- Email: [email protected]
Development of diabetic nephropathy in Japanese patients with insulin-dependent diabetes mellitus: Tokyo women's medical college epidemiologic study
J Diab Comp 1994; 8:7-12
Development of Diabetic Ne hropathy in Japanese Patients With Insu Pin-Dependent Diabetes Mellitus: Tokvo Women’s Medical College Epidemiologic JStudy Hiroki Yokoyama, Yasuko Uchigata, Toshika Otani, Akiko Maruyama, Kawori Yano-Aoki, Sachiko Kanematsu, Tadasu Kasahara, Nobuo Matsuura, and Yasue Omori
ABSTRACT To clarify the development of diabetic nephropathy in Japanese insulin-dependent diabetes mellitus (IDDM), 373 patients with IDDM who had no proteinuria at the first visit to our Diabetes Center were evaluated. The incidence of persistent proteinuria increased rapidly between 10 and 19 years of diabetes duration, and only a few new cases occurred thereafter. Patients whose ages at onset of IDDM were 9-17 years (n = 167) and 18-29 years (n = 90) had rapid development of persistent proteimuia compared to the 0 to B-year group (n = 116) (p < 0.02 and p < 0.003, respectively). Females (n = 233) developed persistent proteinuria to a greater extent until 24 years of diabetes duration than males (n = 140) (p = 0.17). Development of proteinuria did not vary according to calendar year of diagnosis of IDDM or diabetes duration at the first visit. Renal insufficiency (serum creatinine of 2.0 mg/dL or
greater) followed the onset of proteinuria; 609’0 of the patients with the onset of IDDM between 1951 and 1969 developed renal insufficiency 10 years after the onset of proteinuria, whereas 30% of patients with the onset of IDDM after 1970 developed this condition. Development of renal insufficiency did not vary according to sex, age at onset of IDDM, or age at onset of proteinuria. Renal failure requiring dialysis therapy occurred within 4 years after renal insufficiency. In conclusion, development of diabetic nephropathy in Japanese IDDM exhibits three stages. The onset of proteinuria appears to be influenced by age at onset of IDDM and sex. Incidence of renal insufficiency seems to be decreasing in patients with recent onset of IDDM, however, once it occurs, renal failure requiring dialysis therapy develops within 4 years. (Journal of Diabetes and Its Complications 8;1:7-12, 1994.)
INTRODUCTION
in the number of Japanese patients with IDDM of a long duration. As the duration of IDDM becomes longer, late-onset diabetic complications become more serious; indeed, the number of patients who develop diabetic nephropathy and require dialysis therapy at a younger age is now increasing in Japan.4 Diabetic nephropathy has become a major life-threatening complication in Japan as it is in the United States5 and Europe.6 The prevention of this complication is, therefore, of great importance. The development of diabetic nephropathy in IDDM
he incidence of insulin-dependent diabetes mellitus (IDDM) in Japanese is 1.0-2.01 100,000,1-3 much lower than that of lo-301 100,000 in Caucasians.3 However, recent improvements in diabetes care have led to an increase
T
Diabetes Center, Tokyo Women’s Medical College, Tokyo, Japan Reprint requests tobe sent to: Dr. Hiroki Yokoyama, Steno Diabetes Center, Neils Steensens Vej 2, 2820 Gentofte, Denmark. 0 1994 ]ownal
of Diabetes and
Its Complications
8 YOKOYAh4A ET AL.
JDiabComp1994;8:7-12
TABLE 1. CLINICAL FEATURES OF SUBJECTS IN THE STUDY Year at Onset of Insulin-Dependent Diabetes Mellitus (IDDM) 1951-1969 n
Female % Age at onset of IDDM Diabetes duration at the first visit O-4 years 5-10 years 11-26 years
1970-1979
1980-1984
77 66.2 10.4 f 6.6
179 63.1 12.5 f 7.4
117 61.1 15.5 + 6.4
7 12 58
41 74 64
78 39 0
P
NS” <0.0001b
ax2 test. bMann-Whitney U test.
has been described through some stages; microalbuminuria, proteinuria, decreasing of glomerular filtration rate, and renal failure requiring dialysis.‘e9 It is now of prime importance to determine the factors that are associated with the development of microalbuminuria, proteinuria, and renal dysfunction in Japanese IDDM patients. The measurement of microalbuminuria has been carried out in efforts to prevent diabetic nephropathy at the early stage; however, such measurements have been used routinely for only about 10 years, whereas proteinuria and renal function measurements have been followed for more than 20 years. More than 1,100 patients who were diagnosed as having diabetes before the age of 30 years were referred to the Diabetes Center of Tokyo Women’s Medical College by primary care practitioners between 1951 and 1985; about 40% of these patients had IDDM.‘OIn this study, we examined the development of diabetic nephropathy in these patients to clarify the natural history of diabetic nephropathy in Japanese IDDM patients, and to assess the development of each stage of nephropathy with respect to sex, age at onset of IDDM, and calendar year of onset of IDDM.
