Diabetes Care 30:3070-3076, 2007 DOI: 10.2337/dc07-0895 © 2007 by the American Diabetes Association
Incidences, Treatments, Outcomes, and Sex Effect on Survival in Patients With End-Stage Renal Disease by Diabetes Status in Australia and New Zealand (1991–2005)
1 Australia and New Zealand Dialysis and Transplant Registry, Woodville, South Australia, Australia Address correspondence and reprint requests to Emmanuel Villar, MD, PhD, ANZDATA Registry, The Queen Elizabeth Hospital, 28 Woodville Rd., Woodville South, South Australia 5011, Australia. E-mail: emmanuel.villar{at}anzdata.org.au
OBJECTIVE—We aimed to update the epidemiology of type 1 and type 2 diabetic patients among the incident end-stage renal disease (ESRD) population in Australia and New Zealand (ANZ) and to determine whether outcome is worse for diabetic women, as described in the general population. RESEARCH DESIGNS AND METHODS—All resident adults of ANZ who began renal replacement therapy (RRT) from 1 April 1991 to 31 December 2005 were included using data from the ANZ Dialysis and Transplant Registry. Incidence rates, RRT, and survival were analyzed. Risk factors for death were assessed using Cox regression.
RESULTS—The study included 1,284 type 1 diabetic (4.5%), 8,560 type 2 diabetic (30.0%), and 18,704 nondiabetic (65.5%) patients. The incidence rate of ESRD with type 2 diabetes increased markedly over time (+10.2% annually, P < 0.0001). In patients aged <70 years, rates of renal transplantation in type 1 diabetic, type 2 diabetic, and nondiabetic patients were 41.8, 6.5 (P < 0.0001 vs. other patients), and 40.9% (P = 0.56 vs. type 1 diabetic patients), respectively. Compared with nondiabetic patients, the adjusted hazard ratio (HR) for death was 1.64 (P < 0.0001) in type 1 diabetes and 1.13 (P < 0.0001) in type 2 diabetes. Survival rates per 5-year period improved by 6% in type 1 diabetic patients (P = 0.36), by 9% in type 2 diabetic patients (P < 0.0001), and by 5% in nondiabetic patients (P = 0.001). In type 2 diabetic patients aged CONCLUSIONS—The incidence of ESRD with type 2 diabetes increased markedly. Despite high access to renal transplants, type 1 diabetic patients had a poor prognosis after starting RRT. Survival improved significantly in type 2 diabetic patients during the study period. Older type 2 diabetic women had a worse prognosis than older type 2 diabetic men.
Abbreviations: ANZ, Australia and New Zealand ANZDATA, Australia and New Zealand Dialysis and Transplant Registry eGFR, estimated glomerular filtration rate ESRD, end-stage renal disease RRT, renal replacement therapy RTx, renal transplantation
Diabetes is associated with high mortality in the general population (1,2). Worse prognosis has also been reported in diabetic women compared with diabetic men (3,4). End-stage renal disease (ESRD) in patients with type 2 diabetes has increased dramatically worldwide during the last few decades, and diabetes is associated with worse survival among patients undergoing dialysis (5–7). Nevertheless, a study in Denmark showed that the survival rate of patients with ESRD who had type 2 diabetes has improved during the 1990–2005 period (8). Available studies on patients with ESRD who have type 1 and type 2 diabetes have shortcomings because analyses were limited to patients with diabetic nephropathy (6–7), did not differentiate the two types of diabetes (9), were short-term (10), or were based on single-center experiences (11). The aim of the present study was to examine the epidemiology and long-term survival of patients with incident ESRD by diabetes status (type 1 diabetes, type 2 diabetes, and no diabetes) in Australia and New Zealand (ANZ) and to determine whether outcomes were different between the sexes among patients with diabetes.
