Risk Factors for Microalbuminuria and Macroalbuminuria in Type 2 Diabetic Patients: A 9-year follow-up study

Several risk factors have been related to the development of diabetic nephropathy (DN) in type 2 diabetic patients, such as hyperglycemia, arterial hypertension, dyslipidemia, and smoking (1–5). Higher urinary albumin excretion rate (UAER) levels, even within the normal range, have been suggested to predict the development of DN in type 2 diabetic patients (1,2). Glomerular hyperfiltration has been investigated as a putative risk factor with conflicting results (6,7).

The aim of this study was to analyze risk factors for micro- and macroalbuminuria in a cohort of 52 normoalbuminuric type 2 diabetic patients (UAER <20 μg/min, 30 men, aged 53 ± 6 years, diabetes duration 6 years). Baseline clinical and renal evaluation (glomerular filtration rate [GFR] and UAER measurements) was performed from January 1988 through December 1989 (8). Patients were reevaluated between January 1998 and March 2000; they were followed-up for a median of 9.3 years (range 2.4–11.6). All patients gave written informed consent before participating.

Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. UAER was measured by radioimmunoassay (DPC, Los Angeles) at baseline and by immunoturbidimetry at follow-up (R = 0.98 for both methods) in random urine samples and was confirmed by 24-h collections of sterile urine over a 6-month period (interassay coefficient of variation [CV] 6.9% and intra-assay CV 3.8%). Micro- and macroalbuminuria were defined as UAER values of 20–200 and >200 μg/min, respectively, and were confirmed twice (9).

A total of 14 (27%) patients developed microalbuminuria, and 2 (4%) developed macroalbuminuria. These patients had higher baseline fasting plasma glucose (FPG) (12.10 ± 3.94 vs. 9.05 ± 3.33 mmol/l, P = 0.006) and UAER (median 5.9 vs. 3.2 μg/min, P = 0.0057) (Fig. 1) and a higher proportion of nonproliferative retinopathy (44 vs. 8%, P = 0.0057) than persistently normoalbuminuric patients. In a Cox regression analysis (backward stepwise), only UAER (hazard ratio [HR] 1.24, 95% CI 1.11–1.39, P = 0.0002) and retinopathy at baseline (9.3, 2.5–34.8, P = 0.001) remained significantly related to micro- and macroalbuminuria; blood pressure, GFR, and plasma glucose were excluded from the model. Of 16 micro- and macroalbuminuric patients, 5 presented baseline UAER >10 μg/min (χ² test, P = 0.0016). On the other hand, none of the persistently normoalbuminuric patients presented initial UAER above that level. Therefore, a Cox regression analysis was also performed with baseline UAER as an independent categorical variable (values above or below 10 μg/min). The HR for UAER >10 μg/min was 29.4 (95% CI 6.26–138.7, P = 0.0001), and the HR for retinopathy was 11.9 (3.0–47.2, P = 0.0004). FPG, mean arterial blood pressure, and GFR were excluded from the model.

There were no differences between the groups regarding the use of β-blockers (two users in each group) and ACE inhibitors (two patients in the persistently normoalbuminuric group and none in the other). GFR values (118 ± 22 vs. 125 ± 20 ml · min⁻¹ · 1.73 m⁻²) and the number of hyperfiltering patients (22 vs. 31%), respectively, were not different between the groups at baseline.

The observed cumulative incidence of 31% observed in our study is similar to that reported in other studies after a similar follow-up period: 34% in Finland (2) and 51% in Israel (5).

Gall et al. (1) described a significantly higher baseline albuminuria in patients who progressed compared with those who remained normoalbuminuric (14 vs. 7 mg/24 h), and UAER was significantly related to the development of DN in Cox regression. These data also suggest that levels of UAER below the critical value of 20 μg/min recommended by the American Diabetes Association (9) could be already signaling the presence of renal damage.

Diabetic retinopathy was also a strong risk factor and is probably a marker of the presence of microvascular disease rather than a risk factor per se, because nephropathy and retinopathy seem to share the same environmental predisposing factors, such as hyperglycemia and arterial hypertension.

In conclusion, higher normal UAER and nonproliferative retinopathy are predictors of micro- and macroalbuminuria. These data suggest that the currently recommended cutoff value of UAER used to predict development of micro- and macroalbuminuria should be lowered.