as having IDDM at the first visit, the onset was investigated by interview and review of previous medical records. Before 1979, blood glucose control was monitored by several physicians at our center according to the levels of urinary glucose and blood glucose on visits. After 1980, measurement of glycohemoglobin and self-monitoring of blood glucose has become available; these measurements have since been used as major indicators of blood glucose control. Proteinuria was checked at every visit (once a month) with Albustix (Miles-Sankyo, Tokyo, Japan) (detection limit 30 mg/dL or greater) after the first visit. When three of the four tests were positive for proteinuria without the occurrence of menstruation, urinary tract infection, orthostatic proteinmia, or pregnancy, the patient was determined to have persistent proteinuria. The onset of proteinuria was defined as the first recorded persistently positive sample. Serum chemistry, including creatinine (Jaffe’s method), was examined at least once a year, and twice or more for patients with persistent proteinuria. The date was recorded when the persistent proteinuria was detected, and when the-serum creatinine level exceeded 2.0 mg/dL, which was defined as renal insufficiency. For patients who unSUBJECTS AND METHODS derwent dialysis therapy because azotemia, overhyThe study population comprised all patients who had dration, or acidosis were not corrected by conservative visited the Diabetes Center, Tokyo Women’s Medical therapy, the date of the initiation of dialysis was also College, in whom IDDM had been diagnosed between recorded. 1951 and 1984 and before the age of 30 years. The popdaThe follow-up was calculated from the diagnosis of tion consisted of 448 patients (175 males and 273 feIDDM to the development of proteinuria, or for those males), of whom 44 already had persistent proteinuria individuals who were free from proteinuria, to the end with uncertain onset. Fifteen of the remaining 404 patients were not followed because of incomplete regis- of the follow-up (June 30, 1992). The follow-up from persistent proteinuria to serum creatinine elevation of tration. Sixteen patients had nondiabetic proteinuria. The remaining 373 patients were entered in the study. 2.0 mg/dL or greater, and from the serum creatinine The criteria for diagnosis of IDDM were, according elevation to the commencement of dialysis therapy to the report of the World Health Organization were also investigated. The development to each stage (WHO),‘l onset with ketoacidosis or symptoms of hy- was analyzed by Kaplan-Meier’s life-table analysis. perglycemia with requirement for insulin within 1 The log-rank test was used to test the significance of month after the onset. For patients already diagnosed the difference among the curves.
DEVELOPMENT
J Diab Camp 1994; 8:7-12
Age at onset of IDDM FIGURE 1 Age at onset and sex distribution of 373 Japanese subjects with insulin-dependent diabetes mellitus (IDDM). Numbers on the top of bar indicate numbers of patients.
RESULTS Clinical Feature of Subjects. Table 1 shows the clinical features of the 373 subjects according to the calendar year at onset of IDDM. No difference was found in the male/female ratio among the three groups, i.e., those diagnosed before 1969, between 1970 and 1979,
and between 1980 and 1984. Patients diagnosed between 1980 and 1984 were characterized by an older age at onset of IDDM and shorter duration of diabetes at the first visit. The distribution of age at onset of IDDM is shown in Figure 1. Age 9-11 years was the peak age of onset, followed by 12-14 and 6-8 years. The mean age at onset in females was slightly greater than that in males (13.8 f 7.5 versus 11.6 f 6.3 years, p < 0.01). Natural History of Nephropathy. Persistent proteinuria developed in 57 of the 373 patients during 5,487 person-years of observation. The incidence of development according to duration of diabetes, expressed in successive 5-year intervals, is shown in Table 2.
OF NEPHROPATHY
IN JAPANESE IDDM 9
The incidence was law during the first 10 years, and rather high at lo-14 and 15-19 years. There were only a few new cases after 20 years. Table 3 shows the incidence of renal insufficiency with creatinine elevation 2.0 mg/dL or greater. Renal insufficiency developed in 21 patients during 5,701 person-years of observation. The incidence was 5.4/1,000 person-years at lo-14 years; this increased, reaching 19.8/1,000 person-years at 20-24 years. Dialysis therapy was initiated in 14 patients during 5,771 person-years of observation, the peak incidence being 15.9/1,000 person-years at 20-24 years (data not shown). The cumulative incidences of persistent proteinuria, renal insufficiency, and dialysis in relation to duration of IDDM are depicted in Figure 2. The rate of persistent proteinuria reached 35% at 26 years of diabetes duration and remained at this level thereafter. Analysis of Development of Persistent Proteinuria. Analysis with respect to the age at onset of IDDM was carried out; the patients were divided into three groups shown in Figure 3. Patients in the 0- to B-year group (n = 116) developed proteinuria significantly more slowly than those in the 9- to l7-year group (n = 167) (p < 0.02) and the 18- to 29-year group (n = 90) (p < 0.003). Figure 4 shows the development of proteinuria according to sex; female patients (n = 233) developed proteinuria to a greater extent until 24 years of diabetes duration than males (n = 140) (p = 0.17). Analysis according to the calendar year at onset of IDDM and diabetes duration at the first visit to the Diabetes Center, revealed no influence on the development of persistent proteinuria (data not shown). Analysis of Development of Renal Insufficiency. The cumulative incidence of renal insufficiency reached 60% at 10 years after the onset of proteinuria shown in Figure 5 (n = 57). When the data was analyzed according to the year at onset of IDDM, there was a tendency of declining incidence of renal insufficiency
TABLE 2. INCIDENCE RATES OF PERSISTENT PROTEINURIA AMONG PATIENTS WITH JAPANESE INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), ACCORDING TO 5-YEAR INTERVAL OF DURATION Duration of IDDM (years)
Number of Patients”
Number of Person-Yearsb
Number of New Casesb
Incidence Rate per 1,000 Person-Years
o-4 5-9 10-14 15-19 20-24 25-29 30-34 35-41
373 373 280 150 77 29 13 2
1828 1646 1062 546 271 99 29 6
0 8 27 16 4 1 1 0
0 4.9 25.4 29.3 14.8 10.1 34.5 0
’ Without persisfent proteinuria at the beginning of each interval. b Dun’ng each interval.
