Antonio Pacilli

Serum Uric Acid and Risk of CKD in Type 2 Diabetes

BACKGROUND AND OBJECTIVE Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m2 and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m2, albuminuria, and their combination at 4 years. RESULTS At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m2 with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m2, and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m2. The incidence of eGFR <60 ml/min per 1.73 m2 increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m2. CONCLUSIONS Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.

Development and validation of a predicting model of all-cause mortality in patients with type 2 diabetes.

OBJECTIVE To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed up for 7.40 ± 2.15 and 4.51 ± 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected. RESULTS Nine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82–0.94) in the GMS and 0.82 (0.76–0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed. CONCLUSIONS We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals.

The ENPP1 Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals: Evidence for Interaction With Obesity in Diabetic Patients

OBJECTIVE Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80–2.70) in GHS, 2.31 (95% CI 1.22–4.34) in TVAS, and 1.36 (95% CI 0.88–2.10) in CREED, and 1.56 (95% CI 1.15–2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding.

Role of relationship between HbA1c, fibrinogen and HDL-cholesterol on cardiovascular disease in patients with type 2 diabetes mellitus

OBJECTIVE To assess the impact of relationship between glycated hemoglobin (HbA(1c)), fibrinogen and HDL-cholesterol (HDL-c) on cardiovascular disease in type 2 diabetes. METHODS We investigated i) the relationship of HbA1c, fibrinogen and HDL-c in 375 coronary artery disease (CAD)-negative and 320 CAD-positive diabetic patients and ii) the association between clustering of these three factors and incident major cardiovascular events in 317/320 CAD-positive patients. RESULTS i) The relationships between HbA1c and both fibrinogen and HDL-c and between HDL-c and fibrinogen were significant only in CAD-positive patients (β = 10.655, p = 0.002; β = -1.056, p = 0.013; β = -1.751, p = 0.000008, respectively); ii) patients with worse-than-median levels of the three factors showed higher risk for major cardiovascular events than others (HR: 2.22, 95%CI = 1.23-4.02, p = 0.008). Both findings were independent of LDL-c, blood pressure or ongoing therapies. CONCLUSION Our findings suggest interwoven actions of poor glycemic control, low grade inflammation and low HDL-c on atherosclerotic processes in type 2 diabetes.

Plasma triglycerides and HDL-C levels predict the development of diabetic kidney disease in subjects with type 2 diabetes: The AMD annals initiative

OBJECTIVE Despite the achievement of blood glucose, blood pressure, and LDL cholesterol (LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high among patients with type 2 diabetes. This observational retrospective study investigated whether diabetic dyslipidemia—that is, high triglyceride (TG) and/or low HDL cholesterol (HDL-C) levels—contributes to this high residual risk for DKD. RESEARCH DESIGN AND METHODS Among a total of 47,177 patients attending Italian diabetes centers, 15,362 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, normoalbuminuria, and LDL-C ≤130 mg/dL completing a 4-year follow-up were analyzed. The primary outcome was the incidence of DKD, defined as either low eGFR (<60 mL/min/1.73 m2) or an eGFR reduction >30% and/or albuminuria. RESULTS Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction >30%, 23.2% albuminuria, and 4% albuminuria and either eGFR <60 mL/min/1.73 m2 or an eGFR reduction >30%. TG ≥150 mg/dL increased the risk of low eGFR by 26%, of an eGFR reduction >30% by 29%, of albuminuria by 19%, and of developing one abnormality by 35%. HDL-C <40 mg/dL in men and <50 mg/dL in women were associated with a 27% higher risk of low eGFR and a 28% risk of an eGFR reduction >30%, with a 24% higher risk of developing albuminuria and a 44% risk of developing one abnormality. These associations remained significant when TG and HDL-C concentrations were examined as continuous variables and were only attenuated by multivariate adjustment for numerous confounders. CONCLUSIONS In a large population of outpatients with diabetes, low HDL-C and high TG levels were independent risk factors for the development of DKD over 4 years.

Achievement of therapeutic targets in patients with diabetes and chronic kidney disease: insights from the Associazione Medici Diabetologi Annals initiative

BACKGROUND Chronic kidney disease (CKD) entails a worse cardiovascular outcome. The aim of our work was to study the relationship between CKD and the achievement of recommended targets for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) in a real-life sample of patients with type 2 diabetes mellitus (T2DM). METHODS We analysed a sample of 116 777 outpatients from the Network of the Italian Association of Clinical Diabetologists; all patients had T2DM and at least one measurement of HbA1c, LDL-c, BP, serum creatinine and albuminuria in the year 2010. The outcome was the achievement of HbA1c, LDL-c and BP values as recommended by International Guidelines. RESULTS In the entire sample, the mean value of HbA1c was 7.2 ± 1.2%, of LDL-c was 102 ± 33 mg/dL and of BP was 138/78 ± 19/9 mmHg. CKD and its components were associated with poor glycaemic and BP control, notwithstanding greater use of glucose and BP-lowering drugs, while no association was found with LDL-c values. Factors independently related to unsatisfactory glycaemic control included female gender, body mass index, duration of disease and high albuminuria. Men, older people and those taking statins were more likely to reach LDL-c target levels. Male gender, age and high albuminuria strongly affected the achievement of BP targets. CONCLUSIONS CKD or its components, mainly high albuminuria, are associated with failure to reach therapeutic targets, especially for HbA1c and BP, despite a greater use of drugs in patients with T2DM.