We performed a prospective study including all patients aged 16 years who began chronic renal replacement therapy (RRT) in ANZ from 1 April 1991 to 31 December 2005. We used data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry (5). Patients were followed until death or 31 December 2005. Data collection consisted of information on patient demographic characteristics, cause of ESRD, comorbidities at start of RRT (presence of type 1 diabetes, type 2 diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease, or chronic lung disease; BMI; and smoking status), estimated glomerular filtration rate (eGFR) at the first RRT, details of RRT modality and of renal transplantation (RTx), and date and cause of death. BMI (ratio of weight in kilograms to the square of height in meters at commencement of RRT) was analyzed in categories: underweight <18 kg/m2, normal weight 18–24.9 kg/m2, overweight 25–29.9 kg/m2, and obese 30 kg/m2. Smoking status at the start of RRT was categorized as never, former, or current smoker. eGFR was determined by the simplified Modification of Diet in Renal Disease formula (12) in patients who began RRT after 1 April 1998 because data on serum creatinine before the first RRT were collected after this date.
When appropriate, univariate comparisons were performed using a Times to RTx or to death were examined with Kaplan-Meier models and Cox regression for multivariate analyses. RTx outcomes were examined in patients aged <70 years. Cox models to analyze variations in access to RTx by diabetes status per 5-year periods (1991–1995, 1996–2000, and 2001–2005) were adjusted for age, sex, primary renal disease, comorbidities at the first RRT, BMI categories, and smoking status and were stratified on racial origin, state where RRT was started (seven states in Australia and one in New Zealand), and initial RRT modality. Causes of death were classified into sudden death, cardiovascular, infection, malignancy, and other causes. In survival analyses, death from any cause was the end point. In multivariate survival analysis, diabetes status (type 1 diabetic, type 2 diabetic, or nondiabetic) was the variable of interest. We also examined the evolution of all-cause and cause-specific mortality over 1991–2005 by using the period of the first RRT (1991–1995, 1996–2000, and 2001–2005) as the parameter of interest. Models were adjusted for age, sex, primary renal disease, comorbidities at the first RRT, BMI categories, and smoking status. eGFR at the start of RRT was modeled as a fractional polynomial function (analyses restricted to patients who started RRT from 1 April 1998). Cox regression was stratified on racial origin group, year of the first RRT (1991–2005) with the exception of analysis by period of the first RRT, state where RRT was started, initial RRT modality, and RTx during the study period. We checked for interactions between variables by including multiplicative terms in Cox regression. If significant interactions were found, we performed stratified survival analysis as described above. Validity of the Cox proportional hazard assumption was checked by tests based on Shoenfeld's residuals. All statistical analyses were performed with S-PLUS 6.0 Software Professional Release 2 (Insightful).
Baseline patient characteristics Type 1 diabetic patients were the youngest, and type 2 diabetic patients were the oldest (P < 0.0001) (Table 1). Rates of cardiovascular disease were higher in diabetic than in nondiabetic patients (P < 0.0001). Type 2 diabetic patients had higher average BMI (P < 0.0001). The proportion of current smokers was higher in type 1 diabetic patients (P < 0.0001).
Proportions of type 1 and type 2 diabetes in Caucasoid, in Australian Aboriginal, and in Maori/Pacific Islander patients were 5.3 and 20.9%, 1.5 and 70.9%, and 2.6 and 64.1%, respectively (P < 0.0001). Sex ratios (male to female) in these groups were 1.5, 0.76, and 1.25, respectively (P < 0.0001). Average ages at the first RRT were 58.8 ± 16, 49.9 ± 11.9, and 53.0 ± 12.9 years, respectively (P < 0.0001).
ESRD incidence rates by diabetes status
Standardized incidence rates of ESRD with associated type 2 diabetes rose from 10.6 per million populations in 1991 to 48.8 per million populations in 2005 in Australia. In New Zealand, they varied between 23.9 per million populations in 1991 and 68.7 per million populations in 2002. Across countries, the average annual change was +10.2% per year (+9.6–+10.8%). For incidence of ESRD at age <60 years with associated type 2 diabetes, the increase was +8.7% (+7.7–+9.7%) in Australia and +5.3% (+3.9–+6.8%) in New Zealand. For ESRD at age 60 years with associated type 2 diabetes, the increase was +11.7% (+10.8–+12.6) and +11.5% (+9.7–+13.4%), respectively (P < 0.001 compared with those for patients aged <60 years of the same country). Standardized incidence rates of ESRD without diabetes increased significantly (+1.5% [+1.1–+1.8%] in Australia and +2.9% [+2.1–+3.8%] in New Zealand).
