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Microalbuminuria cannot predict cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus
ELSEVIER
Microalbuminuria Cannot Predict Cardiovascular Death in Japanese Subjects With Non-Insulin-Dependent Diabetes Mellitus A.
Shin-ichi Araki, Ryuichi Kikkawa, Masakazu Haneda, Daisuke Koya, Masaki Togawa, Ping-Mao Liang, and Yukio Shigeta
ABSTRACT In order to examine whether the existence
of
microalbuminuria can predict the development of overt proteinuria and cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM), we investigated 47 patients for a IO-year follow-up period. Patients were divided into two groups by the initial values of urinary albumin excretion rates. The percentage of patients who developed overt proteinuria during the follow-up period was significantly higher in patients who were initially classified as
INTRODUCTION n Caucasians with non-insulin-dependent diabetes mellitus (NIDDM), microalbuminuria has been reported to prove predictive not simply of overt proteinuria but also of early cardiovascular mortality. l, 2 We have previously shown that, in Japanese subjects with NIDDM, the rate of development of overt proteinuria is significantly faster in microalbuminuric subjects than in normoalbuminuria subjects.3 However, it its not known whether microalbuminuria can predict cardiovascular death in Japanese subjects
I
Third Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan Reprint requests to be sent to: Dr. Shin-ichi Araki, Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-21, Japan. Journal of Diabetes and Its Complications 1995; 9:323-325 0 Elsevier Science Inc., 1995 655 Avenue of the Americas, New York, NY 10010
microalbuminuric group (63.6%) than in normoalbuminuric group (17.4%). During the follow-up period, one of the patients with normoalbuminuria had died of congestive heart failure, while four of those with microalbuminuria had died; one of stroke and three from noncardiovascular diseases. These results indicate that the existence of microalbuminuria had the predictive power for the development of overt proteinuria, but not for cardiovascular death in Japanese subjects with NIDDM. (Journal of Diabetes and Its Complications 9;4:323-325, 1995.)
with NIDDM. To clarify this point, we performed a lo-year follow-up study in Japanese subjects with NIDDM . METHODS A total of 47 Japanese subjects with NIDDM with Albustix-negative urine (19 male and 28 female) were studied. In 1985, clinical examinations including the measurement of urinary albumin excretion rate (AER) in 24-h urine samples, fasting plasma glucose (FPG), HbA1, total cholesterol (TC), triglycerides (TG), and blood pressure (BP) were carried out. According to the value of AER, the subjects were divided into two groups; normoalbuminuric group (AER < 15 uglmin) and microalbuminuric group (15 uglmin 5 AER < 200 uglmin). Information on life/death status and cause of death was sought in 1994. Relevant information on dead patients was obtained from hospital records. In 1056-8727/95/$9.50 SSDI 1056-8727(95)00025-W
] Diab Comp 1995; 9:323-325
324 ARAKI ET AL.
TABLE 1. CLINICAL CHARACTERISTICS
OF PATIENTS GROUPED ACCORDING TO ALBUMIN EXCRETION RATE IN 1985
Normoalbuminuria
Microalbuminuria
p value
30 10:20 58 f 11 10.3 + 7.2 22.7 + 2.9 147 f 36 9.0 f 1.7 208 f 37 116 f 65 127 f 19 73 f 11 10 (33%) 5.1 f 4.7
17 9:s 60 + 12 10.1 f 5.2 21.9 f 2.4 171 + 80 10.0 f 2.1 199 f 31 113 + 39 137 f 23 75 f 10 7 (41%) 55.0 + 43.7
NS NS NS NS NS NS NS NS NS NS NS p < 0.01
Number Gender (male:female) Age (year) DM duration (year) BMI (kg/m2) FPG (mg/dL) I-IbAl (%) TC (mg/dL) TG (mg/dL) Systolic BP (mm Hg) Diastolic BP (mm Hg) Hypertension (%) AER (pglmin)
DM, diabetes m&us; BMI, body-mass index; FPG, fasting plasma glucose; HbAI, glycosylated hemoglobin; TC, total cholesterol; TG, triglyceride; _ _ BP, blood pressure; AER, albumin-excretion rate. Significance according to x2 test or Student t test.
1994, AER was measured in 34 patients tending our hospital. Hypertension was defined as systolic Hg, diastolic BP 2 95 mm Hg or taking sive drugs. Data are shown as mean + analysis was carried out with Student
who were atBP L 160 mm antihypertenSD. Statistical t and x2 test.
croalbuminuria had died; one from stroke, one from liver cirrhosis, and two from neoplasms. Thus, unlike the studies of Caucasian subjects with NIDDM, we could not confirm the relationship between microalbuminuria and cardiovascular death in Japanese subjects with NIDDM.
