RESUMO
BACKGROUND: C-terminal agrin fragment (CAF), cleavage product of agrin, was previously correlated with kidney function in renal transplant patients. This article studies the predictive value of CAF for long-term outcomes in renal transplant recipients. METHODS: In this observational cohort study, serum CAF, creatinine and blood-urea-nitrogen (BUN) concentrations and eGFR (CKD-EPI) were assessed 1-3 months after transplantation in 105 patients undergoing kidney transplantation. Cox regression models were used to analyse the predictive value of all parameters concerning all-cause mortality (ACM), graft loss (GL), doubling of creatinine/proteinuria at the end of follow-up. RESULTS: Median follow-up time was 3.1 years. The mean concentrations were 191.9±152.4 pM for CAF, 176±96.8 µmol/L for creatinine, 12.6±6.2 mmol/L for BUN and 44.9±21.2 mL/min for CKD-EPI formula, respectively. In univariate analysis CAF and BUN concentrations predicted ACM (CAF: HR=1.003, 1.1-fold risk, p=0.043; BUN: HR=1.037, 1.3-fold risk, p=0.006). Concerning GL, CAF (HR=1.006, 3.1-fold risk, p<0.001), creatinine (HR=2.396, 2.6-fold risk, p<0.001), BUN (HR=1.048, 1.7-fold risk, p=0.001) and eGFR (CKD-EPI) (HR=0.941, 0.45-fold risk reduction, p=0.006) showed a statistically significant association. CAF was the only parameter significantly associated with doubling of proteinuria (HR=1.005, 1.7-fold risk, p<0.001). In multiple regression analysis (CAF only) the association remained significant for GL and doubling of proteinuria but not ACM. CONCLUSIONS: Early postoperative serum CAF appears to be a useful tool for the assessment of long-term outcomes in renal transplant recipients. Most importantly it represents a promising predictor for the development of proteinuria.
Assuntos
Agrina/sangue , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto , Transplante de Rim , Fragmentos de Peptídeos/sangue , Proteinúria/sangue , Proteinúria/diagnóstico , Nitrogênio da Ureia Sanguínea , Estudos de Coortes , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Total C-terminal agrin fragment (tCAF) is a new biomarker that was previously correlated with kidney function. This article studies the validity of tCAF as a biomarker for kidney function in chronic kidney disease (CKD). METHODS: Plasma tCAF, serum creatinine (Cr), cystatin C (CyC), blood urea-nitrogen (BUN) concentrations and estimated glomerular filtration rate (eGFR CKD-EPIcrea-cystatin) were assessed in 426 individuals [71 without CKD (CKD 0°) and 355 CKD patients]. In addition to descriptive statistics, univariate correlation between tCAF and biomarkers/eGFR was calculated; multiple linear regression modeling was applied between logarithmic (log) tCAF and log eGFR and adjusted for demographic data. The same methods were used to analyze the association of demographic factors and the different biomarkers adjusted for eGFR. RESULTS: Mean tCAF levels were 1012.2±789.9 pM. tCAF correlated with all biomarkers/eGFR in univariate analysis (eGFR: r=-0.77, Cr: r=0.74, BUN: r=0.66, CyC: r=0.75). Linear regression modeling revealed an excellent coefficient estimate between log tCAF and log eGFR (CKD-EPIcrea-cystatin) (-0.91, p<0.001). tCAF was the parameter least associated with demographic parameters in both univariate and multivariate regression modeling (only with age, coefficient estimate r=-0.159, p=0.001 in multivariate regression). CONCLUSIONS: In conclusion, tCAF is a promising biomarker for the assessment of kidney function in CKD patients showing an excellent correlation with eGFR and being less influenced by demographic parameters compared to conventional biomarkers. These preliminary results encourage further evaluation of tCAF in larger CKD cohorts and other clinical settings such as acute renal failure.
Assuntos
Agrina/sangue , Testes de Função Renal , Fragmentos de Peptídeos/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIMS: This study compares the peritoneal elimination of the low-molecular-weight-protein (LMWP) C-terminal agrin fragment (tCAF, size 22 kDa), a promising biomarker for kidney function, in continuous cycling peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD). METHODS: 103 sets of serum, 24h-urine and dialysate samples were obtained in 15 CCPD (63 sets) and 11 CAPD (40 sets) patients. Total, renal and peritoneal substrate removals/clearances were measured/calculated for tCAF, creatinine, blood-urea-nitrogen (BUN), cystatin C and albumin and correlated with the peritoneal transport type. RESULTS: Serum und urine concentrations of all biomarkers did not differ between both groups, urinary substrate removal was higher in CAPD patients for all biomarkers due to better residual renal function. Peritoneal substrate removal of tCAF and albumin were significantly higher in CAPD (tCAF: 35.3 vs. 19.3 µg/d, p<0.001; albumin: 4.3 vs. 3.7 g/d, p=0.001), whereas cystatin C and creatinine did not differ between CAPD and CCPD (cystatin: 7.7 vs. 6.1 mg/d, p=0.08, creatinine: 423.9 vs. 456.7 mg/d, p=0.241). BUN was better removed by CCPD (4846.6 vs. 3393.4 mg/d, p<0.001). CAPD patients with high-transporter characteristics had a higher peritoneal tCAF removal compared to high-average-transporters (49.8 vs. 28.4 µg/d, p<0.001), no differences could be detected in CCPD patients between these groups. CAPD patients using icodextrin twice/day had higher peritoneal clearance of tCAF compared to once daily (4.4 vs. 2.8 l/wk/1.73 m2 body-surface-area, p<0.001). CONCLUSIONS: CAPD was superior to CCPD concerning peritoneal tCAF removal. This finding was pronounced in high-transporters and CAPD patients using icodextrin twice daily.
