Giuseppe Penno

relation of Glucose Tolerance to Complications of Pregnancy in Nondiabetic Women

Abstract An increase in fetal and maternal complications has been documented in cases of gestational diabetes, but the glucose levels that predict an increased risk have not been clearly defined. We evaluated the frequency of several neonatal complications (macrosomia, congenital anomalies, perinatal mortality, and prematurity) and maternal complications (toxemia, cesarean section, or both) in relation to glucose tolerance in 249 women in the third trimester of pregnancy. None of the women had previous evidence of diabetes, and all had normal results on an oral glucose-tolerance test, according to accepted criteria. On the basis of their two-hour plasma glucose levels, women were divided into three groups: A (glucose <100 mg per deciliter), B (glucose 100 to 119 mg per deciliter), and C (glucose 120 to 164 mg per deciliter). The higher two-hour plasma glucose levels were associated with a significant increase in the incidence of macrosomia (9.9, 15.5, and 27.5 percent in Groups A, B, and C, respectively),...

Clinical significance of nonalbuminuric renal impairment in type 2 diabetes.

Objective 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. Methods 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. Results 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. Conclusions 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.

Microalbuminuria and Pulse Pressure in Hypertensive and Atherosclerotic Men

To identify the biological covariates of microalbuminuria (albuminuria >/=15 microg/min) in nondiabetic subjects, brachial blood pressure, echocardiographic left ventricular mass, and other cardiovascular and metabolic parameters were evaluated in 211 untreated males (38 normal controls, 109 uncomplicated stage 1 to 3 essential hypertensives, and 64 patients with clinically stable atherosclerotic peripheral vascular disease either with [n=44] or without [n=20] essential hypertension) with normal cardiac and renal function. Compared with normoalbuminuric subjects, microalbuminuric subjects (n=67) were characterized by higher systolic blood pressure, comparable diastolic blood pressure, and, therefore, wider pulse pressure. Greater prevalence of hypertension, peripheral vascular disease, left ventricular hypertrophy, and reduced HDL cholesterol values further distinguished microalbuminuric from normoalbuminuric subjects in univariate comparisons. The risk of microalbuminuria increased by ascending pulse pressure quintiles in age-corrected logistic regression models, in which pulse pressure was more predictive than systolic pressure and was independent of mean pressure. When microalbuminuric status was regressed against a series of dichotomous (vascular and active smoker status) and continuous (age, pulse and mean pressure, left ventricular mass index, and HDL and LDL cholesterol) variables, only pulse pressure, left ventricular mass index, and smoking status were independent predictors. The association of increased albuminuria with wider pulse pressure, a correlate of the pulsatile hemodynamic load and conduit vessel stiffness as well as an important cardiovascular risk factor, may explain why microalbuminuria predicts cardiovascular events in nondiabetic subjects. The independence from concomitant vascular disease also suggests that wider pulse pressure, rather than representing a simple marker for atherosclerotic disease, influences albuminuria directly.

Low-Grade Inflammation and Microalbuminuria in Hypertension

Background—Albuminuria and C-reactive protein (CRP), a marker of systemic low-grade inflammation, are frequently elevated in essential hypertension and predict cardiovascular prognosis independent of conventional risk factors. However, in spite of their potentially important links, the interrelationships between the 2 parameters have not been explored in depth in hypertensive patients. Methods and Results—Albuminuria (the mean of 3 overnight urine collections), high-sensitive CRP (hs-CRP), 24-hour blood pressure (BP), weight, lipids, poststimulative (75 g PO) plasma glucose, insulin, and insulin sensitivity by the homeostasis model assessment model were evaluated in 220 never treated, nondiabetic, uncomplicated essential hypertensive men. Albuminuria ≥15 &mgr;g/min was defined as microalbuminuria and hs-CRP values above and below median (2.3 mg/L) as high and low, respectively. Concentric left ventricular hypertrophy was diagnosed by echocardiography, and a full-blown metabolic syndrome was identified in presence of hypertension and at least 3 of following: obesity, subclinical hyperglycemia, low high-density lipoprotein (HDL) and high triglycerides. Microalbuminuria was present in 54 patients, 29 with high hs-CRP characterized by higher 24-hour systolic BP, postload glucose, body mass index, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking than those with either isolated microalbuminuria (n=27) or normoalbuminuria. Conclusions—Microalbuminuria accompanied by evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk. In contrast, isolated microalbuminuria may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis.

Non-diabetic microalbuminuria, endothelial dysfunction and cardiovascular disease

Subclinical increases in albuminuria (microalbuminuria) predict morbid events, but the reasons for that are still not understood in full. This paper reviews the existing evidence regarding the relationships of non-diabetic microalbuminuria and cardiovascular disease, the underlying assumption being that endothelial dysfunction contributes both to atherosclerotic macrovascular disease and renal microvascular disease of which albuminuria is a marker. Much data support that concept, and suggest a preferential link with endothelial activation in response to acute and subclinical inflammatory stimulation, although further studies are needed to establish the exact cause-effect mechanisms. Epidemiological studies also show associations with cardiovascular events, and some recent prospective results also indicate the power of micro-albuminuria to predict risk independently from conventional atherogenic factors. Thus, micro-albuminuria might be considered as an integrated marker of cardiovascular risk sensitive to systemic vascular status in addition to other parameters such as blood pressure levels, glucose metabolism, smoking habits, a profile rather unique among the prognostic predictors available to stratify risk in hypertensive patients.

