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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 10 3814-3820
Copyright © 2006 by The Endocrine Society

Long-Term Mortality and Incidence of Renal Dialysis and Transplantation in Type 1 Diabetes Mellitus

M. Stadler1, M. Auinger1, C. Anderwald1, T. Kästenbauer, R. Kramar, C. Feinböck, K. Irsigler, F. Kronenberg and R. Prager

Division of Genetic Epidemiology (M.S., F.K.), Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck 6020, Austria; Third Medical Department of Metabolic Diseases and Nephrology (M.S., M.A., C.F., R.P.), Lainz Hospital, Vienna 1130, Austria; Ludwig Boltzmann Institute of Metabolic Diseases and Nutrition (M.S., T.K., C.F., K.I., R.P.), Vienna, Austria; Division of Endocrinology and Metabolism (C.A.), Department of Internal Medicine 3, Medical University Vienna, Vienna 1090, Austria; Austrian Dialysis and Transplantation Registry (R.K.), Klinikum Kreuzschwestern, Third Internal Department, Wels 4600, Austria; and Karl Landsteiner Institute of Metabolic Diseases and Nephrology (M.S., M.A., T.K., R.P.), Vienna, Austria

Address all correspondence and requests for reprints to: Marietta Stadler, M.D., Hietzing Hospital, Third Medical Department, Wolkersbergenstrasse 11130 Vienna, Austria. E-mail: marietta.stadler{at}wienkav.at.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 References
 
Aims: We investigated long-term mortality and requirement of renal replacement therapy (RRT) in type 1 diabetes mellitus (T1DM) to study risk factors and late complication incidence of T1DM in a prospective cohort study at Lainz Hospital, Vienna, Austria.

Methods: In 1983–1984, T1DM patients [n = 648; 47% females, 53% males; age, 30 ± 11 yr; T1DM duration, 15 ± 9 yr; body mass index, 24 ± 4 kg/m2; glycated hemoglobin (HbA1c), 7.6 ± 1.6%] were stratified into HbA1c quartiles [1st, 5.9 ± 0.5% (range, 4.2–6.5%); 2nd, 6.9 ± 0.3% (6.6–7.4%); 3rd, 7.9 ± 0.3% (7.5–8.4%); and 4th, 9.6 ± 1.3% (8.5–14.8%)]. Twenty years later, both endpoints (death and RRT) were investigated by record linkage with national registries.

Results: At baseline, creatinine clearance, blood pressure, and body mass index were comparable among the HbA1c quartiles, whereas albuminuria was more frequent in the 4th quartile (+15%; P < 0.03). After the 20-yr follow-up, 13.0% of the patients had died [rate, 708 per 100,000 person-years (95% confidence interval, 557–859)], and 5.6% had received RRT [311 per 100,000 person-years (95% confidence interval, 210–412)]. Patients with the highest HbA1c values (4th quartile) had a higher mortality rate and a greater incidence of RRT (P < 0.04). In the Cox proportional hazards analysis, age, male gender, increased HbA1c, albuminuria, and reduced creatinine clearance were predictors of mortality (P < 0.05). Predictors of RRT were albuminuria (P < 0.001), reduced creatinine clearance (P < 0.001), and belonging to the 4th HbA1c quartile (P = 0.06). In Kaplan-Meier analysis, mortality was linearly associated with poor glycemia, whereas RRT incidence appeared to rise at a HbA1c threshold of approximately 8.5%.

Conclusion/Interpretation: In the Lainz T1DM cohort, 13.0% mortality and 5.6% RRT were directly associated with and more frequently found in poor glycemia, showing that good glycemic control is essential for the longevity and quality of life in T1DM.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Conclusions
 References
 
TYPE 1 DIABETES MELLITUS (T1DM) is associated with severe late complications, including end-stage renal failure, which may result in renal replacement therapy (RRT) (1). In addition, mortality rates are high in patients with T1DM (1). Interestingly, during the first 20 yr of T1DM, most of the excess mortality is attributed to renal failure; after this period, it is considered to result largely from cardiovascular events (2, 3).

