Progression of microalbuminuria in type 1 diabetes: Ten-year prospective observational study

Kidney International, Vol. 68 (2005), pp. 1446–1450

Progression of microalbuminuria in type 1 diabetes: Ten-year prospective observational study PETER ROSSING, PHILIP HOUGAARD, and HANS-HENRIK PARVING Steno Diabetes Center, Gentofte, Denmark; Novo Nordisk, Biostatistics, Bagsvaerd, Denmark; and Faculty of Health Science, University of Aarhus, Aarhus, Denmark

In patients with diabetes, the presence of persistent microalbuminuria is an established predictor of development of overt diabetic nephropathy, progressive renal insufficiency and increased risk of cardiovascular disease, in both type 1 and 2 diabetes [1–4]. Approximately 30% of type 1 diabetic patients may develop diabetic nephropathy within 25 years of diabetes, although recent data suggest a declining incidence [5, 6]. In the original studies demonstrating the predictive value of microalbuminuria, up to 80% of patients with microalbuminuria progressed to overt diabetic nephropathy. Recently, it has been suggested that microalbuminuria may not be as sensitive and specific as predictor of diabetic nephropathy as originally suggested [7]. Observational studies have found regression from microalbuminuria to normoalbuminuria in a substantial fraction of patients with type 1 diabetes and microalbuminuria [8]. Furthermore, it has been suggested from uncontrolled studies of patients with long duration of diabetes that microalbuminuria is not a good predictor of progression to overt nephropathy in longstanding type 1 diabetic patients [9]. We conducted a 10-year observational follow-up study of a large cohort of type 1 diabetic patients to elucidate putative risk markers for the progression from microalbuminuria to overt diabetic nephropathy. We have previously demonstrated the presence of poor glycemic control, retinopathy, smoking, and elevated urinary albumin excretion within normal range to be predictors of development of microalbuminuria [10]. In the present study, the factors involved in progression from microalbuminuria to overt nephropathy are evaluated, as well as the predictive value of microalbuminuria in longstanding type 1 diabetes for the development of overt diabetic nephropathy. In addition, we wanted to determine the annual rate of progression in urinary albumin excretion rate in microalbuminuric patients.


C

2005 by the International Society of Nephrology

METHODS We asked all 1024 patients with type 1 diabetes that satisfied certain criteria and were attending the outpatient clinic at Hvidore ¨ Hospital (now Steno Diabetes Center) in 1984 to participate [11]. The criteria were age 18 years or older, duration of diabetes 5 years or more, and age 40 years or under at onset of diabetes. Forty-two patients were excluded because they had been referred by one of us (H.H.P.) and one or more 24-hour urine collections were obtained from 957 (97%) of the remainder. Eighteen patients were excluded from follow-up. Thus, 939 patients were followed up until January 1, 1995 or death (N = 207) or emigration (N = 36). At baseline, 181 had microalbuminuria (31 to 299 mg/24 hours) and during follow up a further 153 patients of the 593 patients with normoalbuminuria (≤30 mg/24 hours) at baseline developed microalbuminuria. Clinical data at baseline are presented in Table 1. All the patients were white. Patients gave informed consent and the local ethics committee approved the study. Procedures and methods in the baseline study were as described [11]. Twenty-four–hour urinary albumin excretion was measured in sterile urine by radioimmunoassay as they were obtained, with a sensitivity of 0.5 mg/L and an interassay coefficient of variation of 9%. Measurements were done at baseline and during regular follow-up in our outpatient clinic. Microalbuminuria and macroalbuminuria were defined as urinary albumin excretion 31 to 299 mg and 300 mg or more, respectively, per 24 hours in at least two out of three consecutive samples [12]. Urine samples were taken routinely at least once a year. When values were abnormal, samples were requested at all subsequent visits. Time of onset of microalbuminuria and overt nephropathy during follow-up were defined as the first recorded positive urine sample in a series of three fulfilling the above criteria. Arterial blood pressure was measured once on the right arm with a standard clinical sphygmomanometer (cuff size 25 × 12) after 10 minutes’ sitting. During follow up blood pressure was measured at least yearly; hypertension was defined and treated according to World 1446

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Table 1. Clinical data at baseline in 334 type 1 diabetic patients having or developing microalbuminuria during a 10-year follow-up period, according to progression to overt diabetic nephropathy Progressors Nonprogressors (N = 93) (N = 241) Men % Age years Duration of diabetes years Hemoglobin A1c % Retinopathy (none, simplex, proliferative) % Arterial blood pressure mmHg Albuminuria mg/24 hr Smoker %

56 37 (14) 19 (11) 9.6 (1.9) 18/61/21

51 41 (14)a 22 (11)a 9.1 (1.9)a 15/62/93

Data are mean (SD) or median (range). a < P 0.05.