10 YOKOYAMA ET AL.
I Diab Gnnp 1994; 8:7-12
TABLE 3. INCIDENCE RATES OF RENAL INSUFFICIENCY” AMONG PATIENTS WITH JAPANESE INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), ACCORDING TO 5-YEAR INTERVAL OF DURATION Duration of IDDM (years)
Number of Patientsb
o-4 5-9 10-14 15-19 20-24 25-29 30-34 35-41
373 373 288 173 89 35 13 3
Number of
Incidence Rate per 1,000
Number of
Person-Yearsc
New Cases’
Person-Years 0 0
1828 1668 1107 642 303 113 32 8
5.4 9.3 19.8 9.6 0 0
’ Criteria: serum creatinine level 2.0 mg/dL or greater. b Without renal insufi~cy
at the beginning
ofeachinter&.
c During each interval.
in patients with more recent onset, although the difference was not significant. Analysis according to sex, age at onset of IDDM, and age at onset of proteinuria revealed no influence on the development of renal insufficiency (data not shown). Figure 6 shows the development of renal failure requiring dialysis therapy after the elevation of creatinine of 2.0 mg/dL or greater; the cumulative incidence reached 100% at 4 years. DISCUSSION
It was difficult to investigate and report development of diabetic nephropathy in Japanese IDDM patients because of the low incidence and few hospitals with more than 100 such patients. Although the population in our study was based on a single institution, the clinical features according to sex and age at onset of IDDM are the same as those cited in previous studies of Japanese IDDM, 12-14and the diabetes duration at
PERSISTENT RENAL
the first visit had no influence on the incidence of proteinuria. These features may suggest the subjects in our study to be representative of the Japanese IDDM population. We demonstrated the natural history of diabetic nephropathy in Japanese IDDM patients, and found critical clinical features in its development. The incidence of proteinuria was high at lo-19 years of diabetes duration, and few cases occurred after 20 years. The cumulative incidence reached 35% at 26 years of diabetes duration and did not increase thereafter. This finding is consistent with the previous reports from the Steno hospitaV and the Joslin clinic,16 in which it was shown that only 30%-40% of IDDM patients developed proteinuria, and which suggested that the majority of patients with IDDM would not develop proteinuria despite a long duration of IDDM. With regard to the age at onset of IDDM and the development of proteinuria, patients with onset of
AGE AT ONSET
PAOTEINURII
80 -
INSUFFICIENCY ____DIALYSIS ..........
80 I
-
OF IODH
O-1
VELRSln~llS~
S-11
VEARSln=ISll mm__-
I SGSVEARS In=801 ..........
:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40 1 20 I
10
20
30
4
DURATION OF IDDM (YEARS)
FIGURE 2 Cumulative incidence ofpersistent proteinuti,
renal insuficiency, and renal failure requiring dialysis in relation to duration of insulin-dependent diabetes mellitus (IDDM) in 373 Japanese IDDM patients.
0
-
.A
’ cI
10
20
30
40
DURATION OF IDDM (YEARS)
FIGURE 3 Cumulative incidence of persistent proteinuria in lapanese patients whose age at onset of insulin-dependent diabetes mellitus (IDDM) was at O-8 years (n = 126), 9-17 yeurs (n = 167), and 18-29 yeurs (n = 90).
DEVELOPMENT OF NEPHROPATHY IN JAPANESE IDDM
J Diab Comp 1994; 8:7-12
11
%M~LE(n=2331 _____
-_
DURATION
OF IODM (YEARS)
4 Cumulative incidence of persistent proteinuria in male (n = 140) and female (n = 233) insulin-d~~d~t diabetes mellitus (IDDM) patients. FIGURE
IDDM before the age of 8 years had the slowest development, the cumulative incidence in this group reaching only 20% at 24 years. This was concordant with previous reports from the Steno hospital15 and Joslin clinic.16Patients with onset of IDDM at the age of 1829 years exhibited rapid development of proteinuria, the same as that in patients 9-17 years old; this result was in conflict with a report from the Steno hospitaP3 in which slower development was demonstrated in patients with onset of IDDM at the age of 20-30 years. Kostraba et al.*’ found that the influence of prepubertal duration on the development of microvascular complications was minimal. It is also likely that, in Japanese IDDM, microvascular complications develop slower in the prepubertal stage. It is unknown whether this is related to hormone or psychosocial behaviors. A female preponderance in the development of proteinuria was observed in our study, although it was
YEARS
AFTER
ONSET
OF PROTEINURIA
Cumulative incidence ofrenal insufficiency after onset in Japanese patients with insulin-dependent diabetes mellitus UDDM) (n = 57). Renal insufficiency was defined as serum creatinine level 2.0 mg/dL or greater. FIGURE 5
ofprofeinuria
YEARS
AFTER
ELEVATION
OF CREATININE
22,Omg/dI
FIGURE 6 Cumulative incidence of renal failtire requiring dialysis after exceeding creatinine of 2.0 mg/dL or greater (n = 21).
