RESUMO
INTRODUCTION: Chronic kidney disease is avery common and complex chronic disease. Uncovering the pathological patterns of CKD on the molecular level of bio-fluids and tissue appears to be both vital and promising for a more favorable outcome. We reviewed recently discovered proteomics biomarkers for CKD to provide new insight into disease pathology. AREAS COVERED: We review the application of proteome analysis in the context of CKD with various etiologies within the last 5 years. Proteins and peptides associated with CKD as derived from multiple sources (urine, blood and tissue) are reported along with their various biological pathways. EXPERT OPINION: A systematic and theoretical comprehension of the CKD pathology is essential for its successful management. The underlying complexity of the disease further requires specific conditions for reliable and interpretable results. In this context, clinical proteomics has resulted in first encouraging findings in CKD. A more complete understanding of the biological pathways related to the disease, based on the scope of a holistic proteomic approach, could improve substantially the management of CKD, especially when in conjunction with the current trend of personalized medicine.
Assuntos
Proteômica , Insuficiência Renal Crônica , Biomarcadores , Humanos , Peptídeos , ProteomaRESUMO
BACKGROUND: The early detection and treatment of diabetic nephropathy (DN) is of crucial importance as patients with diabetes mellitus represent the largest proportion of patients on dialysis, with the highest morbidity and mortality. Currently, the first clinical sign of incipient DN is microalbuminuria, but its precision is not optimal. Many studies now report that proteins and peptides are new biomarkers in urine that primarily depict the pathophysiology of DN and thus allow for improved diagnosis of DN. OBJECTIVES: The presentation of new concepts for the early detection and treatment of DN for better patient management. MATERIAL AND METHODS: A systematic literature search was carried out. RESULTS: Many potential markers have been described in the search for new biomarkers to diagnose DN by urinary proteome analysis. However, many of these studies were not meaningful due to the small number of samples. This limitation led to inadequate validation of proteins that could not be confirmed as markers. However, the diagnostic benefit of CKD 273, a multimarker of 273 protein fragments, was sustainably demonstrated for the early diagnosis of DN. This multi-marker shows significant advantages in the precision of diagnosis and prognosis compared to albuminuria. Furthermore, many of its peptide markers map the molecular pathophysiology of DN. CONCLUSIONS: Clinical urinary proteome analysis shows great benefits and is already an appropriate tool for the early detection of incipient DN.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/urina , Proteoma/análise , Proteômica/métodos , Albuminúria/diagnóstico , Albuminúria/urina , Biomarcadores/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/urina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/urina , Diagnóstico Precoce , HumanosRESUMO
The genetic rs12917707-G>T variant in uromodulin (UMOD) has been associated with renal function, chronic kidney disease and hypertension with the minor T-allele showing a protective effect. Hypertension and nephrotoxicity are adverse effects of chronic cyclosporine treatment. We tested whether UMOD rs12917707-T in donor kidneys associates with long-term graft survival in 393 Caucasian patients with stable graft function for more than 10 weeks after kidney transplantation treated with a cyclosporine-based maintenance therapy (mean graft survival 9 years). Presence of the donor T-allele had no effect on blood pressure, serum creatinine 1 year after transplantation, and on number of acute graft rejections during the first year. No significant effect on overall graft survival was observed in Kaplan-Meier analysis (P=0.65). In death-censored adjusted multivariate analysis, presence of donor T-allele associated with a significant lower hazard ratio of 0.67 (95% confidence interval: 0.46-0.97, P=0.05) for graft loss. This protective effect of the donor T-allele on graft loss observed in multivariate adjusted analysis justifies further investigations including patients treated with similar or other immunosuppressive regimens.
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Ciclosporina/farmacologia , Genótipo , Sobrevivência de Enxerto/genética , Imunossupressores/farmacologia , Transplante de Rim/tendências , Uromodulina/genética , Adulto , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Tempo , Doadores de Tecidos , Resultado do TratamentoRESUMO
AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/urina , Hipoglicemiantes/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Proteoma/análise , Adolescente , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteoma/metabolismo , Proteômica/métodos , Medição de Risco , Urinálise/métodos , Adulto JovemRESUMO
Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.