RESULTS Baseline Characteristics of Subjects. Clinical features of the subjects with and without microalbuminuria are shown in Table 1. In 1985, 30 subjects were normoalbuminuric and 17 subjects were microalbuminuric. Subjects with microalbuminuria could not be distinguished from those without microalbuminuria by any of the parameters shown in Table 1 except AER in 1985, though the values of HbAl and systolic blood pressure were slightly higher in the subjects with microalbuminuria. Development and Progression of Diabetic Nephropathy. In 1994, 23 of 30 normoalbuminuric subjects and 11 of 17 microalbuminuric subjects who had been regularly attending our hospital during the follow-up period were again evaluated. as shown in Figure 1, three subjects developed microalbuminuria (13.0%) and four developed overt proteinuria (17.4%) of 23 normoalbuminuric subjects. In contrast, of 11 microalbuminuric subjects, six subjects progressed to overt proteinuria (54.5%) and one progressed to chronic renal failure (9.1%). Therefore, the development of overt proteinuria was significantly (p < 0.01) frequent in subjects with microalbuminuria. Mortality During the Follow-Up Period. During the follow-up period, 5 of 47 subjects (10.6%) had died. One of subjects with normoalbuminuria had died from congestive heart failure, while four of those with mi-
DISCUSSION The present study was performed to clarify the predictive power of microalbuminuria for diabetic nephropathy and cardiovascular death in Japanese subjects with NlDDM. In Caucasian subjects with NlDDM, Mogensen4 has reported that 22% of microalbuminuric subjects developed overt proteinuria after a lo-year follow-up period. As in our previous report,3 the present study confirmed his results in Japanese subjects with NIDDM but, interestingly, the rate of the progression from microalbuminuria to overt proteinuria (63.6%) appears much higher here than in his report. This ob-
1994
1985 Normoalbuminuria (23)
Normoalbuminuria (16) Microalbuminuria (3) Overt proteinuria (4)
69.6%
Normoalbuminuria
18.2%
(2)
Microalbuminuria (11) 6
13.0% IT.4 %
Microalbuminuria 18.2% (2) Overt proteinuria 54.5 % (6) Chronic(;;nal failure 9.1 q.
1
P
1
63.6% 1
FIGURE 1 The development and progression ofdiabetic nephropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM) during IO-year follow-up period.
1 Diab Camp 1995; 9:323-325
MICROALBUMINURIA
servation may suggest that renal complications might progress faster in Japanese subjects than in Caucasian subjects. Microalbuminuria is known to be a risk factor for cardiovascular death in Caucasian subjects with NIDDM. Mattock et al.’ have reported that microalbuminuria is a significant risk marker for cardiovascular mortality in NIDDM, independent of the other risk factors in a prospective study of 141 NIDDM patients. Similarly, Jarret et al.’ reported that AER was strongly predictive of all-cause (mainly cardiovascular) mortality in a retrespective study of 44 NIDDM patients. However, our results could not confirm this relationship. This different effect of microalbuminuria on cardiovascular death between Japanese and Caucasian subjects with NIDDM may be explained by a difference in mortality in the general population, a difference in the diet, or some genetic factors. A prospective study on a larger number of patients might be necessary to clarify this point. In summary, although the number of subjects studied was relatively small, the results may indicate that
DOES NOT PREDICT DEATH IN NIDDM
325
microalbuminuria in Japanese subjects with NIDDM is a predictor for the development of diabetic nephropathy, but we could not confirm the predictive power of microalbuminuria for cardiovascular death in these patients. _ REFERENCES 1. MattockMB, MorrishNJ, VibertiG, Keen H, Fitzgerald
2.
AR, Jackson G: Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 41:736-741, 1992.
Jarrett mund ity in 17-19,
RJ, Viberti GC, Argyropoulos A, Hill RD, MahU, Murrels TJ: Microalbuminuria predicts mortalnon-insulin-dependent diabetes. Diabetic Med 1: 1984.
3. Haneda M, Kikkawa R, Togawa M, Koya D, Kajiwara
4
N, Uzu T, Shigeta Y: High blood pressure is a risk factor for the development of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes mellitus.\ Diabet Complicafions 6:181-185, 1992. Mogensen
CE: Microalbuminuria
predicts clinical prodiabetes.
. teinuria and early mortality in maturity-onset N Engl ] Med 310:356-360, 1984.
