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1.
J Am Heart Assoc ; 8(18): e013558, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31510823

RESUMO

Background Increased renal resistive index (RRI) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ-carboxyglutamate) protein (MGP) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho-uncarboxylated MGP [dp-ucMGP]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP were associated with increased RRI. Methods and Results We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Levels of dp-ucMGP were measured in plasma by sandwich ELISA. RRI was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp-ucMGP and RRI. We adjusted for common determinants of RRI as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp-ucMGP and 64±5% for RRI. After multivariable adjustment, dp-ucMGP was positively associated with RRI (P=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (<38 years; P=0.62), whereas it was significant in older age groups (38-55 and >55 years; P=0.016 and P<0.001, respectively). Conclusions Levels of dp-ucMGP are positively and independently associated with RRI after adjustment for common determinants of RRI, cardiovascular risk factors, and renal function. The stronger association among older adults is probably due, in part, to age-related arterial stiffness. RRI thus seems to reflect the global atherosclerotic burden in a general adult population.

2.
Kidney Int ; 96(4): 890-905, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301888

RESUMO

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.

3.
Swiss Med Wkly ; 149: w20090, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31154659

RESUMO

The objectives were to determine urinary iodine concentration (UIC) in day and night samples collected over a 24-hour period and evaluate the usual dietary iodine intake distribution from this collection. We propose a method by which the prevalence of inadequacy can be calculated from a single 24-hour collection, reducing the burden on participants and the study costs. The samples from 1128 participants were collected between 2009 and 2013 within the framework of the Swiss Kidney Project on Genes observational cohort study; 1024 samples were suitable for statistical evaluation of iodine analysis. Participants were over 18, resident in Switzerland and of European ancestry. Over 24 hours, urine was collected as night-time (bedtime until and including first morning urine) and day-time (the remainder) samples. Associations with variables, in particular to estimated glomerular filtration rate (eGFR), were investigated using mixed models. The 24-hour median UICs were 73 and 96 µg/l for women (n = 542) and men (n = 482), respectively; 24-hour median intakes (derived from the corresponding excretion) were 127 and 156 µg/d, respectively. Day and night excretions were normalised to 24-hour excretion values and the usual intake distribution calculated by the US National Cancer Institute method. The Estimated Average Requirement cut-point method was used to calculate the prevalence of inadequacy, estimated at 14% for women and 4% for men; above the target of 2-3%. We conclude that segregating 24-hour urine into day and night collections is sufficient to determine the prevalence of iodine inadequacy in the population and reduces the burden on participants by sparing a second 24-hour collection. No association between iodine intake and eGFR was found.

4.
PLoS One ; 14(3): e0214549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30925175

RESUMO

OBJECTIVE: Urinary steroid metabolomics by GC-MS is an established method in both clinical and research settings to describe steroidogenic disorders. However, population-based reference intervals for adults do not exist. METHODS: We measured daytime and night time urinary excretion of 40 steroid metabolites by GC-MS in 1128 adult participants of European ancestry, aged 18 to 90 years, within a large population-based, multicentric, cross-sectional study. Age and sex-related patterns in adjacent daytime and night time urine collections over 24 hours were modelled for each steroid metabolite by multivariable linear mixed regression. We compared our results with those obtained through a systematic literature review on reference intervals of urinary steroid excretion. RESULTS: Flexible models were created for all urinary steroid metabolites thereby estimating sex- and age-related changes of the urinary steroid metabolome. Most urinary steroid metabolites showed an age-dependence with the exception of 6ß-OH-cortisol, 18-OH-cortisol, and ß-cortol. Reference intervals for all metabolites excreted during 24 hours were derived from the 2.5th and 97.5th percentile of modelled reference curves. The excretion rate per period of metabolites predominantly derived from the adrenals was mainly higher during the day than at night and the correlation between day and night time metabolite excretion was highly positive for most androgens and moderately positive for glucocorticoids. CONCLUSIONS: This study gives unprecedented new insights into sex- and age-specificity of the human adult steroid metabolome and provides further information on the day/night variation of urinary steroid hormone excretion. The population-based reference ranges for 40 GC-MS-measured metabolites will facilitate the interpretation of steroid profiles in clinical practice.

