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.A large body of evidence suggests that individuals with chronic kidney disease (CKD) are more likely to die, particularly from cardiovascular disease (CVD), than to progress to end-stage renal disease (ESRD) (1), although recent findings seem to favor progression (2). In fact, although CVD risk is particularly increased in patients with ESRD, where CVD mortality accounts for the vast majority of deaths (3), even mild-to-moderate renal impairment is associated with CVD, as shown in the general population (4) and in subjects with type 2 diabetes (5).For clinical and epidemiologic purposes, CKD is currently classified into five stages, according to the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI). Classification is based on the presence or absence of kidney damage, as manifested by pathologic abnormalities or by disease markers such as micro- or macroalbuminuria, and glomerular filtration rate (GFR), as calculated by the use of estimating equations from serum creatinine measurements. Although stages 1–2 CKD are identified by evidence of kidney damage, stages 3–5 CKD are defined solely on the basis of estimated GFR (eGFR), irrespective of albuminuria (6). Because staging systems for disease classification should assign people with worse prognoses to more advanced stages, based on that introduced by the NKF KDOQI, subjects with an eGFR <60 mL/min/1.73 m² (i.e., stage ≥3 CKD) without albuminuria would carry the same CVD and renal risk as those with albuminuria but a lower risk than individuals with albuminuria and normal or subnormal eGFR, who are assigned to stages 1–2 CKD.In the Third National Health and Nutrition Examination Survey (NHANES III) cohort, increased albuminuria and reduced eGFR were both associated with increased risk of CVD and all-cause mortality overall and within every eGFR and albuminuria category, respectively (7). A recent meta-analysis confirmed that albuminuria, with no threshold, and an eGFR <60 mL/min/1.73 m² are both independent predictors of death and indicated that these two abnormalities are multiplicatively associated with risk of death without evidence of interaction (8). However, in other samples of the general population, the eGFR cutoff point for optimal discrimination of CVD risk was higher (9,10), whereas more recent reports showed that individuals with reduced eGFR without albuminuria are at much lower CVD risk than subjects with albuminuria without reduced eGFR (11–13). Studies in patients with type 2 diabetes showed that albuminuria and reduced eGFR are associated to the same extent with total CVD events (14,15), whereas albuminuria predicts death from CVD better than reduced eGFR (8,16).Thus, although the independent contribution of albuminuria appears to be relevant, it is unclear whether subnormal eGFR levels (i.e., 60–89 mL/min/1.73 m²) and, particularly, reduced eGFR levels (i.e., <60 mL/min/1.73 m²) in the absence of albuminuria are associated with significant CVD risk. This issue is particularly relevant in patients with type 2 diabetes, because reduced eGFR is more common than previously recognized in these individuals (17), and more importantly, it occurs in the absence of albuminuria in most of them (14,18,19).This study assessed the independent association of previous CVD events, either total or by vascular bed, with eGFR and albuminuria as well as with nonalbuminuric CKD, as defined by an eGFR <60 mL/m/1.73 m² without albuminuria, compared with albuminuric CKD with either reduced (stage ≥3 CKD) or nonreduced (stages 1–2 CKD) eGFR, in a large Italian cohort of patients with type 2 diabetes.