RESUMEN
BACKGROUND: African Americans are at increased risk of kidney failure caused by hypertension. The primary objective of the African American Study of Kidney Disease and Hypertension (AASK) Cohort Study is to identify risk factors for progressive kidney disease in African Americans with hypertensive chronic kidney disease in the setting of recommended antihypertensive therapy. STUDY DESIGN, SETTING, & PARTICIPANTS: On completion of the AASK Trial, a randomized, double-blind, 3 x 2 factorial trial, participants who had not yet begun dialysis treatment or undergone kidney transplantation were invited to enroll in a prospective Cohort Study. Cohort Study participants received recommended antihypertensive drug therapy, including high rates of angiotensin-converting enzyme-inhibitor (73%) and angiotensin receptor blocker (10%) use with a blood pressure goal of less than 130/80 mm Hg. PREDICTOR, OUTCOMES, & MEASUREMENTS: Baseline clinical and demographic characteristics are described separately at the baseline of the AASK Trial and Cohort Study. RESULTS: Of 1,094 persons enrolled in the AASK Trial (June 1995 to September 2001; mean age, 55 years; 61% men), 691 enrolled in the AASK Cohort Study (April 2002 to present), 299 died or reached dialysis therapy or transplantation, and 104 declined to participate in the AASK Cohort Study. Mean baseline systolic/diastolic blood pressures were 150/96 mm Hg in the Trial and 136/81 mm Hg in the Cohort Study. Cohort Study participants had greater serum creatinine levels at the start of the Cohort Study (2.3 versus 1.8 mg/dL [203 versus 159 micromol/L]), corresponding to an estimated glomerular filtration rate of 43.8 versus 50.3 mL/min/1.73 m2 (0.73 versus 0.84 mL/s/1.73 m2), than Trial participants and greater urine protein-creatinine ratios (0.38 versus 0.19 mg/mg, respectively). Individuals who were eligible, but declined to participate in the Cohort Study, had greater systolic blood pressure, but similar kidney function. LIMITATIONS: Some parameters, such as iothalamate glomerular filtration rate, urinary albumin level, echocardiogram, and ambulatory blood pressure, were not performed in both the Trial and the Cohort Study, limiting the ability to evaluate changes in these parameters over time. CONCLUSION: Despite well-controlled blood pressure in the AASK Trial, Cohort Study participants still had evidence of progressive chronic kidney disease. Thus, the AASK Cohort Study is well positioned to address its primary objective.
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Hipertensión/complicaciones , Enfermedades Renales/etiología , Negro o Afroamericano , Albuminuria , Antihipertensivos/uso terapéutico , Presión Sanguínea , Estudios de Cohortes , Creatinina/sangre , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etnología , Enfermedades Renales/etnología , Fallo Renal Crónico/etnología , Fallo Renal Crónico/etiología , Masculino , Factores de RiesgoRESUMEN
Previous studies from this laboratory have demonstrated a critical role of cytosolic phospholipase A2 (cPLA2) and arachidonic acid in angiotensin II (Ang II) AT2 receptor-mediated signal transduction in renal epithelium. In primary proximal tubular epithelial cells exposed to hydrogen peroxide (H2O2), both the selective cPLA2 inhibitors and the cPLA2 antisense oligonucleotides significantly attenuated H2O2-induced arachidonic acid liberation and activation of p38(SAPK), ERK1/2, and Akt1. This H2O2-induced kinase activation was significantly attenuated by a Src kinase inhibitor PP2, or by transient transfection of carboxyl-terminal Src kinase (CSK) that maintained Src in the dormant form. Under basal conditions, Src coimmunoprecipitated with epidermal growth factor receptor (EGFR), while H2O2 increased EGFR phosphorylation in the complex. We observed that inhibition of EGFR kinase activity with AG1478 significantly attenuated H2O2-induced p38(SAPK) and ERK1/2 activation, but did not inhibit Akt1 activation. Furthermore, it seems that p38(SAPK) is upstream of ERK1/2 and Akt1, since a p38(SAPK) inhibitor SB203580 significantly blocked H2O2-induced activation of ERK1/2 and Akt1. Interestingly, overexpression of the dominant-negative p38(SAPK) isoform alpha inhibited ERK1/2 but not Akt1 activation. Our observations demonstrate that in these nontransformed cells, activation of cPLA2 is a converging point for oxidative stress and Ang II, which share common downstream signaling mechanisms including Src and EGFR. In addition, p38(SAPK) provides a positive input to both growth and antiapoptotic signaling pathways induced by acute oxidative stress.