5.
J Clin Endocrinol Metab ; 104(6): 2195-2215, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30690465

RESUMO

CONTEXT: Sex steroid hormones exhibit anabolic effects whereas a deficiency engenders sarcopenia. Moreover, supraphysiological levels of glucocorticoids promote skeletal muscle atrophy, whereas physiologic levels of glucocorticoids may improve muscle performance. OBJECTIVE: To study the relationship between both groups of steroid hormones at a physiological range with skeletal muscle mass and function in the general population. DESIGN: Cross-sectional analysis of the associations between urinary excreted androgens, estrogens, glucocorticoids, and steroid hormone metabolite ratios with lean mass and handgrip strength in a population-based cohort. SETTING: Three centers in Switzerland including 1128 participants. MEASURES: Urinary steroid hormone metabolite excretion by gas chromatography-mass spectrometry, lean mass by bioimpedance analysis, and isometric handgrip strength by dynamometry. RESULTS: For lean mass a strong positive association was found with 11ß-OH-androsterone and with most glucocorticoids. Androsterone showed a positive association in middle-aged and older adults. Estriol showed a positive association only in men. For handgrip strength, strong positive associations with androgens were found in middle-aged and older adults, whereas positive associations were found with cortisol metabolites in young to middle-aged adults. CONCLUSIONS: Sex steroids and glucocorticoids are strongly positively associated with skeletal muscle mass and strength in the upper limbs. The associations with muscle strength appear to be independent of muscle mass. Steroid hormones exert age-specific anabolic effects on lean mass and handgrip strength. Deficits in physical performance of aged muscles may be attenuated by androgens, whereas glucocorticoids in a physiological range increase skeletal muscle mass at all ages, as well as muscle strength in particular in younger adults.

6.
PLoS One ; 13(10): e0203903, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308019

RESUMO

BACKGROUND: Although the polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women with vast metabolic consequences, its etiology remains unknown and its diagnosis is still made by exclusion. This study aimed at characterizing a large number of urinary steroid hormone metabolites and enzyme activities in women with and without PCOS in order to test their value for diagnosing PCOS. METHODS: Comparative steroid profiling of 24h urine collections using an established in-house gas-chromatography mass spectrometry method. Data were collected mostly prospectively. Patients were recruited in university hospitals in Switzerland. Participants were 41 women diagnosed with PCOS according to the current criteria of the Androgen Excess and PCOS Society Task Force and 66 healthy controls. Steroid profiles of women with PCOS were compared to healthy controls for absolute metabolite excretion and for substrate to product conversion ratios. The AUC for over 1.5 million combinations of metabolites was calculated in order to maximize the diagnostic accuracy in patients with PCOS. Sensitivity, specificity, PPV, and NPV were indicated for the best combinations containing 2, 3 or 4 steroid metabolites. RESULTS: The best single discriminating steroid was androstanediol. The best combination to diagnose PCOS contained four of the forty measured metabolites, namely androstanediol, estriol, cortisol and 20ßDHcortisone with AUC 0.961 (95% CI 0.926 to 0.995), sensitivity 90.2% (95% CI 76.9 to 97.3), specificity 90.8% (95% CI 81.0 to 96.5), PPV 86.0% (95% CI 72.1 to 94.7), and NPV 93.7% (95% CI 84.5 to 98.2). CONCLUSION: PCOS shows a specific 24h urinary steroid profile, if neglected metabolites are included in the analysis and non-conventional data analysis applied. PCOS does not share a profile with hyperandrogenic forms of congenital adrenal hyperplasias due to single steroid enzyme deficiencies. Thus PCOS diagnosis by exclusion may no longer be warranted. Whether these findings also apply to spot urine and serum, remains to be tested as a next step towards routine clinical applicability.

8.
Am J Transplant ; 18(12): 2965-2976, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29722128

RESUMO

HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m2 , P < .001) or low CNI (difference 7.6 mL/min/1.73 m2 , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m2  and 10.1 mL/min/1.73 m2 , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account.

9.
Mayo Clin Proc ; 93(5): 586-596, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29551227

RESUMO

OBJECTIVE: To assess the influence of caffeine on arterial stiffness by exploring the association of urinary excretion of caffeine and its related metabolites with pulse pressure (PP) and pulse wave velocity (PWV). PARTICIPANTS AND METHODS: Families were randomly selected from the general population of 3 Swiss cities from November 25, 2009, through April 4, 2013. Pulse pressure was defined as the difference between the systolic and diastolic blood pressures obtained by 24-hour ambulatory monitoring. Carotid-femoral PWV was determined by applanation tonometry. Urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured in 24-hour urine collections. Multivariate linear and logistic mixed models were used to explore the associations of quartiles of urinary caffeine and metabolite excretions with PP, high PP, and PWV. RESULTS: We included 863 participants with a mean ± SD age of 47.1±17.6 years, 24-hour PP of 41.9±9.2 mm Hg, and PWV of 8.0±2.3 m/s. Mean (SE) brachial PP decreased from 43.5 (0.5) to 40.5 (0.6) mm Hg from the lowest to the highest quartiles of 24-hour urinary caffeine excretion (P<.001). The odds ratio (95% CI) of high PP decreased linearly from 1.0 to 0.52 (0.31-0.89), 0.38 (0.22-0.65), and 0.31 (0.18-0.55) from the lowest to the highest quartile of 24-hour urinary caffeine excretion (P<.001). Mean (SE) PWV in the highest caffeine excretion quartile was significantly lower than in the lowest quartile (7.8 [0.1] vs 8.1 [0.1] m/s; P=.03). Similar associations were found for paraxanthine and theophylline, whereas no associations were found with theobromine. CONCLUSION: Urinary caffeine, paraxanthine, and theophylline excretions were associated with decreased parameters of arterial stiffness, suggesting a protective effect of caffeine intake beyond its blood pressure-lowering effect.

