Cecilia Fondelli

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.

Generalised reduction of putative endothelial progenitors and CXCR4-positive peripheral blood cells in type 2 diabetes

Aims/hypothesisIn patients with type 2 diabetes, reduced levels of circulating endothelial progenitor cells have been reported and these have been correlated with disease severity. In this study, we examined a panel of markers widely used to identify progenitor and/or stem cells, and determined their association with disease severity in diabetic patients. Since expression of chemokine (C-X-C motif) receptor 4 (CXCR4) has been associated with mobilisation and recruitment of progenitor cells, CXCR4 expression was also analysed.MethodsPeripheral blood mononuclear cells (PBMCs) from 98 patients with type 2 diabetes and 39 control individuals were analysed by flow cytometry for surface marker expression.ResultsCells expressing different combinations of progenitor and/or stem cell markers were severely reduced in PBMCs of diabetic patients compared with those of control participants. Moreover, a number of these putative progenitor cell populations were negatively associated with disease severity. Reduced expression of CXCR4 and CD34/CXCR4-positive cells was also observed in diabetic patients. PBMCs expressing CXCR4 positively correlated with levels of progenitor cells in control participants but not in diabetic patients. Levels of putative progenitor and CXCR4-positive cells were further decreased in patients with diabetic complications, including cardiovascular and microvascular diseases.Conclusions/interpretationA generalised decrease in a range of progenitor cell populations was observed in type 2 diabetic patients. This reduction was also negatively associated with disease severity.

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.

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.

Age, Renal Dysfunction, Cardiovascular Disease, and Antihyperglycemic Treatment in Type 2 Diabetes Mellitus: Findings from the Renal Insufficiency and Cardiovascular Events Italian Multicenter Study

To assess the distribution of antihyperglycemic treatments according to age and renal function and its relationship with cardiovascular disease in type 2 diabetes mellitus (T2DM).

Hemoglobin A1c variability as an independent correlate of cardiovascular disease in patients with type 2 diabetes: a cross-sectional analysis of the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study

BackgroundPrevious reports have clearly indicated a significant relationship between hemoglobin (Hb) A1c change from one visit to the next and microvascular complications, especially nephropathy (albuminuria and albuminuric chronic kidney disease, CKD). In contrast, data on macrovascular disease are less clear. This study was aimed at examining the association of HbA1c variability with cardiovascular disease (CVD) in the large cohort of subjects with type 2 diabetes from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study.MethodsSerial (3–5) HbA1c values obtained during the 2-year period preceding recruitment, including that obtained at the enrolment, were available from 8,290 subjects from 9 centers (out of 15,773 patients from 19 centers). Average HbA1c and HbA1c variability were calculated as the intra-individual mean (HbA1c-MEAN) and standard deviation (HbA1c-SD), respectively, of 4.52±0.76 values. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. Diabetic retinopathy (DR) was assessed by dilated fundoscopy. CKD was defined based on albuminuria, as measured by immunonephelometry or immunoturbidimetry, and estimated glomerular filtration rate, as calculated from serum creatinine.ResultsHbA1c-MEAN, but not HbA1c-SD, was significantly higher (P<0.0001) in subjects with history of any CVD (n. 2,133, 25.7%) than in those without CVD (n. 6,157, 74.3%). Median and interquartile range were 7.78 (7.04-8.56) and 7.49 (6.81-8.31), respectively, for HbA1c-MEAN, and 0.47 (0.29-0.75) and 0.46 (0.28-0.73), respectively, for HbA1c-SD. Logistic regression analyses showed that HbA1c-MEAN, but not HbA1c-SD (and independent of it), was a significant correlate of any CVD. Similar findings were observed in subjects with versus those without any coronary or cerebrovascular event or myocardial infarction. Conversely, none of these measures were associated with stroke, whereas both correlated with any lower limb vascular event and HbA1c-SD alone with ulceration/gangrene. All these associations were independent of known CVD risk factors and microvascular complications (DR and CKD).ConclusionsIn patients with type 2 diabetes, HbA1c variability has not a major impact on macrovascular complications, at variance with average HbA1c, an opposite finding as compared with microvascular disease, and particularly nephropathy.Trial registrationClinicalTrials.Gov NCT00715481

Chronic kidney disease in type 2 diabetes: Lessons from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study.

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study is an ongoing observational survey that examines the role of estimated glomerular filtration rate (eGFR) as an independent predictor of cardiovascular and renal outcomes in 15,773 Italian subjects with type 2 diabetes. The analysis of data collected at the enrollment visit provided a picture of chronic kidney disease (CKD) and its association with other complications, risk factors for cardiovascular disease (CVD) and treatments in a large contemporary cohort. Main results of this analysis were that (a) non-albuminuric renal impairment is the predominant clinical phenotype in patients, particularly women, with reduced eGFR; (b) concordance between CKD and diabetic retinopathy is low, with only a minority of patients with renal dysfunction presenting with any or advanced retinal lesions; (c) the non-albuminuric form is associated with a significant prevalence of CVD, especially at the level of the coronary vascular bed; (d) CKD is associated with hemoglobin (Hb) A1c variability more than with average HbA1c, whereas retinopathy and CVD are not; (e) in elderly individuals with moderate-to-severe eGFR reduction, use of agents which are not recommended, such as sulphonylureas and metformin, is still frequent; and (f) though complications are generally more prevalent in men (except non-albuminuric renal impairment) women show a less favorable CVD risk profile and achieve therapeutic targets to a lesser extent than men, despite the fact that treatment intensity is not lower. These data update existing information on the natural history of CKD in patients with type 2 diabetes.

Hypertriglyceridemia Is Independently Associated with Renal, but Not Retinal Complications in Subjects with Type 2 Diabetes: A Cross-Sectional Analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study.

Objective Atherogenic dyslipidemia seems to play a major role in microvascular complications and in residual microvascular risk after statin therapy, which reduces triglycerides up to 40%. We assessed whether raised TG levels are associated with an increased burden from microvascular complications in patients with type 2 diabetes. Methods Subjects from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study (n=15,773) were divided in 4 groups depending on whether they had plasma triglycerides below (NTG, 67.8%) or above (HTG, 32.2%) 1.7 mmol/L and were (42.4%) or not on (57.6%) statin therapy. Estimated GFR (eGFR) was calculated from serum creatinine, albuminuria was measured by immunonephelometry or immunoturbidimetry, and retinopathy was evaluated by fundus examination. Results HTG subjects, either with or without statin, had higher prevalence of albuminuria, reduced eGFR and chronic kidney disease (CKD), especially the albuminuric forms, but not of retinopathy, than NTG subjects. In contrast, cardiovascular disease and advanced DR were more prevalent in subjects on statin than in those not, independently of triglyceride levels. Logistic regression analysis confirmed that HTG, without or with statin, was independently associated with micro and macroalbuminuria, mildly to severely reduced eGFR, and all CKD phenotypes, but not with retinopathy. The adjusted odd ratios for CKD increased linearly for every 0.26 mmol/L increase (approximately one decile) in triglyceride levels. The increase was higher with increasing severity of albuminuria, eGFR loss and CKD phenotype as well as in subjects receiving than in those not receiving statin treatment. Conclusions Triglycerides are associated with CKD, but not retinopathy in subjects with type 2 diabetes, independently of statin treatment. These data point to a possible role of hypertriglyceridemia in the development of CKD, though it remains to be demonstrated that diabetic individuals might benefit from triglyceride reduction with statins and eventually with combination therapy with fibrates. Trial Registration www.ClinicalTrials.gov NCT00715481