Competing-Risk Analysis of ESRD and Death among Patients with Type 1 Diabetes and Macroalbuminuria

Abstract

Patients with both type 1 diabetes and CKD have an increased risk of adverse outcomes. The competing risks of death and ESRD may confound the estimates of risk for each outcome. Here, we sought to determine the major predictors of the cumulative incidence of ESRD and pre-ESRD mortality in patients with type 1 diabetes and macroalbuminuria while incorporating the competing risk for the alternate outcome into a Fine-Gray competing-risks analysis. We followed 592 patients with macroalbuminuria for a median of 9.9 years. During this time, 56 (9.5%) patients died and 210 (35.5%) patients developed ESRD. Predictors of incident ESRD, taking baseline renal function and the competing risk for death into account, included an elevated HbA 1c , elevated LDL cholesterol, male sex, weight-adjusted insulin dose, and a shorter duration of diabetes. By contrast, predictors of pre-ESRD death, taking baseline renal function and the competing risk for ESRD into account, included only age, the presence of established macrovascular disease, and elevated cholesterol levels. This competing-risks approach has potential to highlight the appropriate targets and strategies for preventing premature mortality in patients with type 1 diabetes. 22: 537-544, 201122: 537-544, . doi: 10.1681 The presence of overt nephropathy in patients with type 1 diabetes from Finland is associated with an increased risk of premature mortality that is over nine times that observed in the age-gender matched general population. 1 A number of different factors potentially contribute to this risk, including poor glycemic control and dyslipidemia. Epidemiologic understanding of the role different factors may play in these adverse outcomes has potentially been limited by cause-specific analyses that fail to take into account competing risks. 2 In particular, in individuals with macroalbuminuria, the outcomes of death and ESRD have important competing effects. For example, analysis of the predictors of ESRD needs to take into account the risk of dying before ESRD. Equally, the consequence of analyzing the predictors of death while taking into account the (proximal) risk of ESRD effectively limits exposure time to the pre-ESRD milieu and "hastens" exposure to the different risks associated with renal replacement therapy. This kind of analysis may be best performed within the paradigm of a formal competing-risks (Fine-Gray) proportional-hazards regression model, which estimates the cumulative incidence of an outcome while accounting for the competing risks of an J Am Soc Nephrol

Risk for ESRD in Type 1 Diabetes Remains High Despite Renoprotection

“…Finally, the outcomes for patients with T1D and macroalbuminuria appear to vary among treatment centers. Although the current experience of patients of the Joslin Clinic is similar to that of patients in the FinnDiane study in Finland, 13 it appears to contrast strikingly with that of a similar cohort of patients at Steno Memorial Hospital in Denmark. 14 Before renoprotective therapies became standard care, macroalbuminuria heralded progression of nephropathy to ESRD, approximately 50% within 10 years and 75% within 15 years.…”

“…A similarly undiminished risk is reported for Finland. 13 Furthermore, this undiminished risk seems to be true for nondiabetic CKD patients as well. For example in African Americans with hypertensive CKD, progression to ESRD appears relentless, even in a setting that achieved a low BP goal and almost universal renoprotective therapy.…”

Renal Outcomes in Patients with Type 1 Diabetes and Macroalbuminuria

“…Compared with the 16% 10-year cumulative incidence of ESRD reported here, the 10-year cumulative incidence of ESRD was 3%-14% and 13%-30% among participants with macroalbuminuria and baseline eGFR$60 ml/min per 1.73 m 2 in the FinnDiane and Joslin type 1 diabetes cohorts, respectively. 8,9 However, the risk of progression is not absolute: the majority of people with incident macroalbuminuria maintained an eGFR$60 ml/min per 1.73 m 2 through 15 years of follow-up, suggesting that macroalbuminuria does not represent an intractable course to GFR loss. Data from other type 1 diabetes cohorts spanning the last two decades also support stability of GFR in a substantial fraction of people with macroalbuminuria and intact GFR.…”

Differential mortality and the excess burden of end-stage renal disease among First Nations people with diabetes mellitus: a competing-risks analysis

“…Agarwal and associates 25 and Derose and colleagues 26 examined the predictors of end-stage renal disease versus death among people with all-cause chronic kidney disease, as did the FinnDiane Study Group among people with type 1 diabetes. 13 We are not aware of any other population-based studies that have examined the contribution of competing risks to ethnicity-based disparities in diabetes-related endstage renal disease between indigenous and nonindigenous peoples. However, our findings are consistent with the results of a study comparing Pima Indians with onset of type 2 diabetes in youth or adulthood.…”

“…2,6 We previously evaluated the most appropriate competing-risks methodology for analyzing this kind of data 11 and, on the basis of that evaluation, used Fine and Gray models for the current analysis, as has been proposed by others. 13 The limitations of the study include our inability to control for important predictors of end-stage renal disease and death without end-stage renal disease, such as glycemic, blood pressure and lipid control, and related changes in medical practice, such as the introduction of angiotensinconverting enzyme inhibitors, 30 that occurred during the course of the study period. However, these factors would not have affected the difference in age of diabetes onset between First Nations and non-First Nations people.…”