HbA1c Variability as an Independent Correlate of Nephropathy, but Not Retinopathy, in Patients With Type 2 Diabetes: The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study

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.

Gender differences in cardiovascular disease risk factors, treatments and complications in patients with type 2 diabetes: the RIACE Italian multicentre study

Poorer control of risk factors for cardiovascular disease (CVD) has been reported in diabetic women, as compared with diabetic men. It has been proposed that this finding is due to gender disparities in treatment intensity. We investigated this hypothesis in a large contemporary cohort of subjects with type 2 diabetes.

Diverging association of reduced glomerular filtration rate and albuminuria with coronary and noncoronary events in patients with type 2 diabetes: The renal insufficiency and cardiovascular events (RIACE) Italian multicenter study

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.

Early Left Ventricular Mechanics Abnormalities in Prehypertension: A Two-Dimensional Strain Echocardiography Study

BACKGROUND Prehypertension predicts established hypertension. In this study, the aim was to analyze left ventricular (LV) mechanics in borderline prehypertensive (pre-HT) and hypertensive (HT) subjects through two-dimensional (2D)-strain echocardiography and then evaluate possible relations between cardiac parameters and insulin metabolism (homeostasis model assessment of insulin resistance (HOMA(IR)). METHODS Seventy-four consecutive newly diagnosed, untreated HT were divided, on the basis of their office blood pressure (BP) measurements, confirmed by ambulatory BP monitoring (ABPM), in 41 borderline pre-HT (ABPM: 122.5 +/- 6.7/76.2 +/- 5.2 mm Hg) and 33 never-treated mild HT (ABPM: 138.3 +/- 7.3/87.6 +/- 7.1 mm Hg). Thirty-three healthy normotensive (NT) controls (ABPM: 114.8 +/- 6.3/73.1 +/- 6.1 mm Hg) (P < 0.0001) were also studied (NT). All subjects performed 2D color Doppler and pulsed-wave tissue Doppler imaging (PW-TDI). RESULTS Left ventricular mass (LVM) was significantly higher in pre-HT (39.2 +/- 8.7 g/m(2.7)) and in HT (43.6 +/- 8.5 g/m(2.7)) compared with NT (30.9 +/- 7.4 g/m(2.7)) (P < 0.0001). A mild LV diastolic dysfunction was found both with Doppler mitral flow velocity and PW-TDI at mitral annulus level analysis. Longitudinal 2D strain in pre-HT (-18.9% +/- 3.4) and in HT (-18.0% +/- 3.3) was significantly lower than in NT (-23.9% +/- 3.0) (P < 0.002). These LV abnormalities were associated with systolic ABPM, LVM, and HOMA(IR). CONCLUSIONS Early abnormalities of LV longitudinal systolic deformation were found both in pre-HT and HT, together with a mild LV diastolic dysfunction. In both groups this early cardiac systolic and diastolic dysfunction is associated to insulin resistance, systolic pressure load, and cardiac remodeling.

Reproducibility of albuminuria in type 2 diabetic subjects. Findings from the Renal Insufficiency And Cardiovascular Events (RIACE) study

BACKGROUND Measurement of urinary albumin excretion (UAE) shows important intra-individual variability suggesting the need for multiple assessments. This study aimed at investigating the reproducibility of UAE in type 2 diabetes. METHODS UAE was obtained from two to three samples collected in a 3- to 6-month period from 4062 of the 15 773 type 2 diabetic subjects participating in the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study in 2007-08. UAE was assessed as albumin excretion rate (AER) in 24-h urine collections from 833 subjects and albumin:creatinine ratio (A/C) in early-morning urine samples from 3229 patients. Albuminuria was measured by immunonephelometry or immunoturbidimetry. RESULTS The median coefficient of variation (CV) was 32.5% (interquartile range: 14.3-58.9). Concordance rate between a single UAE and the geometric mean of multiple measurements was 94.6% for normoalbuminuria, 83.5% for microalbuminuria, 91.1% for macroalbuminuria and 90.6% for albuminuria (micro + macro). CV was significantly higher (P < 0.01) for AER measurement than for A/C and with immunoturbidimetry than with immunonephelometry, whereas concordance rates were similar between the two modalities of urine collection and the two assay methods. Receiver-operating characteristic (ROC) plots demonstrated a good performance of single UAE in predicting the geometric mean of multiple measures at the cut-off level of both microalbuminuria (ROC(AUC) 0.926; 95% confidence interval: 0.915-0.937) and macroalbuminuria (ROC(AUC) 0.950; 95% confidence interval: 0.927-0.973). CONCLUSIONS Data from this large cohort indicate that, in type 2 diabetic subjects, a single UAE value, thought to be encumbered with high intra-individual variability, is an accurate predictor of nephropathy stage for clinical and epidemiological purposes.