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Citosol/enzimología , Riñón/metabolismo , Estrés Oxidativo , Fosfolipasas A/metabolismo , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Secuencia de Bases , Cartilla de ADN , ADN Complementario , Epitelio/metabolismo , Fosfolipasas A2RESUMEN
The risk of cardiovascular (CV) and renal complications begins at a relatively low blood pressure (BP), and this risk is associated with such disorders as metabolic syndrome. When comparing older antihypertensive agents with newer agents, for the most part no significant differences have been seen in rates of CV events. However, rapidly controlling BP is critical to reduce event rates, particularly rates of stroke. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers consistently decrease the rate of onset of type 2 diabetes.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Enfermedades Cardiovasculares/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Medicina Basada en la Evidencia , Humanos , Hipertensión/complicaciones , Hipertensión/etnología , Síndrome Metabólico/complicaciones , Síndrome Metabólico/prevención & control , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The most striking feature of life is biodiversity. However, mechanisms of biodiversity remain poorly understood, as most protein orthologues of different species are highly homologous in sequence and identical in function. Interestingly, recent evidence has demonstrated heterogeneity for a G protein-coupled angiotensin II (Ang II) type 2 (AT(2)) receptor in both ligand binding and induction of arachidonic acid (AA) release. The present study investigated the properties of AT(2) receptors in closely related species. METHODS: AT(2) receptors cloned from human, rabbit, rat, and mouse were expressed in Chinese hamster ovary cells (CHO-K1), African green monkey kidney cells (COS-1), and human embryonic kidney (HEK)-293 cells and characterized in ligand binding and signal transductions. Critical residues in rabbit AT(2) receptor attributable to heterogeneity were examined using both gain-of-function and loss-of-function approaches with mutagenesis. RESULTS: The newly cloned rabbit AT(2) receptor exhibits distinct biochemical and biologic properties compared to its highly homologous orthologues (91% in overall amino acid sequence) of rat, mouse, and human. All these orthologues activate SH2 domain-containing phosphatase-1 (SHP-1) and show similar binding affinities for Ang II and AT(2)-specific ligands CGP42112A and PD123319. However, reducing agent dithiothreitol (DTT) inactivates the rabbit orthologue but potentiates the others in ligand binding, a hallmark of AT(2) versus AT(1) receptor subtypes. Most interestingly, rabbit AT(2) receptor, but not the other orthologues, induces AA release in various cell systems when stimulated by both Ang II and CGP42112A, the peptide antagonist. Mutagenesis studies and sequence analyses further indicate that residues His(106), Asp(188), and Thr(293) are responsible for the DTT inactivation and residues Val(209) and Val(249) are partially responsible for AA release. CONCLUSION: These results deny the coexistence of an additional AT(2) subtype in rabbit proximal tubule cells and demonstrate for the first time the presence of functional diversity for closely related Eutherian orthologues of a G protein-coupled receptor (GPCR) that are more than 90% homologous in the amino acid sequence.