not significant. This preponderance was also observed in the development of proliferative retinopathy, in which it was significant (manuscript in preparation). It is unknown whether this feature is due to genetic, hormonal, or environmental factors. A report by the Diabetes Epidemiology Research International Mortality Study Group has shown that the mortality rate of Japanese female IDDM patients is twice that of Japanese males, predominantly due to diabetic kidney disease.** It is 1ikeIy that Japanese women may have an increased risk of development of microvascular complications in IDDM. There may be cross-country differences in the development of microvascular complications, as male preponderance has been observed in other countries.*5,19 The influence of the calendar year at onset of IDDM on development of proteinuria was negligible in our study, whereas, in the Steno hospitaF5 and Joslin clinic,16 a declining incidence of proteinuria was reported in patients with onset of IDDM in the 1950s compared with the incidence of proteinuria in patients with onset in the 1930s. One explanation for this is that our study did not extend as far as the 1930s. Another explanation may be a participation bias in our study, as our subjects with onset of IDDM before 1969 were younger at onset, had a longer duration at the first visit, and had no proteinuria at that time. The calendar year at the onset of IDDM, however, seemed to have some influence on the development of renal insufficiency. Recent antihypertensive treatment and protein restriction with adequate calorie intake, while patients are receiving insulin treatment is likely to have been effective in reducing the incidence of renal insufficiency . In conclusion, we demonstrated the natural history of diabetic nephropathy in Japanese IDDM patients, and found that the cumulative incidence of proteinuria
12
YOKOYAMAET AL.
was 35% at 26 years of diabetes duration. Onset of IDDM after age 9 years was associated with an increased risk of the development of proteinuria. Renal insufficiency developed in 30% of patients within 4 years after the onset of proteinuria, and all of these patients resulted in renal failure within the following 4 years. A decreasing incidence of renal insufficiency after the onset of proteinuria was observed in patients whose onset of IDDM occurred after 1970. REFERENCES 1. Matsuura N, Fukushima N, Fujita K, Abe K, Yamada Y, Kashiwao N, Fujieda K, Kato T, Mikami Y, Nohara Y, Fukuda K, Okuno A, Taguchi T, Oyanagi K: Epidemiologic survey of juvenile-onset insulin-dependent diabetes mellitus (IDDM) in Hokkaido, Japan. Tohoku J Exp Med lU(supp1): 181-189, 1983. 2.
Diabetes Epidemiology Research IntemationaI Group: Geographic patterns of childhood insulin-dependent diabetes meIIitus. Diabetes 37:1113-1119, 1990.
J Diab Cmp
9. FriedmanEA: Naturalhistoryof diabeticnepluopathy. In: Eli A Friedmanand CharlesM Peterson(ed), Diabetic Nephroputhy. Strategyfor Therapy. Boston, Martinus Nijhoff, 1986, pp. 65-84.
10. Otani T, Yokoyama H, Higami Y, Kasahara T, Uchigata Y, Hirata Y: Age at onset and type of Japanese younger diabetics in Tokyo. Diabetes Res Clin Pratt 10:241-244, 1990.
11. World Health Organization Expert Committee on Diabetes Mellitus: Technical report series 727, Geneva, World Health Organization, 1985.
12.
Miki E, Maruyama H: Juvenile-onset diabetes meIIitus in Japan. The results of the first nation-wide survey. 1. Jpn Diabetes Sot 15:38X, 1972.
13.
Hibi I, Tanae A, Maruyama H, Tsuchiya H, Isshiki H, Matsuura N, Kitagawa T: Juvenile-onset type diabetes in Japan: Current status. Report of the Child Diabetes Research Committee, the Ministry of Health and Welfare, Japan, 1980-1981.
14.
Tajima N, Laporte RE, Hibi I, Kitagawa T, Fujita H, Drash A: A comparison of the epidemiology of youthonset insuhn-dependent diabetes meIIitus between Japan and the United States (Allegheny County, Pennsylvania). Diabetes Care B(supp1 1):17-23, 1985.
3. Diabetes Epidemiology Research International Group:
Secular trends in incidence of childhood IDDM in 10 countries. Diabetes 39858-864, 1990.
4. Registry Committee of Japanese Society for Dialysis
Therapy: Present status of maintenance dialysis for diabetic renal failure. J Jpn Sot Dialysis Ther 25:1095-1104, 1992.
5. Dorman JS, LaPorte RE, Kuller LH, Cruickshanks KJ,
Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL: The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results. Diabetes 33:271-276, 1984.
6. Anderson AR, Christiansen JS, Andersen JK, Kreiner
S, Decker? T: Diabetic nephropathy in type 1 (insuhndependent) diabetes: An epidemiological study. Diubetologia 25:496-501, 1983.
7. Kussman JM, Goldstein HH, Gleason RE: The clinical course of diabetic nephropathy. IAlMA 236:1861-1863, 1976.
a. Mogensen CE, Christensen CK, Vittinghus E: The
stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32 (suppl2):64-78, 1983.
1994; 8:7-12
15. Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Nerup J, Decker? T: Declining incidence of persistent proteinuria in type I (insulin-dependent) diabetic patients in Denmark. Diabetes 36:205-209, 1987. 16. Krolewski A, Warram JH, Christheb AR, Busick E, Kahn CR: The changing natural history of nephropathy in type 1 diabetes. Am 1 Med 78:785-793, 1985. Kostraba JN, Dorman JS, Orchard TJ, Becked DJ, Ohki Y, Ellis D, Doft BH, Lobes LA, LaPorte RE, Drash AL: Contribution of diabetes duration before puberty to development of microvascular complications in IDDM subjects. Diabetes Cure 12:686-693, 1989. 18. Diabetes Epidemiology Research International MortaIity Study Group: International evaluation of causespecific mortality and IDDM. Diabetes Cure 14:55-60, 1990. 19. Klein R, Klein BEK, Mose SE, Davis MD, DeMets DL: The Wisconsin epidemiology study of diabetic retinopathy: koteinuria and retinopathy in a population of diabetic persons diagnosed prior to 30 years of age. In: Diabetic Renal-Retinal Syndrome 3. New York, Grune and Stratton, 1986, pp. 245-264.