Assuntos
Agrina/sangue , Agrina/urina , Taxa de Depuração Metabólica/fisiologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/urina , Diálise Peritoneal Ambulatorial Contínua/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: The C-terminal agrin fragment (CAF) is a cleavage product of agrin, the major proteoglycan of the glomerular basement membrane. This article studies if CAF could serve as a biomarker for renal function in renal transplant recipients. MATERIAL AND METHODS: We measured serum CAF and creatinine concentrations and calculated estimated glomerular filtration rate (eGFR) (MDRD) in 96 healthy individuals and in 110 end-stage renal disease patients undergoing kidney transplantation before and after transplantation. Correlation between CAF and creatinine concentrations/eGFR was calculated as within-patient (cWP) and between-patient correlations (cBP). Moreover, we evaluated the association of CAF with delayed graft function (DGF). The diagnostic value of CAF for early detection of DGF compared to creatinine was evaluated by receiver operating characteristics (ROC) analysis. RESULTS: CAF concentrations strongly correlated with creatinine (r = 0.86 (cWP), r = 0.74 (cBP)) and eGFR (MDRD) (r = 0.86 (cWP), r = 0.77 (cBP)). Pre-transplant (pre-Tx) CAF concentrations were 19-fold higher than in healthy individuals (1,115.0 (258.4-3,990.0) vs. 56.6 (20.0-109.5) pM). After transplantation, CAF decreased significantly faster than creatinine (postoperative days 1-3 (POD 1-3): 562.8 (101.6-2,113.0) pM; creatinine: pre-Tx 6.9 (3.1-15.7), POD 1-3: 6.4 (1.7-12.7) mg/dl, p < 0.001). Stable concentrations were reached 1-3 months after transplantation for CAF and creatinine (CAF 145.1 (6.7-851.0) pM; creatinine 1.6 (0.7-8.0) mg/dl). CAF concentrations at POD 1-3 were significantly associated with DGF and outperformed creatinine in early detection of DGF (area under the curve (AUC) CAF 80.7% (95% CI 72.3-89.1%) vs. AUC creatinine 71.3% (95% CI 61.8-81.1%), p = 0.061). CONCLUSION: CAF is a promising new and fast biomarker for kidney function and may serve as a new tool for the early detection of DGF.
Assuntos
Agrina/sangue , Biomarcadores/sangue , Transplante de Rim , Rim/metabolismo , Idoso , Agrina/química , Área Sob a Curva , Creatinina/sangue , Função Retardada do Enxerto/sangue , Feminino , Membrana Basal Glomerular/metabolismo , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Estrutura Terciária de Proteína , Proteoglicanas/sangue , Curva ROC , Estudos Retrospectivos , Fatores de TempoRESUMO
OBJECTIVE: Adipocyte fatty acid-binding protein (A-FABP) abundantly expressed in mature adipocytes and activated macrophages has dramatic effects on atherosclerosis in mice. Whether this pathophysiological role of A-FABP may also apply to atherosclerotic disease in humans is still unknown. This study investigated associations among serum A-FABP levels, cardiovascular risk factors, and long-term secondary cardiovascular disease (CVD) outcome in patients with coronary heart disease. METHODS AND RESULTS: Serum A-FABP levels were measured in 1069 patients with prevalent coronary heart disease and a 10-year prospective follow-up was conducted (median, 119.5 [interquartile range, 74.1-120.6] months). During this period 204 patients (incidence, 24.0/1000 patient-years) experienced a secondary cardiovascular disease event (defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal cerebrovascular stroke). At baseline, circulating A-FABP was positively associated with a cluster of metabolic and inflammatory risk factors and independently predicted the presence of the metabolic syndrome (odds ratio per unit increase of natural log-transformed A-FABP, 2.95; 95% CI, 2.22-3.92, P<0.001). On long-term follow-up, subjects with high baseline A-FABP showed an increased risk for secondary cardiovascular disease events (hazard ratio per unit increase, 1.52; 95% CI, 1.18-1.95; P=0.001), which was attenuated after multivariable adjustment (hazard ratio 1.30; 95% CI, 0.98-1.73). In contrast, A-FABP remained significantly associated with cardiovascular death even after multivariable adjustment (hazard ratio, 1.75; 95% CI, 1.17-2.62, P=0.007). CONCLUSIONS: Circulating A-FABP levels are associated with long-term prognosis in patients with coronary heart disease and may represent an important pathophysiological mediator of atherosclerosis, which may point to a new target of treatment options.