RRT modalities on the 90th day and access to RTx
Crude survival and causes of death
Among type 1 diabetic patients, 627 (48.8%) died during the study period. Proportions of sudden death, cardiovascular, infection, malignancy, and other cause as cause of death were in men and in women 27.2, 40.4, 11.3, 3.3, and 17.8% and 18.7, 34.8, 19.5, 2.0, and 25.0%, respectively (P = 0.01). Among type 2 diabetic patients, 4,997 (58.4%) died. Proportions were 17.9, 42.2, 14.7, 4.6, and 20.6% and 15.7, 41.0, 15.9, 3.7, and 23.7%, respectively (P = 0.01). Among nondiabetic patients, 8,393 (44.9%) died. Proportions were 14.9, 35.7, 13.4, 11.5, and 24.5% and 12.2, 35.4, 15.4, 8.7, and 28.3%, respectively (P < 0.0001). Causes of death were significantly different between patient groups by diabetes status (P < 0.0001). Over time, there was a decrease in adjusted rates of cardiovascular death (adjusted HR 0.96 [95% CI 0.92–0.99] per 5-year period, P = 0.04), death from infectious disease (0.89 [0.83–0.95], P = 0.003), and sudden death (0.88 [0.83–0.94], P < 0.0001), whereas rates of malignancy death increased (1.19 [1.08–1.30], P = 0.0002). These trends were similar in the three patient groups.
Multivariate survival analysis in the whole cohort
Multivariate survival analysis by diabetes status There was a significant interaction between sex and diabetes status (P = 0.0004). Female sex was significantly associated with higher risk for death in type 2 diabetic patients (adjusted HR for death in women versus men 1.08 [95% CI 1.015–1.16], P = 0.02). Sex was not associated with survival in type 1 diabetic (1.12 [0.87–1.46], P = 0.38) and in nondiabetic patients (0.95 [0.91–1.005], P = 0.07).
In type 2 diabetes, there was a significant interaction between sex and age (P < 0.0001). The adjusted HR for death in women versus men was 0.93 (95% CI 0.83–1.04) (P = 0.20) in type 2 diabetic patients aged <60 years (n = 3,762) and 1.19 (1.08–1.30) (P = 0.0003) in type 2 diabetic patients aged No other significant interactions were found with race, cause of ESRD (diabetic nephropathy versus other causes of ESRD), and BMI. Results were unchanged when follow-up was censored at the time of transplant and/or RRT modality switches and when analyses were adjusted for eGFR. In type 1 diabetic patients, survival did not change over time (adjusted HR 0.94 [0.83–1.07] per 5-year period, P = 0.36), whereas it significantly improved by 9% per 5-year period in type 2 diabetic patients (0.91 [0.87–0.95], P < 0.0001) and by 5% in nondiabetic patients (0.95 [0.92–0.98], P = 0.001).
This study in ANZ showed a large increase in the incidence rate of ESRD with associated type 2 diabetes from 1991 to 2005, which was especially marked in type 2 diabetic patients aged 60 years (+11.5% per year). The incidence of ESRD with associated type 1 diabetes remained stable. After adjustment for age, sex, and risk factors for death, type 1 diabetes had a greater effect on survival in patients with ESRD than in type 2 diabetic patients compared with nondiabetic patients. In each patient group, the proportions of cardiovascular, infection, and sudden death decreased over the study period, whereas rates of malignancy death increased. Female sex was associated with worse outcome than male sex in type 2 diabetic patients aged 60 years. This difference did not appear to be explained by the different comorbid conditions, age, race, causes of ESRD, BMI at first RRT, or RRT modalities. The strength of this analysis is that type 1 diabetes and type 2 diabetes are separately reported in a prospective and population-based study. Previous analyses may have been biased because they only included patients with diabetic nephropathy and because nephropathy may have been misclassified if it was not biopsy proven. Despite an increase of about +3% per year in the incidence of childhood type 1 diabetes in ANZ during the last decades (13,14), the incidence of RRT with associated type 1 diabetes remained stable between 1991 and 2005. The difference in trends between general and ESRD populations may indicate improvements in care of type 1 diabetic patients due to treatment with ACE inhibitors and aggressive glycemic control available since 1980 (15). High transplant rates, including simultaneous kidney-pancreas transplant, remained stable over time. The higher risk for death in type 1 diabetic than in type 2 diabetic patients was not explained by risk factors in the multivariate analyses. This difference should be accounted for by differences in diabetes duration and severity or glycemic control. These data were not available for analysis, and the result should be interpreted with this limitation in mind.