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Barorreflexo/fisiologia , Vasoespasmo Coronário/fisiopatologia , Vasoespasmo Coronário/terapia , Terapia por Estimulação Elétrica/métodos , Hipertensão/fisiopatologia , Hipertensão/terapia , Pressão Sanguínea/fisiologia , Seio Carotídeo/fisiopatologia , Terapia por Estimulação Elétrica/instrumentação , Eletrodos Implantados , Desenho de Equipamento , Frequência Cardíaca/fisiologia , Sistema Nervoso Parassimpático/fisiopatologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
BACKGROUND AND AIMS: The adipokine adipocyte fatty acid binding protein (AFABP) is positively associated with the development of the metabolic syndrome, diabetes mellitus, and cardiovascular disease. We hypothesized that AFABP also increases with deteriorating renal function. METHODS AND RESULTS: Serum AFABP levels were quantified by enzyme linked immunosorbent assay in 532 patients with chronic kidney disease (CKD) covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5 (study population 1). Furthermore, AFABP was measured in 32 patients before and within 30 h after elective unilateral nephrectomy, a model of acute kidney dysfunction (AKD) (study population 2). Moreover, circulating AFABP was investigated in rats undergoing bilateral nephrectomy (BNE) as compared to sham-operated animals. Median serum AFABP levels adjusted for age, gender, and body mass index significantly increased with increasing eGFR category (G1: 22.0 µg/l; G2: 34.6 µg/l; G3: 56.7 µg/l; G4: 95.2 µg/l; and G5: 173.9 µg/l). Furthermore, renal dysfunction remained positively associated with AFABP in multivariate analysis in this cohort. In patients undergoing unilateral nephrectomy, AFABP increased significantly after surgery (42.1 µg/l) as compared to pre-surgical values (29.3 µg/l). Furthermore, relative changes of post-to-pre-surgical AFABP levels were independently associated with relative changes of post-to-pre-surgical creatinine concentrations. After BNE in rats, AFABP increased significantly as compared to sham-operated animals. CONCLUSIONS: We show that AFABP is significantly elevated in CKD and AKD patients. Furthermore, measures of renal function are associated with circulating AFABP. Moreover, animal experiments indicate that AFABP levels strongly depend on renal function.
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Injúria Renal Aguda/sangue , Adipócitos/metabolismo , Proteínas de Ligação a Ácido Graxo/sangue , Insuficiência Renal Crônica/sangue , Adipocinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Índice de Massa Corporal , Creatinina/sangue , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nefrectomia , Ratos , Adulto JovemRESUMO
The risk of cytomegalovirus (CMV) reactivation among hemodialysis (HD) patients is unknown. In 52 HD patients from a single center, CMV serology and quantitative PCR were performed. The detection limit of PCR was 20 copies/ml. Here, PCR ruled out CMV viremia, despite CMV-IgM seropositivity in 15.4% patients.
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Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/isolamento & purificação , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Ativação Viral , Citomegalovirus/genética , Citomegalovirus/imunologia , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Testes Sorológicos , Viremia/diagnósticoRESUMO
The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6+/-3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29-0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.
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Ciclosporina/uso terapêutico , Citocromo P-450 CYP3A/genética , Imunossupressores/uso terapêutico , Transplante de Rim , Estudos de Coortes , Genótipo , Humanos , Análise de SobrevidaRESUMO
Hyperparathyroidism is generally classified into a primary and secondary form. The primary form is caused by an autonomous adenomatous hypertrophy and/or hyperplasia of parythyroideal glands without known cause in most of the patients. Resulting elevated levels of parathyroid hormone cause elevation of serum calcium, subsequently followed by cerebral symptoms, fatigue and calcinosis of vessels and kidneys. The mainstay of secondary HPT is the initial vitamin D deficiency such as associated with kidney failure. Via an increased PTH secretion, calcium homeostasis will be maintained together with ongoing hyperplasia of the parathyroidea. Therapeutic approaches are related to pathophysiological mechanisms. While surgical removal of adenomatous glands is the mainstay of therapy in primary and late secondary forms, during the still regulated initial period of secondary HPT supplementation of vitamin D and/or sensitation of parathyroideal Calcium-sensing-receptors are therapy of choice.