Assuntos
Doenças Cardiovasculares/epidemiologia , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Proteínas de Ligação a Ácido Graxo/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Distribuição de Qui-Quadrado , Doença das Coronárias/mortalidade , Progressão da Doença , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prevalência , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
Midregional proadrenomedullin (MR-proADM) is elevated in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the association of MR-proADM with the grade of coronary artery stenosis, presence of coronary artery soft plaques and coronary artery calcification score (CACS), determined by 64-multislice computed tomography (MSCT) in patients without known prior cardiovascular disease. This retrospective study included 107 patients undergoing MSCT for confirmation (or exclusion) of coronary artery disease. MR-proADM levels were measured in all patients. The assessment of coronary artery stenoses, CACS and soft coronary plaques was made by MSCT using known criteria. The MR-proADM [median (25th-75th percentiles)] level was 0.33 (0.21-0.43) nmol/l. The MR-proADM level was 0.28 (0.22-0.40) nmol/l in patients with coronary stenoses ≥50% (n = 23) versus 0.33 (0.27-0.40) nmol/l in patients with coronary stenoses <50% (n = 83, P = 0.59), 0.33 (0.26-0.40) nmol/l in patients with soft plaques (n = 56) versus 0.33 (0.25-0.41) nmol/l in patients without soft plaques (n = 50, P = 0.73) and 0.33 (0.25-0.39) nmol/l in patients with CACS <200 (n = 81) versus 0.32 (0.26-0.44) nmol/l in patients with CACS ≥200 (n = 26, P = 0.77). In multivariate analysis, the MR-proADM level was a significant correlate of coronary artery stenoses [odds ratio (OR) = 0.93; 95% confidence interval (CI) 0.86-0.99; P = 0.026] and soft plaques (OR = 0.94; 95% CI 0.90-0.99; P = 0.015) but not of CACS (OR = 0.98; 95% CI 0.93-1.03; P = 0.36). A decreased MR-proADM level is an independent correlate of the presence of coronary artery disease and of soft atherosclerotic plaques. Patients with decreased MR-proADM levels may need invasive examinations to diagnose more severe forms of coronary artery disease.
Assuntos
Adrenomedulina/sangue , Doença da Artéria Coronariana/diagnóstico , Estenose Coronária/diagnóstico , Vasos Coronários/patologia , Fragmentos de Peptídeos/sangue , Precursores de Proteínas/sangue , Calcificação Vascular/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Angiografia Coronária/métodos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/patologia , Estenose Coronária/sangue , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/patologia , Vasos Coronários/química , Regulação para Baixo , Feminino , Alemanha , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Análise Multivariada , Razão de Chances , Placa Aterosclerótica , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Calcificação Vascular/sangue , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/patologiaRESUMO
BACKGROUND: Due to anatomical reasons a position-dependent renal allograft artery stenosis is being discussed (e.g. only in patient's upright position). The tortuous course of the allograft artery complicates the direct, angle-dependent measurement of maximum systolic flow velocities (vmax). So indirect signs such as intraparenchymal vmax and resistance index might be helpful, but it is unknown how these values change physiologically when patient's body position changes. PATIENTS AND METHODS: We examined renal allografts of 60 patients (38 male, 22 female) with stable graft function using B-Mode-, colour-coded duplex-sonography and pulsed-wave-Doppler. We measured vmax and RI-values of three interlobar arteries in the cortex and allograft artery in the hilus in patients standing upright and in horizontal position. Corresponding values were analyzed for significant differences. RESULTS: Intraparenchymal RI-values and vmax were significantly reduced in patients upright compared to the horizontal position (16 %, MW=0.59 vs. MW=0.70, p < 0.001 resp. 6 %, MW=30.18 cm/s vs. MW=32.17 cm/s, p = 0.045). Similar results could be detected in the renal hilus. CONCLUSIONS: Patients with stable graft-function show significant, position-dependent differences of the intraparenchymal and hilar RI-values and maximal systolic flow velocities. These changes of Doppler parameters has to be kept in mind for the correct diagnosis of a position dependent allograft artery stenosis.