For type 2 diabetes, the overall 10.2% annual increase in ANZ is consistent with studies in Europe and the U.S. over comparable periods (6,7). The increase was higher in patients aged
These results highlighted the specific epidemiology of diabetes and ESRD in the Australasian population. Two-thirds of Australian Aboriginal and Maori/Pacific Islander patients with ESRD had type 2 diabetes at the start of RRT, which was significantly different from the situation in the Caucasoid population ( After the first RRT, overall survival was short in type 2 diabetic patients, with median survival times of <3.5 years, similar to reports from Europe (8,11) and the U.S. (9,12). Less than 10% of type 2 diabetic patients received RTx, as in France (20) and the U.S. (21). Adjusted rates of RTx declined over the study period among type 2 diabetic patients but remained stable in the other two groups. Survival rates improved with a decrease in cardiovascular death. We hypothesize that improvements in dialysis management and in cardiovascular treatments may explain this improvement over time.
Moreover, female sex was significantly associated with death in type 2 diabetic patients aged Although it remains controversial (24), worse prognosis has also been reported in women than in men in the non-ESRD diabetic population who do not have diabetes (3,4). In diabetic subjects without chronic kidney disease, most studies have found that this difference was not accounted for by traditional risk factors (25). Higher risk for death in women may be related to interactions between cardiovascular risk factors and menopause (26), a stronger inverse association between coronary disease and cholesterol level in women, and differences in coagulation and in patterns of obesity and hyperinsulinemia (2–4,25,26). In summary, this study confirms that incidences, treatments, and survivals are different between ESRD patients with type 1 and type 2 diabetes. Future studies of patients with ESRD and diabetes should differentiate between these two groups to provide interpretable results. ESRD remains a dreadful complication in patients with type 1 diabetes, and great effort to prevent kidney disease in these young patients is needed. A marked increase in the incidence rate of ESRD with associated type 2 diabetes was seen over the study period. The study emphasizes the burden of ESRD with associated type 2 diabetes in Australian Aboriginal and in Maori/Pacific Islander populations. Prevention of renal impairment (27), nephroprotection in patients with overt nephropathy, early referral to nephrologists (28), and access to RTx (29) may improve the prognosis of type 2 diabetic patients. This study also highlights the poorer prognosis in older type 2 diabetic women compared with older type 2 diabetic men. This finding deserves further explanatory studies.
We acknowledge all registry participants, especially the nephrologists and professionals who collected the data and conducted the quality control studies. The ANZDATA Registry is funded by the Australian Government Department of Health of Ageing, by the New Zealand Ministry of Health, and by Kidney Health Australia. The Registry has also received contributions from various pharmaceutical and dialysis companies on an unrestricted basis. E.V. is supported by research grants from the Hospices Civils de Lyon and from Novartis and Roche.
Published ahead of print at http://care.diabetesjournals.org on 11 September 2007. DOI: 10.2337/dc07-0895. Sponsors have not been involved in any way in the study design, data interpretation, and manuscript editing. The interpretation of reported data are the responsibility of the authors and in no way should be seen as an official interpretation of the ANZDATA Registry. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Received for publication May 8, 2007. Accepted for publication September 8, 2007.
This article has been cited by other articles:
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||