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Cálcio/sangue , Hiperparatireoidismo Primário/terapia , Hiperparatireoidismo Secundário/terapia , Hormônio Paratireóideo/sangue , Deficiência de Vitamina D/terapia , Adenoma/diagnóstico , Adenoma/fisiopatologia , Adenoma/terapia , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/fisiopatologia , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/fisiopatologia , Hiperplasia , Glândulas Paratireoides/patologia , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/fisiopatologia , Neoplasias das Paratireoides/terapia , Paratireoidectomia , Receptores de Detecção de Cálcio/efeitos dos fármacos , Receptores de Detecção de Cálcio/fisiologia , Vitamina D/uso terapêutico , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/fisiopatologiaRESUMO
BACKGROUND: Steroid resistance and steroid dependence constitute a major problem in the treatment of minimal-change disease and focal segmental glomerulosclerosis (FSGS). Cyclophosphamide and cyclosporine are well-established alternative immunomodulating agents, whereas data on FK 506 (tacrolimus) are rare. METHODS: The present work provides data from 10 patients of an open, monocentric, non-randomized, prospective trial. Five patients with steroid-dependent minimal-change nephrotic syndrome, 1 patient with steroid-refractory minimal-change disease and 4 patients with steroid-refractory FSGS were started on tacrolimus at trough levels of 5 10 microg/l. In case of steroid-dependence, prednisolone was tapered off in presence oftacrolimus within one month. RESULTS: Within 6 months, complete remission was achieved in 5 patients (50%) and partial remission in 4 patients (40%), yielding a final response rate of 90%. One patient was primarily resistent to tacrolimus (steroid-refractory minimal-change), another patient became secondarily resistant to tacrolimus after an initial remission (steroid-refractory FSGS). Average proteinuria significantly decreased by 77% from 9.5 +/- 1.4 - 2.2 +/- 1.1 g/day (p < 0.01). Serum protein significantly raised from 55.0 +/- 1.9 - 64.6 +/- 1.9 g/l (p < 0.01). Tacrolimus induced non-significant increases of blood glucose (4.9 +/- 0.1 - 5.1 +/- 0.2 mmol/l), systolic blood pressure (131.4 +/- 7.1 - 139.0 +/- 7.6 mmHg) and creatinine (93.2 +/- 13.9 103.2 +/- 15.3 mmol/l). Five patients have been tapered off tacrolimus so far, nephrotic syndrome relapsed in 4 of them (80%). Relapse occurred at tacrolimus levels between 2.6 and 6.9 ng/ml. CONCLUSIONS: Our data suggest that tacrolimus may be a promising alternative to cyclosporine both in steroid-resistant and steroid-dependent nephrotic syndrome.
Assuntos
Síndrome Nefrótica/tratamento farmacológico , Esteroides/uso terapêutico , Tacrolimo/uso terapêutico , Adulto , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Proteínas Sanguíneas/análise , Creatinina/urina , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/tratamento farmacológico , Prednisolona/uso terapêutico , Proteinúria/tratamento farmacológico , Esteroides/farmacologiaRESUMO
Beyond polyuria following psychogenic polydipsia, in a more narrow sense, this condition may be classified into impaired water re-absorption (i) due to tubular injury or (ii) relative or absolute loss of function of antidiuretic hormone (ADH). Tubular injury may be caused by different toxins affecting the ascending Henle loop as hypercalciuria, drugs and antibiotics as tubular necrosis. ADH deficiency, either absolute or relative, occurs with central or peripheral diabetes insipidus, which is based on synthesis failure or loss of peripheral efficacy of ADH due to receptor malfunction. Diagnosis of polyuria rests upon a thirst challenge in conjunction with laboratory studies of osmolality in serum and urine, which discloses the non-function of the hypothalamic-renal axis. Administration of ADH may differentiate between central and peripheral diabetes insipidus.
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Nefropatias/diagnóstico , Nefropatias/urina , Poliúria/diagnóstico , Poliúria/urina , Vasopressinas/urina , Humanos , Nefropatias/complicações , Poliúria/etiologia , Guias de Prática Clínica como Assunto , Padrões de Prática MédicaRESUMO
Recently, an allelic variant of the angiotensinogen gene (AGT 235T) has been associated with increased risk of hypertension. However, this finding has not been confirmed by all investigators. A meta-analysis was performed to examine the association between the AGT 235T-allele and hypertension in whites and to identify potential reasons for the controversial results. All relevant articles published between 1992 and 1996 were identified through multiple sources. The studies were methodologically appraised, and the frequency of the AGT 235T-allele was extracted. The 235T-allele frequency was pooled using the common odds ratio (OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day test. Together these studies present data on 5493 patients. The AGT 235T-allele was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29; P<.0001). This association increased in studies with positive family history (OR: 1.42; 95% CI: 1.25 to 1.61, P<.0001), recruitment of cases from referral centers (OR: 1.39; 95% CI: 1.20 to 1.62, P<.0001), and more severe hypertension (OR: 1.34; 95% CI: 1.22 to 1.47, P<.0001). However, the presence of methodological problems in all studies gives rise to serious concerns regarding bias and confounding. Despite a statistically significant, albeit weak, association between the AGT 235T variant and hypertension that has been confirmed through sensitivity analysis, this finding has to be interpreted with caution, as the methodological weaknesses of the individual studies are likely to have biased the outcome of the meta-analysis. Clearly, more rigorous methods need to be applied in association studies on the genetics of human hypertension.
