These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE Characteristics and Prognosis of Normoalbuminuric Type 1 Diabetic Patients Per L. Poulsen, MD, PHD Intervention in type 1 diabetic patients with increased urinary albumin excretion (UAE) represents a great step forward in modern diabetology. At the moment, the consensus calls for antihypertensive treatment in normotensive type 1 diabetic patients with persistent microalbuminuria. However, recent data indicate that substantial pathophysiological changes have already taken place at the microalbuminuric stage. Thus, prevention of progression from normo- to microalbuminuria would be a major clinical turning point. A considerable number of potential risk factors for progression to microalbuminuria have been proposed, among which are blood pressure elevation and disturbancies in circadian blood pressure variation. We performed 24-h ambulatory blood pressure (AMBP) monitoring in 115 normoalbuminuric (UAE <20 µg/min) patients, along with performing an assessment of circadian blood pressure and heart rate (HR) variation and a short-term power spectral analysis of RR interval oscillations. Patients with UAE above the median had significantly higher systolic and diastolic AMBP compared to the low normoalbuminuric group. The difference in blood pressure between the two groups was most pronounced for the night blood pressure (P< 0.01 and 0.02). A positive correlation between UAE and circadian variation (described as diastolic night/day ratio) was present—that is, the higher the normoalbuminuria, the more blunted the night/day ratio. The patients characterized by a combination of high-normal UAE and blunted circadian variation also proved to have significantly higher HbA1c values, higher 24-h mean arterial blood pressure, and lower vagal activity. In conclusion, high-normal UAE, poor metabolic control, and cigarette smoking are at present the only established risk factors for progression from normo- to microalbuminuria. However, new data emphasizes the close relation between blood pressure and albumin excretion. Pathophysiological abnormalities (poorer glycemic control, higher blood pressure, and attenuated vagal activity) tend to cluster in patients characterized by high-normal UAE and blunted circadian variation of blood pressures, and this patient group might constitute a putative high-risk group. Diabetes Care 22 (Suppl. 2):B72–B75, 1999 In the past 2 decades, intervention for type 1 diabetic patients with increased urinary albumin excretion (UAE) has been introduced at earlier and earlier stages. At the moment, the consensus calls for antihypertensive treatment in normotensive type 1 diabetic patients with persistent microalbuminuria (1). However, recent data indicate that substantial pathophysiological changes have already taken place when the microalbuminuric stage is reached. Blood pressure is elevated with an attenuated circadian rhythm (2–5), and vagal function is impaired with an abnormal sympathovagal interaction (6,7). In addition, new findings indicate abnormalities in kidney ultrastructure in type 1 diabetic patients with microalbuminuria (8,9). In the light of the abnormalities associated with microalbuminuria, prevention of progression to microalbuminuria would represent a major clinical breakthrough. On the basis of observations—primarily from cross-sectional studies but also from some longitudinal studies—a number of possible risk factors for development of microalbuminuria in type 1 diabetic patients have been proposed: high-normal UAE (5,10–12), poor metabolic control (5,10–13), cigarette smoking (11,14), hyperfiltration (15,16), endothelial dysfunction (17), familial factors (18,19), and blood pressure elevation with blunted circadian variation (10,11,20). Regarding the latter, patients with normoalbuminuria, with microalbuminuria, and with macroalbuminuria show a step-wise increase in diastolic night/day (N/D) blood pressure, i.e., a more blunted circadian variation with more advanced levels of diabetic nephropathy (21). In an extension of this finding, we found in a 3-year follow-up study (5) that the patients who progressed from normo- to microalbuminuria were already characterized at baseline by a diminished reduction in nocturnal diastolic blood pressure and higher UAE compared with both nonprogressors (i.e., patients who were persistently normoalbuminuric) and healthy control subjects. This pattern persisted at follow-up. However, it should be noted that at both baseline and follow-up, a considerable overlap between the values of the progressors and the two other groups was observed. It thus could be hypothesized that patients with a combination of high-normal UAE and a tendency toward a blunted circadian variation in blood pressure constitute a specific high-risk group. To further evaluate this hypothesis, we present here a further analysis of data recently published (22). In this study with normoalbuminuric type 1 diabetic patients, we observed a significant positive correlation between UAE and diastolic N/D ratio, i.e., the higher the normoalbuminuria, the more blunted the circadian blood pressure variation.
