In type 2 diabetes, prevalence of nonalbuminuric renal impairment is increasing worldwide, though its clinical significance remains unclear. This large-cohort study aimed at evaluating the association of this phenotype with cardiovascular risk factors and other complications. Type 2 diabetic patients from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study (n = 15 773), visiting consecutively 19 hospital-based Diabetes Clinics in years 2007–2008, were examined. Serum creatinine was assessed by the Jaffe method; albuminuria was measured by immunonephelometry or immunoturbidimetry. Of patients with renal impairment, as identified by an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2, 56.6% were normoalbuminuric, 30.8% were microalbuminuric, and 12.6% were macroalbuminuric. Percentages were similar when GFR was estimated using the more accurate Chronic Kidney Disease Epidemiology Collaboration equation instead of the simplified Modification of Diet in Renal Disease formula, and were independent of age, thus indicating that the increasing prevalence of this phenotype does not reflects misclassification of elderly patients. Nonalbuminuric renal impairment was not associated with HbA1c and correlated less strongly with retinopathy and hypertension than albuminuria, either alone or associated with reduced eGFR. It was associated with a higher prevalence of cardiovascular disease (CVD) than albuminuria alone, but lower than albuminuric renal impairment. Female sex correlated with nonalbuminuric renal impairment and male sex with the albuminuric forms. These data show that type 2 diabetic patients with nonalbuminuric renal impairment exhibit distinct clinical features, suggesting predominance of macroangiopathy as underlying renal pathology, and that this phenotype is associated with significant CVD burden.

OBJECTIVE—The presence of an enhanced cortisol secretion in patients with type 2 diabetes is debated. In type 2 diabetic subjects, cortisol secretion was found to be associated with the complications and metabolic control of diabetes. We evaluated cortisol secretion in 170 type 2 diabetic subjects and in 71 sex-, age-, and BMI-matched nondiabetic subjects. RESEARCH DESIGN AND METHODS—In all subjects, we evaluated ACTH at 8:00 a.m. in basal conditions and serum cortisol levels at 12:00 p.m. (F24) and at 9:00 a.m. after a 1-mg overnight dexamethasone suppression test and 24-h urinary free cortisol (UFC). In diabetic patients, we evaluated the presence of chronic complications (incipient nephropathy, asymptomatic neuropathy, background retinopathy, and silent macroangiopathy). Patients were subdivided according to the absence (group 1, n = 53) or presence (group 2, n = 117) of diabetes complications. RESULTS—In group 2, UFC (125.2 ± 4.6 nmol/24 h) and F24 (120.6 ± 4.1 nmol/l) were higher than in group 1 (109.2 ± 6.8 nmol/24 h, P = 0.057, and 99.7 ± 6.1 nmol/l, P = 0.005, respectively) and in nondiabetic patients (101.7 ± 5.9 nmol/24 h, P = 0.002, and 100.3 ± 5.3 nmol/l, P = 0.003, respectively). In diabetic patients, the number of complications was associated with F24 (R = 0.345; P < 0.0001) and diabetes duration (R = 0.39; P < 0.0001). Logistic regression analysis showed that the presence of diabetes complications was significantly associated with F24, sex, duration of diabetes, and glycated hemoglobin. CONCLUSIONS—In type 2 diabetic subjects, hypothalmic-pituitary-adrenal activity is enhanced in patients with diabetes complications and the degree of cortisol secretion is related to the presence and number of diabetes complications.

OBJECTIVE: To examine the association of hemoglobin (Hb) A1c variability with microvascular complications in the large cohort of subjects with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study. RESEARCH DESIGN AND METHODS: Serial (3–5) HbA1c values collected in a 2-year period before enrollment were available from 8,260 subjects from 9 centers (of 15,773 patients from 19 centers). HbA1c variability was measured as the intraindividual SD of 4.52 ± 0.76 values. Diabetic retinopathy (DR) was assessed by dilated funduscopy. Chronic kidney disease (CKD) was defined based on albuminuria, as measured by immunonephelometry or immunoturbidimetry, and estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. RESULTS: Median and interquartile range of average HbA1c (HbA1c-MEAN) and HbA1c-SD were 7.57% (6.86–8.38) and 0.46% (0.29–0.74), respectively. The highest prevalence of microalbuminuria, macroalbuminuria, reduced eGFR, albuminuric CKD phenotypes, and advanced DR was observed when both HbA1c parameters were above the median and the lowest when both were below the median. Logistic regression analyses showed that HbA1c-SD adds to HbA1c-MEAN as an independent correlate of microalbuminuria and stages 1–2 CKD and is an independent predictor of macroalbuminuria, reduced eGFR, and stages 3–5 albuminuric CKD, whereas HbA1c-MEAN is not. The opposite was found for DR, whereas neither HbA1c-MEAN nor HbA1c-SD affected nonalbuminuric CKD. CONCLUSIONS: In patients with type 2 diabetes, HbA1c variability affects (albuminuric) CKD more than average HbA1c, whereas only the latter parameter affects DR, thus suggesting a variable effect of these measures on microvascular complications.

OBJECTIVE: Although a reduced estimated glomerular filtration rate (eGFR) was shown to be a powerful independent predictor of cardiovascular disease (CVD), other studies suggested that it confers a much lower risk than albuminuria alone, whereas the combination of the two abnormalities is associated with multiplicative risk. This study aimed at assessing the independent association of previous CVD events, either total or by vascular bed, with eGFR and albuminuria and chronic kidney disease (CKD) phenotypes. RESEARCH DESIGN AND METHODS: This cross-sectional study evaluated 15,773 patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study in 19 outpatient diabetes clinics in years 2007–2008. Albuminuria was assessed by immunonephelometry or immunoturbidimetry. GFR was estimated by the simplified Modification of Diet in Renal Disease Study and the Chronic Kidney Disease-Epidemiology Collaboration equation. CKD was defined as an eGFR <60 mL/min/1.73 m2 or micro- or macroalbuminuria. Major acute CVD events were adjudicated based on hospital discharge records or specialist visits. RESULTS: CVD risk increased linearly with eGFR decline and albuminuria and became significant for values <78 mL/min/1.73 m2 and ≥10.5 mg/24 h, respectively. Beyond traditional CVD risk factors, total CVD showed an independent association with albuminuria alone (odds ratio 1.20 [95% CI 1.08–1.33]), reduced eGFR alone (1.52 [1.34–1.73]), and both abnormalities (1.90 [1.66–2.19]). However, coronary events were associated predominantly with reduced eGFR alone, whereas cerebrovascular and peripheral events showed a stronger correlation with the albuminuric CKD phenotypes. CONCLUSIONS: These data, although cross-sectional, show that reduced eGFR, irrespective of albuminuria, is associated with significant CVD, particularly in the coronary district.