Health Organization criteria (≥160/95). Hemoglobin A 1c (HbA 1c ) concentration was measured at least yearly with an isoelectric focusing method (normal range 4.1% to 6.1%, data comparable to the Diabetes Control and Complications Trial values) [abstract; Bergstrom ¨ J, et al, Diabetologia 38:A184, 1995]. The same observer carried out ophthalmoscopy through dilated pupils. Patients were categorized as having “any” retinopathy in the presence of background or proliferative retinopathy. Patients were classified as smokers if they smoked one or more cigarettes daily in 1984 based on case records. Socioeconomic class [I (i.e., university degree) to V (unskilled)] was determined from length of education and occupation, based on case record information [13]. Statistical methods The unpaired t test was used to compare continuous variables and the v 2 test to evaluate proportions. The urinary albumin excretion rate was logarithmically transformed before analysis due to its skewed distribution and is presented as geometric mean and 95% confidence interval. P values <0.05 (two-sided) were considered significant. The annual progression rate for urinary albumin excretion rate was evaluated by a mixed model. The patient levels reflect past experiences and were treated as separate parameters. The slope of albumin excretion rate on time was modeled as a function of the explanatory factors and random variation. The measurements were also subject to measurement error (including short-term variation in excretion rate). To avoid the confounding effect of antihypertensive medication on the progression rate, only observations prior to initiation of any antihypertensive medication, including diuretics, was included. Cox’s proportional hazards multiple regression analyses were used to examine the baseline variables predictive of progression to macroalbuminuria. Results are described as relative risk (hazard ratio). The models included those baseline variables that were a priori considered to be potentially important predictors of progressors

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or that were found to be significantly different at baseline when we compared the two groups. This included gender, age at onset of diabetes, presence of retinopathy, arterial blood pressure, log urinary albumin excretion rate, HbA 1c , height, social class, serum creatinine, and smoking. Age at onset of diabetes demonstrated a nonlinear relationship with the risk for progression, with a minimum of age at onset of approximately 15 years and was therefore entered in the model as (age at onset – 15)2 . Stepwise backward selection was used. The time scale was time since diagnosis of diabetes (implying that times were truncated). The software used was SAS version 6.11, proc mixed. For each year of follow-up, the median value for all urine collections during that year was used. RESULTS Rate of progression of urinary albumin excretion rate Based on the 181 patients with microalbuminuria at baseline, the annual mean (SE) progression rate of urinary albumin excretion rate was found to be 6.2% (1.7)/year. Due to the confounding effect of antihypertensive medication on the urinary albumin excretion rate we excluded observations on antihypertensive medication, and in order to increase the accuracy a minimum of three measurements without antihypertensive edications were required. The annual progression rate was then found to be 11.1% (2.6)/year (N = 117 having at least three measurements without antihypertensive medications). To evaluate the impact of putative progression promoters (i.e., factors responsible for the variation in progression rate), a stepwise regression analysis applying mixed models with progression of albumin excretion rate as the dependent variable was performed. It revealed that elevated HbA 1c was the only factor significantly associated with faster progression of albumin excretion rate in patients with microalbuminuria at baseline and not receiving antihypertensive medications (3.6% change in slope per 1% change in HbA 1c ) (P < 0.01). The following independent baseline variables were excluded from the final model: age at onset of diabetes, gender, height, arterial blood pressure, log albumin excretion rate, retinopathy (any), smoking (yes/no), social class (I to V) and serum creatinine. Progression to overt nephropathy Patients were followed for up to 10 years, mean (SD) 7.9 years (2.6), and 59 of the 181 patients who had microalbuminuria at baseline (33%) developed overt diabetic nephropathy (persistent urinary albumin excretion rate >300 mg/24 hours). The incidence of overt nephropathy was dependent on the duration of diabetes, with a maximum of 10.2% per year in microalbuminuric patients with 10 to 15 years of diabetes duration (Fig. 1). Fortyfive percent of patients with duration of diabetes less than