10.
Am J Hypertens ; 31(7): 784-791, 2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29481641

RESUMO

BACKGROUND: While the positive relationship between urinary sodium excretion and blood pressure (BP) is well established for middle-aged to elderly individuals using office BP, data are limited for younger individuals and ambulatory BP measurements. METHODS: Our analysis included 2,899 individuals aged 18 to 90 years from 2 population-based studies (GAPP, Swiss Kidney Project on Genes in Hypertension [SKIPOGH]). Participants with prevalent cardiovascular disease, diabetes, or on BP-lowering treatment were excluded. In SKIPOGH, 24-hour urinary sodium excretion was used as a measure of sodium intake, while in GAPP it was calculated from fasting morning urinary samples using the Kawasaki formula. Multivariable linear regression models were used to assess the relationships of 24-hour urinary salt excretion with office and ambulatory BP measurements. RESULTS: Mean age, ambulatory BP, sodium excretion, and estimated glomerular filtration rate in GAPP and SKIPOGH were 35 and 44 years, 123/78 and 118/77 mm Hg, 4.2 and 3.3 g/d, and 110 and 99 ml/min/1.73 m2, respectively. A weak linear association was observed between 24-hour ambulatory systolic BP and urinary sodium excretion (ß (95% confidence interval [CI]) per 1 g increase in sodium excretion (0.33 % (0.09; 0.57); P = 0.008). No significant relationships were observed for 24-hour ambulatory diastolic BP (ß (95% CI) (0.13 % (-0.15; 0.40) P = 0.37). When repeating the analyses in different age groups, all BP indices appeared to have stronger relationships in the older age groups (>40 years). CONCLUSIONS: In these large cohorts of healthy adults, urinary sodium excretion was only weakly associated with systolic 24-hour ambulatory BP.

11.
J Clin Endocrinol Metab ; 103(2): 748-758, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29077874

RESUMO

Context: Urinary cadmium (Cd) excretion is associated with cancer and cardiovascular morbidity. A potential mechanism could be disturbance of steroidogenesis in gonads and adrenal glands. Objective: We tested whether urinary excretion of Cd is correlated with that of cortico- and sex steroid metabolites in the general adult population. Setting: The Swiss Kidney Project on Genes in Hypertension is a multicentric, family-based population study. Measures: Urinary excretions of steroid hormone metabolites and Cd were measured with separate day and night collections. Associations were analyzed by mixed linear models. Results: Urinary Cd and testosterone excretions in men were significantly correlated (respective day and night ß values [standard error (SE)], 1.378 [0.242], P < 0.0005; and 1.440 [0.333], P < 0.0005), but not in women [0.333(0.257), P = 0.2; and 0.674 (0.361), P = 0.06]. Urinary Cd and cortisol excretions were positively associated in both sexes [day: ß = 0.475 (SE, 0.157), P = 0.0025, and 0.877 (SE, 0.194), P < 0.0005, respectively; night: ß = 0.875 (SE, 0.253), P < 0.0005 and 1.183 (SE, 0.277), P = 0.00002, respectively]. Cd excretion was correlated with mineralocorticoid metabolites excretion, except tetrahydroaldosterone, in both sexes (P < 0.01). There was an independent effect of Cd on sex hormone and corticosteroid synthesis and an interdependent effect on gluco- and mineralcorticoid production. Conclusion: Our findings provide evidence for a global stimulating effect on steroid synthesis already at low-dose Cd exposure. These findings might explain the association of Cd with diseases such as steroid-sensitive cancers or metabolic disorders.


