1 Department of Pediatrics, Umeå University Hospital, Umeå and 2 Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden
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Abstract |
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Methods. A cohort of diabetic children was followed up at a mean duration of 29±3 years. All 75 children treated in one hospital with diabetes duration 8 years were prospectively followed for 8 years examining GFR, AER, blood pressure and HbA1c. After another 810 years, 60 of them were traced for endpoint follow-up.
Results. Seven patients (12%) developed macroalbuminuria, i.e. persistent overnight AER>200 mg/min, 12 (20%) developed persistent microalbuminuria (AER 15200 mg/min) and 17 (28%) transient microalbuminuria (>15 mg/min on two consecutive occasions, normalized at endpoint). One baseline screening value of 24-h AER>15 mg/min predicted 93% of patients with persistent micro or macroalbuminuria. The negative predictive value was 78%. Six of seven macroalbuminuric and 10 of 12 microalbuminuric patients had a baseline GFR above the normal limit of the method (125 ml/min/1.73 m2). When adjusted for diabetes duration, increased GFR predicted macro or microalbuminuria (odds ratios=5.44, P=0.04). The positive predictive value for having an increased baseline GFR was 53%.The negative predictive value was 77%. Stratification for HbA1c did not change the effect of an increased GFR.
Conclusions. At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.
Keywords: albuminuria; cumulative incidence; glomerular filtration rate; type-1 diabetes
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Introduction |
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Early diabetes is characterized, both clinically and experimentally, by an increase in glomerular filtration rate (GFR) and renal plasma flow (RPF) [3,4]. Experimental studies in diabetic animals have demonstrated that increased intraglomerular flow and pressure, associated with glomerular hyperfiltration, may damage the renal structure [5]. Studies in human type-1 diabetes have also indicated that glomerular hyperfiltration is a risk factor for nephropathy [68], although this remains controversial [9,10]. The mechanisms responsible for such a possible deleterious effect of early renal functional changes have not been fully evaluated. Glomerular hyperfiltration is promoted by hyperglycaemia, which is also a major risk factor for diabetic nephropathy per se [11]. In a previous study, we found that an increased GFR, independent of the degree of metabolic control, present in early type-1 diabetes predicted the development of incipient diabetic nephropathy 8 years later [12].
The aim of the present study was to determine in the same cohort of patients, the prevalence of diabetic nephropathy and the predictive value of a screening value of albumin excretion rate (AER) and GFR on diabetic nephropathy after another 810 years of follow-up, i.e. after a mean diabetes duration of 29 years.
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Subjects and methods |
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Sixteen to 18 years after the baseline examination, the original group of patients was traced and asked to participate in a final follow-up study. Sixty patients 34.5±2.8 (mean±SD) years old with a mean duration of 29.0 (range 2535) years were traced and agreed to participate. Two patients from the original cohort had died due to reasons unrelated to diabetes (leukaemia and the Moya Moya disease), nine patients were not traced and four patients declined to participate. One patient had died in renal failure due to overt nephropathy and was, thus, included in the statistical analyses. At baseline, clinical characteristics did not differ between the 15 non-participants and the 60 participants (Table 1).
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Baseline methods
Initial GFR was estimated using a single inulin injection technique. Polfructosan (Inutest Laevosan Gesellschaft 25%; Linz, Austria) was injected at a dose corresponding to 12 ml/m2 body surface area and several blood samples were taken between 5 and 180 min after the injection. Polyfructosan in blood was determined by the anthron method. Clearance was calculated from a two-compartment analysis [15]. GFR was measured after ordinary insulin dose and breakfast between 08:00 and 12:00. All samples were fermented to reduce the possible interference by blood glucose with inulin values.
AER was analysed in 24-h urine collections by an RIA method (Phadebas®, Pharmacia, Uppsala, Sweden). In a previous study in children and adolescents, we found that the upper normal limit of AER was 18.5 mg/min in 24-h urine collection [16]. To increase the power of the present study we arbitrarily chose 15 mg/min as the screening value. At 8-years of follow up AER was analysed from both 24-h urine and at least two overnight urine samples.