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Incidence, % per year

25

20

15

10

5

0

5-9

10-14 15-19 20-24 25-29 30-34 35-39 40-44 Duration of diabetes

Table 2. Cox regression analysis of risk factors for progression to overt nephropathy in type 1 diabetic patients with microalbuminuria, censored at onset of antihypertensive therapy (93 events, N = 334) Relative risk (95% CI) P value Log 10 U-albumin excretion rate mg/24 hr Hemoglobin A1c % (age at onset-15)2

2.07 (1.31–3.26) 1.13 (1.03–1.24) 1.0015 (1.0003–1.0028)

<0.01 <0.01 <0.02

Sex, duration of diabetes, arterial blood pressure, S-creatinine, height, retinopathy, smoking, and social class were not included in the final model.

15 years progressed to overt nephropathy in contrast to 26% of patients with duration of diabetes exceeding 15 years (P = 0.01). At baseline 16% were on antihypertensive medications, and at end of follow-up it was 76% [mainly angiotensin-converting enzyme (ACE) inhibition]. When all 334 patients with microalbuminuria at baseline or during follow-up were evaluated, 93 patients (28%) progressed to overt diabetic nephropathy. To evaluate the impact of putative progression promoters on time to development of overt nephropathy, a Cox regression analysis of progression to diabetic nephropathy (93 cases), including all patients with microalbuminuria at baseline or during follow-up (N = 334) using the same putative predictors of progression, and excluding patients at start of antihypertensive medications, demonstrated elevated HbA 1c (P < 0.01), urinary albumin excretion rate (P < 0.001), and (age at onset – 15)2 (P < 0.01) as predictors (Table 2). Patients were divided based on quintiles of urinary albumin excretion rate to illustrate the impact of the level of urinary albumin excretion rate on rate of progression to overt nephropathy (Fig. 2) demonstrating that particularly in patients with values exceeding 100 mg/24 hours was there an increased risk for progression to overt nephropathy.

45+

Fig. 1. Observed incidence (95% confidence interval) of overt diabetic nephropathy in 181 type 1 diabetic patients with microalbuminuria at baseline followed for up to 10 years.

A regression to persistent normal urinary albumin excretion rate at the end of follow-up was seen in 53 (16%) of the patients who had microalbuminuria at baseline or developed persistent microalbuminuria during the follow up period, in 55% of the cases this was seen after initiation of antihypertensive treatment. DISCUSSION During 10-year follow-up the presence of microalbuminuria (urinary albumin excretion rate 31 to 299 mg/24 hours) predicted progression to overt nephropathy (≥300 mg/24 hours) in 33% of type 1 diabetic patients or an incidence of 3.3 per 100 person-years, whereas 16% of the patients had regressed to normoalbuminuria (drug induced in approximately half of the patients). Levels of HbA 1c and urinary albumin excretion rate at baseline were associated with the progression to overt nephropathy and a nonlinear effect of age at onset was observed with the smallest risk for progression with age at onset of 15 years. We observed an annual increase in urinary albumin excretion rate of 11.1% in patients who were not receiving antihypertensive therapy, whereas it was 6.2% if observations on antihypertensive medication were included, and glycated hemoglobin was the only factor being significantly associated with the increase in urinary albumin excretion. The initial observational studies evaluating the risk for progression to overt nephropathy in microalbuminuric type 1 diabetic patients indicated that the risk was approximately 80% within 6 to 14 years (i.e., 6 to 10 per 100 person-years) [1, 2, 14], but these studies included patients with shorter duration of diabetes compared to the present study. Subsequent observational and intervention studies have found highly varying rates of progression ranging from 2 [15] to 13 [16] per 100 personyears. The difference in progression rates is probably explained by differences in diagnostic criteria for micro- and

