 geral foi de 91,05RU/mL±67,47. Foi observada eTFG menor que 45mL/minuto/1,73m² em 33,3%, e 25(OH) vitamina D <20ng/mL estava presente em 59% de todos os participantes. A tabela 1 mostra todos os participantes agrupados por tercis do FGF23 para investigar diferenças demográficas, clínicas, laboratoriais e de capacidade funcional.

Tabela 1. Parâmetros demográficos, clínicos e laboratoriais da população do estudo por tercis de níveis de fator de crescimento de fibroblastos 23.

Características	Todos (n=144)	FGF23 (RU/mL)			Valor de p
Características	Todos (n=144)	1^o tercil <54,4 (n=47)	2^o tercil 54,4-92,6 (n=48)	3^o tercil ≥92,6 (n=49)	Valor de p
Idade, anos	85,4±4,1	85,6±3,8	84,1±3,0^a	86,6±4,9^b	0,011
Sexo					0,931
Masculino	38 (26,4)	13 (27,7)	13 (27,1)	12 (24,5)
Feminino	106 (73,6)	34 (72,3)	35 (72,9)	37 (75,5)
Raça					0,069
Branca	96 (66,7)	26 (55,3)	32 (66,7)	38 (77,6)
Não branca	48 (33,3)	21 (44,7)	16 (33,3)	11 (22,4)
Número de doenças crônicas	4,4±1,9	3,9±1,9^a	4,5±1,6	4,9±2,0^b	0,018
Número de medicamentos de uso regular	5,9±2,7	4,9±2,1^a	6,2±2,6^b	6,5±3,1^b	0,008
Suplementos de vitamina D	59 (41,3)	15 (31,9)	23 (47,9)	21 (43,8)	0,260
Peso, kg	70,7±78,9	65,1±12,5	82,4±135,6	64,7±13,8	0,687
Índice de massa corporal, kg/m²	26,8±4,3	27,4±4,0	26,5±4,1	26,5±4,9	0,562
25(OH)D, ng/mL	19,2±8,4	19,6±8,6	20,8±9,6	17,3±6,4	0,110
25(OH)D – categoria, ng/mL					0,183
<20ng/mL	85 (59,0)	26 (55,3)	25 (52,1)	34 (69,4)
≥20ng/mL	59 (41,0)	21 (44,7)	23 (47,9)	15 (30,6)
PTH, pg/mL	62,6±33,4	53,9±29,2	63,1±27,8	70,5±40,0	0,060*
Cálcio, mg/dL	9,3±0,5	9,3±0,5	9,4±0,4	9,4±0,5	0,428
Fósforo, mg/dL	3,4±1,1	3,2±0,5	3,3±0,4	3,7±1,8	0,091*
Hemoglobina, g/dL	13,4±1,3	13,9±1,2^b	13,3±1,3^a	13,1±1,3^a	0,012
Creatinina, mg/dL	0,96±0,28	0,87±0,19^a	0,97±0,24^b	1,04±0,35^b	0,007
Cistatina C, mg/L	1,50±0,37	1,32±0,28^c	1,49±0,29^a	1,69±0,43^b	<0,001
eTFG, mL/minuto/1,73m²	51±14	58±12^b	50±12^a	45±14^a	<0,001
eTFG – categoria, mL/minuto/1,73m²					<0,001
<45mL/minuto/1,73m²	48 (33,3)	6 (12,8)^a	17 (35,4)	25 (51,0)^b
≥45mL/minuto/1,73m²	96 (66,7)	41 (87,2)	31 (64,6)	24 (49,0)
Capacidade funcional
Educação, anos	4,5±3,8	4,4±3,7	5,1±4,6	3,9±2,9	0,720*
EDG	3,9±2,7	3,4±2,2	3,9±2,9	4,4±2,8	0,259*
MMSE	24,2±3,4	23,7±3,2	24,5±3,6	24,5±3,3	0,466
TFV	12,9±3,5	12,5±3,4	12,9±3,6	13,3±3,7	0,562
AIVD	18,8±2,5	19,0±2,6	19,3±2,1	18,2±2,8	0,156*
Força de preensão manual, kgf^†
Todos	21,8±9,0	23,5±12,4	21,6±6,3	20,5±7,2	0,283
Masculino	30,2±11,4	35,0±17,1	27,5±5,7	28,0±6,2	0,130*
Feminino	18,8±5,4	18,9±5,6	19,3±5,0	18,1±5,6	0,612
Tempo para levantar-se e sentar-se (segundos)^‡	20,3±8,4	22,1±10,4	19,2±7,6	19,6±6,7	0,451*

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Resultados expressos como média (± desvio padrão), n (%). Letras sobrescritas diferentes indicam médias diferentes de comparações múltiplas. * Valor de p: nível descritivo do teste χ² ou Kruskal-Wallis/análise de variância; ^† n=143 (masculino/feminino: 38/105); ^‡ n=136 (de 140 testados, 136 cumpriram a tarefa). FGF23: fator de crescimento de fibroblastos 23; 25(OH)D: 25(OH) vitamina D; PTH: hormônio da paratireoide; eTFG: estimativa da taxa de filtração glomerular; EDG: Escala de Depressão Geriátrica; MEEM: Miniexame do Estado Mental; TFV: Teste de Fluência Verbal; AIVD: Atividade Instrumental da Vida Diária.