Blood pressure was measured prior to the GFR examination after 15 min of rest in a supine position, using a standard mercury manometer with an appropriately sized cuff. Diastolic blood pressure was read at the disappearance of the Korotkoff sounds. All blood pressure measurements were performed by the same observer.
HbA1c was (initially) analysed by an isoelectric focusing technique (LKB Ampholine PAGplate, LKB, Stockholm, Sweden).
Endpoint methods
For measurement of AER all patients were asked to deliver, by mail, two timed overnight urine samples to the Department of Clinical Chemistry at Norrlands University Hospital in Umeå. AER was analysed by an immunoturbidimetric method [17] using an automated spectrophotometer (Hitachi 911). If only one urinary test was positive, the patient was asked for a third sample. Forty-three of the 60 patients delivered urinary samples. The rest of the patients data on AER was obtained from hospital files and estimated with either RIA or an immunoturbidimetric method. These methods are both very sensitive and have very small methodological variations. We have previously compared these two methods and found them to have an excellent correlation (r=0.91) [16], thus, making a systematic bias unlikely.
HbA1c was collected from medical records. Laboratory methods of HbA1c differ in different medical centres. However, the three laboratories used by the respective diabetic clinics collaborated in a national quality assessment programme. During the year of this study the mean coefficient of variation between the methods was only 3% (EQUALIS reference laboratory).
Data on blood pressure levels, antihypertensive medication and prevalence of retinopathy were collected from medical records. Thus, the definition on simplex or proliferative retinopathy was defined locally. All patients defined as having proliferative or pre-proliferative retinopathy had been treated with photocoagulation. Table 1 shows that all characteristics, except for the AER were similar between groups.
Statistical methods
The Student's t-test for unmatched design or 2 analysis was used for comparison between groups. Paired t-test was used for comparisons between GFR-values at baseline and at 8 years of follow-up. Crude odds ratios and stratifications and 95% confidence limits were calculated using the Mantel-Haenszel method. For comparisons of survival time (i.e. remaining normoalbuminuric at the end of the study) the log rank procedure was used. In all analyses patients with transient microalbuminuria were excluded. The positive and negative predictive values of AER and GFR were calculated. The positive predictive value here means the fraction of patients who initially had an increased AER or GFR screening value, and who had developed persistent micro- or macroalbuminuria at endpoint. The negative predictive value means the fraction of patients who initially had a normal AER or GFR value and did not develop micro or macroalbuminuria. Mean (95% confidence interval) is given if not otherwise stated.
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Results |
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Baseline values of sex, age at onset, blood pressure, blood glucose 90 min after breakfast and HbA1c were similar in patients developing macro or microalbuminuria as in those that remained normoalbuminuric. Baseline AER was significantly higher among patients developing micro and macroalbuminuria compared with the normoalbuminuric group (Table 1). Baseline mean GFR tended to be higher in patients with persistent macro or microalbuminuria at endpoint than in normoalbuminuric patients. GFR-values at baseline, 4 and 8 years of follow-up are presented for each group in Table 2
. A significant decline in GFR was seen after 8 years in patients who had developed macroalbuminuria at endpoint.
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Six of the seven patients who developed persistent macroalbuminuria and 10 of the 12 with persistent microalbuminuria, had initial GFR exceeding the upper normal limit (>125 ml/minx1.73 m2 b.s). As 30 of the patients had initially increased GFR (according to this definition) the positive predictive value of screening value of GFR, exceeding the upper normal limit was 23% for macroalbuminuria and 53% (16/30) for micro or macroalbuminuria. The negative predictive value was 77% (10/13).