Assuntos
Angiotensinogênio/genética , Variação Genética , Hipertensão/genética , População Branca/genética , Alelos , Biometria/métodos , Bases de Dados Bibliográficas , Frequência do Gene , Humanos , MEDLINE , Razão de Chances , Sensibilidade e EspecificidadeRESUMO
Recent studies have identified a novel polymorphism (C825T) of the gene encoding the beta3 subunit of heterotrimeric G proteins (Gbeta3) associated with enhanced activation of G proteins, which appears to be more common in hypertensive patients. In the present study we examine the relationship between this genetic variant and hypertension in 479 white patients with established essential hypertension recruited from the hypertension clinic of the Universitätsklinikum Benjamin Franklin in Berlin, Germany, and 1000 normotensive gender- and age-matched controls. All patients were screened for the presence of secondary hypertension and were further characterized by ambulatory blood pressure measurements performed in 295 treated and 184 untreated patients. Genotype distribution for the Gbeta3-C825T genotype in patients (CC=204, CT=224, TT=51) was significantly different from that in controls (CC=514, CT=412, TT=74; chi2=11.5, P<0.01), and the T allele was associated with an odds ratio of 1.5 (95% CI, 1.1 to 2.2) versus non-T carriers for the presence of hypertension. However, in both the whole group and the untreated subgroup, blood pressure levels between the genotypic groups were virtually identical. Furthermore, age of onset of hypertension and number of antihypertensive medications (in treated patients) were similar between the genotypic groups. Thus, while our data confirm the association between the Gbeta3-C825T variant and essential hypertension, they do not support the hypothesis that this marker is associated with more severe blood pressure in patients with already established hypertension.
Assuntos
Pressão Sanguínea , Proteínas de Ligação ao GTP/genética , Hipertensão/genética , Adulto , Idoso , Monitorização Ambulatorial da Pressão Arterial , Feminino , Genótipo , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Análise de RegressãoRESUMO
BACKGROUND AND AIMS: A functional single-nucleotide variant of the gene encoding the beta3 subunit of heterotrimeric G proteins (Gbeta3 C825T), associated with enhanced G-protein activation and increased activity of the sodium-proton exchanger (NHE1), has been implicated in the development of hypertension. Given the possible involvement of NHE1 in sodium homeostasis, we tested the hypothesis that the Gbeta3 825T allele determines the response of the renin-angiotensin system and blood pressure to dietary salt restriction. METHODS: Young normotensive men (20-30 years old, n = 193) were recruited within the framework of the Berlin Salt-Sensitivity Trial and studied on low- (20 mmol/day) and high-salt (220 mmol/day) dietary protocols. Subjects were characterized for parameters of the renin-angiotensin system and blood pressure response and genotyped for the Gbeta3 C825T polymorphism. RESULTS: The genotype distribution was in Hardy-Weinberg equilibrium (CC = 90, CT = 81 and TT = 22). The responses of the renin-angiotensin system and blood pressure to the dietary protocol were virtually identical between the genotypic groups. Furthermore, when subjects were classified as salt-resistant (n = 145) or salt-sensitive (n = 48), genotype distribution was comparable between the two groups (salt-resistant: TT = 17, CT = 60, CC = 68, qT = 0.32; salt-sensitive: TT = 5, CT = 21, CC = 22, qT = 0.32). CONCLUSION: These findings do not support the hypothesis that the Gbeta3 C825T polymorphism determines the response of the renin-angiotensin system to salt depletion or can serve as an early genetic marker of salt sensitivity in young normotensive men.