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Receptor de Angiotensina Tipo 2/metabolismo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Ácido Araquidónico/metabolismo , Secuencia de Bases , Sitios de Unión/genética , Células CHO , Células COS , Línea Celular , Chlorocebus aethiops , Clonación Molecular , Cricetinae , ADN Complementario/genética , Ditiotreitol/farmacología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Cinética , Ligandos , Ratones , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Fosforilación , Proteína Fosfatasa 1 , Proteína Tirosina Fosfatasa no Receptora Tipo 6 , Proteínas Tirosina Fosfatasas/metabolismo , Conejos , Ratas , Receptor de Angiotensina Tipo 2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Especificidad de la EspecieRESUMEN
African Americans represent a population with the highest prevalence of hypertension in the world, associated with earlier onset, more severity, poorer control rates, and more cardiovascular and renal complications than White Americans. The high prevalence of type 2 diabetes mellitus in African Americans, compared with Whites, compounds the excessive burden of cardiovascular and kidney disease. The Hypertension in African American Working Group of the International Society of Hypertension in Blacks recently developed a consensus document that presented a practical, evidence-based approach aimed at achieving better blood pressure control. It was thought that a new approach, targeted at US Blacks, was needed to achieve better blood pressure control and enhanced target tissue protection. Key elements of the document include (i) emphasis on the importance of therapeutic lifestyle modification such as weight loss, decreased sodium ingestion, increased potassium intake, exercise, and weight loss, to name a few; (ii) recommendation of combination antihypertensive agents because of the high prevalence of individuals with >15 mm Hg above SBP goal and/or 10 mmHg above DBP goal (140/90 unless there is also diabetes and/or kidney disease with >1 g proteinuria daily). Effective combinations include beta-adrenoceptor antagonist/diuretic, ACE inhibitor/diuretic, ACE inhibitor/calcium channel antagonist, and angiotensin receptor antagonist/diuretic; and (iii) the recommendations do not differ from other racial/ethnic groups where specific or compelling indications for the use of specific classes of antihypertensive agents exist.
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Negro o Afroamericano , Hipertensión/terapia , Guías de Práctica Clínica como Asunto , Antihipertensivos/uso terapéutico , Determinación de la Presión Sanguínea/normas , Humanos , Hipertensión/epidemiología , Estilo de VidaRESUMEN
In renal clinical trials, both slope-based and time-to-event renal outcomes have been used. These outcomes are typically based on estimates of GFR obtained using creatinine or iothalamate GFR (iGFR). The African American Study of Kidney Disease and Hypertension (AASK) was a trial in 1094 African Americans with hypertensive nephrosclerosis, which examined the effects of two levels of BP control and three antihypertensive regimens. This study compared the effects of the AASK interventions on outcomes based on serum creatinine with corresponding outcomes based on iGFR using 9742 matched pairs of iGFR and serum creatinine measurements. The iGFR-based outcomes included (1) a time-to-event composite outcome including a 50% GFR decline, ESRD, or death; (2) a composite outcome including a 50% GFR decline or ESRD; (3) mean decline in GFR in the first 3 mo after randomization (acute slope); (4) mean decline in GFR starting 3 mo after randomization (chronic slope); and (5) mean decline in GFR from baseline (total slope). The corresponding creatinine-based outcomes were (1) a composite of doubling of serum creatinine, ESRD, or death and (2) a composite of doubling of serum creatinine or ESRD and acute, chronic, and total slopes defined by the mean change in estimated GFR (eGFR), where eGFR was estimated from a regression equation for GFR depending primarily on serum creatinine and developed in AASK enrollees. Mean changes in iGFR and eGFR were also compared under extended models that allowed for the possibility that the rate of GFR decline may change over time during the chronic phase. an apparent acceleration in rate of decline of renal function over time was found. Subtle differences were observed between effects of the interventions on some of the creatinine and iGFR slope-based outcomes, but the main conclusions of the trial were similar for the serum creatinine and iothalamate-based measurements. This has important implications for the design of clinical trials with renal outcomes.
