Distribution of CVD and Retinopathy in Patients With T2DM
Distribution of CVD and Retinopathy in Patients With T2DM
In this cross-sectional analysis, we used the data collected at the baseline visit for the RIACE Italian Multicenter Study, an observational, prospective cohort study on the impact of eGFR on morbidity and mortality from CVD in subjects with type 2 diabetes.
The RIACE cohort consisted of 15,933 Caucasian patients with type 2 diabetes, attending consecutively 19 hospital-based Diabetes Clinics of the National Health Service throughout Italy (see The RIACE Study Group) in years 2007–2008. Exclusion criteria were dialysis or renal transplantation. The study protocol was approved by the locally appointed ethics committees. Then, quality and completeness of data were controlled and 160 patients were excluded due to implausible or missing values and the remaining 15,773 subjects were subsequently analyzed.
All patients underwent a structured interview to collect the following information: age, smoking status, known diabetes onset and duration, current glucose-, blood pressure (BP)- and lipid-lowering therapy, with indication of the class of drug. Weight and height were assessed and body mass index (BMI) calculated, then BP was measured with a sphygmomanometer after a 5-min rest. Hemoglobin A1c (HbA1c) was measured by high-performance liquid chromatography using DCCT-aligned methods; triglycerides, total and HDL cholesterol were determined by standard analytical methods.
The presence of CKD was assessed by measuring albuminuria and serum creatinine. As previously reported in detail, albumin excretion rate was obtained from 24-hour urine collections or calculated from albumin/creatinine ratio in first-morning urine samples, in the absence of symptoms and signs of urinary tract infection or other interfering clinical conditions. Albuminuria was measured in one-to-three fresh urine samples for each patient by immunonephelometry or immunoturbidimetry and, in case of multiple measurements, the geometric mean was used for analysis. In subjects with multiple measurements (4,062 with at least two and 2,310 with three values), concordance rate between the first value and the geometric mean was >90% for all classes of albuminuria. Patients were then assigned to one of the following categories of albuminuria (mg/24 hours): normoalbuminuria (<30), microalbuminuria (30–299), or macroalbuminuria (≥300). Serum (and urine) creatinine was measured by the modified Jaffe method. One to three measurements were obtained for each patients and eGFR was calculated by the four-variable Modification of Diet in Renal Disease Study equation, using the mean serum creatinine value in case of multiple measures, as previously reported. Patients were then assigned to one of the following categories of eGFR (mL/min/1.73 m): 1 (≥90); 2 (60–89); 3 (30–59); 4 (15–29); and 5 (<15). All measurements were undertaken from a standardized protocol across study centers.
The presence of DR was assessed by an expert ophthalmologist with dilated fundoscopy. Patients were classified into the following categories: absent DR, mild, moderate or severe non-proliferative DR (NPDR), proliferative DR (PDR), or maculopathy, according to the Global Diabetic Retinopathy Project Group. For further analysis, patients with NPDR of mild or moderate degree were classified as having non-advanced DR, whereas those with severe NPDR or pre-PDR, PDR, maculopathy alone (i.e. without NPDR or PDR), or blindness were grouped into the advanced, sight-threatening DR category. DR grade was assigned based on the worst eye.
Prevalent CVD was assessed from medical history by recording previous documented major acute CVD events, including myocardial infarction, stroke, foot ulcer or gangrene, amputation, coronary, carotid, and lower limb revascularization. CVD events were adjudicated based on hospital discharge records by an ad hoc committee in each center.
Based on eGFR and albuminuria levels, patients were stratified according to the NKF's KDOQI, AKDN and KDIGO classifications (Figure 1) in no CKD and stages 1–5, risk categories 0–4, and low, moderate, high and very high risk, respectively.
(Enlarge Image)
Figure 1.
NFK's KDOQI, AKDN risk category, and KDIGO CKD classification systems. NFK's KDOQI classification: stage 0 (green), 1 (yellow), 2 (orange), 3 (red), 4 (brown), and 5 (blue); AKDN alternate system: risk category 0 (green), 1 (yellow), 2 (orange), 3 (red), and 4 (brown); KDIGO classification: risk category low (green), moderate (yellow), high (orange), and very high (red).
Clinical data were then derived for subjects assigned to each CKD stage or risk category, together with prevalence of CVD and DR according to eGFR and albuminuria categories as well as CKD stages or risk categories. Differences among CKD stages or risk categories were evaluated using the following statistical tests: one-way ANOVA and Kruskall-Wallis for parametric and non-parametric continuous variables, respectively, and Pearson χ for categorical variables. A Mantel-Haenszel linear-by-linear association χ test for linear trend was applied for evaluating variation of prevalence values with increasing eGFR and albuminuria categories (i.e. from G0 to G5 and from A1 to A3, respectively) as well as with increasing CKD stage or risk category.
Multiple logistic regression analyses with backward variable selection (probability for removal >0.10) were performed to assess the relation of each complication with CKD stages or risk categories as well as with subcategories of AKDN risk categories 1, 2 and 3 and KDIGO risk categories moderate and high, independently of the following confounders: age, gender, smoking habits, diabetes duration, HbA1c, anti-hyperglycemic treatment, triglycerides, HDL cholesterol, dyslipidemia (elevated LDL cholesterol and/or specific treatment), and hypertension (elevated systolic and/or diastolic BP and/or specific treatment).