When looking at a GFR above 125 ml/min/1.73m2 as a risk factor for micro or macroalbuminuria the crude odds ratio (95% confidence limits) was 3.81 (0.90; 16.1), P=0.063. When stratifying for initial HbA1c dichotomized according to the mean value of normoalbuminuric patients (12.0%) the Mantel-Haenzsel rate ratio was similarly, 3.67 (0.90; 15), P=0.07. It was also necessary to stratify for duration of diabetes, which ranged between 25 and 35 years, and it was found that the odds ratio for having an elevated baseline GFR then increased to 5.44 (1.02; 28.6, P=0.04). There was no significant heterogeneity between strata for any of the stratification procedures. Figure 1 shows a KaplanMeier plot of the percentage remaining normoalbuminuric and with baseline GFR above the normal range compared to those with a normal GFR (log rank test P=0.05).
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Discussion |
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In agreement with our previous report [12] half of the patients with initial glomerular hyperfiltration developed micro or macroalbuminuria. In terms of prediction in this rather limited group of patients, GFR was clearly a less strong predictor than only one screening value of AER>15 mg/min in 24-h urine 18 years before. It should be kept in mind though, that using an elevated screening value of AER increases the probability that it will be a strong predictor, as these patients already at baseline are closer to the endpoint chosen. The crude odds ratio for an increased GFR was only borderline statistically significant. This may partly be explained by the small sample size of this study, yielding a low power. However, when adjusting for diabetes duration, a clearly significant increase in risk was noted. When stratifying for the other obvious confounder, a poor metabolic control at baseline, the odds ratio was not significantly changed. The positive predictive value of an increased GFR was 53%. Thus, hyperfiltration is not a sufficient determinant for nephropathy but mightwhen accompanied by other metabolic or hemodynamic characteristics of diabetesbe a contributor of this complication. Our results agree with the retrospective studies by Mogensen et al. [6,7] as well as a 10-year follow-up study by Chiarelli et al. [8] showing a strong predictive value for a GFR >140 ml/min/173 m2 on the occurrence of microalbuminuria. Our clinical findings are also in accordance with the findings of Berg et al. [19], showing that in normoalbuminuric patients early diabetic structural changes in kidney biopsies were related to long standing hyperfiltration in young diabetic patients. The findings are also in accordance with our own results in microalbuminuric type-1 diabetic patients showing independent influence of long-term HbA1c, diabetes duration and preceding glomerular hyperfiltration on basement membrane thickness and overall glomerulopathy changes [20]. In contrast, the retrospective study by Lervang et al. [9] found no difference in the initial median GFR between patients with increased compared with normal AER at follow-up 18 years later. One explanation to the diverging results may be that in some of the patients in the latter study, initial data were collected at diagnosis of diabetes i.e. prior to insulin treatment. It is known that, at onset of type-1 diabetes, GFR may be substantially elevated before start of insulin treatment [3]. In a 10-year follow-up study by Yip et al. [10] glomerular hyperfiltration was not found to be a risk factor for diabetes nephropathy. However, our study populations are not comparable regarding age and diabetes duration and the follow-up period in our study is clearly much longer.
The reducing effect of antihypertensive treatment on elevated AER is well known [21]. Therefore, we believe it is justified to classify patients as having micro or macroalbuminuria although AER levels have been normalized due to antihypertensive treatment. In agreement with our previous report [12], the initial high mean HbA1c values had decreased over the years with a rather wide variability of HbA1c. This study had a limited power to detect a clear-cut association between initial HbA1c values and the development of micro or macroalbuminuria. Nor could we find a significant correlation between baseline GFR and baseline HbA1c. However we still adjusted in the analysis by stratification procedures for HbA1c when studying GFR as a predictor.
In conclusion, after a mean diabetes duration of 29 years in this hospital based cohort of Swedish childhood onset diabetic patients, only 12% developed persistent macroalbuminuria and 20% developed microalbuminuria. A screening value of 24-h AER >15 mg/min 18 years before was a strong predictor. Although the present study does not enable us to identify the pathogenic role of glomerular hyperfiltration, a high baseline GFR was also a significant risk factor for the development of macro or microalbuminuria when adjusting for duration.
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Acknowledgments |
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Notes |
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References |
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