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Negro o Afroamericano/estadística & datos numéricos , Creatinina/sangre , Tasa de Filtración Glomerular , Hipertensión Renal/diagnóstico , Ácido Yotalámico , Fallo Renal Crónico/diagnóstico , Adolescente , Adulto , Anciano , Antihipertensivos/uso terapéutico , Medios de Contraste/administración & dosificación , Femenino , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/etnología , Radioisótopos de Yodo , Ácido Yotalámico/administración & dosificación , Fallo Renal Crónico/etnología , Modelos Lineales , Masculino , Persona de Mediana Edad , Dinámicas no LinealesRESUMEN
OBJECTIVES: We report on a subanalysis of the effects of losartan and atenolol on cardiovascular events in black patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. BACKGROUND: The LIFE study compared losartan-based to atenolol-based therapy in 9,193 hypertensive patients with left ventricular hypertrophy (LVH). Overall, the risk of the primary composite end point (cardiovascular death, stroke, myocardial infarction) was reduced by 13% (p = 0.021) with losartan, with similar blood pressure (BP) reduction in both treatment groups. There was a suggestion of interaction between ethnic background and treatment (p = 0.057). METHODS: Exploratory analyses were performed that placed LIFE study patients into black (n = 533) and non-black (n = 8,660) categories, overall, and in the U.S. (African American [n = 523]; non-black [n = 1,184]). RESULTS: A significant interaction existed between the dichotomized groups (black/non-black) and treatment (p = 0.005); a test for qualitative interaction was also significant (p = 0.016). The hazard ratio (losartan relative to atenolol) for the primary end point favored atenolol in black patients (1.666 [95% confidence interval (CI) 1.043 to 2.661]; p = 0.033) and favored losartan in non-blacks (0.829 [95% CI 0.733 to 0.938]; p = 0.003). In black patients, BP reduction was similar in both groups, and regression of electrocardiographic-LVH was greater with losartan. CONCLUSIONS: Results of the subanalysis are sufficient to generate the hypothesis that black patients with hypertension and LVH might not respond as favorably to losartan-based treatment as non-black patients with respect to cardiovascular outcomes, and do not support a recommendation for losartan as a first-line treatment for this purpose. The subanalysis is limited by the relatively small number of events.
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Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Hipertensión/prevención & control , Hipertrofia Ventricular Izquierda/complicaciones , Losartán/uso terapéutico , Anciano , Anciano de 80 o más Años , Antihipertensivos/administración & dosificación , Pueblo Asiatico , Atenolol/administración & dosificación , Población Negra , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Europa (Continente) , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/genética , Hipertensión/mortalidad , Losartán/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Estados Unidos , Población BlancaRESUMEN
Human proximal tubule epithelial cell lines are potentially useful models to elucidate the complex cellular and molecular details of water and electrolyte homeostasis in the kidney. Samples of normal adult human kidney tissue were obtained from surgical specimens, and S1 segments of proximal convoluted tubules were microdissected, placed on collagen-coated culture plate inserts, and cocultured with lethally irradiated 3T3 fibroblasts. Primary cultures of proximal tubule epithelial cells were infected with a replication-defective retroviral construct encoding either wild-type or temperature-sensitive simian virus 40 large T-antigen. Cells forming electrically resistive monolayers were selected and expanded in culture. Three cell lines (HPCT-03-ts, HPCT-05-wt, and HPCT-06-wt) were characterized for proximal tubule phenotype by electron microscopy, electrophysiology, immunofluorescence, Southern hybridization, and reverse transcriptase-polymerase chain reaction. Each of the three formed polarized, resistive epithelial monolayers with apical microvilli, tight junctional complexes, numerous mitochondria, well-developed Golgi complexes, extensive endoplasmic reticulum, convolutions of the basolateral plasma membrane, and a primary cilium. Each exhibited succinate, phosphate, and Na,K- adenosine triphosphatase (ATPase) transport activity, as well as acidic dipeptide- and adenosine triphosphate-regulated mechanisms of ion transport. Transcripts for Na(+)-bicarbonate cotransporter, Na(+)-H(+) exchanger isoform 3, Na,K-ATPase, parathyroid hormone receptor, epidermal growth factor receptor, and vasopressin V2 receptor were identified. Furthermore, immunoreactive sodium phosphate cotransporter type II, vasopressin receptor V1a, and CLIC-1 (NCC27) were also identified. These well-differentiated, transport-competent cell lines demonstrated the growth, immortalization, and differentiation potential of normal, adult, human proximal tubule cells and consequently have wide applicability in cell biology and renal physiology.