Houve diferença em idade, número de doenças crônicas e número de medicamentos de uso regular nos tercis do FGF23. O grupo com maior FGF23 era ligeiramente mais velho que o do segundo tercil (p=0,011). Aqueles com menor número médio de doenças e menor uso de medicamentos estavam no primeiro tercil (p=0,018 e 0,008, respectivamente). A creatinina teve o menor valor médio nos grupos com menor FGF23 (p<0,007), e houve aumento da cistatina C sérica à medida que o FGF23 aumentou (p<0,001). A eTFG foi maior no primeiro tercil (p<0,001). A distribuição dos participantes com eTFG <45mL/minuto/1,73m²foi diferente nos tercis de FGF23, com a maior proporção de participantes no terceiro tercil e a menor no primeiro tercil (p<0,001). Os níveis médios mais elevados de hemoglobina foram encontrados no primeiro tercil de FGF23.

A capacidade funcional não mostrou diferença entre os tercis de FGF23. Como houve desempenho diferente por gênero na força de preensão manual (média para homens de 30,2kgf, com DP ±11,4, e para mulheres de 18,8kgf, com DP ±5,4; p=0,0001), avaliou-se a força de preensão por gênero nos tercis de FGF23, e também não houve associação significativa.

De acordo com a tabela 2, no grupo com alta eTFG (≥45mL/minuto/1,73m²), a média de FGF23 no grupo com menor nível de 25(OH) vitamina D (<20ng/mL) foi maior que no grupo com 25(OH) vitamina D acima de 20ng/mL. O modelo de regressão linear múltipla foi ajustado para avaliar os efeitos simultâneos de idade, cor, número de doenças e medicamentos, 25(OH) vitamina D, eTFG, hemoglobina, creatinina, cistatina C, PTH e fósforo no FGF23. Como havia indicações de comportamentos distintos do FGF23 por níveis de vitamina D e eTFG (Tabela 2), foi incluída a interação entre 25(OH) vitamina D e eTFG no modelo. Os resultados dos modelos de regressão inicial e final são mostrados na tabela 3. Apenas a cistatina C permaneceu significativa no modelo final (p=0,001). Assim, para um aumento de 1mg/L de cistatina C, em média, ocorreu aumento de 83,71RU/mL no FGF23.

Tabela 2. Medidas resumidas dos níveis de fator de crescimento de fibroblastos 23 de acordo com a taxa de filtração glomerular estimada e 25(OH) vitamina D.

	eTFG <45mL/minuto/1,73m²		eTFG ≥45mL/minuto/1,73m²		Valor de p
	25(OH)D <20ng/mL	25(OH)D ≥20ng/mL	25(OH)D <20ng/mL	25(OH)D ≥20ng/mL	Valor de p
FGF23, pg/mL					<0,001
Média ± DP	138,6±93,1	109,2±84,0	75,6±42,8^a	68,5±41,7^b
IC95%	104,4-172,7	66,00-152,4	63,9-87,3	55,5-81,5
n (%)	31 (21,5)	17 (11,8)	54 (37,5)	42 (29,2)

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Valor de p: nível descritivo do teste de Kruskal-Wallis. Teste de Kolmogorov-Smirnov (p<0,001). Letras sobrescritas diferentes indicam médias diferentes de comparações múltiplas. eTFG: estimativa da taxa de filtração glomerular; 25(OH)D: 25(OH) vitamina D; FGF23: fator de crescimento de fibroblastos 23; DP: desvio-padrão; IC95%: intervalo de confiança de 95%.

Tabela 3. Estimativas dos coeficientes e respectivo intervalo de confiança de 95% dos modelos de regressão linear múltipla em níveis de fator de crescimento de fibroblastos 23.