Assuntos
Transplante de Rim/efeitos adversos , Rim/irrigação sanguínea , Rim/diagnóstico por imagem , Posicionamento do Paciente , Obstrução da Artéria Renal/diagnóstico por imagem , Artéria Renal/diagnóstico por imagem , Ultrassonografia Doppler , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fluxo Sanguíneo Regional , Artéria Renal/fisiopatologia , Obstrução da Artéria Renal/etiologia , Obstrução da Artéria Renal/fisiopatologia , Circulação Renal , Transplante Homólogo , Resultado do Tratamento , Ultrassonografia Doppler em Cores , Ultrassonografia Doppler de PulsoRESUMO
BACKGROUND: The poor cardiovascular survival of patients with renal insufficiency is improved by transplantation. Carotid-femoral pulse wave velocity (PWV) is able to predict independently overall and cardiovascular mortality. PWV is elevated in renal insufficiency. Consequently, PWV may change according to the improvement in renal function after kidney transplantation. METHODS: In a cross-sectional setting, PWV was determined in 40 renal transplant recipients (RTx) and compared to the PWV of 40 age- and gender-matched patients with comparable renal insufficiency (CKD) and 40 age- and gender-matched hemodialysis patients (HD). RESULTS: RTx and CKD patients had comparable eGFR (RTx: 42.9 ± 18.4, CKD: 48.3 ± 29.1 mL/min/1.73 m(2)) and protein/creatinine ratio (RTx: median 172.5, 25th percentile 97.75, 75th percentile 344.5, CKD: median 183.272, 25th percentile 100.00, 75th percentile 470.00 mg/g creatinine). There was no significant difference in PWV between RTx 3-12 months post-transplant and CKD or HD patients (RTx: 9.65 ± 1.57, CKD: 9.98 ± 3.91, HD: 10.27 ± 2.89 m/s; n = 20 pairs). Similarly, PWV in transplant patients >12-month post-transplant was similar to that of CKD and HD patients (RTx: 9.71 ± 2.23, CKD: 9.36 ± 2.74, HD: 9.84 ± 3.41 m/s; n = 20 pairs). DISCUSSION: We could not detect significant differences in PWV comparing RTx with age- and gender-matched CKD patients.
Assuntos
Aorta/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Falência Renal Crônica/fisiopatologia , Transplante de Rim , Diálise Renal , Rigidez Vascular , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Pulsátil , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Fetuin-A is a negative acute-phase protein, which acts as a potent calcification inhibitor and an antagonist of transforming growth factor-ß. Thus, fetuin-A levels are influenced by chronic inflammation and actively affect fibrosis and calcification processes, respectively. Graft rejection, interstitial fibrosis and tubular atrophy, chronic inflammation and calcification are common causes for kidney allograft loss. This study evaluated whether pretransplant fetuin-A levels predict long-term graft survival and rejection episodes in patients after kidney transplantation. METHODS: In 206 renal transplant recipients pretransplant fetuin-A levels were measured in serum by ELISA. During the 36 months' active follow-up (median 1,249 days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival). RESULTS: Pretransplant fetuin-A levels did not differ among patients with incident graft failures as compared to patients with functional graft after long-term follow-up or rejection episodes (fetuin-A: 393.6 ± 46 vs. 384.4 ± 69 vs. 405 ± 27.4 µg/ml). In logistic regression analysis, pretransplant fetuin-A levels did not correlate with graft failure after 3 years' follow-up (p = 0.895). In COX regression analysis, fetuin-A levels were not associated with the time to graft loss. Moreover, fetuin-A levels correlated neither with renal and metabolic parameters nor with cellular or humoral rejection episodes. CONCLUSION: Pretransplant levels of fetuin-A are not a predictor for renal allograft loss or rejection episodes after 36 months' follow-up in transplant recipients.
Assuntos
Rejeição de Enxerto/sangue , Sobrevivência de Enxerto/fisiologia , Transplante de Rim/fisiologia , Rim/fisiologia , alfa-2-Glicoproteína-HS/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Rim/patologia , Transplante de Rim/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Tempo , Transplante Homólogo/patologia , Transplante Homólogo/fisiologia , Resultado do TratamentoRESUMO
POSH (plenty of SH3) is a scaffold protein that has been shown to act as an E3 ubiquitin ligase. Here we report that POSH stimulates the ubiquitination of Kir1.1 (ROMK) and enhances the internalization of this potassium channel. Immunostaining reveals the expression of POSH in the renal cortical collecting duct. Immunoprecipitation of renal tissue lysate with ROMK antibody and glutathione S-transferase pulldown experiments demonstrated the association between ROMK and POSH. Moreover, immunoprecipitation of lysates of HEK293T cells transfected with ROMK1 or with constructs encoding the ROMK-N terminus or ROMK1-C-Terminus demonstrated that POSH binds to ROMK1 on its N terminus. To study the effect of POSH on ROMK1 channels, we measured potassium currents with electrophysiological methods in HEK293T cells and in oocytes transfected or injected with ROMK1 and POSH. POSH decreased potassium currents, and the inhibitory effect of POSH on ROMK channels was dose-dependent. Biotinylation assay further showed that POSH decreased surface expression of ROMK channels in HEK293T cells transfected with ROMK1 and POSH. The effect of POSH on ROMK1 channels was specific because POSH did not inhibit sodium current in oocytes injected with ENaC-alpha, beta, and gamma subunits. Moreover, POSH still decreased the potassium current in oocytes injected with a ROMK1 mutant (R1Delta373-378), in which a clathrin-dependent tyrosine-based internalization signal residing between amino acid residues 373 and 378 is deleted. However, the inhibitory effect of POSH on ROMK channels was absent in cells expressing with dominant negative dynamin and POSHDeltaRING, in which the RING domain was deleted. Expression of POSH also increased the ubiquitination of ROMK1, whereas expression of POSHDeltaRING diminished its ubiquitination in HEK293T cells. The notion that POSH may serve as an E3 ubiquitin ligase is also supported by in vitro ubiquitination assays in which adding POSH increased the ROMK ubiquitination. We conclude that POSH inhibits ROMK channels by enhancing dynamin-dependent and clathrin-independent endocytosis and by stimulating ubiquitination of ROMK channels.