Microalbuminuria Cannot Predict Cardiovascular Death in Japanese Subjects With Non-Insulin-Dependent Diabetes Mellitus A.
Shin-ichi Araki, Ryuichi Kikkawa, Masakazu Haneda, Daisuke Koya, Masaki Togawa, Ping-Mao Liang, and Yukio Shigeta
ABSTRACT In order to examine whether the existence
of
microalbuminuria can predict the development of overt proteinuria and cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM), we investigated 47 patients for a IO-year follow-up period. Patients were divided into two groups by the initial values of urinary albumin excretion rates. The percentage of patients who developed overt proteinuria during the follow-up period was significantly higher in patients who were initially classified as
INTRODUCTION n Caucasians with non-insulin-dependent diabetes mellitus (NIDDM), microalbuminuria has been reported to prove predictive not simply of overt proteinuria but also of early cardiovascular mortality. l, 2 We have previously shown that, in Japanese subjects with NIDDM, the rate of development of overt proteinuria is significantly faster in microalbuminuric subjects than in normoalbuminuria subjects.3 However, it its not known whether microalbuminuria can predict cardiovascular death in Japanese subjects
I
Third Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan Reprint requests to be sent to: Dr. Shin-ichi Araki, Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-21, Japan. Journal of Diabetes and Its Complications 1995; 9:323-325 0 Elsevier Science Inc., 1995 655 Avenue of the Americas, New York, NY 10010
microalbuminuric group (63.6%) than in normoalbuminuric group (17.4%). During the follow-up period, one of the patients with normoalbuminuria had died of congestive heart failure, while four of those with microalbuminuria had died; one of stroke and three from noncardiovascular diseases. These results indicate that the existence of microalbuminuria had the predictive power for the development of overt proteinuria, but not for cardiovascular death in Japanese subjects with NIDDM. (Journal of Diabetes and Its Complications 9;4:323-325, 1995.)
with NIDDM. To clarify this point, we performed a lo-year follow-up study in Japanese subjects with NIDDM . METHODS A total of 47 Japanese subjects with NIDDM with Albustix-negative urine (19 male and 28 female) were studied. In 1985, clinical examinations including the measurement of urinary albumin excretion rate (AER) in 24-h urine samples, fasting plasma glucose (FPG), HbA1, total cholesterol (TC), triglycerides (TG), and blood pressure (BP) were carried out. According to the value of AER, the subjects were divided into two groups; normoalbuminuric group (AER < 15 uglmin) and microalbuminuric group (15 uglmin 5 AER < 200 uglmin). Information on life/death status and cause of death was sought in 1994. Relevant information on dead patients was obtained from hospital records. In 1056-8727/95/$9.50 SSDI 1056-8727(95)00025-W
] Diab Comp 1995; 9:323-325
324 ARAKI ET AL.
TABLE 1. CLINICAL CHARACTERISTICS
OF PATIENTS GROUPED ACCORDING TO ALBUMIN EXCRETION RATE IN 1985
Normoalbuminuria
Microalbuminuria
p value
30 10:20 58 f 11 10.3 + 7.2 22.7 + 2.9 147 f 36 9.0 f 1.7 208 f 37 116 f 65 127 f 19 73 f 11 10 (33%) 5.1 f 4.7
17 9:s 60 + 12 10.1 f 5.2 21.9 f 2.4 171 + 80 10.0 f 2.1 199 f 31 113 + 39 137 f 23 75 f 10 7 (41%) 55.0 + 43.7
NS NS NS NS NS NS NS NS NS NS NS p < 0.01
Number Gender (male:female) Age (year) DM duration (year) BMI (kg/m2) FPG (mg/dL) I-IbAl (%) TC (mg/dL) TG (mg/dL) Systolic BP (mm Hg) Diastolic BP (mm Hg) Hypertension (%) AER (pglmin)
DM, diabetes m&us; BMI, body-mass index; FPG, fasting plasma glucose; HbAI, glycosylated hemoglobin; TC, total cholesterol; TG, triglyceride; _ _ BP, blood pressure; AER, albumin-excretion rate. Significance according to x2 test or Student t test.
1994, AER was measured in 34 patients tending our hospital. Hypertension was defined as systolic Hg, diastolic BP 2 95 mm Hg or taking sive drugs. Data are shown as mean + analysis was carried out with Student
who were atBP L 160 mm antihypertenSD. Statistical t and x2 test.
croalbuminuria had died; one from stroke, one from liver cirrhosis, and two from neoplasms. Thus, unlike the studies of Caucasian subjects with NIDDM, we could not confirm the relationship between microalbuminuria and cardiovascular death in Japanese subjects with NIDDM.