	Modelo inicial		Modelo final
	Coeficiente (IC95%)	Valor de p	Coeficiente (IC95%)	Valor de p
Idade, anos	-0,80 (-3,62-2,03)	0,578
Não branca	-10,66 (-34,03-12,72)	0,369
Número de doenças crônicas	-0,25 (-7,04-6,54)	0,942
Número de medicamentos de uso regular	3,31 (-1,34-7,97)	0,161
25(OH)D <20ng/mL	6,49 (-20,14-33,12)	0,631
eTFG <45mL/minuto/1,73m²	5,48 (-36,25-47,21)	0,795
25(OH)D*eTFG	7,76 (-39,2-54,73)	0,744
Hemoglobina, g/dL	-3,32 (-12,46-5,83)	0,474
Creatinina, mg/dL	-15,36 (-71,44-40,72)	0,589
Cistatina C, mg/L	71,06 (15,23-126,9)	0,013	84,19 (57,56-110,82)	<0,001
PTH, pg/mL	0,13 (-0,22-0,47)	0,477
Fósforo	13,49 (-6,59-33,56)	0,186
R², %	28,8		21,6
n (%)	134		144

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Kolmogorov-Smirnov: modelo inicial (p<0,001) e final (p<0,001). 25(OH)D*eTFG: interação entre 25(OH)D e eTFG em classes. IC95%: intervalo de confiança de 95%; 25(OH)D: 25(OH) vitamina D; eTFG: estimativa da taxa de filtração glomerular; PTH: hormônio da paratireoide; R²: coeficiente de determinação.

DISCUSSÃO

O FGF23 sérico não foi associado à função cognitiva nem ao desempenho físico em indivíduos independentes com 80 anos ou mais. Ainda, idosos com níveis mais elevados de FGF23 eram mais velhos, tinham níveis mais baixos de hemoglobina, mais comorbidades, polifarmácia e maior comprometimento da função renal. Essas variáveis podem estimar o estado geral de saúde do idoso e, assim, sugerir que o FGF23 pode ser um biomarcador do envelhecimento, mas o FGF23 não serve como biomarcador na perspectiva funcional do envelhecimento saudável.

Um estudo realizado com 2.977 idosos, com média de idade de 78 anos,^(18,19) mostrou que os níveis séricos de FGF23 se correlacionaram com o estado geral de saúde, como encontrado neste estudo; além disso, os autores também mostraram a associação do FGF23 com o fenótipo de fragilidade. No entanto, quando cada componente da fragilidade medida pelo desempenho físico foi avaliado individualmente, verificou-se que a duplicação do FGF23 foi associada a uma probabilidade 22% maior de lentidão medida pelo teste de velocidade de marcha, mas sem nenhuma correlação com a fraqueza medida pela força de preensão, de acordo com os presentes resultados. Esse grupo de idosos era mais jovem e tinha eTFG maior do que a deste estudo, o que reflete um nível sérico mais baixo de FGF23 nesse grupo. É possível que haja um contraponto entre o aumento do FGF23 devido ao declínio da função renal com o envelhecimento ou por um estilo de vida saudável, com maior taxa de atividade física.⁽⁸⁾ Nenhuma dessas análises abordou possíveis estímulos endógenos, como o exercício físico regular.

A população deste estudo apresentou bom desempenho cognitivo e capacidade de realizar tarefas diárias para a vida comunitária (pontuação das AIVDs). A homogeneidade dos voluntários dificultou mostrar essas associações com o FGF23. Porém, o desempenho físico foi mais diversificado. Nossa população teve bom desempenho em média nos membros superiores, já que a fraqueza clinicamente relevante é a força de preensão manual de menos de 26kgf para homens e 16kgf para mulheres.⁽¹⁹⁾ Porém, para os membros inferiores, nossos pacientes tiveram desempenho ruim, em média, na capacidade cronometrada de se levantar de uma cadeira, com mais de 16,7 segundos.⁽¹⁶⁾ Em ambas as medidas, a heterogeneidade intragrupo é relevante.

Em adultos mais velhos que vivem na comunidade, características comuns de envelhecimento foram associadas ao FGF23, como redução da eTFG e DRC, hipertrofia ventricular esquerda, insuficiência cardíaca, doença cardiovascular, aumento da massa gorda, dislipidemia e aumento da mortalidade.^(20-24) Neste estudo, os pacientes com doença cardiovascular foram excluídos. Os presentes resultados mostram que o FGF23 sérico foi relacionado ao comprometimento da função renal. Por exemplo, entre aqueles com eTFG <45mL/minuto/1,73m², os níveis de FGF23 foram significativamente mais elevados. Isso condiz com o FGF23 ser um biomarcador precoce para disfunção renal.^(20,25) Outro índice fundamental na função renal foi a associação entre cistatina C e FGF23. Para cada aumento de 1mg/L na cistatina C, houve aumento de aproximadamente 85 unidades de FGF23. Isso condiz com a noção de que a cistatina C é um biomarcador melhor da função renal para octogenários do que a creatinina, porque a cistatina C não é afetada pela massa muscular e pela ingestão de proteína na dieta. Como o FGF23 participa da regulação do fosfato e do metabolismo da vitamina D, esperava-se encontrar associação com eles. Entre aqueles com eTFG acima de 45mL/minuto/1,73m², houve correlação entre os níveis mais baixos de 25(OH) vitamina D e os níveis mais altos de FGF23 sérico.