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Regulação da Expressão Gênica/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitinação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Clatrina/genética , Clatrina/metabolismo , Dinaminas/genética , Dinaminas/metabolismo , Canais Epiteliais de Sódio/biossíntese , Canais Epiteliais de Sódio/genética , Humanos , Túbulos Renais Coletores , Oócitos/citologia , Oócitos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Sinais Direcionadores de Proteínas/fisiologia , Estrutura Terciária de Proteína/fisiologia , Ratos , Ratos Sprague-Dawley , Ubiquitina-Proteína Ligases/genética , Xenopus laevisRESUMO
Transient prehypertensive treatment (TPT) causes prolonged antihypertensive and cardioprotective effects. Reduced angiotensin sensitivity has been attributed to those effects. We hypothesize that prehypertensive preconditioning by angiotensin II type 1 receptor (AT1R) blockade improves cardiovascular protection of late-onset AT1R blockade in a model of spontaneous hypertensive heart-failure rats (SHHF/Mcc-fa(cp)). TPT (4-8 weeks of age) consisted of AT1R blockade (5 mg/kg candesartan) or vehicle. Candesartan-pretreated SHHF (5 mg/kg/day candesartan; weeks 4-8) received during adulthood (20-28 weeks of age) either candesartan at a dose of 1.5 or 5 mg/kg/day or vehicle. Vehicle-pretreated SHHF received either candesartan (5 mg/kg/day) or vehicle during adulthood. Blood pressure telemetry and longitudinal echocardiography were performed between weeks 20 and 28. Final examination included cardiac and vascular morphometry and measurement of the AT1R signaling and receptor internalization (ATRAP). Combined juvenile and adult AT1R blockade caused lower mean arterial pressure (MAP) than adult AT1R blockade alone (84 +/- 5 versus 97 +/- 5 mm Hg; P < 0.05). Cardiac and vascular hypertrophy was lower. Juvenile treatments were associated with a reduced cardiovascular AT1R expression and enhanced ATRAP expression. Combined juvenile and reduced adult AT1R blockade resulted in MAP similar to that with adult AT1R blockade alone (92 +/- 3 versus 97 +/- 5 mm Hg). We conclude that prehypertensive preconditioning improves adult treatment effects in SHHF. Those effects correlate with reduced cardiovascular AT1R expression and enhanced receptor internalization, suggesting reduced angiotensin sensitivity in pretreated SHHF. Moreover, preconditioning allows a reduction of adult AT1R blockade without loss of protection. Therefore, prehypertensive preconditioning may offer a tool to improve treatment efficacy in humans.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Cardiomegalia/prevenção & controle , Hipertensão/prevenção & controle , Fatores Etários , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Benzimidazóis/uso terapêutico , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/biossíntese , Tetrazóis/uso terapêutico , Fatores de Tempo , Túnica Média/efeitos dos fármacos , Túnica Média/patologia , UltrassonografiaRESUMO
BACKGROUND: Ambigous results exist on fetuin-A as marker for vascular disease in type 2 diabetes. This study aims to define the role of fetuin-A as marker for micro- and macrovascular disease in a high risk population of patients with type 2 diabetes mellitus and early diabetic nephropathy. METHODS: Fetuin-A serum levels were assessed by ELISA in a cross-sectional setting in 153 patients with type 2 diabetes. Associations of fetuin-A with metabolic, inflammatory and vascular markers were studied. Atherosclerotic burden was assessed by ankle-brachial-index (ABI) as well as detection of common carotid artery intima-media thickness (IMT). RESULTS: Levels of fetuin-A were lower in male than in female patients (0.49 ± 0.15 vs. 0.56 ± 0.20 g/L, p = 0.02). In addition, there was an inverse correlation with age (r = -0.20, P = 0.01). Bivariate correlations adjusted for age and gender revealed no significant correlations with metabolic parameters, except for a weak inverse correlation with serum adiponectin (r = -0.19, p = 0.02). Regarding parameters of micro- and macrovascular disease, fetuin-A was significantly associated with ABI (r = 0.18, p = 0.04), while there was no association with IMT (r = -0.07, p = n.s). Patients with an ABI < 0.9 had lower fetuin A levels than patients with an ABI 0.9-1.3 or > 1.3 (0.43 ± 0.10 vs. 0.52 ± 0.17 vs. 0.54 ± 0.18 g/L p = 0.05). Neither GFR nor albuminuria were associated with fetuin-A serum levels. Patients with prevalent neuropathy did not have altered fetuin-A levels compared to diabetic controls. In step-wise logistic regression analysis including age, gender, HbA1c, total cholesterol, glomerular filtration rate and fetuin-A, only total cholesterol (ß = 0.01, p = 0.02) and fetuin-A (ß = -5.99, p = 0.03) proved to be independent predictors of an ABI < 0.9. CONCLUSIONS: The results of this cross-sectional study suggest that lower fetuin-A levels are associated with macrovascular late complications in high-risk type 2 diabetes patients while there are no associations of fetuin-A with metabolic status or microvascular complications.