All p values were two-sided, and a p value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, Illinois, USA).
Methods
Study Cohort
In this cross-sectional analysis, we used the data collected at the baseline visit for the RIACE Italian Multicenter Study, an observational, prospective cohort study on the impact of eGFR on morbidity and mortality from CVD in subjects with type 2 diabetes.
The RIACE cohort consisted of 15,933 Caucasian patients with type 2 diabetes, attending consecutively 19 hospital-based Diabetes Clinics of the National Health Service throughout Italy (see The RIACE Study Group) in years 2007–2008. Exclusion criteria were dialysis or renal transplantation. The study protocol was approved by the locally appointed ethics committees. Then, quality and completeness of data were controlled and 160 patients were excluded due to implausible or missing values and the remaining 15,773 subjects were subsequently analyzed.
Measurements
All patients underwent a structured interview to collect the following information: age, smoking status, known diabetes onset and duration, current glucose-, blood pressure (BP)- and lipid-lowering therapy, with indication of the class of drug. Weight and height were assessed and body mass index (BMI) calculated, then BP was measured with a sphygmomanometer after a 5-min rest. Hemoglobin A1c (HbA1c) was measured by high-performance liquid chromatography using DCCT-aligned methods; triglycerides, total and HDL cholesterol were determined by standard analytical methods.
The presence of CKD was assessed by measuring albuminuria and serum creatinine. As previously reported in detail, albumin excretion rate was obtained from 24-hour urine collections or calculated from albumin/creatinine ratio in first-morning urine samples, in the absence of symptoms and signs of urinary tract infection or other interfering clinical conditions. Albuminuria was measured in one-to-three fresh urine samples for each patient by immunonephelometry or immunoturbidimetry and, in case of multiple measurements, the geometric mean was used for analysis. In subjects with multiple measurements (4,062 with at least two and 2,310 with three values), concordance rate between the first value and the geometric mean was >90% for all classes of albuminuria. Patients were then assigned to one of the following categories of albuminuria (mg/24 hours): normoalbuminuria (<30), microalbuminuria (30–299), or macroalbuminuria (≥300). Serum (and urine) creatinine was measured by the modified Jaffe method. One to three measurements were obtained for each patients and eGFR was calculated by the four-variable Modification of Diet in Renal Disease Study equation, using the mean serum creatinine value in case of multiple measures, as previously reported. Patients were then assigned to one of the following categories of eGFR (mL/min/1.73 m): 1 (≥90); 2 (60–89); 3 (30–59); 4 (15–29); and 5 (<15). All measurements were undertaken from a standardized protocol across study centers.
The presence of DR was assessed by an expert ophthalmologist with dilated fundoscopy. Patients were classified into the following categories: absent DR, mild, moderate or severe non-proliferative DR (NPDR), proliferative DR (PDR), or maculopathy, according to the Global Diabetic Retinopathy Project Group. For further analysis, patients with NPDR of mild or moderate degree were classified as having non-advanced DR, whereas those with severe NPDR or pre-PDR, PDR, maculopathy alone (i.e. without NPDR or PDR), or blindness were grouped into the advanced, sight-threatening DR category. DR grade was assigned based on the worst eye.
Prevalent CVD was assessed from medical history by recording previous documented major acute CVD events, including myocardial infarction, stroke, foot ulcer or gangrene, amputation, coronary, carotid, and lower limb revascularization. CVD events were adjudicated based on hospital discharge records by an ad hoc committee in each center.
Statistical Analysis
Based on eGFR and albuminuria levels, patients were stratified according to the NKF's KDOQI, AKDN and KDIGO classifications (Figure 1) in no CKD and stages 1–5, risk categories 0–4, and low, moderate, high and very high risk, respectively.
(Enlarge Image)
Figure 1.
NFK's KDOQI, AKDN risk category, and KDIGO CKD classification systems. NFK's KDOQI classification: stage 0 (green), 1 (yellow), 2 (orange), 3 (red), 4 (brown), and 5 (blue); AKDN alternate system: risk category 0 (green), 1 (yellow), 2 (orange), 3 (red), and 4 (brown); KDIGO classification: risk category low (green), moderate (yellow), high (orange), and very high (red).
Clinical data were then derived for subjects assigned to each CKD stage or risk category, together with prevalence of CVD and DR according to eGFR and albuminuria categories as well as CKD stages or risk categories. Differences among CKD stages or risk categories were evaluated using the following statistical tests: one-way ANOVA and Kruskall-Wallis for parametric and non-parametric continuous variables, respectively, and Pearson χ for categorical variables. A Mantel-Haenszel linear-by-linear association χ test for linear trend was applied for evaluating variation of prevalence values with increasing eGFR and albuminuria categories (i.e. from G0 to G5 and from A1 to A3, respectively) as well as with increasing CKD stage or risk category.
Multiple logistic regression analyses with backward variable selection (probability for removal >0.10) were performed to assess the relation of each complication with CKD stages or risk categories as well as with subcategories of AKDN risk categories 1, 2 and 3 and KDIGO risk categories moderate and high, independently of the following confounders: age, gender, smoking habits, diabetes duration, HbA1c, anti-hyperglycemic treatment, triglycerides, HDL cholesterol, dyslipidemia (elevated LDL cholesterol and/or specific treatment), and hypertension (elevated systolic and/or diastolic BP and/or specific treatment).
All p values were two-sided, and a p value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, Illinois, USA).