Assuntos
Alelos , Pressão Sanguínea/genética , DNA/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Hipertensão/genética , Polimorfismo Genético/genética , Sódio na Dieta/efeitos adversos , Sódio/metabolismo , Adulto , Dieta Hipossódica , Marcadores Genéticos , Genótipo , Humanos , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Masculino , Reação em Cadeia da Polimerase , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Trocadores de Sódio-Hidrogênio/metabolismoRESUMO
BACKGROUND AND AIMS: A single-nucleotide variant of the angiotensinogen gene (AGT 235T) has been associated with essential hypertension and increased plasma levels of angiotensinogen. This variant may also serve as a genetic marker for the increased blood pressure response to dietary salt intake, but the relationship between AGT genotype and salt sensitivity has not been studied until now. We therefore examined the relationship between the AGT 235T genotype and the blood pressure response to short-term dietary salt restriction in young normotensive men. SUBJECTS AND METHODS: A total of 187 young normotensive men were characterized for family history of hypertension, salt sensitivity, plasma parameters of the renin-angiotensin system under high- and low-salt diets, and the AGT 235T genotype. RESULTS: While the T allele was significantly associated with a positive family history of hypertension (chi2 = 7.0; P< 0.03) and higher plasma angiotensinogen levels (P< 0.015) and renin activity (P < 0.037), blood pressure under both diets was not significantly affected by the AGT genotype. When the subjects were classified into salt-resistant and salt-sensitive groups, genotypic distribution was nearly identical between both groups (frequency of T allele: 0.45 versus 0.46). CONCLUSION: Our findings demonstrate that the AGT 235T allele is significantly associated with a positive family history of hypertension, but is not an important determinant of the blood pressure response to dietary salt intake in young normotensive subjects. It is therefore unlikely that the AGT 235T genotype can serve as an early genetic marker of salt sensitivity.
Assuntos
Angiotensinogênio/genética , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/genética , Cloreto de Sódio na Dieta/farmacologia , Adulto , Angiotensinogênio/sangue , Angiotensinogênio/metabolismo , Estudos Cross-Over , Genótipo , Humanos , Masculino , Mutação Puntual , Sistema Renina-Angiotensina , Método Simples-Cego , População Branca/genéticaRESUMO
OBJECTIVE: To test the hypothesis that the Hpa II variant of the atrial natriuretic peptide gene (ANP), which has been reported to be more common among black hypertensives than it is among normotensive controls, is related to the response of blood pressure to salt intake in normotensive Caucasians. METHODS: One hundred and three young (aged 19-35 years) male volunteers were fed a low-salt diet (20 mmol NaCl/day) for 2 weeks and a supplement of either 200 mmol NaCl/day (slow sodium) or placebo for 1 week each in a randomized double-blind cross-over order. Salt sensitivity was defined as a significant (P < 0.05) decrease in resting mean arterial blood pressure by > 3 mmHg under the low-salt diet. The genotype was determined by amplification of genomic DNA extracted from peripheral leukocytes and subsequent digestion of the amplicon with Hpa II restriction enzyme. RESULTS: According to the above definition, 27 subjects were salt sensitive. There were no significant differences in age, body-mass index and waist:hip ratio between the salt-sensitive and salt-resistant groups. Only salt-sensitive subjects displayed a significantly higher blood pressure under the high-salt diet (increase in mean arterial pressure 5.6 +/- 2.4 mmHg, P < 0.001). The prevalence of the ANP-Hpa II wild-type (w) allele did not differ between the salt-sensitive (qw = 1.0, qm = 0) and the salt-resistant group (qw = 0.96, qm = 0.04). Furthermore, the salt-induced response of blood pressure did not differ between homozygotes (ww) and heterozygotes (wm). CONCLUSIONS: Our findings do not support the hypothesis that the ANP-Hpa II polymorphism is a marker for salt sensitivity in young Caucasian normotensives.