RESEARCH DESIGN AND METHODS— A total of 115 type 1 diabetic patients were consecutively recruited from outpatient clinics at our hospital and at two nearby hospitals. Patients had to be normoalbuminuric (UAE <20 µg/min in at least two out of three overnight collections) and without other chronic diseases. None received (or had earlier received) antihypertensive or other medical treatment apart from insulin. UAE was measured by radioimmunoassay and expressed as the geometric mean of three overnight collections made within 1 week. HbA1c was determined by high-performance liquid chromatography (nondiabetic range 4.4–6.4%). Mean age was 38 ± 9.6 years; mean duration of diabetes was 18 ± 10.0 years; and mean HbA1c was 8.4 ± 1.1%. Ambulatory blood pressure was measured by an oscillometric technique (Spacelabs 90207) (23) with readings at 20-min intervals for 24 h. Measurements were performed during a day with normal activities at home or at work. Patients' reported sleeping times were implemented in the calculation of day and night blood pressure (24). Autonomic function was assessed by short-term (three times for 5 min) power spectral analysis of RR interval oscillations (VariaPulse TF3) (25), as this technique has proven to be more sensitive than ordinary bedside tests in the detection of early autonomic neuropathy (6,26,27). The high-frequency (0.15–0.50 Hz) oscillations are mediated purely by vagal activity, whereas the low-frequency oscillations in the upright position are mediated by interaction of sympathetic and vagal activity (28,29). Results are expressed as means ± SD except for UAE, which, because of the skewness of the data, is presented as the geometric mean with 95% CI (calculated by taking the log of the data, computing the mean and 95% CI of the transformed data, and then taking the antilog of mean and 95% CI). Data are analyzed by two-factor (high/low UAE and high/low N/D ratio) analysis of variance. In addition, subgroups are compared with the group with the combination of high UAE and high N/D ratio (presumed to be a high-risk group) using Dunnett's test.
RESULTS— Patients were divided according to median UAE value (4.2 µg/min) and median diastolic N/D ratio (81%), thus forming four groups of patients. Clinical characteristics of patients in these four groups are given in Table 1. Data for blood pressure, glycemic control, and autonomic function are shown in Table 2 and Fig. 1. It will be noticed that the patients characterized by a combination of high-normal UAE and blunted circadian variation had significantly higher HbA1c values, significantly higher mean arterial blood pressure, and significantly attenuated indices for vagal function.
CONCLUSIONS— In patients characterized by high-normal UAE and blunted circadian variation of blood pressures, the present analysis demonstrates a clustering of pathophysiological abnormalities, such as poorer glycemic control, higher blood pressure, and attenuated vagal activity. This finding might indicate that this group of patients carries a higher risk of progression, but this indication can be confirmed only by longitudinal studies. Despite the fact that patients in this study were strictly normoalbuminuric and normotensive, we found clear associations between albumin excretion and blood pressure as well as autonomic indices. Our data indicate that albumin excretion should be considered as a continuum; although demarcation from a clinical point of view is an operational necessity, the natural history does not indicate abrupt transitions. Changes both in blood pressure and autonomic function are detectable before transition to microalbuminuria, provided methods with sufficient sensitivity are utilized. Apart from improving glycemic control and continuing antismoking campaigns, ACE-i or A-II receptor antagonist intervention in selected normoalbuminuric high-risk patients (high-normal UAE, high-normal blood pressure with attenuated circadian variation, and poor glycemic control, in addition to a duration of diabetes relevant to the development of incipient nephropathy) would be of interest, especially if sensitive determinations of blood pressure, endothelial function, autonomic function, and kidney function as well as ultrastructure were included. References 2. Mathiesen ER, Oxenboll B, Johansen K, Svendsen PA, Deckert T: Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 26:406–410, 1984 3. 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O'Brien E, Mee F, Atkins N, O'Malley K: Accuracy of the SpaceLabs 90207 determined by the British Hypertension Society protocol. J Hypertens 9:573–574, 1991 24. Hansen KW, Poulsen PL, Mogensen CE: Ambulatory blood pressure and abnormal albuminuria in type 1 diabetic patients. Kidney Int Suppl 45:S134–S140, 1994 25. Sallinger J, Vychodil R, Pumprla J, Opavsky J, Stejskal P, Vaverka F, Bula J: Telemetric computer-aided system for non-invasive examination of heart rate variability, type VariaPulse TF3. Comput Cardiol (IEEE Proc):437–440, 1995 26. Ewing DJ, Neilson JM, Shapiro CM, Stewart JA, Reid W: Twenty four hour heart rate variability: effects of posture, sleep, and time of day in healthy controls and comparison with bedside tests of autonomic function in diabetic patients. Br Heart J 65:239–244, 1991 27. Malpas SC, Maling TJB: Heart-rate variability and cardiac autonomic function in diabetes. Diabetes 39:1177–1181, 1990 28. Pomeranz B, Macaulay RJ, Caudill MA, Kutz I, Adam D, Gordon D, Kilborn KM, Barger AC, Shannon DC, Cohen RJ, Benson H: Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 248:H151–H153, 1985 29. Hayano J, Sakakibara Y, Yamada A, Yamada M, Mukai S, Fujinami T, Yokoyama K, Watanabe Y, Takata K: Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects. Am J Cardiol 67:199–204, 1991 From Medical Department M (Diabetes and Endocrinology), Aarhus Kommunehospital, Aarhus, Denmark. Address correspondence and reprint requests to Per Løgstrup Poulsen, Department of Medicine M (Diabetes and Endocrinology), Aarhus Kommunehospital, DK 8000 Aarhus C, Denmark. E-mail: logstrup@dadlnet.dk. Received for publication 27 May 1998 and accepted in revised form 16 October 1998. Abbreviations: AMBP, ambulatory blood pressure; N/D, night/day; UAE, urinary albumin excretion. This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