17.
Development of Diabetic Ne hropathy in Japanese Patients With Insu Pin-Dependent Diabetes Mellitus: Tokvo Women’s Medical College Epidemiologic JStudy Hiroki Yokoyama, Yasuko Uchigata, Toshika Otani, Akiko Maruyama, Kawori Yano-Aoki, Sachiko Kanematsu, Tadasu Kasahara, Nobuo Matsuura, and Yasue Omori
ABSTRACT To clarify the development of diabetic nephropathy in Japanese insulin-dependent diabetes mellitus (IDDM), 373 patients with IDDM who had no proteinuria at the first visit to our Diabetes Center were evaluated. The incidence of persistent proteinuria increased rapidly between 10 and 19 years of diabetes duration, and only a few new cases occurred thereafter. Patients whose ages at onset of IDDM were 9-17 years (n = 167) and 18-29 years (n = 90) had rapid development of persistent proteimuia compared to the 0 to B-year group (n = 116) (p < 0.02 and p < 0.003, respectively). Females (n = 233) developed persistent proteinuria to a greater extent until 24 years of diabetes duration than males (n = 140) (p = 0.17). Development of proteinuria did not vary according to calendar year of diagnosis of IDDM or diabetes duration at the first visit. Renal insufficiency (serum creatinine of 2.0 mg/dL or
greater) followed the onset of proteinuria; 609’0 of the patients with the onset of IDDM between 1951 and 1969 developed renal insufficiency 10 years after the onset of proteinuria, whereas 30% of patients with the onset of IDDM after 1970 developed this condition. Development of renal insufficiency did not vary according to sex, age at onset of IDDM, or age at onset of proteinuria. Renal failure requiring dialysis therapy occurred within 4 years after renal insufficiency. In conclusion, development of diabetic nephropathy in Japanese IDDM exhibits three stages. The onset of proteinuria appears to be influenced by age at onset of IDDM and sex. Incidence of renal insufficiency seems to be decreasing in patients with recent onset of IDDM, however, once it occurs, renal failure requiring dialysis therapy develops within 4 years. (Journal of Diabetes and Its Complications 8;1:7-12, 1994.)
INTRODUCTION
in the number of Japanese patients with IDDM of a long duration. As the duration of IDDM becomes longer, late-onset diabetic complications become more serious; indeed, the number of patients who develop diabetic nephropathy and require dialysis therapy at a younger age is now increasing in Japan.4 Diabetic nephropathy has become a major life-threatening complication in Japan as it is in the United States5 and Europe.6 The prevention of this complication is, therefore, of great importance. The development of diabetic nephropathy in IDDM
he incidence of insulin-dependent diabetes mellitus (IDDM) in Japanese is 1.0-2.01 100,000,1-3 much lower than that of lo-301 100,000 in Caucasians.3 However, recent improvements in diabetes care have led to an increase
T
Diabetes Center, Tokyo Women’s Medical College, Tokyo, Japan Reprint requests tobe sent to: Dr. Hiroki Yokoyama, Steno Diabetes Center, Neils Steensens Vej 2, 2820 Gentofte, Denmark. 0 1994 ]ownal
of Diabetes and
Its Complications
8 YOKOYAh4A ET AL.
JDiabComp1994;8:7-12
TABLE 1. CLINICAL FEATURES OF SUBJECTS IN THE STUDY Year at Onset of Insulin-Dependent Diabetes Mellitus (IDDM) 1951-1969 n
Female % Age at onset of IDDM Diabetes duration at the first visit O-4 years 5-10 years 11-26 years
1970-1979
1980-1984
77 66.2 10.4 f 6.6
179 63.1 12.5 f 7.4
117 61.1 15.5 + 6.4
7 12 58
41 74 64
78 39 0
P
NS” <0.0001b
ax2 test. bMann-Whitney U test.
has been described through some stages; microalbuminuria, proteinuria, decreasing of glomerular filtration rate, and renal failure requiring dialysis.‘e9 It is now of prime importance to determine the factors that are associated with the development of microalbuminuria, proteinuria, and renal dysfunction in Japanese IDDM patients. The measurement of microalbuminuria has been carried out in efforts to prevent diabetic nephropathy at the early stage; however, such measurements have been used routinely for only about 10 years, whereas proteinuria and renal function measurements have been followed for more than 20 years. More than 1,100 patients who were diagnosed as having diabetes before the age of 30 years were referred to the Diabetes Center of Tokyo Women’s Medical College by primary care practitioners between 1951 and 1985; about 40% of these patients had IDDM.‘OIn this study, we examined the development of diabetic nephropathy in these patients to clarify the natural history of diabetic nephropathy in Japanese IDDM patients, and to assess the development of each stage of nephropathy with respect to sex, age at onset of IDDM, and calendar year of onset of IDDM.