Assuntos
Fator Natriurético Atrial/genética , Pressão Sanguínea/genética , Polimorfismo de Fragmento de Restrição , Sódio na Dieta/administração & dosagem , Adulto , Alelos , Sequência de Bases , Estudos Cross-Over , Primers do DNA/genética , Desoxirribonuclease HpaII , Dieta Hipossódica , Método Duplo-Cego , Resistência a Medicamentos/genética , Humanos , MasculinoRESUMO
OBJECTIVE: To examine whether the angiotensinogen M235T and angiotensin converting enzyme insertion/deletion (I/D) variants are related to the severity of hypertension in patients with established essential hypertension. DESIGN: A cross-sectional study. SETTING: The hypertension clinic of the Benjamin Franklin University Hospital, Free University of Berlin. PARTICIPANTS: Three hundred and forty-three consecutive Caucasian patients who presented with treated or untreated (n = 115) hypertension were enrolled into the study. Twenty-two patients were excluded from analysis because they had secondary hypertension. MAIN OUTCOME MEASURES: Angiotensinogen M235T and angiotensin-converting enzyme I/D genotypes, 24 h ambulatory blood pressure values, the number of antihypertensive medications administered and left ventricular dimensions assessed by two-dimensional echocardiography. RESULTS: Neither the angiotensinogen nor the angiotensin converting enzyme genotype was related significantly to the average ambulatory blood pressure and left ventricular dimensions in hypertensives. Furthermore, neither the number of antihypertensive medications administered to treated patients nor blood pressure levels in untreated patients (n = 115) differed significantly between the genotypic groups. CONCLUSIONS: These results do not support the hypothesis that the studied molecular variants of the renin-angiotensin system may represent clinically useful markers of the severity of hypertension in Caucasians with established essential hypertension.
Assuntos
Pressão Sanguínea/genética , Variação Genética , Hipertensão/genética , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/genética , Adulto , Idoso , Angiotensinogênio/genética , Estudos Transversais , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genéticaRESUMO
OBJECTIVE: Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, the T allele of a polymorphism in the 5'-flanking region of the CYP11B2 gene (C-344T) has been reported to be more frequent in hypertensives than in normotensives, and has also been associated with increased plasma aldosterone levels. We therefore hypothesized that this variant may be related to increased blood-pressure response to dietary salt intake. SUBJECTS AND METHODS: We genotyped 1 63 young normotensive men recruited within the framework of the Berlin Salt-Sensitivity Trial (BeSST) for the CYP11B2 C-344T polymorphism. Subjects were characterized for family history of hypertension, plasma parameters of the renin-angiotensin-aldosterone system and blood-pressure response to a high (220 mmol/day) and low (20 mmol/day) salt diet RESULTS: The frequency of the -344T allele (0.45) was similar to that reported previously and genotype distribution was in Hardy-Weinberg equilibrium (CC, n = 55; CT, n = 71; TT, n = 37). There was a trend towards a higher frequency of the T allele in subjects with a positive family history of hypertension (0.48 versus 0.42), but the C-344T genotype was not related to blood pressure under either diet Furthermore, when subjects were classified into salt-sensitive and salt-resistant groups, allelic distribution did not differ between the two groups (qT = 0.43 versus qT = 0.45). While renin activity and plasma aldosterone levels were not related to genotype, plasma angiotensinogen was significantly higher in T-allele carriers under both the high (P = 0.02) and low (P = 0.008) salt diet. CONCLUSION: Our findings do not support the hypothesis that the C-344T polymorphism of the CYP11B2 gene is associated with salt sensitivity or increased activity of the renin-angiotensin system in young normotensive subjects. It is, therefore, unlikely that the C-344T polymorphism is a genetic marker for salt sensitivity in young normotensive Caucasian men.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP11B2/genética , Hipertensão/genética , Polimorfismo Genético/genética , Cloreto de Sódio/administração & dosagem , População Branca/genética , Adulto , Aldosterona/sangue , Alelos , Angiotensinogênio/sangue , Antropometria , Estudos Cross-Over , Dieta Hipossódica , Resistência a Medicamentos , Frequência do Gene , Genótipo , Humanos , Masculino , Polimorfismo Genético/fisiologia , Renina/sangue , Método Simples-Cego , Cloreto de Sódio/farmacologiaRESUMO
BACKGROUND: A mutation in the gene for the angiotensin II type 1 (AT1) receptor (A1166C) has been reported to be associated with primary hypertension. OBJECTIVE: To determine whether this observation could be confirmed with a different population sample. DESIGN: We examined 414 individuals with primary hypertension and 172 normotensive controls. METHODS: The mutation in the gene for the AT1 receptor was detected using restriction polymerase chain reaction. CONCLUSIONS: We detected no association of the AT1 receptor polymorphism with hypertension, but a trend towards a decreased prevalence of the 1166C allele among hypertensive patients with a late age at diagnosis (> or = 50 years) was observed.