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Diferenciación Celular , Línea Celular , Proliferación Celular , Células Epiteliales/citología , Células Epiteliales/fisiología , Túbulos Renales Proximales/citología , Animales , Transporte Biológico , Biomarcadores , Polaridad Celular , Células Cultivadas , Técnicas de Cocultivo , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Iones/metabolismo , Túbulos Renales Proximales/metabolismo , Proteínas de la Membrana/metabolismo , Microscopía Electrónica de Transmisión , Fenotipo , Retroviridae/genética , Retroviridae/metabolismoRESUMEN
BACKGROUND: Recent evidence from this laboratory have demonstrated a critical role of phospholipase A2 (PLA2) and arachidonic acid in angiotensin II type 2 (AT2) receptor-mediated kinase activation in renal epithelium independent of phosphoinositide- specific phospholipase C (PLC) and without the necessity of eicosanoid biosynthesis. In the present study, we investigated whether cyclic stress phosphorylates and activates the mitogen-activated protein kinase (MAPK) pathway and whether PLA2 activation mediates mechanotransduction in renal epithelial cells. The rational for studying kidney epithelial cells relates to their similarity to podocytes, which undergo mechanical stretch related to changes in intraglomerular pressure. METHODS: To produce strain or stretch, primary cultures of rabbit proximal tubular cell cells are grown in tissue culture wells having a collagen-coated Silastic deformable membrane bottoms and applying vacuum to the well to generate alternating cycles of stretch and relaxation (30 cycles/min). RESULTS: We found that cyclic stretching of rabbit proximal tubular cells caused a time- and intensity-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK 1/2) in proximal tubular cells as detected by its phosphorylation. In addition, mechanical stretch induced PLA2 activation and a subsequent rapid release of arachidonic acid. Inhibition of PLA2 by mepacrine and methyl arachidonyl fluorophosphonate ketone (AACOCF3) attenuated both arachidonic acid release and ERK 1/2 activation by cyclic stretch, supporting the importance of PLA2 as a mediator of mechanotransduction in renal proximal tubular cells. A requirement for extracellular Ca2+ and stretch-activated Ca2+ channels was also documented. Complete inhibition of ERK 1/2 by PD98059, a MAPK kinase (MEK) inhibitor, did not suppress stretch- induced PLA2 activation and arachidonic acid release, suggesting the later events were upstream of ERK 1/2. Cyclic stretch also caused rapid phosphorylation of the EGF receptor kinase and c-Src. Furthermore, arachidonic acid itself induced time- and dose-dependent phosphorylation of c-Src. In addition, the c-Src inhibitor PP2 and selective EGF receptor kinase inhibitor AG1478 attenuated both ERK 1/2 and EGF receptor phosphorylation by cyclic stretch. CONCLUSION: PLA2 dependence for ERK 1/2 activation in response to cyclic stretch in proximal tubular epithelial cells was established in this report. In addition, these findings indicate cyclic stretch increased the tyrosine phosphorylation of the EGF receptor and c-Src and that c-Src acts upstream of the EGF receptor to mediate its phosphorylation, whereby both are critical for stretch- induced ERK 1/2 activation in rabbit proximal tubular cells. These observations documents for the first time a mechanism of mechanical stretch-induced kinase activation mediated by stretch activated Ca2+ channels and PLA2-dependent release of arachidonic acid.