as having IDDM at the first visit, the onset was investigated by interview and review of previous medical records. Before 1979, blood glucose control was monitored by several physicians at our center according to the levels of urinary glucose and blood glucose on visits. After 1980, measurement of glycohemoglobin and self-monitoring of blood glucose has become available; these measurements have since been used as major indicators of blood glucose control. Proteinuria was checked at every visit (once a month) with Albustix (Miles-Sankyo, Tokyo, Japan) (detection limit 30 mg/dL or greater) after the first visit. When three of the four tests were positive for proteinuria without the occurrence of menstruation, urinary tract infection, orthostatic proteinmia, or pregnancy, the patient was determined to have persistent proteinuria. The onset of proteinuria was defined as the first recorded persistently positive sample. Serum chemistry, including creatinine (Jaffe’s method), was examined at least once a year, and twice or more for patients with persistent proteinuria. The date was recorded when the persistent proteinuria was detected, and when the-serum creatinine level exceeded 2.0 mg/dL, which was defined as renal insufficiency. For patients who unSUBJECTS AND METHODS derwent dialysis therapy because azotemia, overhyThe study population comprised all patients who had dration, or acidosis were not corrected by conservative visited the Diabetes Center, Tokyo Women’s Medical therapy, the date of the initiation of dialysis was also College, in whom IDDM had been diagnosed between recorded. 1951 and 1984 and before the age of 30 years. The popdaThe follow-up was calculated from the diagnosis of tion consisted of 448 patients (175 males and 273 feIDDM to the development of proteinuria, or for those males), of whom 44 already had persistent proteinuria individuals who were free from proteinuria, to the end with uncertain onset. Fifteen of the remaining 404 patients were not followed because of incomplete regis- of the follow-up (June 30, 1992). The follow-up from persistent proteinuria to serum creatinine elevation of tration. Sixteen patients had nondiabetic proteinuria. The remaining 373 patients were entered in the study. 2.0 mg/dL or greater, and from the serum creatinine The criteria for diagnosis of IDDM were, according elevation to the commencement of dialysis therapy to the report of the World Health Organization were also investigated. The development to each stage (WHO),‘l onset with ketoacidosis or symptoms of hy- was analyzed by Kaplan-Meier’s life-table analysis. perglycemia with requirement for insulin within 1 The log-rank test was used to test the significance of month after the onset. For patients already diagnosed the difference among the curves.
DEVELOPMENT
J Diab Camp 1994; 8:7-12
Age at onset of IDDM FIGURE 1 Age at onset and sex distribution of 373 Japanese subjects with insulin-dependent diabetes mellitus (IDDM). Numbers on the top of bar indicate numbers of patients.
RESULTS Clinical Feature of Subjects. Table 1 shows the clinical features of the 373 subjects according to the calendar year at onset of IDDM. No difference was found in the male/female ratio among the three groups, i.e., those diagnosed before 1969, between 1970 and 1979,
and between 1980 and 1984. Patients diagnosed between 1980 and 1984 were characterized by an older age at onset of IDDM and shorter duration of diabetes at the first visit. The distribution of age at onset of IDDM is shown in Figure 1. Age 9-11 years was the peak age of onset, followed by 12-14 and 6-8 years. The mean age at onset in females was slightly greater than that in males (13.8 f 7.5 versus 11.6 f 6.3 years, p < 0.01). Natural History of Nephropathy. Persistent proteinuria developed in 57 of the 373 patients during 5,487 person-years of observation. The incidence of development according to duration of diabetes, expressed in successive 5-year intervals, is shown in Table 2.
OF NEPHROPATHY
IN JAPANESE IDDM 9
The incidence was law during the first 10 years, and rather high at lo-14 and 15-19 years. There were only a few new cases after 20 years. Table 3 shows the incidence of renal insufficiency with creatinine elevation 2.0 mg/dL or greater. Renal insufficiency developed in 21 patients during 5,701 person-years of observation. The incidence was 5.4/1,000 person-years at lo-14 years; this increased, reaching 19.8/1,000 person-years at 20-24 years. Dialysis therapy was initiated in 14 patients during 5,771 person-years of observation, the peak incidence being 15.9/1,000 person-years at 20-24 years (data not shown). The cumulative incidences of persistent proteinuria, renal insufficiency, and dialysis in relation to duration of IDDM are depicted in Figure 2. The rate of persistent proteinuria reached 35% at 26 years of diabetes duration and remained at this level thereafter. Analysis of Development of Persistent Proteinuria. Analysis with respect to the age at onset of IDDM was carried out; the patients were divided into three groups shown in Figure 3. Patients in the 0- to B-year group (n = 116) developed proteinuria significantly more slowly than those in the 9- to l7-year group (n = 167) (p < 0.02) and the 18- to 29-year group (n = 90) (p < 0.003). Figure 4 shows the development of proteinuria according to sex; female patients (n = 233) developed proteinuria to a greater extent until 24 years of diabetes duration than males (n = 140) (p = 0.17). Analysis according to the calendar year at onset of IDDM and diabetes duration at the first visit to the Diabetes Center, revealed no influence on the development of persistent proteinuria (data not shown). Analysis of Development of Renal Insufficiency. The cumulative incidence of renal insufficiency reached 60% at 10 years after the onset of proteinuria shown in Figure 5 (n = 57). When the data was analyzed according to the year at onset of IDDM, there was a tendency of declining incidence of renal insufficiency
TABLE 2. INCIDENCE RATES OF PERSISTENT PROTEINURIA AMONG PATIENTS WITH JAPANESE INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), ACCORDING TO 5-YEAR INTERVAL OF DURATION Duration of IDDM (years)
Number of Patients”
Number of Person-Yearsb
Number of New Casesb
Incidence Rate per 1,000 Person-Years
o-4 5-9 10-14 15-19 20-24 25-29 30-34 35-41
373 373 280 150 77 29 13 2
1828 1646 1062 546 271 99 29 6
0 8 27 16 4 1 1 0
0 4.9 25.4 29.3 14.8 10.1 34.5 0
’ Without persisfent proteinuria at the beginning of each interval. b Dun’ng each interval.
10 YOKOYAMA ET AL.
I Diab Gnnp 1994; 8:7-12
TABLE 3. INCIDENCE RATES OF RENAL INSUFFICIENCY” AMONG PATIENTS WITH JAPANESE INSULIN-DEPENDENT DIABETES MELLITUS (IDDM), ACCORDING TO 5-YEAR INTERVAL OF DURATION Duration of IDDM (years)
Number of Patientsb
o-4 5-9 10-14 15-19 20-24 25-29 30-34 35-41
373 373 288 173 89 35 13 3
Number of
Incidence Rate per 1,000
Number of
Person-Yearsc
New Cases’
Person-Years 0 0
1828 1668 1107 642 303 113 32 8
5.4 9.3 19.8 9.6 0 0
’ Criteria: serum creatinine level 2.0 mg/dL or greater. b Without renal insufi~cy
at the beginning
ofeachinter&.
c During each interval.
in patients with more recent onset, although the difference was not significant. Analysis according to sex, age at onset of IDDM, and age at onset of proteinuria revealed no influence on the development of renal insufficiency (data not shown). Figure 6 shows the development of renal failure requiring dialysis therapy after the elevation of creatinine of 2.0 mg/dL or greater; the cumulative incidence reached 100% at 4 years. DISCUSSION
It was difficult to investigate and report development of diabetic nephropathy in Japanese IDDM patients because of the low incidence and few hospitals with more than 100 such patients. Although the population in our study was based on a single institution, the clinical features according to sex and age at onset of IDDM are the same as those cited in previous studies of Japanese IDDM, 12-14and the diabetes duration at
PERSISTENT RENAL
the first visit had no influence on the incidence of proteinuria. These features may suggest the subjects in our study to be representative of the Japanese IDDM population. We demonstrated the natural history of diabetic nephropathy in Japanese IDDM patients, and found critical clinical features in its development. The incidence of proteinuria was high at lo-19 years of diabetes duration, and few cases occurred after 20 years. The cumulative incidence reached 35% at 26 years of diabetes duration and did not increase thereafter. This finding is consistent with the previous reports from the Steno hospitaV and the Joslin clinic,16 in which it was shown that only 30%-40% of IDDM patients developed proteinuria, and which suggested that the majority of patients with IDDM would not develop proteinuria despite a long duration of IDDM. With regard to the age at onset of IDDM and the development of proteinuria, patients with onset of
AGE AT ONSET
PAOTEINURII
80 -
INSUFFICIENCY ____DIALYSIS ..........
80 I
-
OF IODH
O-1
VELRSln~llS~
S-11
VEARSln=ISll mm__-
I SGSVEARS In=801 ..........
:. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40 1 20 I
10
20
30
4
DURATION OF IDDM (YEARS)
FIGURE 2 Cumulative incidence ofpersistent proteinuti,
renal insuficiency, and renal failure requiring dialysis in relation to duration of insulin-dependent diabetes mellitus (IDDM) in 373 Japanese IDDM patients.
0
-
.A
’ cI
10
20
30
40
DURATION OF IDDM (YEARS)
FIGURE 3 Cumulative incidence of persistent proteinuria in lapanese patients whose age at onset of insulin-dependent diabetes mellitus (IDDM) was at O-8 years (n = 126), 9-17 yeurs (n = 167), and 18-29 yeurs (n = 90).
DEVELOPMENT OF NEPHROPATHY IN JAPANESE IDDM
J Diab Comp 1994; 8:7-12
11
%M~LE(n=2331 _____
-_
DURATION
OF IODM (YEARS)
4 Cumulative incidence of persistent proteinuria in male (n = 140) and female (n = 233) insulin-d~~d~t diabetes mellitus (IDDM) patients. FIGURE
IDDM before the age of 8 years had the slowest development, the cumulative incidence in this group reaching only 20% at 24 years. This was concordant with previous reports from the Steno hospital15 and Joslin clinic.16Patients with onset of IDDM at the age of 1829 years exhibited rapid development of proteinuria, the same as that in patients 9-17 years old; this result was in conflict with a report from the Steno hospitaP3 in which slower development was demonstrated in patients with onset of IDDM at the age of 20-30 years. Kostraba et al.*’ found that the influence of prepubertal duration on the development of microvascular complications was minimal. It is also likely that, in Japanese IDDM, microvascular complications develop slower in the prepubertal stage. It is unknown whether this is related to hormone or psychosocial behaviors. A female preponderance in the development of proteinuria was observed in our study, although it was
YEARS
AFTER
ONSET
OF PROTEINURIA
Cumulative incidence ofrenal insufficiency after onset in Japanese patients with insulin-dependent diabetes mellitus UDDM) (n = 57). Renal insufficiency was defined as serum creatinine level 2.0 mg/dL or greater. FIGURE 5
ofprofeinuria
YEARS
AFTER
ELEVATION
OF CREATININE
22,Omg/dI
FIGURE 6 Cumulative incidence of renal failtire requiring dialysis after exceeding creatinine of 2.0 mg/dL or greater (n = 21).