RESULTS Baseline Characteristics of Subjects. Clinical features of the subjects with and without microalbuminuria are shown in Table 1. In 1985, 30 subjects were normoalbuminuric and 17 subjects were microalbuminuric. Subjects with microalbuminuria could not be distinguished from those without microalbuminuria by any of the parameters shown in Table 1 except AER in 1985, though the values of HbAl and systolic blood pressure were slightly higher in the subjects with microalbuminuria. Development and Progression of Diabetic Nephropathy. In 1994, 23 of 30 normoalbuminuric subjects and 11 of 17 microalbuminuric subjects who had been regularly attending our hospital during the follow-up period were again evaluated. as shown in Figure 1, three subjects developed microalbuminuria (13.0%) and four developed overt proteinuria (17.4%) of 23 normoalbuminuric subjects. In contrast, of 11 microalbuminuric subjects, six subjects progressed to overt proteinuria (54.5%) and one progressed to chronic renal failure (9.1%). Therefore, the development of overt proteinuria was significantly (p < 0.01) frequent in subjects with microalbuminuria. Mortality During the Follow-Up Period. During the follow-up period, 5 of 47 subjects (10.6%) had died. One of subjects with normoalbuminuria had died from congestive heart failure, while four of those with mi-
DISCUSSION The present study was performed to clarify the predictive power of microalbuminuria for diabetic nephropathy and cardiovascular death in Japanese subjects with NlDDM. In Caucasian subjects with NlDDM, Mogensen4 has reported that 22% of microalbuminuric subjects developed overt proteinuria after a lo-year follow-up period. As in our previous report,3 the present study confirmed his results in Japanese subjects with NIDDM but, interestingly, the rate of the progression from microalbuminuria to overt proteinuria (63.6%) appears much higher here than in his report. This ob-
1994
1985 Normoalbuminuria (23)
Normoalbuminuria (16) Microalbuminuria (3) Overt proteinuria (4)
69.6%
Normoalbuminuria
18.2%
(2)
Microalbuminuria (11) 6
13.0% IT.4 %
Microalbuminuria 18.2% (2) Overt proteinuria 54.5 % (6) Chronic(;;nal failure 9.1 q.
1
P
1
63.6% 1
FIGURE 1 The development and progression ofdiabetic nephropathy in patients with non-insulin-dependent diabetes mellitus (NIDDM) during IO-year follow-up period.
1 Diab Camp 1995; 9:323-325
MICROALBUMINURIA
servation may suggest that renal complications might progress faster in Japanese subjects than in Caucasian subjects. Microalbuminuria is known to be a risk factor for cardiovascular death in Caucasian subjects with NIDDM. Mattock et al.’ have reported that microalbuminuria is a significant risk marker for cardiovascular mortality in NIDDM, independent of the other risk factors in a prospective study of 141 NIDDM patients. Similarly, Jarret et al.’ reported that AER was strongly predictive of all-cause (mainly cardiovascular) mortality in a retrespective study of 44 NIDDM patients. However, our results could not confirm this relationship. This different effect of microalbuminuria on cardiovascular death between Japanese and Caucasian subjects with NIDDM may be explained by a difference in mortality in the general population, a difference in the diet, or some genetic factors. A prospective study on a larger number of patients might be necessary to clarify this point. In summary, although the number of subjects studied was relatively small, the results may indicate that
DOES NOT PREDICT DEATH IN NIDDM
325
microalbuminuria in Japanese subjects with NIDDM is a predictor for the development of diabetic nephropathy, but we could not confirm the predictive power of microalbuminuria for cardiovascular death in these patients. _ REFERENCES 1. MattockMB, MorrishNJ, VibertiG, Keen H, Fitzgerald
2.
AR, Jackson G: Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 41:736-741, 1992.
Jarrett mund ity in 17-19,
RJ, Viberti GC, Argyropoulos A, Hill RD, MahU, Murrels TJ: Microalbuminuria predicts mortalnon-insulin-dependent diabetes. Diabetic Med 1: 1984.
3. Haneda M, Kikkawa R, Togawa M, Koya D, Kajiwara
4
N, Uzu T, Shigeta Y: High blood pressure is a risk factor for the development of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes mellitus.\ Diabet Complicafions 6:181-185, 1992. Mogensen
CE: Microalbuminuria
predicts clinical prodiabetes.
. teinuria and early mortality in maturity-onset N Engl ] Med 310:356-360, 1984.