Comparative studies in Finland, Japan, and the United States have reported conflicting data concerning mortality in T1DM patients. The Diabetes Epidemiology Research International (DERI) Study compared mortality among T1DM patients, based on population-based registries from different countries. After follow-up periods of 16 to 18 yr, Japanese T1DM patients had a 2-fold higher mortality rate than those in Finland (4). The Allegheny cohort in the United States revealed a mortality rate similar to that in Japan (4, 5, 6). Analysis from the Finnish Diabetes register revealed a cumulative mortality of 6.8% at 20 yr and 15.0% at 30 yr after diabetes diagnosis, and the cumulative incidence of end-stage renal disease was 2.2 and 7.8%, respectively (7). However, neither the DERI study nor the latter study provided data on the patients’ glycemic control or kidney function.

After a 10-yr follow-up, 22% of Danish T1DM patients had died. On the other hand, a German study reported a relatively lower mortality rate of 7% after 10 yr, whereas the incidence of RRT in those patients was 5% (8, 9). The Pittsburgh Epidemiology of Diabetes Complications Study (EDC) revealed a decreasing trend by diagnosis year for mortality and renal failure. At 30-yr disease duration, cumulative mortality decreased from 39 to 29%, and renal failure rates decreased from 31 to 18% (10).

This study was initiated in the early 1980s to assess the future need for RRT in patients with T1DM and to ensure an adequate supply of dialysis units at Austria’s largest diabetes outpatient ward. The primary aim of this prospective study was to investigate mortality and the incidence of RRT in 648 T1DM patients after 20 yr of observation. A further aim was to determine the most predictive risk factors for premature death and renal failure in these patients, who had undergone a precise clinical baseline examination.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Conclusions
 References
 
Study design: prospective cohort study

Patients. In 1983 and 1984, 648 patients with known T1DM were admitted to the outpatient ward of the 3rd Department of Medicine at Lainz Hospital, now called Hietzing Hospital (Vienna, Austria), for routine annual examinations. T1DM had been diagnosed before the age of 30 yr in all patients, and insulin treatment had been started within the first year after diagnosis. The patients were included in the chronological order of their examinations, so that all type 1 diabetic patients of our outpatients ward at that time became study participants. The examination included precise history taking, an anthropometric assessment, and clinical examination. Blood was taken for routine laboratory measurements, including glycated hemoglobin (HbA1c) and serum creatinine. Overnight urine samples were collected for albuminuria screening. Patients consented in writing to the investigation procedure and to their data being recorded and processed. The data collected at the baseline investigation constituted the basis of the present study.

Laboratory procedures. HbA1c was measured with a HPLC device (Diamat, Bio-Rad, Munich, Germany). Determination of albumin in urine was performed with urine dipsticks (Combur8Test; Roche Molecular Biochemicals, Mannheim, Germany). In case of a positive result, subsequent quantitative analysis was performed to distinguish between micro- and macroalbuminuria. Urine samples containing microalbumin concentrations between 30 and 299 µg/min were considered as microalbuminuric, and concentrations of 300 µg/min and above were macroalbuminuric. Creatinine clearance and glomerular filtration rate (GFR) were calculated using the Cockcroft-Gault and Modification of Diet in Renal Disease 2 (MDRD 2) formulas, respectively (11, 12).

Endpoint assessment. To analyze the patients’ mortality and the incidence of RRT, we performed a computer-assisted record linkage with the national death registry (Statistics Austria) and the Austrian dialysis and transplantation registry (ÖDTR, Wels, Austria). The national death registry notes all deaths, including their dates and causes, whereas the ÖDTR records all patients with end-stage renal disease receiving hemodialysis or peritoneal dialysis and/or kidney transplantation (13).