Os participantes deste estudo formam uma população homogênea com múltiplas comorbidades, mas com capacidade de autocuidado preservada e apenas leve autorrelato de dependência para tarefas relacionadas à vida comunitária. Embora o estado nutricional não tenha sido avaliado em detalhes, o IMC estava em condições adequadas. Sua homogeneidade poderia explicar nossa dificuldade em encontrar associações entre o FGF23 e os aspectos físicos e mentais investigados. Por outro lado, nossa abordagem na avaliação de diferentes domínios da capacidade funcional apontou algumas divergências na capacidade física intragrupo. O tamanho relativamente pequeno da amostra pode ter limitado o poder do estudo para detectar tais associações. Além disso, o tamanho da amostra comprometeu nossa capacidade de realizar algumas análises de subgrupos (especialmente em homens). Também não foi possível estabelecer um ponto de corte abaixo do qual a eTFG poderia estar previsivelmente associada a um aumento no FGF23. Outros fatores, não abordados neste estudo, principalmente a prática de atividade física regular, podem ter influenciado nos resultados e devem ser investigados em estudos futuros. Apesar da dificuldade em estimar a TFG em idosos, usamos a equação CKD EPI-creatinina-cistatina C previamente validada em 95 indivíduos desta coorte.⁽²⁶⁾

CONCLUSÃO

O fator de crescimento de fibroblastos 23 não foi significativamente associado ao desempenho funcional em idosos independentes residentes na comunidade com 80 anos ou mais, mas esteve associado com idade, comorbidades, medicamentos e taxa de filtração glomerular estimada. Até onde se sabe, este foi o primeiro estudo a avaliar a associação entre o fator de crescimento de fibroblastos 23 e o desempenho funcional em idosos independentes.

AGRADECIMENTOS

Este estudo teve apoio da Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)] (2011/12753-8). Agradecemos aos funcionários que realizaram este estudo na Universidade Federal de São Paulo (UNIFESP) e nos laboratórios do Departamento de Endocrinologia da Columbia University, e a todos os voluntários, por sua dedicação.

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PERMALINK

Association between fibroblast growth factor 23 and functional capacity among independent elderly individuals

Lara Miguel Quirino Araújo

Patrícia Ferreira do Prado Moreira

Clineu de Mello Almada Filho

Luciano Vieira de Araújo

Aline Granja Costa

Ricardo de Castro Cintra Sesso

John P Bilezikian

Marise Lazaretti-Castro

Maysa Seabra Cendoroglo

ABSTRACT

Objective

Methods

Results

Conclusion

INTRODUCTION

OBJECTIVE

METHODS

Study participants

Measurements

Functional capacity

Laboratory measurements

Data analyses

RESULTS

Table 1. Demographic, clinical, and laboratory parameters of the study population by tertiles of fibroblast growth factor 23 levels.

Table 2. Summarized measures of fibroblast growth factor 23 levels according to estimated glomerular filtration rate and 25 OH vitamin D.

Table 3. Estimates of the coefficients and respective 95% confidence interval of the multiple linear regression models on fibroblast growth factor 23 levels.

DISCUSSION

CONCLUSION

ACKNOWLEDGEMENTS

REFERENCES

Associação entre fator de crescimento de fibroblastos 23 e capacidade funcional em idosos independentes

Lara Miguel Quirino Araújo

Patrícia Ferreira do Prado Moreira

Clineu de Mello Almada Filho

Luciano Vieira de Araújo

Aline Granja Costa

Ricardo de Castro Cintra Sesso

John P Bilezikian

Marise Lazaretti-Castro

Maysa Seabra Cendoroglo

RESUMO

Objetivo

Métodos

Resultados

Conclusão

INTRODUÇÃO

OBJETIVO

MÉTODOS

Participantes do estudo

Medidas

Capacidade funcional

Medidas laboratoriais

Análise dos dados

RESULTADOS

Tabela 1. Parâmetros demográficos, clínicos e laboratoriais da população do estudo por tercis de níveis de fator de crescimento de fibroblastos 23.

Tabela 2. Medidas resumidas dos níveis de fator de crescimento de fibroblastos 23 de acordo com a taxa de filtração glomerular estimada e 25(OH) vitamina D.

Tabela 3. Estimativas dos coeficientes e respectivo intervalo de confiança de 95% dos modelos de regressão linear múltipla em níveis de fator de crescimento de fibroblastos 23.

DISCUSSÃO

CONCLUSÃO

AGRADECIMENTOS

ACTIONS

PERMALINK

RESOURCES

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