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Túbulos Renales Proximales/enzimología , Sistema de Señalización de MAP Quinasas/fisiología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfolipasas A/metabolismo , Animales , Ácido Araquidónico/metabolismo , Calcio/metabolismo , Canales de Calcio/metabolismo , Células Cultivadas , Receptores ErbB/metabolismo , Túbulos Renales Proximales/citología , Masculino , Proteína Quinasa 3 Activada por Mitógenos , Fosfolipasas A2 , Conejos , Estrés Mecánico , Tritio , Familia-src Quinasas/metabolismoRESUMEN
Salt sensitivity (SS) has been linked to human hypertension. We examined ethnic differences in the relation between SS; erythrocyte sodium (Na+i), calcium (Ca2+i), potassium (K+i), and magnesium (Mg2+i); and sodium pump activity in African-American (AA) and white women. In a crossover protocol, similar numbers of normotensive, hypertensive, AA, and white women were randomized to 7 days of a 20 meq/d and a >200 meq/d salt diet (n=199). After an overnight inpatient stay, group differences in supine blood pressure (BP), heart rate, erythrocyte cations, and sodium pump activity were measured. The prevalence of SS (53.5% vs 51%) and salt resistance (26.3% vs 30.0%) was similar in both races. Greater mean BP increase with salt loading was seen in AA vs white hypertensives but not between the normotensive women. In hypertensives, increase in mean arterial pressure was 12.6 vs 8.2 mm Hg in AAs vs whites, respectively (P<0.01), and for systolic BP, it was 23 vs 14.8 mm Hg (P<0.01). Higher Na+i and Ca2+i were noted in SS and salt-intermediate AA than in the corresponding white subjects. Na+i, Ca2+i, and the ratios of Na+i to K+i and of Ca2+i to Mg2+i were positively correlated with salt responsiveness in AA but not in white women. Sodium pump activity was similar between groups, although the change in maximal activity trended to vary inversely with SS in AA. In closely matched AA and white women, the prevalence of SS is similarly high in both races, although the magnitude of BP increase is greater in AA hypertensives. In AA but not in whites, SS is positively associated with Na+i, Ca2+i, and the ratios of Na+i to K+i and of Ca2+i to Mg2+i.
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Población Negra , Hipertensión/etnología , Sodio en la Dieta/farmacología , Población Blanca , Presión Sanguínea/efectos de los fármacos , Cationes/metabolismo , Estudios Cruzados , Eritrocitos/metabolismo , Femenino , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Persona de Mediana Edad , Posmenopausia , Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
An interim analysis of the AASK trial at three years demonstrates a renoprotective effect [slower decline in glomerular filtration rate (GFR), delayed onset of significant decrease in GFR, end-stage renal disease (ESRD) or death, and a decrease in urinary protein excretion] of the angiotensin converting enzyme (ACE) inhibitor, ramipril, as compared to the dihydropyridine calcium channel blocker (DHP-CCB), amlodipine, in patients with mild-to-moderate renal insufficiency. The beneficial effect occurred in the presence of similar levels of blood pressure control and was apparent in patients with proteinuric (beyond the threshold of "dipstick positive" proteinuria, 300 mg/day) and non-proteinuric hypertensive nephrosclerosis. At the time of the interim analysis, the effectiveness of the beta-blocker metoprolol was not significantly different from that of the ACE inhibitor. The data suggest that DHP-CCBs should be used with caution in the presence of mild-to-moderate renal insufficiency.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Negro o Afroamericano , Hipertensión Renal/tratamiento farmacológico , Nefroesclerosis/dietoterapia , Ramipril/uso terapéutico , Insuficiencia Renal/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Amlodipino/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Hipertensión Renal/etnología , Metoprolol/uso terapéutico , Nefroesclerosis/etnología , Insuficiencia Renal/etnologíaRESUMEN
BACKGROUND: Clinical trials of nephropathy in people with type 2 diabetes mellitus have not examined the effects of systolic blood pressure (SBP) or pulse pressure (PP) on the time to end-stage renal disease (ESRD) or death. OBJECTIVES: To evaluate the impact of baseline and treated SBP, diastolic blood pressure (DBP), and PP on composite and individual outcomes including doubling of serum creatinine, ESRD, or death in participants of the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) With the Angiotensin II Antagonist Losartan (RENAAL) Study; to assess the specific effect of the angiotensin receptor blocker losartan potassium on composite and renal outcomes; and to explore the implications of dihydropyridine calcium channel blockers as concurrent therapy on composite and renal outcomes. DESIGN: A Cox proportional hazards regression model was used to assess the hazard risk profile of baseline SBP (categories: <130, 130-139, 140-159, 160-179, and > or =180 mm Hg), DBP (categories: <70, 70-79, 80-89, 90-99, and > or =100 mm Hg), and PP (categories: <60, 60-69, 70-79, 80-89, and > or =90 mm Hg) on renal outcomes. PARTICIPANTS: The study comprised 1513 participants with established nephropathy and hypertension associated with type 2 diabetes. INTERVENTIONS: The RENAAL study was a randomized, placebo-controlled study of losartan vs placebo, with other agents added to achieve the goal of a trough BP (ie, BP immediately prior to the next dosing) below 140/90 mm Hg, and had a mean follow-up of 3.4 years. MAIN OUTCOME MEASURES: The primary analysis was time to composite end point