Statistical analysis

Overall and gender-specific mortality rates and the RRT incidence per 100,000 person-years follow-up were calculated. To assess the effects of glycemic control, patients were stratified into baseline HbA1c quartiles (Table 1Go). Differences between groups were assessed by performing {chi}2 tests for categorical variables. Continuous variables were analyzed with ANOVA or Kruskal-Wallis and post hoc testing using the Student-Newman-Keuls test and the Dunn test, respectively. Mortality and the incidence of RRT were analyzed with Kaplan-Meier curves. The log-rank test was used to determine statistical differences between the survival curves with respect to HbA1c quartiles and gender. Multiple Cox proportional hazards regression analysis was used to calculate adjusted risk estimates, based on the data of all T1DM patients whose baseline HbA1c values were available (n = 500). The model describing mortality risk and RRT used survival time and RRT-free survival as dependent variables, respectively. Baseline characteristics of surviving and deceased patients, and patients with and without RRT, respectively, whose values differed at a P value < 0.10, were considered for the Cox regression analysis. The final model was verified by forward stepwise Cox regression analysis. All statistical calculations were performed with SPSS (SPSS Inc., Chicago, IL), STATISTICA (StatSoft, Tulsa, OK), and/or MedCalc (MedCalc Software, Mariakerke, Belgium) computer software. Data are presented as means ± SD unless otherwise indicated. For differences between groups, the level of significance was set at P < 0.05.


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  		TABLE 1. Baseline patient characteristics, mortality, and the incidence of RRT in the total cohort, in women and men, and according to baseline HbA1c quartiles

 

   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Conclusions
 References
 
Baseline characteristics.

Table 1Go shows major anthropometric and clinical data of the total cohort, both genders, and HbA1c quartiles. At baseline, patients were 29.9 ± 11.2 yr old, had a disease duration of 15.2 ± 8.8 yr, and had experienced onset of the disease at the age of 15.5 ± 7.8 yr.

Women and men did not differ in terms of HbA1c, age, diabetes duration, diabetes onset, prevalence of micro- and macroalbuminuria, and body mass index (BMI), but men had higher blood pressure, creatinine clearance, and GFR than women.

When divided into baseline HbA1c quartiles, the patients did not differ in terms of BMI, blood pressure, creatinine clearance, or GFR. However, patients in the 4th HbA1c quartile were younger and had a shorter diabetes duration compared with the 2nd (P < 0.03), but not the 1st or 3rd quartiles. Prevalence of microalbuminuria was approximately twice as high in the 4th compared with the 1st (P < 0.03), but not the 2nd and 3rd quartiles. Macroalbuminuria was approximately twice as frequent in 4th as in 1st and 2nd quartiles (P < 0.005).

Overall mortality and the incidence of RRT.

Eighty-four patients (13%) died during the observation period, resulting in a mortality rate of 708 per 100,000 person-years [95% confidence interval (CI), 557–859]. The main causes of death were vascular events (38%; n = 32), followed by diabetes-associated deaths (29%; n = 24), and malignancy (17%; n = 17) (more precisely listed in Table 2Go). Thirty-six patients (5.6%) received RRT [incidence of 311 per 100,000 person-years (95% CI, 210–412)] (Table 1Go), and more than half (n = 19) of them underwent at least one kidney transplantation during the subsequent follow-up period.


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  		TABLE 2. The underlying causes of death as documented on the death certificates for the total cohort, women, and men

 
Gender-related differences in mortality and the incidence of RRT.

Men had a higher mortality rate than women (P < 0.02; relative risk, 1.6; 95% CI, 1.1–2.4; Fig. 1AGo and Table 1Go). However, men and women did not differ with regard to the incidence of RRT (Fig. 1BGo and Table 1Go).


Figure 1
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  		FIG. 1. Overall mortality (A) and overall incidence of RRT (B) from the baseline examination to the end of the study are analyzed with Kaplan-Meier curves. Men are represented by thick lines and women by thin lines.