Predictors of chronic kidney disease in type 2 diabetes: A longitudinal study from the AMD Annals initiative

AbstractThe identification of clinical predictors for the development of chronic kidney disease is a critical issue in the management of patients with type 2 diabetes mellitus.We evaluated 27,029 patients with type 2 diabetes mellitus and estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and normoalbuminuria from the database of the Italian Association of Clinical Diabetologists network. Primary outcomes were eGFR <60 mL/min/1.73 m2 and normoalbuminuria; albuminuria and eGFR ≥60 mL/min/1.73 m2; and eGFR <60 mL/min/1.73 m2 and albuminuria. Secondary outcomes were eGFR <60 mL/min/1.73 m2 and albuminuria. Measurements: eGFR from serum creatinine by chronic kidney disease epidemiology collaboration equation (CKD-EPI), urinary albumin excretion, HbA1c, triglycerides, high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c), blood pressure, and body mass index.Over a 4-year period, 33.2% of patients (n = 8973) developed chronic kidney disease, 10.3% (n = 2788) showed a decline in eGFR <60 mL/min/1.73 m2, 18.4% (n = 4978) developed albuminuria, and 4.5% (n = 1207) developed both features. Relative risk ratios (RRRs) for age (1.37, P < 0.001 by 5 years), sex (0.77, P < 0.001 for being male), body mass index (1.03, P < 0.001 by 1 kg/m2), triglycerides (1.02, P < 0.001 by 10 mg/dL), and LDL-c (0.97, P = 0.004 by 10 mg/dL) were independently related to the onset of eGFR reduction. Age (1.08, P < 0.001 by 5 years), sex (1.36, P < 0.001 for being male), body mass index (1.02, P < 0.001 by 1 kg/m2), triglycerides (1.01, P = 0.02 by 10 mg/dL), HDL-c, and LDL-c (0.97, P = 0.008 and 0.99, P = 0.003 by 5 and 10 mg/dL, respectively) were related to the onset of albuminuria. HbA1c and the intensity of antihypertensive treatment showed a weaker association with renal outcome.Reduction in eGFR and albuminuria showed distinct sets of risk factors, suggesting that different mechanisms are involved in the development of these 2 components of diabetic kidney disease.

Normoalbuminuric renal impairment and all-cause mortality in type 2 diabetes mellitus

A growing body of evidences indicate that, in patients with type 2 diabetes mellitus (T2DM), reduced glomerular filtration rate (GFR) is a strong predictor not only of endstage renal disease but also of all-cause mortality [1]. The relationship between low GFR and mortality rate in diabetic patients with normoalbuminuria, a condition known as normoalbuminuric renal impairment [2], is still debated [1, 3] and has been here investigated. We studied two previously described cohorts of patients with T2DM, followed-up for all-cause mortality [4]: the ‘‘Gargano Mortality Study’’ (GMS, n = 786) and the ‘‘Foggia Mortality Study’’ (FMS, n = 972). Estimated GFR (eGFR) from serum creatinine by Epidemiology Chronic Kidney Disease formula was defined as low when \60 ml/min/1.73 m. Albuminuria (albumin/creatinine ratio, ACR) was defined as normal when\2.5/3.5 mg/ mmol in males/females. In GMS (follow-up = 7.4 years) and in FMS (followup = 4.0 years), 156 and 135 patients died with a similar age adjusted annual incidence rate of 2.0 and 2.1 %, respectively. The proportion of patients with low eGFR (i.e., eGFR \60/ml/min/1.73 m) was 20.1 % in the GMS and 22.2 % in the FMS. To increase statistical power, the two samples were pooled (n = 1,758) and stratified in four groups on the basis of the presence/absence of albuminuria and low eGFR. While patients with no albuminuria and no low eGFR had the lowest mortality rate (1.6 % personyear), those with both albuminuria and low eGFR had the highest one (8.4 % person-year), with the other two groups being at intermediate risk (Table 1). Of note in the specific context of our primary aim, as compared to individuals with normal eGFR, those with low eGFR had a similarly increased mortality risk in patients with normoalbuminuria and in those with albuminuria (HR = 1.74, P = 0.002 and 1.67, P = 0.006, after adjusting for sex, age, HbA1c,

Variability in HbA1c, blood pressure, lipid parameters and serum uric acid, and risk of development of chronic kidney disease in type 2 diabetes

Variability in HbA1c and blood pressure is associated with the risk of diabetic kidney disease (DKD). No evidence exists on the role of variability in lipids or serum uric acid (UA), or the interplay between the variability of different parameters, in renal outcomes.

Epidemiology of diabetic kidney disease in adult patients with type 1 diabetes in Italy: The AMD-Annals initiative

Patients with type 1 diabetes mellitus are at increased risk of death. This risk appears to be modulated by kidney dysfunction. The aim of this study was to evaluate the prevalence of diabetic kidney disease (DKD), its traits, and clinical correlates in a large sample of patients with type 1 diabetes.