Assuntos
Corticosteroides/metabolismo , Cádmio/urina , Hormônios Esteroides Gonadais/metabolismo , Hipertensão/metabolismo , Adulto , Idoso , Aldosterona/análogos & derivados , Aldosterona/urina , Estudos de Coortes , Família , Feminino , Hormônios Esteroides Gonadais/urina , Humanos , Hipertensão/urina , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Mineralocorticoides/urina , Testosterona/urina
12.
J Am Soc Nephrol ; 29(1): 335-348, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29093028

RESUMO

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

13.
Kidney Int ; 92(6): 1536-1543, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28888328

RESUMO

The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population-based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m2, and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m2. The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population.


Assuntos
Eletrólitos/metabolismo , Homeostase/genética , Rim/fisiopatologia , Eliminação Renal/genética , Adulto , Estudos de Coortes , Biologia Computacional , Eletrólitos/sangue , Eletrólitos/urina , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Software , Suíça
14.
Nutr Metab (Lond) ; 13: 81, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27891166

RESUMO

BACKGROUND: Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population. METHODS: We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self-administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis. RESULTS: In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine (p < 0.001), whereas reported intakes of decaffeinated coffee and other caffeinated beverages showed no association. In ROC analysis, optimal discrimination between individuals consuming less than one caffeinated coffee/week, vs. at least one coffee, was obtained for 24-h urinary paraxanthine (Area Under Curve (AUC) = 0.868, 95% Confidence Interval (CI) [0.830;0.906]), with slightly lower performance for theophylline and caffeine, whereas theobromine did not allow any discrimination. CONCLUSION: Our results suggest that reported consumption of caffeinated coffee is positively associated with 24-h urinary excretion of caffeine, paraxanthine, and theophylline, and may be used as a marker of caffeine intake for epidemiological studies.

15.
Kidney Int ; 90(3): 648-57, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27370409

RESUMO

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate homeostasis. Circulating FGF23 is elevated in chronic kidney disease (CKD) and independently associated with poor renal and cardiovascular outcomes and mortality. Because the study of FGF23 in individuals with normal renal function has received little attention, we examined in a large, population-based study of 1128 participants the associations of FGF23 with markers of mineral metabolism and renal function. The median estimated glomerular filtration rate (eGFR) of the cohort was 105 ml/min per 1.73 m(2), and the median plasma FGF23 was 78.5 RU/ml. FGF23 increased and plasma 1,25-dihydroxyvitamin D3 decreased significantly below an eGFR threshold of 102 and 99 ml/min per 1.73 m(2), respectively. In contrast, plasma parathyroid hormone increased continuously with decreasing eGFR and was first significantly elevated at an eGFR of 126 ml/min per 1.73 m(2). On multivariable analysis adjusting for sex, age, body mass index, and GFR, FGF23 was negatively associated with 1,25-dihydroxyvitamin D3, and urinary absolute and fractional calcium excretion but not with serum calcium or parathyroid hormone. We found a positive association of FGF23 with plasma phosphate, but no association with urinary absolute or fractional phosphate excretion and, unexpectedly, a positive association with tubular maximum phosphate reabsorption/GFR. Thus, in the absence of CKD, parathyroid hormone increases earlier than FGF23 when the eGFR decreases. The increase in FGF23 occurs at a higher eGFR threshold than previously reported and is closely associated with a decrease in 1,25-dihydroxyvitamin D3. We speculate that the main demonstrable effect of FGF23 in the setting of preserved renal function is suppression of 1,25-dihydroxyvitamin D3 rather than stimulation of renal phosphate excretion.


Assuntos
Calcitriol/sangue , Fatores de Crescimento de Fibroblastos/sangue , Taxa de Filtração Glomerular/fisiologia , Rim/fisiologia , Fosfatos/sangue , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Calcitriol/metabolismo , Cálcio/sangue , Cálcio/urina , Estudos Transversais , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/metabolismo , Fosfatos/urina , Eliminação Renal/fisiologia
16.
Psychoneuroendocrinology ; 67: 76-85, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26881833

RESUMO

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.


Assuntos
Alostase/genética , Alostase/fisiologia , Estilo de Vida , Classe Social , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Am J Hypertens ; 29(4): 484-93, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26297028