 
Mortality and the incidence of RRT in the HbA1c quartiles.

Mortality increased linearly, starting with 7.1% in the 1st quartile of HbA1c and peaking at 18.9% in the 4th quartile (overall, P < 0.01) (Table 1Go and Fig. 2AGo). The 1st and 4th HbA1c quartiles did not differ in any of the baseline characteristics, except for higher prevalence of micro- and macroalbuminuria in the latter (Table 1Go).


Figure 2
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  		FIG. 2. Kaplan-Meier estimates of survival curves for baseline HbA1c quartiles. The HbA1c quartiles 1 (Q1, black squares), 2 (Q2, white triangles), 3 (Q3, black triangles), and 4 (Q4, white squares) are compared for (A) survival and (B) the incidence of RRT until the end of the study.

 
Compared with the 1st HbA1c quartile, the 4th HbA1c quartile revealed a greater incidence of RRT (4th, 9.4% vs. 1st, 2.4%; P < 0.04) (Table 1Go and Fig. 2BGo). The incidence of RRT was also higher in the 4th quartile (9.4%) when compared with the pooled 1st to 3rd HbA1c quartiles (4.0%; P < 0.04).

Multiple Cox proportional hazards regression analysis

Survival. Surviving and deceased patients differed in terms of gender, the incidence of RRT, diabetes duration, age, blood pressure, BMI, HbA1c, creatinine clearance, GFR, and prevalence of micro- and macroalbuminuria. These variables were therefore included in the first model. The stepwise forward regression performed with the remaining variables revealed that increased HbA1c, prevalence of micro- or macroalbuminuria, higher age, reduced creatinine clearance, and male gender independently increased the risk of death (Table 3AGo). Mortality risk increased by 21% with every percentage point HbA1c increment, and male gender was associated with a 2-fold higher risk. Mortality risk increased approximately 2-fold and 4-fold in patients with micro- and macroalbuminuria, respectively, compared with patients with normoalbuminuria (Table 3AGo). Because creatinine clearance and prevalence of albuminuria (both parameters of renal function) were not independent of each other, we designed a second model without the parameter albuminuria. In this model (Table 3BGo), predictors of survival remained the same as in the first model, and the estimates remained almost the same.


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  		TABLE 3. Association of different variables with all-cause mortality and the incidence of RRT using multiple Cox proportional hazards regression models

 
RRT-free survival. Patients with RRT differed from patients without RRT in terms of diabetes duration, age of diabetes manifestation, blood pressure, creatinine clearance, prevalence of micro- and macroalbuminuria, and HbA1c. Stepwise forward Cox regression revealed that higher creatinine clearance and absence of micro- or macroalbuminuria were predictors of RRT-free survival. The hazard ratio for RRT was approximately 3-fold increased in patients with microalbuminuria compared with patients with normoalbuminuria and increased an additional approximately 3-fold in patients with macroalbuminuria in comparison with microalbuminuric T1DM patients (Table 3CGo). In a model without the factor albuminuria (Table 3DGo), RRT-free survival depended on both creatinine clearance and HbA1c quartile (Table 3DGo), the latter indicating that patients of the 1st to 3rd HbA1c quartiles had an approximately 2-fold longer RRT-free survival (P = 0.06 vs. patients of the 4th HbA1c quartile).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Conclusions
 References
 
In this prospective study, we examined mortality and the incidence of RRT in a cohort of 648 T1DM patients and performed a risk factor analysis. After a 20-yr observation period, 13.0% of the patients had died (mortality rate, 708 per 100,000 person-years), and 5.6% had received RRT (incidence of RRT, 311 per 100,000 person-years), indicating a markedly higher risk for these endpoints in the presence of poor glycemic control and diabetic nephropathy. Factors at baseline that were associated with a greater risk of mortality were higher age, higher HbA1c values, presence of micro- or macroalbuminuria, lower creatinine clearance, and male gender, whereas the presence of micro- or macroalbuminuria and reduced creatinine clearance were also predictors for RRT. Patients in the 4th HbA1c quartile had a 2-fold higher risk for RRT.

