Considerations about the threshold value of microalbuminuria in patients with diabetes mellitus: lessons from an 8-year follow-up study of 599 patients

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Abstract

Objective: To examine the validity of the time honored threshold value for microalbuminuria of 30 mg/24 h, by analyzing an 8-year follow-up data of 599 patients with diabetes mellitus type 2, normal blood pressure and base-line albumin excretion rate (AER) ≤30 mg/24 h. Patients: The patients were allocated to three groups according to the baseline values of AER. Group I: 0–10 mg/24 h; Group II: 10.1–20 mg/24 h; Group III: 20.1–30 mg/24 h. Results: Progression to microalbuminuria during follow-up occurred in 25.3, 47.3 and 85.3% of the patients in Group I, II and III, respectively. Compared to Group I, the risk to progress to microalbuminuria was 2.34 (95% CI 1.32–4.43, P=0.029) in patients of Group II and 12.36 (95% CI 8.9–16.5, P=0.0001) in Group III. The average annual decline in glomerular filtration rate (GFR) was 1.19, 1.64 and 2.52 ml/min per year, respectively in the three groups. The correlation between baseline AER values and subsequent decline in GFR was exponential without a clear threshold value. Compared to Group I, the odds ratio for any cardiovascular end point (e.g. death, non-fatal myocardial infarction etc.) was 1.9 (95% CI 0.8–2.5, P=0.22) for patients of Group II and 9.8 (95% CI 6.7–12.3, P=0.001) for Group III. Conclusions: The present study shows that patients with baseline AER values of 20.1–30 mg/24 h show an accelerated decline in GFR and significantly higher risk for cardiovascular events than patients with AER values below 20 mg/24 h. Though AER is obviously a continuous variable, the arbitrary threshold value for screening and for preventive strategies should probably be set at 20 rather than at 30 mg/24 h.

Introduction

The predictive value of microalbuminuria for the subsequent development of nephropathy as well as cardiovascular disease in diabetic patients is now well established [1], [2], [3], [4]. Whether microalbuminuria and cardiovascular disease are causally related or reflect a common derangement (e.g. endothelial dysfunction) has not been hitherto settled [5]. Microalbuminuria is defined as albumin excretion rate (AER) of 30–299 mg/24 h or urinary albumin–creatinine ratio of 3–30 μg/mg [6], [7], [8]. This definition is arbitrary however, AER being indeed a continuous variable. Values in the high normal range were associated with accelerated progression to nephropathy in both type 1 and type 2 diabetes [6], [7], [8], [9], [10] and with increased mortality in the elderly general population [11]. Periodic screening for microalbuminuria is rapidly gaining acceptance in view of the emerging potential of intensive therapies to preserve kidney function and reduce morbidity and mortality in diabetic patients [12], [13]. Screening procedures require a well-defined threshold between normal and abnormal. Such a threshold may, however, be difficult to define in an apriori continuous variable and will, in any case, remain arbitrary. We have, therefore, chosen to try and redefine the threshold value of albumin excretion rate by examination of the correlation between three categories of AER, all within the normal range and the subsequent risk of nephropathy and cardiovascular events.

The present report analyses further the data of a prospective, long term follow-up study [14] on 599 patients with recently diagnosed type 2 diabetes mellitus, normal blood pressure values and initially ‘normal’ urinary albumin excretion rate (>30 mg/24 h). The lessons which may be learned form further subdivision of normoalbuminuria and their bearing on screening and therapeutic policies are the aim of this analysis.

Section snippets

Patients

The AER was determined during 1986 and 1987 in 850 consecutive patients with type 2 diabetes mellitus whose urine was negative for protein, using a standard dipstick test. The recruitment procedure, inclusion criteria and protocol were described in detail elsewhere [14]. In brief, patients were 40–60 years old, with diabetes diagnosed after age 40 and of <5 years duration. The blood pressure values were 140/90 mmHg or lower, serum creatinin was ≤124 μmol/l (1.4 mg/dl), body mass index (BMI) was

Results

Four patients discontinued the follow-up during the first 2 years and could not be traced. The data of 18 patients were incomplete. Thus, the analysis of renal outcome and of cardiovascular end-points and death was performed on 599 patients.

Twenty-four patients died during the follow-up period. The cause of death was related to coronary heart disease in 15 patients, cerebrovascular disease in two, malignancy in three, motor-vehicle crash in one and unknown in three.

The baseline characteristics

Discussion

The results of this 8-year follow-up study indicate that the subdivision of the initially normoalbuminuric patients into three groups delineated by their baseline AER was indeed valid for the prediction of a subsequent decline in renal function as well as of the risk of mortality and major manifestations of cardiovascular disease.

Group III with baseline AER values between 20.1 and 30 mg/24 h comprised 18% of the study group. The subsequent outcome of these patients both in terms of renal

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