Assuntos
Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Idoso , Índice Tornozelo-Braço , Doenças Cardiovasculares/epidemiologia , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/epidemiologia , Doenças das Artérias Carótidas/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/metabolismo , Prevalência , Fatores de Risco , Distribuição por Sexo , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/metabolismo , alfa-2-Glicoproteína-HSRESUMO
Pulsatile stress is defined as product of pulse pressure (PP) and heart rate (HR) and is largely regulated by arterial stiffness in general and specifically with reference to patients with renal insufficiency by sympathetic nerve activity. Direct effects of the pulsatile stress on heart, coronary system and ultimately cardiovascular survival have been documented whereas no data exist relating to renal transplant patients. We analysed the relation of macrocirculatory disturbance to microcirculatory defects in 92 renal transplant recipients. Therefore, we investigated aortic stiffness by carotid-femoral pulse wave velocity (PWV), pulsatile stress and albuminuria. Pulsatile stress, not PWV was associated with the extent of albuminuria (r = 0.29; P < 0.01 and r = 0.06; P = 0.6 respectively), which was confirmed in multivariate stepwise regression analysis (P = 0.008). Dividing the data in tertiles of pulsatile stress revealed an eightfold increased risk for microalbuminuria and 12.2-fold increased risk for macroalbuminuria comparing upper with lower tertile of pulsatile stress. Pulsatile stress, not PWV correlates with albuminuria and predicts the degree of albuminuria in renal transplant recipients. Therefore, pulsatile stress reflects an easy and cost-effective marker for renal microcirculatory defects in renal transplant patients.
Assuntos
Albuminúria/fisiopatologia , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Transplante de Rim/fisiologia , Adulto , Aorta/fisiopatologia , Velocidade do Fluxo Sanguíneo/fisiologia , Resistência Capilar/fisiologia , Estudos de Coortes , Elasticidade , Feminino , Humanos , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Fluxo Pulsátil/fisiologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Toll-like receptors (TLRs) are an evolutionarily conserved family of cell membrane receptors that are part of the innate immunity system playing an important role as a first response to tissue injury. TLR2 and TLR4 are constitutively expressed on renal epithelium, and their expression is enhanced following renal ischemia/reperfusion (I/R) injury. Genetic deletion of either TLR2 or TLR4 protects from renal I/R injury. However, it is not known whether deletion of both combined protects the kidney more than a deletion of either one alone. Therefore, we performed renal I/R injury in mice lacking TLR2, TLR4, and TLR2/4, respectively. Our results demonstrate that there are no significant differences regarding protection from renal I/R injury in TLR2/4((-/-)) compared with either TLR2((-/-)) or TLR4((-/-)) gene-targeted mice as determined by histological evaluation and renal functional parameters. Furthermore, there was no difference in the number of apoptotic tubular cells and in nuclear translocation of nuclear factor kappa-B (NF-kappaB) between the TLR-gene-targeted groups. In parallel, in vitro experiments did not demonstrate an additional effect of the double genetic deletion compared with the single gene deletion with respect to tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 production in hypoxic isolated proximal tubular epithelial cells of the respective animals. In conclusion, a double genetic deletion of TLR2 and TLR4 confers a similar protection following renal I/R injury compared with single deletions of TLR2 and TLR4.
Assuntos
Imunidade Inata , Nefropatias/prevenção & controle , Rim/imunologia , Traumatismo por Reperfusão/prevenção & controle , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Interleucina-8/metabolismo , Rim/patologia , Nefropatias/imunologia , Nefropatias/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The serum- and glucocorticoid-inducible kinase 1 (SGK1) is a serine threonine protein kinase activated through the phosphatidylinositol 3-kinase (PI3-kinase) pathway and counteracting apoptosis. Protein expression and activation of SGK1 are increased in various models of cell stress. The present study explored the role of SGK1 in renal hypoxia/ischemia induced apoptosis. HEK 293 cells were exposed in vitro to hypoxia/reoxygenation (H/R), which increased SGK1 transcript levels, SGK1 protein abundance and SGK1 phosphorylation. H/R injury further enhanced the percentage of apoptotic cells, an effect significantly blunted by prior SGK1 overexpression. In vivo renal ischemia/reperfusion (I/R) injury increased SGK1 transcript levels and SGK1 protein abundance. I/R enhanced apoptosis, an effect significantly more pronounced in gene targeted mice lacking SGK1. In conclusion, SGK1 is up-regulated and counteracts apoptosis following H/R in vitro and ischemia In vivo.