of doubling of serum creatinine, ESRD, or death. RESULTS: A baseline SBP range of 140 to 159 mm Hg increased risk for ESRD or death by 38% (P =.05) compared with those below 130 mm Hg. In a multivariate model, every 10-mm Hg rise in baseline SBP increased the risk for ESRD or death by 6.7% (P =.007); the same rise in DBP decreased the risk by 10.9% (P =.01) when adjusting for urinary albumin-creatinine ratio, serum creatinine, serum albumin, hemoglobin, and hemoglobin A1c. Those randomized to the losartan group with a baseline PP above 90 mm Hg had a 53.5% risk reduction for ESRD alone (P =.003) and a 35.5% risk reduction for ESRD or death (P =.02) compared with the placebo group. CONCLUSIONS: Baseline SBP is a stronger predictor than DBP of renal outcomes in those with nephropathy resulting from type 2 diabetes. Those with the highest baseline PP have the highest risk for nephropathy progression but also garner the greatest risk reduction with SBP lowered to less than 140 mm Hg.
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Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Losartán/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Fallo Renal Crónico/prevención & control , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
Hypertensive kidney disease commonly progresses. The primary objective of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study is to determine prospectively the course of kidney function and risk factors for kidney disease progression in African Americans with hypertensive kidney disease who receive recommended anti-hypertensive therapy. The AASK Cohort Study is a prospective, observational study that is an extension of the AASK trial. The AASK trial tested the effects of three medications used as initial anti-hypertensive therapy (ramipril, metoprolol, and amlodipine) and two levels of BP control. Of the 1094 trial participants, approximately 650 to 700 individuals who have not reached ESRD will likely enroll in the Cohort Study. Risk factors to be studied include environmental, genetic, physiologic, and socioeconomic variables. The primary renal outcome is a composite clinical outcome defined by doubling of serum creatinine, ESRD, or death. Medication treatment for hypertension, beginning with the angiotensin converting enzyme inhibitor ramipril, is offered to all participants. In this fashion, the study directly controls two of the major determinants of kidney disease progression: treatment of hypertension and use of renoprotective, anti-hypertensive medication. The minimum duration of follow-up in the Cohort Study is 5 yr (total of 9 to 12 yr, including the period of the AASK trial). Ultimately, data from the AASK Cohort Study should enhance our understanding of the risk factors and processes that determine the progression of kidney disease. Such results might eventually lead to new strategies that delay or prevent ESRD.
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Negro o Afroamericano/estadística & datos numéricos , Hipertensión/epidemiología , Fallo Renal Crónico/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Incidencia , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Medición de Riesgo , Distribución por Sexo , Tasa de Supervivencia , Estados UnidosRESUMEN
The African American Study of Kidney Disease and Hypertension (AASK) is a multicenter randomized clinical trial designed to test the effectiveness of three anti-hypertensive drug regimens and two levels of BP control on the progression of hypertensive kidney disease. Participants include African-American men and women aged 18 to 70 yr who have hypertensive kidney disease and GFR between 20 and 65 ml/min per 1.73 m(2). The three anti-hypertensive drug regimens include an angiotensin converting enzyme inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine) or a beta-blocker (metoprolol) as initial therapy. The BP control levels are a lower goal (mean arterial pressure,
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Antihipertensivos/administración & dosificación , Negro o Afroamericano/estadística & datos numéricos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Fallo Renal Crónico/diagnóstico , Adolescente , Antagonistas Adrenérgicos beta/administración & dosificación , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/complicaciones , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Medición de Riesgo , Resultado del Tratamiento , Estados UnidosRESUMEN
African Americans have a higher prevalence and greater severity of hypertension compared with whites and therefore have a higher prevalence of many disease-related complications, such as coronary heart disease, stroke, and end-stage renal disease. Minorities have been, until recently, underrepresented in large clinical trials, leading to a lack of outcome data for these patient groups. However, accumulating data confirm the benefit of aggressive blood pressure-lowering therapy in this population. These studies also show that most patients require combination therapy to achieve adequate blood pressure reduction, particularly high-risk patient groups that have lower target blood pressure goals. All of the available antihypertensive agents are effective in African Americans. Recent studies suggest that regimens containing a thiazide-type diuretic are unsurpassed in blood pressure lowering and prevention of major clinical complications, and they cost less. Thus, while other agents may be required for selected clinical indications or for blood pressure control, diuretics should be drugs of first choice or included in most antihypertensive regimens especially in African American hypertensives.