RESUMO

BACKGROUND: Genome-wide association studies have linked CYP17A1 coding for the steroid hormone synthesizing enzyme 17α-hydroxylase (CYP17A1) to blood pressure (BP). We hypothesized that the genetic signal may translate into a correlation of ambulatory BP (ABP) with apparent CYP17A1 activity in a family-based population study and estimated the heritability of CYP17A1 activity. METHODS: In the Swiss Kidney Project on Genes in Hypertension, day and night urinary excretions of steroid hormone metabolites were measured in 518 participants (220 men, 298 women), randomly selected from the general population. CYP17A1 activity was assessed by 2 ratios of urinary steroid metabolites: one estimating the combined 17α-hydroxylase/17,20-lyase activity (ratio 1) and the other predominantly 17α-hydroxylase activity (ratio 2). A mixed linear model was used to investigate the association of ABP with log-transformed CYP17A1 activities exploring effect modification by urinary sodium excretion. RESULTS: Daytime ABP was positively associated with ratio 1 under conditions of high, but not low urinary sodium excretion (P interaction <0.05). Ratio 2 was not associated with ABP. Heritability estimates (SE) for day and night CYP17A1 activities were 0.39 (0.10) and 0.40 (0.09) for ratio 1, and 0.71 (0.09) and 0.55 (0.09) for ratio 2 (P values <0.001). CYP17A1 activities, assessed with ratio 1, were lower in older participants. CONCLUSIONS: Low apparent CYP17A1 activity (assessed with ratio 1) is associated with elevated daytime ABP when salt intake is high. CYP17A1 activity is heritable and diminished in the elderly. These observations highlight the modifying effect of salt intake on the association of CYP17A1 with BP.


Assuntos
Pressão Sanguínea , Hipertensão/enzimologia , Esteroide 17-alfa-Hidroxilase/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/urina , Pressão Sanguínea/genética , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Estudos Transversais , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Genótipo , Hereditariedade , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Natriurese , Fenótipo , Fatores de Risco , Sódio/urina , Cloreto de Sódio na Dieta/efeitos adversos , Esteroide 17-alfa-Hidroxilase/genética , Esteroides/urina , Especificidade por Substrato , Suíça , Fatores de Tempo , Urinálise , Adulto Jovem
18.
Clin J Am Soc Nephrol ; 11(1): 70-80, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26683888

RESUMO

BACKGROUND AND OBJECTIVES: Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age±SD, 45±17 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53±11 years) with fresh spot morning urine samples. We calculated eGFRs using the CKD-Epidemiology Collaboration formula and by 24-hour creatinine clearance. RESULTS: In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR<90 ml/min per 1.73 m(2). CONCLUSION: Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.


Assuntos
Túbulos Renais/fisiologia , Uromodulina/urina , Adulto , Idoso , Albuminúria/urina , Biomarcadores , Eletrólitos/urina , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar
19.
Diabetes ; 65(3): 803-17, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631737

RESUMO

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.


Assuntos
Albuminúria/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Túbulos Renais/metabolismo , Adulto , Idoso , Albuminúria/etiologia , Animais , Catepsina C/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Feminino , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ratos , Receptores de Superfície Celular/genética , Sulfotransferases/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
20.
J Hypertens ; 33(10): 2061-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26203966

RESUMO

BACKGROUND: Blood pressure (BP) is known to aggregate in families. Yet, heritability estimates are population-specific and no Swiss data have been published so far. We estimated the heritability of ambulatory and office BP in a Swiss population-based sample. METHODS: The Swiss Kidney Project on Genes in Hypertension is a population-based family study focusing on BP genetics. Office and ambulatory BP were measured in 1009 individuals from 271 nuclear families. Heritability was estimated for SBP, DBP, and pulse pressure using a maximum likelihood method implanted in the Statistical Analysis in Genetic Epidemiology software. RESULTS: The 518 women and 491 men included in this analysis had a mean (±SD) age of 48.3 (±17.4) and 47.3 (±17.7) years, and a mean BMI of 23.8 (±4.2) and 25.9 (±4.1) kg/m, respectively. Narrow-sense heritability estimates (±standard error) for ambulatory SBP, DBP, and pulse pressure were 0.37 ±â€Š0.07, 0.26 ±â€Š0.07, and 0.29 ±â€Š0.07 for 24-h BP; 0.39 ±â€Š0.07, 0.28 ±â€Š0.07, and 0.27 ±â€Š0.07 for day BP; and 0.25 ±â€Š0.07, 0.20 ±â€Š0.07, and 0.30 ±â€Š0.07 for night BP, respectively (all P < 0.001). Heritability estimates for office SBP, DBP, and pulse pressure were 0.21 ±â€Š0.08, 0.25 ±â€Š0.08, and 0.18 ±â€Š0.07 (all P < 0.01). CONCLUSIONS: We found significant heritability estimates for both ambulatory and office BP in this Swiss population-based study. Our findings justify the ongoing search for the genetic determinants of BP.


Assuntos
Pressão Sanguínea/genética , Hipertensão , Adulto , Determinação da Pressão Arterial , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Suíça/epidemiologia , Hipertensão do Jaleco Branco/epidemiologia , Hipertensão do Jaleco Branco/genética
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