RESUMEN
BACKGROUND: Aboriginal Australians are at high risk of cardiovascular, metabolic and renal diseases, resulting in a marked reduction in life expectancy when compared to the rest of the Australian population. This is partly due to recognized environmental and lifestyle risk factors, but a contribution of genetic susceptibility is also likely. METHODS: Using results from a comprehensive survey of one community (N = 1350 examined individuals), we have tested for familial aggregation of plasma glucose, arterial blood pressure, albuminuria (measured as urinary albumin to creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR), and quantified the contribution of variation at four candidate genes (ACE; TP53; ENOS3; MTHFR). RESULTS: In the subsample of 357 individuals with complete genotype and phenotype data we showed that both UACR (h2 = 64%) and blood pressure (sBP h2 = 29%, dBP, h2 = 11%) were significantly heritable. The ACE insertion-deletion (P = 0.0009) and TP53 codon72 polymorphisms (P = 0.003) together contributed approximately 15% of the total heritability of UACR, with an effect of ACE genotype on BP also clearly evident. CONCLUSIONS: While the effects of the ACE insertion-deletion on risk of renal disease (especially in the setting of diabetes) are well recognized, this is only the second study to implicate p53 genotype as a risk factor for albuminuria - the other being an earlier study we performed in a different Aboriginal community (McDonald et al., J Am Soc Nephrol 13: 677-83, 2002). We conclude that there are significant genetic contributions to the high prevalence of chronic diseases observed in this population.
Asunto(s)
Albuminuria/genética , Genes p53 , Hipertensión/genética , Nativos de Hawái y Otras Islas del Pacífico/genética , Peptidil-Dipeptidasa A/genética , Adolescente , Adulto , Anciano , Albuminuria/orina , Presión Arterial/genética , Glucemia/genética , Creatinina/orina , Femenino , Genotipo , Tasa de Filtración Glomerular/genética , Humanos , Mutación INDEL , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III/genética , Linaje , Fenotipo , Polimorfismo Genético , Adulto JovenRESUMEN
BACKGROUND: In comparison to the well established changes in compliance that occur at the large vessel level in diabetes, much less is known about the changes in compliance of the cardiovascular system at the end-organ level. The aim of this study was therefore to examine whether there was a correlation between resistance of the intrarenal arteries of the kidney and compliance of the left ventricle, as estimated by measurements of diastolic function, in subjects with type 2 diabetes. METHODS: We studied 167 unselected clinic patients with type 2 diabetes with a kidney duplex scan to estimate intrarenal vascular resistance, i.e. the resistance index (RI = peak systolic velocity-minimum diastolic velocity/peak systolic velocity) and a transthoracic echocardiogram (TTE) employing tissue doppler studies to document diastolic and systolic ventricular function. RESULTS: Renal RI was significantly higher in subjects with diastolic dysfunction (0.72 +/- 0.05) when compared with those who had a normal TTE examination (0.66 +/- 0.06, p < 0.01). Renal RI values were correlated with markers of diastolic dysfunction including the E/Vp ratio (r = 0.41, p < 0.001), left atrial area (r = 0.36, p < 0.001), the E/A ratio (r = 0.36, p < 0.001) and the E/E' ratio (r = 0.31, p < 0.001). These associations were independent of systolic function, hypertension, the presence and severity of chronic kidney disease, the use of renin-angiotensin inhibitors and other potentially confounding variables. CONCLUSION: Increasing vascular resistance of the intrarenal arteries was associated with markers of diastolic dysfunction in subjects with type 2 diabetes. These findings are consistent with the hypothesis that vascular and cardiac stiffening in diabetes are manifestations of common pathophysiological mechanisms.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/fisiopatología , Diástole/fisiología , Arteria Renal/fisiología , Resistencia Vascular/fisiología , Disfunción Ventricular Izquierda/fisiopatología , Adulto , Anciano , Adaptabilidad , Diabetes Mellitus Tipo 2/complicaciones , Ecocardiografía , Femenino , Humanos , Riñón/irrigación sanguínea , Masculino , Persona de Mediana Edad , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
OBJECTIVE: To investigate the role of intrarenal vascular disease in the pathogenesis of nonalbuminuric renal insufficiency in type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 325 unselected clinic patients who had sufficient clinical and biochemical information to calculate an estimated glomerular filtration rate (eGFR) using the Modified Diet in Renal Disease six-variable formula, at least two estimations of urinary albumin excretion rates (AER), and a renal duplex scan to estimate the resistance index of the interlobar renal arteries. The resistance index, measured as part of a complications surveillance program, was compared in patients with an eGFR < or >or=60 ml/min per 1.73 m(2) who were further stratified into normo- (AER <20), micro- (20-200), or macroalbuminuria (> 200 microg/min) categories. RESULTS: Patients with an eGFR <60 ml/min per 1.73 m(2) had a higher resistance index of the renal interlobar arteries compared with patients with an eGFR >or=60 ml/min per 1.73 m(2). However, the resistance index was elevated to a similar extent in patients with an eGFR <60 ml/min per 1.73 m(2) regardless of albuminuric status (normo- 0.74 +/- 0.01, micro- 0.73 +/- 0.01, and macroalbuminuria resistance index 0.75 +/- 0.11). Multiple regression analysis revealed that increased age (P < 0.0001), elevated BMI (P = 0.0001), decreased eGFR (P < 0.01), and decreased diastolic blood pressure (P < 0.01), but not an increased AER, were independently associated with an elevated resistance index in patients with impaired renal function. CONCLUSIONS: Subjects with type 2 diabetes and reduced glomerular filtration rate had similar degrees of intrarenal vascular disease, as measured by the intrarenal arterial resistance index, regardless of their AER status. The pathological mechanisms that determine the relationship between impaired renal function and AER status in subjects with type 2 diabetes remain to be elucidated.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/orina , Fallo Renal Crónico/etiología , Anciano , Albuminuria/etiología , Nefropatías Diabéticas/diagnóstico por imagen , Nefropatías Diabéticas/etiología , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Arteria Renal/diagnóstico por imagen , Arteria Renal/fisiología , Ultrasonografía , Enfermedades Vasculares/etiologíaRESUMEN
OBJECTIVE: To determine the prevalence and characteristics of patients with type 2 diabetes who have impaired renal function, defined as a glomerular filtration rate (GFR) <60 ml. min(-1). 1.73 m(-2), and normoalbuminuria. RESEARCH DESIGN AND METHODS: A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic (99m)Tc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria. RESULTS: A total of 109 patients (36%) had a GFR <60 ml. min(-1). 1.73 m(-2). The overall prevalence of normo-, micro-, and macroalbuminuria was 43 of 109 (39%), 38 of 109 (35%), and 28 of 109 (26%), respectively. Compared with patients with macroalbuminuria, those with normoalbuminuria were more likely to be older and female. After excluding patients whose normoalbuminuric status was possibly related to the initiation of a renin-angiotensin system (RAS) inhibitor before the start of the study, the prevalence of a GFR <60 ml. min(-1). 1.73 m(-2) and normoalbuminuria was 23%. Temporal changes in GFR in a subset of 34 of 109 (32%) unselected patients with impaired renal function were available for comparison over a 3- to 10-year period. The rates of decline in GFR (ml. min(-1). 1.73 m(-2). year(-1)) of -4.6 +/- 1.0, -2.8 +/- 1.0, and -3.0 +/- 07 were not significantly different for normo- (n = 12), micro- (n = 12), and macroalbuminuric (n = 10) patients, respectively. CONCLUSIONS: These results suggest that patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric.