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A correction has been published: N Engl J Med 1994;330(8):584.
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Background The high relative mortality among patients with insulin-dependent diabetes mellitus results mainly from diabetic nephropathy. The cumulative incidence of nephropathy of 25 to 30 percent among patients who had had diabetes for 25 years remained stable from 1950 to the early 1980s. In a population study, we assessed recent trends in the incidence of diabetic nephropathy.
Methods We studied all 213 patients in whom insulin-dependent diabetes mellitus was diagnosed before the age of 15 years between 1961 and 1980 in a district in southeastern Sweden. Ninety-two percent of the patients were followed from the onset of diabetes to 1991 or to death. Patients with persistent albuminuria (positive Albustix test) were considered to have diabetic nephropathy. Glycosylated hemoglobin was measured periodically in all patients, beginning in 1980.
Results The cumulative incidence of persistent albuminuria after 25 years of diabetes decreased from 30.0 percent among the patients in whom diabetes developed in the period 1961 to 1965 to 8.9 percent among those in whom it developed from 1966 to 1970 (P = 0.01). After 20 years of diabetes, the cumulative incidence decreased from 28.0 percent among the patients in whom diabetes developed from 1961 to 1965 to 5.8 percent among those in whom it developed from 1971 to 1975 (P = 0.01). Persistent albuminuria has not yet developed in any patient in whom diabetes was diagnosed in the period 1976 to 1980. The average glycosylated hemoglobin value decreased from 7.4 percent in the period 1980 to 1985 to 7.0 percent from 1986 to 1991 (P<0.001). The mean glycosylated hemoglobin value was higher in the patients with persistent albuminuria than the patients with no albuminuria (8.1 percent vs. 7.1 percent, P<0.001).
Conclusions During the past decade the cumulative incidence of diabetic nephropathy, as manifested by persistent albuminuria, among patients who have had diabetes for 25 years has decreased substantially, probably as a result of improved glycemic control.
There have been substantial changes in the treatment of diabetes in the past 20 years. Self-monitoring by measurement of urinary glucose and, more recently, blood glucose has become routine; together with better education and better adjustment of treatment to the patient's lifestyle, self-monitoring has led to improved metabolic control. Using these methods of management, we began a prospective, population-based, long-term follow-up study of complications in young patients less than 15 years old with insulin-dependent diabetes, starting in 1973 at the University Hospital in Linkoping, Sweden. We report here on the incidence of diabetic nephropathy among patients with diabetes diagnosed in two decades (from 1961 to 1980) and the importance of glycemic control in relation to the development of nephropathy.
Methods
Patients
We studied all 213 patients with insulin-dependent diabetes beginning before the age of 15 years who lived within the catchment area of the Pediatric Clinic, University Hospital, Linkoping, Sweden, between 1961 and 1980.
During the 1960s, the standard insulin regimen consisted of a single morning dose of long-acting insulin, sometimes with a dose of short-acting insulin. Patients were advised to eat regular meals and to limit their intake of simple carbohydrates and fat. In 1971 a team that included physicians, a nurse who educated patients about their diabetes, a dietitian, a social worker, and later a psychologist was formed at the clinic. Patients were seen at least every three months until they left school at the age of 18 to 20 years, at which time their care was transferred to the Department of Internal Medicine, where the same routines were followed. The number of daily insulin injections increased from one to two in the 1970s to two to five in the 1980s, a change facilitated by the introduction of pen-type injectors in 1984. As multiple injections were introduced, the proportion of patients receiving short-acting insulin increased from 10 to 20 percent in the early 1970s to 60 percent in the 1980s, and some patients used insulin pumps during the latter period. Regular self-monitoring of urinary glucose three times daily became routine in 1971, and self-monitoring of blood glucose and periodic measurement of glycosylated hemoglobin began in 1980. Psychosocial support, group education, camps, and regular evening lectures for parents also became important elements of the treatment program in the early 1970s6.
Measurement of Urinary Protein
In all, 197 of the patients (92.5 percent) were followed from the onset of diabetes to 1991 or death (10 patients). The remaining 16 patients (7.5 percent) were followed until their most recent clinic visit.
All patients were tested for proteinuria at their regular clinic visits, with the use of reagent-impregnated strips (Albustix, Ames, Bridgend, United Kingdom). The 154 patients who still lived in our catchment area were invited to make a special follow-up visit during the period 1990 to 1992, and were asked to collect three timed overnight urine samples for measurement of the albumin excretion rate. Of these patients, 122 (79.2 percent) completed the tests; the remaining 32 patients were examined at routine clinic visits. Thirty of the 49 patients who had moved out of the area responded to a questionnaire and provided data (through their physicians) on albumin excretion rates and antihypertensive treatment.
For the purposes of this study, diabetic nephropathy was defined as persistent albuminuria (a 1+ test result with Albustix, equivalent to the excretion of 
300 mg of albumin per liter). The first year during which albuminuria became persistent was defined as the year of onset of diabetic nephropathy. Microalbuminuria was defined as the excretion of 20 to 200 µg of albumin per minute in at least two of the three timed overnight urine samples collected from 1990 to 1992. The patients were divided into four groups according to year of diagnosis of diabetes: 1961 to 1965, 1966 to 1970, 1971 to 1975, and 1976 to 1980. The groups were similar in their numbers of patients, sex distribution, mean age at onset of diabetes, and percentage followed (Table 1).
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Measurement of Glycosylated Hemoglobin
Glycosylated hemoglobin was determined by ion-exchange chromatography. Between 1980 and 1982, minicolumns were used (Quicksep, Isolab, Akron, Ohio) and the analysis included the labile Schiff-base fraction. From 1982 to 1984 the same method was used after the labile fraction had been eliminated. After 1984 glycosylated hemoglobin was measured by high-performance liquid chromatography (HPLC:Auto A1c HA8810, Kyoto Daichi, Kyoto, Japan). Corresponding values for hemoglobin A1c were calculated from intermethod calibration by the analyzing laboratory. The normal range was 3.2 to 6.0 percent. All values for glycosylated hemoglobin in each patient, a total of 3688 measurements, were included in the analysis. Patients who moved out of the area or died were not included in the analyses of differences in the degree of glycemic control between 1980 and 1985 and between 1986 and 1991 because of difficulties in calculating corresponding values for glycosylated hemoglobin measured at different laboratories.
Statistical Analysis
The cumulative incidence of diabetic nephropathy was calculated for one-year intervals with a life-table method that took into account differences in the interval of follow-up after the first visit. Patients in whom nephropathy did not develop were followed until their examination in the period 1990 to 1992 if they were studied then, the year of their last clinic visit, or the year of death. The calculations were performed according to the algorithm of Lee and Desu (1972) with the SPSS Statistical Package for the Social Sciences7. When incidence rates for the periods 1971 to 1975, 1976 to 1980, 1981 to 1985, and 1986 to 1990 were compared, the duration of diabetes was standardized in five-year intervals by an indirect standardization method. The paired t-test (two-tailed) was used to compare the mean values for glycosylated hemoglobin in each patient during 1980 to 1985 and 1986 to 1991. The average values for glycosylated hemoglobin in patients with persistent albuminuria were compared with those in patients without this feature by an unpaired t-test (two-tailed).
Results
The cumulative incidence of persistent albuminuria in the patients in whom diabetes developed between 1961 and 1965 started to increase after 8 years, reached 28.0 percent after 20 years, and peaked at 23 years, when it reached 30.0 percent (Figure 1). The incidence remained at that level until the end of the study period. The patients in whom diabetes began between 1966 and 1970 had a cumulative incidence of persistent albuminuria of 8.9 percent after having had diabetes for 20 years; no new cases of persistent albuminuria developed thereafter (P = 0.01, as compared with the incidence in patients with onset of diabetes between 1961 and 1965). In the patients in whom diabetes developed between 1971 and 1975, the cumulative incidence after they had had diabetes for 10 years was 5.8 percent, and it remained constant thereafter to the end of the observation period. The difference in the cumulative incidence between the group with onset of diabetes between 1961 and 1965 and the group with onset between 1971 and 1975 (28.0 percent vs. 5.8 percent) was also significant (P = 0.01). No patient in whom diabetes was diagnosed between 1976 and 1980 had persistent albuminuria during the study period.
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The degree of glycemic control as assessed from the glycosylated hemoglobin values improved during the 1980s (Table 2). The glycosylated hemoglobin values decreased significantly between 1980 and 1985 and between 1986 and 1991 in the three groups in which diabetes developed from 1961 to 1975. The group in which diabetes developed from 1976 to 1980 had mean values throughout the 1980s that were similar to those in the three other groups between 1986 and 1991. The patients who did not have microalbuminuria in the period 1990 to 1992 had significantly lower mean glycosylated hemoglobin values between 1981 and 1991 than the patients with microalbuminuria or the patients with persistent albuminuria (mean [±SE], 7.1 ±0.1 percent, 7.7 ±0.2 percent [P = 0.02], and 8.1 ±0.3 percent [P<0.001], respectively).
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Among the patients in the three groups for which 20 years of follow-up was available, four patients -- two in the group in which diabetes developed between 1961 and 1965 -- received antihypertensive treatment before the onset of diabetic nephropathy.