Asunto(s)
Negro o Afroamericano , Enfermedades Cardiovasculares/etnología , Enfermedades Cardiovasculares/prevención & control , Hipertensión/tratamiento farmacológico , Hipertensión/etnología , Antihipertensivos/uso terapéutico , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/etnología , Factores de RiesgoRESUMEN
Outdated and biased attitudes and care standards impede optimal care of hypertension in African Americans. The negative expectations that blood pressure targets cannot be reached must be overcome by systematic and appropriate education and treatment. However, physicians should expect that (1) African American patients with elevated blood pressure benefit from early and intensive management, (2) blood pressure can be maintained at goal with appropriate therapeutic lifestyle changes and medications, and (3) complications related to high blood pressure can be avoided. To bring blood pressure down to the target goal, combination pharmacologic therapy is often required. When extensive efforts to achieve blood pressure control prove unattainable in the primary care setting, consultation with a hypertension specialist should be considered.
Asunto(s)
Negro o Afroamericano/educación , Negro o Afroamericano/psicología , Hipertensión/etnología , Hipertensión/prevención & control , Negro o Afroamericano/estadística & datos numéricos , Antihipertensivos/efectos adversos , Actitud del Personal de Salud , Dieta/efectos adversos , Ejercicio Físico , Objetivos , Conocimientos, Actitudes y Práctica en Salud , Prioridades en Salud , Accesibilidad a los Servicios de Salud/normas , Humanos , Hipertensión/diagnóstico , Estilo de Vida , Cooperación del Paciente/etnología , Rol del Médico , Prejuicio , Atención Primaria de Salud/métodos , Atención Primaria de Salud/normas , Calidad de la Atención de Salud , Factores de Riesgo , Factores Socioeconómicos , Estados Unidos/epidemiologíaRESUMEN
Treatment of hypertension in African Americans has special challenges, including a lack of objective trial data on which to base decisions and differing benefits and responses than with other patients. However, adequate control is possible and should be the goal of treating physicians. This article describes current "best practice" guidance on appropriate treatment of high blood pressure in African Americans. Two patient scenarios offer insight into clinical strategies.
Asunto(s)
Negro o Afroamericano/psicología , Hipertensión/etnología , Hipertensión/prevención & control , Planificación de Atención al Paciente , Guías de Práctica Clínica como Asunto , Atención Primaria de Salud/métodos , Antagonistas Adrenérgicos beta/uso terapéutico , Negro o Afroamericano/educación , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Benchmarking , Presión Sanguínea , Bloqueadores de los Canales de Calcio/uso terapéutico , Dieta Hiposódica , Diuréticos/uso terapéutico , Medicina Basada en la Evidencia , Objetivos , Humanos , Hipertensión/etiología , Estilo de Vida , Masculino , Persona de Mediana Edad , Planificación de Atención al Paciente/normas , Atención Primaria de Salud/normas , Medición de Riesgo , Factores de RiesgoRESUMEN
African Americans have a higher prevalence of hypertension, diabetes, cardiovascular disease (CVD), stroke, and renal disease than white Americans. The high rates of diabetes and hypertension in children and of type 2 diabetes, stroke, and CVD in women are particularly striking. In this article, Drs Sowers, Ferdinand, Bakris, and Douglas examine the biologic, social, and genetic factors that contribute to these health disparities, the risk for which appears in early childhood.