Mortality.

The mortality rate in the Lainz cohort was comparable to that in other large study populations in the United States and Japan but, interestingly, nearly 2-fold higher than that reported in Finland (4, 5). A more precise comparison with these reports is hindered by the fact that the latter studies provided no information on glycemia or late complications of diabetes (4, 14).

In continental Europe, very few studies have examined the long-term survival of T1DM patients. According to the Finnish Diabetes register, mortality was 15.0%, and incidence of end stage renal disease was 7.8% at 30 yr after diabetes diagnosis (7). After 20 yr of observation, patients of the Lainz cohort had a mean diabetes duration of approximately 35 yr. We reported approximately 13% mortality and 6% RRT incidence, which is comparable to the Finnish study (7). The Pittsburgh EDC Study revealed a decreasing trend by calendar year of diagnosis for mortality and renal failure. After a 20-yr disease duration, cumulative mortality fell from 22 to 3.5%, and renal failure rates from 35 to 7%; at 30 yr, from 39 to 29% and from 31 to 18%, respectively (10).

In line with our data, a Danish T1DM study reported a 12% mortality rate after a mean diabetes duration of 20 yr (15). In contrast, a more recent Danish T1DM study reported a 21% mortality rate after a short observation period of 10 yr. The dramatically increased mortality in the latter study is due not only to the longer diabetes duration at baseline and the higher age of the participants but also to poorer glycemic control compared with our patients (8). Significantly, our patients with poorest glycemic control (4th HbA1c quartile) showed a nearly identical mortality rate (19%) (8).

We found that glycemic control is not only a strong and independent, but also a linear, predictor of survival because each percentage point increment of baseline HbA1c increased the risk of mortality by 21%. Presence of micro- and macroalbuminuria was highest in the highest HbA1c quartile, reflecting highest prevalence of nephropathy in patients with bad glycemic control. Nephropathy, age, and gender were also predictors of survival, which is in line with several other reports (1, 9, 15, 16, 17, 18).

RRT incidence.

We found that nephropathy and increased HbA1c are also risk factors for RRT. In our study, the patients’ HbA1c quartiles at baseline did not differ in terms of creatinine clearance but did differ with respect of glycemia. The poor glycemic control in the 4th HbA1c quartile was also reflected in significantly increased prevalence of micro- and macroalbuminuria at baseline.

Within 20 yr, 5.6% of our patients needed RRT. Whereas the first three HbA1c quartiles had a similar requirement of RRT (4.0%), the incidence of RRT in patients in the 4th HbA1c quartile was significantly higher (9.4%; P < 0.04). A large German study on T1DM patients with a mean baseline HbA1c of 8.3% registered a 5% incidence of RRT within a short follow-up period of 10 yr (9, 16). The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) comprising 1210 T1DM patients with a mean baseline HbA1 of 10.0% (corresponding to an HbA1c value of 9.4%), reported a 14% incidence of end-stage renal failure within 10 yr (1). Despite the 2-fold longer observation period in our study, we registered a relatively low RRT rate of 5.6%.

HbA1c.