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70

Cumulative incidence, %

60 50 40 UAER (mg/24h) 176-300

30 20

107-176 65-107

10

47-65 30-47

0 0

1

2

3

4

5

6

7

8

9

10

macroalbuminuria, as well as differences in progression promoters as metabolic control, diabetes duration, blood pressure, and antihypertensive therapy. We have applied generally accepted diagnostic criteria [12, 17]. Some studies have questioned the predictive value of the presence of microalbuminuria [7, 18] and microalbuminuria was even suggested to be a transient phenomenon in most patients in an observational study of 386 patients where 58% of microalbuminuric patients regressed to normoalbuminuria [8]; however, the regression was transient in many patients and follow-up was only up to 6 years. In the present study with up to 10 years’ follow-up, only 16% regressed to persistent normoalbuminuria, and this was most likely explained by antihypertensive medication in more than half of these patients. This is in accordance with our long-term study of an inception cohort of type 1 diabetic patients where only 13% obtained spontaneous regression to normoalbuminuria [19]. We observed that the predictive value of microalbuminuria was highly dependent on duration of diabetes, with the risk for development of overt proteinuria being up to 10% per year in patients with 10 to 15 years’ duration of diabetes, but even in patients with very long duration of diabetes, the presence of microalbuminuria was associated with a risk for development of overt nephropathy of 4% per year. Twenty-six percent of patients with more than 15 years’ duration progressed to overt nephropathy, in contrast to 45% of patients with shorter duration of diabetes. In a 10-year follow-up study of 18 patients from Finland [9], they also observed that 28% of patients with microalbuminuria and more than 15 years diabetes duration developed overt nephropathy; however, this study was uncontrolled as they only included patients with long duration of diabetes. A similar small and uncontrolled study from the United Kingdom, including patients with more than 30 years of diabetes [20] found 32% of 19 patients with microalbuminuria de-

Fig. 2. Cumulative incidence of overt diabetic nephropathy according to quintiles of urinary albumin excretion rate (UAER) level in 334 microalbuminuric type 1 diabetic patients.

veloped overt proteinuria during 7 years’ follow-up. This suggests that microalbuminuria remains a good predictor for progression to overt nephropathy even in patients with long diabetes duration. In accordance with previous observational studies poor glycemic control was associated with a fast annual rate of progression in albuminuria and high risk of progression to overt nephropathy [9, 15, 21–23]. In randomized trials it has, however, been difficult to demonstrate an effect of intensive metabolic control on progression to overt nephropathy [24, 25], maybe due to inadequate sample sizes or insufficient separation in glycemic control between groups. This is in contrast to the beneficial effect demonstrated on the development of microalbuminuria in normoalbuminuric subjects [26, 27]. The present observational study was not designed to evaluate the effect of antihypertensive medication in microalbuminuric patients, but the annual rate of progression in urinary albumin excretion was only 6.2 when measurements on antihypertensive medication was included compared to 11.1% increase per year when measurements on antihypertensive medication was excluded, and during follow-up the frequency of patients on antihypertensive medication increased from 16% to 76% which probably contributes to the lower rate of progression to overt nephropathy compared to the initial studies, as the beneficial effect on progression has been demonstrated in several randomized controlled trials [16, 28, 29]. Despite this arterial blood pressure at baseline was not associated with the risk for progression to overt nephropathy, in accordance with other observational studies [15, 23, 24]. It is possible that changes in blood pressure are only apparent very close to the development of overt nephropathy, it is also possible that changes in blood pressure are so small that more sensitive methods than office blood pressure measurements should be used, such as 24 hours ambulatory blood pressure measurements [30]. It has also been

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suggested that the relationship between blood pressure and albumin excretion depend on the metabolic control [31]. The main analyses of this paper use the time since diagnosis of diabetes as the basic time scale, the analyses were also performed with time since baseline as the time scale. The advantage of the slope analysis is that it is not sensitive toward the choice of time scale.

CONCLUSION Our study supports that the presence of microalbuminuria is associated with a high risk for progression to overt nephropathy. The risk depends on duration of diabetes, but even in patients with long duration of diabetes there is a substantial risk. The study also suggests that potentially modifiable risk factors such as urinary albumin excretion rate and poor metabolic control predict the progression of microalbuminuria in type 1 diabetic patients. Reprint requests to Peter Rossing, Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark. E-mail: [email protected]

12. 13. 14. 15.

16.

17. 18. 19. 20. 21. 22.

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