not significant. This preponderance was also observed in the development of proliferative retinopathy, in which it was significant (manuscript in preparation). It is unknown whether this feature is due to genetic, hormonal, or environmental factors. A report by the Diabetes Epidemiology Research International Mortality Study Group has shown that the mortality rate of Japanese female IDDM patients is twice that of Japanese males, predominantly due to diabetic kidney disease.** It is 1ikeIy that Japanese women may have an increased risk of development of microvascular complications in IDDM. There may be cross-country differences in the development of microvascular complications, as male preponderance has been observed in other countries.*5,19 The influence of the calendar year at onset of IDDM on development of proteinuria was negligible in our study, whereas, in the Steno hospitaF5 and Joslin clinic,16 a declining incidence of proteinuria was reported in patients with onset of IDDM in the 1950s compared with the incidence of proteinuria in patients with onset in the 1930s. One explanation for this is that our study did not extend as far as the 1930s. Another explanation may be a participation bias in our study, as our subjects with onset of IDDM before 1969 were younger at onset, had a longer duration at the first visit, and had no proteinuria at that time. The calendar year at the onset of IDDM, however, seemed to have some influence on the development of renal insufficiency. Recent antihypertensive treatment and protein restriction with adequate calorie intake, while patients are receiving insulin treatment is likely to have been effective in reducing the incidence of renal insufficiency . In conclusion, we demonstrated the natural history of diabetic nephropathy in Japanese IDDM patients, and found that the cumulative incidence of proteinuria
12
YOKOYAMAET AL.
was 35% at 26 years of diabetes duration. Onset of IDDM after age 9 years was associated with an increased risk of the development of proteinuria. Renal insufficiency developed in 30% of patients within 4 years after the onset of proteinuria, and all of these patients resulted in renal failure within the following 4 years. A decreasing incidence of renal insufficiency after the onset of proteinuria was observed in patients whose onset of IDDM occurred after 1970. REFERENCES 1. Matsuura N, Fukushima N, Fujita K, Abe K, Yamada Y, Kashiwao N, Fujieda K, Kato T, Mikami Y, Nohara Y, Fukuda K, Okuno A, Taguchi T, Oyanagi K: Epidemiologic survey of juvenile-onset insulin-dependent diabetes mellitus (IDDM) in Hokkaido, Japan. Tohoku J Exp Med lU(supp1): 181-189, 1983. 2.
Diabetes Epidemiology Research IntemationaI Group: Geographic patterns of childhood insulin-dependent diabetes meIIitus. Diabetes 37:1113-1119, 1990.
J Diab Cmp
9. FriedmanEA: Naturalhistoryof diabeticnepluopathy. In: Eli A Friedmanand CharlesM Peterson(ed), Diabetic Nephroputhy. Strategyfor Therapy. Boston, Martinus Nijhoff, 1986, pp. 65-84.
10. Otani T, Yokoyama H, Higami Y, Kasahara T, Uchigata Y, Hirata Y: Age at onset and type of Japanese younger diabetics in Tokyo. Diabetes Res Clin Pratt 10:241-244, 1990.
11. World Health Organization Expert Committee on Diabetes Mellitus: Technical report series 727, Geneva, World Health Organization, 1985.
12.
Miki E, Maruyama H: Juvenile-onset diabetes meIIitus in Japan. The results of the first nation-wide survey. 1. Jpn Diabetes Sot 15:38X, 1972.
13.
Hibi I, Tanae A, Maruyama H, Tsuchiya H, Isshiki H, Matsuura N, Kitagawa T: Juvenile-onset type diabetes in Japan: Current status. Report of the Child Diabetes Research Committee, the Ministry of Health and Welfare, Japan, 1980-1981.
14.
Tajima N, Laporte RE, Hibi I, Kitagawa T, Fujita H, Drash A: A comparison of the epidemiology of youthonset insuhn-dependent diabetes meIIitus between Japan and the United States (Allegheny County, Pennsylvania). Diabetes Care B(supp1 1):17-23, 1985.
3. Diabetes Epidemiology Research International Group:
Secular trends in incidence of childhood IDDM in 10 countries. Diabetes 39858-864, 1990.
4. Registry Committee of Japanese Society for Dialysis
Therapy: Present status of maintenance dialysis for diabetic renal failure. J Jpn Sot Dialysis Ther 25:1095-1104, 1992.
5. Dorman JS, LaPorte RE, Kuller LH, Cruickshanks KJ,
Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL: The Pittsburgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results. Diabetes 33:271-276, 1984.
6. Anderson AR, Christiansen JS, Andersen JK, Kreiner
S, Decker? T: Diabetic nephropathy in type 1 (insuhndependent) diabetes: An epidemiological study. Diubetologia 25:496-501, 1983.
7. Kussman JM, Goldstein HH, Gleason RE: The clinical course of diabetic nephropathy. IAlMA 236:1861-1863, 1976.
a. Mogensen CE, Christensen CK, Vittinghus E: The
stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32 (suppl2):64-78, 1983.
1994; 8:7-12
15. Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Nerup J, Decker? T: Declining incidence of persistent proteinuria in type I (insulin-dependent) diabetic patients in Denmark. Diabetes 36:205-209, 1987. 16. Krolewski A, Warram JH, Christheb AR, Busick E, Kahn CR: The changing natural history of nephropathy in type 1 diabetes. Am 1 Med 78:785-793, 1985. Kostraba JN, Dorman JS, Orchard TJ, Becked DJ, Ohki Y, Ellis D, Doft BH, Lobes LA, LaPorte RE, Drash AL: Contribution of diabetes duration before puberty to development of microvascular complications in IDDM subjects. Diabetes Cure 12:686-693, 1989. 18. Diabetes Epidemiology Research International MortaIity Study Group: International evaluation of causespecific mortality and IDDM. Diabetes Cure 14:55-60, 1990. 19. Klein R, Klein BEK, Mose SE, Davis MD, DeMets DL: The Wisconsin epidemiology study of diabetic retinopathy: koteinuria and retinopathy in a population of diabetic persons diagnosed prior to 30 years of age. In: Diabetic Renal-Retinal Syndrome 3. New York, Grune and Stratton, 1986, pp. 245-264.
17.