It has been known for a long time that poor glycemic control featuring high HbA1c values is associated with progression of diabetic nephropathy and higher mortality in T1DM (19, 20). The WESDR (21) suggests that about 70% of the incidence of renal insufficiency might be attributed to poor glycemic control (HbA1 > 8.8%, corresponding to HbA1c > 8.2%). The bivariate Kaplan-Meier analysis showed that the relative risk of RRT rises markedly at an HbA1c threshold of 8.5%, whereas multiple regression analysis revealed that status of nephropathy is most predictive of this endpoint. Of note, our patients with poorest glycemic control (4th HbA1c quartile) also showed the highest prevalence of micro- and macroalbuminuria at baseline. It may be concluded that the development of diabetic nephropathy and subsequent renal failure is fostered above this HbA1c threshold. Interestingly, the existence of a glycemic threshold for the development of long-term complications has been under debate for more than 10 yr. Whereas the Diabetes Control and Complications Trial (DCCT) group did not find any HbA1c threshold, Krolewski et al. (22) defined an HbA1c level of 8.1% as the threshold for developing renal damage (22, 23). Taken together, our findings could support an HbA1c target less than 8.5% for the prevention of RRT. However, with regard to long-term survival, the linear direct association between HbA1c and mortality indicates the absence of any glycemic threshold for longevity.

Micro- and macroalbuminuria.

Early stages of diabetic nephropathy with micro- or macroalbuminuria have long been known as important risk factors for end stage renal failure and mortality. Thus, our findings confirm the results of several prospective studies performed in Europe (9, 16) and the United States (1, 17) and outline the clinical importance of screening for micro- and macroalbuminuria.

Gender-related differences.

The risk of mortality was higher among men than among women, whereas the incidence of RRT revealed no gender-related difference. At baseline, both genders did not differ in terms of age, diabetes duration, prevalence of micro- or macroalbuminuria, and BMI, but men had higher blood pressure and creatinine clearance values than women. These gender-related differences are representative of the general population (24, 25). The leading causes of death in our patients were cardio- and cerebrovascular disease (38%), followed by diabetes-associated deaths with and without renal complications (29%) and malignancies (17%). Interestingly, the relative mortality due to cardiovascular events in the T1DM patients was similar in both genders. This finding is in contrast to observations made in the background population, which reveal a lower cardiovascular risk among women in general but is in line with previous studies on coronary artery disease in type 1 diabetic patients (8, 26, 27, 28).

Limitations.

The Lainz cohort was recruited 20 yr ago and represents a cross-section of T1DM patients who were treated at a highly specialized diabetes center. With regard to the effects of glycemic control, our analysis is based on the baseline parameters. With the advent of therapy changes based on the results of DCCT, glycemic control could have improved also in our patients. Nevertheless, all advances in diabetes therapy were available for all patients at our hospital (independently of the health insurance status) and have most likely improved the outcome of patients of all baseline HbA1c quartiles. Measurement of HbA1c by the Diamat HPLC method was established in Lainz hospital in April 1984. Therefore HbA1c data from patients enrolled before were not available. Statistical analysis (using two-tailed Student’s t test and {chi}2 test) was performed to compare those with and without HbA1c and did not yield any significant differences (data not presented).

The death certificate gives only the main cause of death. The codes "E10.9" (ICD-10) and "250.0" (ICD-9) both translate as "diabetes mellitus (type 1)", but unfortunately no further information on comorbidities was available in these patients.


   Conclusions
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
References
 
In type 1 diabetic patients, long-term mortality is linearly associated with poor glycemic control, whereas the incidence of RRT seems to rise at an HbA1c threshold of 8.5%, showing that good glycemic control is essential for the longevity and quality of life in T1DM. In addition, prevalence of micro- and macroalbuminuria markedly increases risk of mortality and RRT.


   Acknowledgments
 
We thank S. Wagner for her careful editing of this manuscript.


   Footnotes
 
This study was supported by grants from the Austrian National Bank (Project 10787 to R.P. and Project 9331 to F.K.) as well as the Austrian Heart Fund (to F.K.).

Disclosure Statement: The authors have nothing to disclose.

First Published Online August 1, 2006

1 M.S., M.A., and C.A. contributed to this work in equal measure. Back

Abbreviations: BMI, Body mass index; CI, confidence interval; GFR, glomerular filtration rate; HbA1c, glycated hemoglobin; RRT, renal replacement therapy; T1DM, type 1 diabetes mellitus.

Received May 16, 2006.

Accepted July 25, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 References
 

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