Assuntos
Proteínas Imediatamente Precoces/metabolismo , Nefropatias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose , Hipóxia Celular , Linhagem Celular , Humanos , Proteínas Imediatamente Precoces/deficiência , Proteínas Imediatamente Precoces/genética , Marcação In Situ das Extremidades Cortadas , Nefropatias/patologia , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Adiponectin is an adipocyte-derived hormone circulating in different multimer complexes. The high-molecular-weight (HMW) complex is likely the active form of this protein and has been recognized as a risk marker for type 2 diabetes and coronary artery disease (CAD). Because quantification of HMW adiponectin by Western blot analysis is time-consuming, novel ELISAs have been developed to simplify measurements in clinical research. However, these enzyme immunoassays have not been cross-validated in larger patient groups. We evaluated 2 individual ELISA systems by comparison to Western blotting for measurement of the distribution of HMW adiponectin in healthy individuals and patients with CAD and type 2 diabetes. METHODS: We measured HMW adiponectin in 204 individuals (83 CAD patients, 81 type 2 diabetes patients, and 40 healthy controls). Correlations, range of agreement, and imprecision of HMW concentrations obtained using 2 commercial ELISAs (#1, ALPCO Diagnostics; #2, Millipore) were evaluated by comparison with quantitative Western blotting. RESULT: Adiponectin results of the ELISAs were significantly correlated with those obtained by Western blotting (both r > 0.75, P < 0.001). Deming regression and Bland-Altman analyses indicated high agreement among the 3 immunoassays. The median difference between HMW adiponectin concentrations measured by ELISA and by Western blot was +0.4 mg/L for ELISA #1 and -0.4 mg/L for ELISA #2 with 95% of value differences <3 mg/L. CONCLUSIONS: Selective measurement of HMW adiponectin by ELISA is feasible; however, individual differences among immunoassays must be considered. The evaluated ELISAs exhibit analytical characteristics that allow their use as equivalent for Western blot analysis in larger clinical and epidemiological groups.
Assuntos
Imunoensaio/métodos , Adiponectina/sangue , Adiponectina/imunologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/imunologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/imunologia , Saúde , Humanos , Peso MolecularRESUMO
BACKGROUND: Nepsilon-carboxymethyllysine (CML) is the major non-cross linking advanced glycation end product (AGE). CML is elevated in diabetic patients and apparent in atherosclerotic lesions. AGEs are associated with hypertension and arterial stiffness potentially by qualitative changes of elastic fibers. We investigated whether CML affects carotid and aortic properties in normoglycemic subjects. METHODS: Hundred-two subjects (age 48.2+/-11.3 years) of the FLEMENGHO study were stratified according to the median of the plasma CML level (200.8 ng/ml; 25th percentile: 181.6 ng/ml, 75th percentile: 226.1 ng/ml) into "high CML" versus "low CML" as determined by ELISA. Local carotid artery properties, carotid intima media thickness (IMT), aortic pulse wave velocity (PWV), blood pressure and fetuin-A were analyzed. In 26 patients after carotidectomy, CML was visualized using immunohistochemistry. RESULTS: According to the CML median, groups were similar for anthropometric and biochemical data. Carotid diameter was enlarged in the "high" CML group (485.7+/-122.2 versus 421.2+/-133.2 microm; P<0.05), in particular in participants with elevated blood pressure and with "high" CML ("low" CML: 377.9+/-122.2 microm and "high" CML: 514.5+/-151.6 microm; P<0.001). CML was associated fetuin-A as marker of vascular inflammation in the whole cohort (r=0.28; P<0.01) and with carotid diameter in hypertensive subjects (r=0.42; P<0.01). CML level had no effect on aortic stiffness. CML was detected in the subendothelial space of human carotid arteries. CONCLUSION: In normoglycemic subjects CML was associated with carotid diameter without adaptive changes of elastic properties and with fetuin-A as vascular inflammation marker, in particular in subjects with elevated blood pressure. This may suggest qualitative changes of elastic fibers resulting in a defective mechanotransduction, in particular as CML is present in human carotid arteries.
Assuntos
Artérias Carótidas/ultraestrutura , Doenças das Artérias Carótidas/sangue , Produtos Finais de Glicação Avançada/sangue , Lisina/análogos & derivados , Adulto , Antropometria , Bélgica/epidemiologia , Biomarcadores , Proteínas Sanguíneas/análise , Artérias Carótidas/química , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/cirurgia , Estudos de Coortes , Elasticidade , Feminino , Humanos , Hipertensão/complicações , Inflamação , Lisina/sangue , Masculino , Mecanotransdução Celular , Pessoa de Meia-Idade , Estudos de Amostragem , Túnica Íntima/ultraestrutura , Ultrassonografia , alfa-2-Glicoproteína-HSRESUMO
AIM: To evaluate the association between fetuin-A level (AHSG), its encoding gene (Thr256Ser) and arterial function in subjects with normal kidney function. INTRODUCTION: The aortic pulse wave velocity (aPWV) is a predictor for cardiovascular mortality. Fetuin-A is a calcification inhibitor and correlates negatively with increased vascular stiffness in dialysis patients. The fetuin-A polymorphism (Thr256Ser) is associated with reduced fetuin levels and accelerated vascular calcification in dialysis patients. Little is known about the role of fetuin-A as an independent predictor for the development of arterial stiffness in healthy subjects. MATERIALS AND METHODS: We studied 116 subjects with normal kidney function (age 47+/-12 years, 50 females and 66 males) of the FLEMENGHO study. Calcium measurements, plasma fetuin-A, its encoding gene (Thr256Ser) and indexes of arterial stiffness, such as aPWV and arterial distensibility, were determined. RESULTS: Fetuin-A levels were negatively correlated with aPWV (r=-0.21, p=0.029). After an adjustment for multiple covariables, fetuin-A levels were independently associated with aPWV (r=-0.30, p=0.022) in males but not in females. Male fetuin-A SerSer carrier had lower fetuin-A levels and higher aPWV (fetuin-A: 61.9+/-29.0 microg/ml; aPWV: 14.3+/-0.9 m/s) as compared to ThrThr (fetuin-A: 109.9+/-54.9 microg/ml; aPWV: 6.4+/-1.3 m/s) and ThrSer carrier (fetuin-A: 100.8+/-52.5 microg/ml; aPWV: 6.6+/-1.3 m/s). Other calcium variables were not significantly associated with arterial stiffness. CONCLUSION: With respect to common calcium variables, only fetuin-A level showed an inverse relation with aPWV in men with normal renal function. Male fetuin-A SerSer carriers demonstrate particularly high aortic stiffness, possibly implying a status of increased cardiovascular risk.