Discussion
In Sweden, all children with diabetes are treated at a hospital pediatric clinic; therefore, we are confident that all new cases of diabetes diagnosed in children between 1961 and 1980 were identified. The design of our study -- fixed groups based on the year of diagnosis of diabetes -- made it comparable with others4,5. Since we were able to follow most of the patients, our ascertainment of the incidence of diabetic nephropathy truly reflected the incidence among all patients with insulin-dependent diabetes. The definition of diabetic nephropathy (persistent proteinuria according to Albustix testing) was similar to that used in other studies4,5,8.
The incidence of persistent albuminuria changed over the years4,5. The cumulative incidence of 30 percent among the patients who had had diabetes for 25 years (after being given a diagnosis between 1961 and 1965) is similar to rates reported in the United States and Denmark4,5,8. The decline in the cumulative incidence to approximately 10 percent among patients in whom diabetes developed between 1966 and 1970 was unexpected. In two other studies, patients in whom diabetes developed between 1966 and 1980 had been followed only until the early 1980s4,5. The greater reduction in the incidence of persistent albuminuria in our study occurred during the latter part of the 1980s in patients whose diabetes was diagnosed between 1966 and 1980.
As in other studies,4,5 the incidence of diabetic nephropathy was highest among patients who had had diabetes for about 15 years. The patterns of the incidence curves in the various groups in our study were similar (Figure 1). With the reservation that the three groups of patients in which diabetes was diagnosed between 1966 and 1980 were followed for a relatively short period (11 to 26 years), the results suggest that albuminuria was prevented rather than delayed. Since the appearance of microalbuminuria is related to the later development of persistent albuminuria,9 the similarities among the four groups in the prevalence of microalbuminuria suggest that the differences in the incidence of persistent albuminuria will persist.
Patients with poor long-term glycemic control are more likely to have microalbuminuria10,11,12,13 and diabetic nephropathy14. Our patients with microalbuminuria or persistent albuminuria had higher mean glycosylated hemoglobin values than the patients in whom albumin excretion was not increased. The importance of strict metabolic control was emphasized in the 1970s and became a principal goal of our treatment. Improvement of glycemic control, reflected by glycosylated hemoglobin values of about 7.0 percent, as in this study, is associated with lower urinary albumin excretion15,16,17 and a decrease in the incidence of diabetic nephropathy18. The decline in the cumulative incidence of persistent albuminuria from 30.0 percent to 8.9 percent is therefore probably a result of improved glycemic control.
Treatment with antihypertensive drugs reduces microalbuminuria in patients with diabetes19,20. The decrease in the cumulative incidence of persistent albuminuria in our study was, however, not related to antihypertensive treatment, since only four patients without diabetic nephropathy were receiving such therapy, and two of them were in the group in which the incidence was highest.
If genetic factors are important in the development of diabetic nephropathy, they must work together with poor glycemic control, or the cumulative incidence of diabetic nephropathy would not have decreased in such an ethnically homogeneous group of patients as ours17,21,22,23.
Diabetic nephropathy in patients with insulin-dependent diabetes mellitus is associated with a high risk of early death,3 the relative mortality among patients with nephropathy being 40 times greater than that among those without it2. Our results confirm the magnitude of this risk: 6 of the 22 patients with nephropathy (27.3 percent) died, as compared with 4 of the 191 patients without nephropathy (2.1 percent). Once a patient has persistent albuminuria, treatment may not prevent progression to renal failure24. Effective treatment of coexistent hypertension seems to reduce renal and cardiovascular mortality among patients with albuminuria25. The cost of caring for American patients with diabetes in end-stage renal failure was about $2 billion in 19901. The reduction in the cumulative incidence of diabetic nephropathy from 30 percent to less than 10 percent among our patients who have had diabetes for 25 years has important implications for the individual patient, the provision of health care, and the costs of treatment of end-stage renal disease in patients with insulin-dependent diabetes mellitus.
Supported by Barndiabetes fonden (the Swedish Child Diabetes Foundation), the Swedish Diabetes Association, and research funds from the counties of Ostergotland and Jonkoping.
We are indebted to Professor Emeritus Yngve Larsson for initiating the study, to Dr. S.-G. Karlander, and to members of departments of internal medicine all over Sweden who provided us with patient data and hospital records, without which this study could not have been performed.
Source Information
From the Departments of Internal Medicine (M.B., H.J.A., B.E.K.) and Pediatrics (G.H., J.L.), University Hospital, Linkoping, Sweden, and the Department of Internal Medicine, Eksjo Hospital, Eksjo, Sweden (M.B.).
Address reprint requests to Dr. Bojestig at the Department of Medicine, Eksjo Hospital, S-575 81 Eksjo, Sweden.
References
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