Assuntos
Aorta/fisiopatologia , Artéria Carótida Primitiva/fisiopatologia , Rim/fisiologia , Resistência Vascular , alfa-Fetoproteínas/metabolismo , Adulto , Alelos , Bélgica , Velocidade do Fluxo Sanguíneo , Calcinose/fisiopatologia , Creatinina/sangue , Creatinina/metabolismo , Feminino , Frequência do Gene , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fluxo Pulsátil , Fatores Sexuais , alfa-Fetoproteínas/genéticaRESUMO
C-terminal agrin fragment (tCAF) is a promising biomarker for glomerular filtration. Data regarding biomarkers that have the ability to predict rapid progression of chronic kidney disease (CKD) are sparse but necessary in order to identify patients at high risk for rapid progression. This study addresses the value of tCAF as a predictor of rapid kidney function decline in CKD patients.We measured plasma tCAF in a retrospective observational cohort study of 277 prevalent CKD patients stage I-V. Using multivariable Cox proportional hazards regression analysis, we evaluated the association of tCAF with end-stage-renal-disease (ESRD), ≥30%-decline of estimated glomerular filtration rate (eGFR) and the composite endpoint of both, adjusting for eGFR, age, systolic blood pressure, proteinuria and diabetes.The median age was 58 [interquartile range 47, 71] years, 36% were female. Median tCAF level was 822 [594, 1232] pM, eGFR was 32 [19, 48] ml/min/1.73 m. tCAF was correlated to eGFR and proteinuria (râ=â-0.76 and râ=â0.49, Pâ<â.001 resp.). During a follow-up of 57.1 [42.9, 71.9] weeks, 36 (13%) patients developed ESRD and 13 (5%) had an eGFR decline of ≥30% (composite endpoint: 49 (18%)). In multivariable analysis, each 100 pM higher tCAF was independently associated with ESRD (hazard ratio (HR) 1.05 (95%-CI 1.02-1.08)), ≥30% eGFR decline (HR 1.10 (1.03-1.18)) and the composite endpoint (HR 1.07 (1.04-1.1)).Plasma tCAF may identify CKD patients at risk for rapid kidney function decline independent of eGFR and other risk factors for eGFR loss such as proteinuria.
Assuntos
Agrina/sangue , Fragmentos de Peptídeos/sangue , Insuficiência Renal Crônica/sangue , Idoso , Biomarcadores/sangue , Creatinina/sangue , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To examine the correlation of plasma fibroblast growth factor (FGF)-23 and serum fetuin A levels with the coronary artery calcification score (CACS) in patients with normal kidney function. BACKGROUND: Vascular calcification is an active process that may be aggravated by hyperphosphataemia and hypercalcaemia. FGF-23 and human fetuin-A have been associated with calcifying arteriosclerosis in renal failure. Plasma FGF-23 was identified as an independent factor negatively associated with peripheral vascular calcification. Fetuin-A acts as a systemic inhibitor of ectopic calcification in dialysis patients and can be correlated to the survival of these patients. Very few data exists on the role of FGF-23 and fetuin-A in coronary calcification of patients without impaired kidney function. MATERIALS AND METHODS: Sixty-four patients, 21 females and 43 males, were subjected to 64-slice coronary computed tomography (CT) to evaluate coronary artery calcification (CAC). Plasma intact FGF-23 was determined by ELISA. Serum fetuin-A concentration were evaluated nephelometrically. RESULTS: Mean plasma FGF-23 level was 20.4 +/- 9.1 pg/ml and serum fetuin-A was 0.46 +/- 0.09 g/l. There was no correlation between FGF-23 (P = 0.777) and fetuin-A (P = 0.767) levels and the CACS. No correlation was found between the presence of noncalcified plaques and coronary artery stenosis (CAS) >or= 50%, and FGF-23 (P = 0.313 and P = 0.775) and fetuin-A levels (P = 0.601 and P = 0.659). CONCLUSION: Plasma intact FGF-23 and serum fetuin-A concentration do not correlate with the CACS, the grade of stenosis or presence of noncalcified plaques of the coronary arteries in patients with normal kidney function.