In a large sample of adults with type 1 diabetes from Finland, an independent, graded association was observed between the presence and severity of chronic kidney disease and all-cause mortality. In this population, excess mortality associated with type 1 diabetes was only observed in individuals with chronic kidney disease (), whereas mortality in participants without chronic kidney disease (66% of the total cohort) was identical to the general population. These results from a stable, nationally representative cohort of adults with type 1 diabetes complement and extend evidence from the last 2 decades showing the link between mortality and chronic kidney disease (3
). These findings highlight the continuing clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.
Our findings in individuals with type 1 diabetes are analogous to the relation between chronic kidney disease and mortality previously described in individuals with type 2 diabetes (21
) and in nondiabetic individuals (22
).The observed association between chronic kidney disease and mortality can be explained by several plausible mechanisms. It has been suggested that kidney damage in individuals with type 1 diabetes reflects more generalized damage to the cardiovascular system leading to cardiovascular disease and subsequently mortality (23
). The association of mortality with proliferative retinopathy (C
) may be explained in the same way. However, impaired kidney function may also directly contribute to hypertension (24
), oxidative stress, insulin resistance (7
), inflammation (8
), dyslipidemia (25
), elevated plasma homocysteine (26
), the accumulation of advanced glycation end products (27
), anemia (28
), left ventricular hypertrophy (29
), arterial calcification (30
), and endothelial dysfunction (31
). Chronic kidney disease is also associated with impaired immune function, which, alongside vascular compromise, probably contributed to the increased frequency of death from infection observed in those with chronic kidney disease.
The observed hazards associated with each stage of kidney disease are similar to those reported in cohort studies >20 years ago (3
), although the absolute mortality in the FinnDiane cohort is significantly lower. Although it is possible to argue that improvements in diabetic management have not led to changes in the relative risk of mortality in individuals with chronic kidney disease, there is little doubt that the absolute risk reduction has been considerable over this time period, via the prevention of chronic kidney disease, and the management of individuals with proteinuria (32
) and/or macrovascular disease, who carry the majority of the risk burden. However, the contemporary hazard associated with chronic kidney disease demonstrated in this study emphasizes that more remains to be done to address this enhanced risk beyond currently available regimens.
This study also demonstrates that estimated GFR is an independent risk factor for mortality in type 1 diabetes. Regardless of the level of albuminuria, those with an estimated GFR <60 ml/min per 1.73 m2
were twice as likely to have died during follow-up. In addition, an elevated estimated GFR was also associated with increased mortality (B
), which was identified by nonlinear analysis (). Although it should be noted that the MDRD equation overestimates renal function in this range and that the ability of this formula to discriminate hyperfiltration from normal function is suboptimal (33
), particularly as a single measurement, it was nonetheless able to stratify mortality risk. In so far as hyperfiltration precedes progressive kidney disease (34
), this association is not surprising, and probably reflects early pathological changes both in the kidney and in other parts of the vasculature.
Although hyperglycemia has been implicated in the development of microvascular complications in type 1 diabetes, an association between glycemic control and mortality has only been observed in some (36
), but not all studies (20
). In the FinnDiane cohort, glycemic control was also independently associated with all-cause mortality (). A significant association between A1C and mortality was also present in individuals with a kidney transplant, consistent with previous reports (38
). However, when modeled as a linear variable, no clear association was observed between A1C and mortality in individuals with normo- or microalbuminuria (P
≥ 0.38). It is possible that this reflects a type II error due to the lower number of deaths in these subgroups. However, when modeled as a multivariate cubic spline (), there was no interaction between A1C and albuminuria (P
> 0.34) in determining mortality, suggesting the impact of poor glycemic control is homogeneous across all levels of albuminuria.
Strengths of our study include its large cohort of individuals with type 1 diabetes, high participation rate, access to subsidized care (75–100% of costs), and contemporary treatment regimens, including a range of insulin regimens, statins, blockers of the RAS, and self-monitoring technologies. Our methods of measuring UAE and serum creatinine were reliable, validated centrally using standardized methodologies. We used validated methods to identify deaths, and all deaths in our cohort were confirmed through death records. Surveillance bias is unlikely, given the uniform vital status follow-up procedures used by our staff masked to participants' chronic kidney disease status levels. In our questionnaire, we had broad data on tobacco or alcohol use, diet, education, socioeconomic status, other possible confounders (e.g., insulin resistance), or the severity of disease (e.g., level of blood pressure). Finally, few changes in diabetes treatment and health care over the short study period will have affected mortality results.
Several study limitations need to be considered. First, our study results may not be generalizable because of selection bias in enrollment and subsequently in ascertainment. Our study was conducted among adults with long-standing diabetes. Consequently, our results may reflect past management practices that are less generalizable to adults with newly diagnosed diabetes. These studies were also limited by the use of broad definitions of diminished kidney function and the inclusion of relatively small numbers of subjects with renal impairment, thus reducing the statistical power to examine different levels of reduced estimated GFR. It is also likely that our clinical history was not sufficiently sensitive to accurately discriminate between the presence or absence of macrovascular disease in this population, given that diabetes is often associated with silent ischemia and that subjects with type 1 diabetes can often have a normal resting electrocardiogram and still have suffered a previous myocardial infarction or have significant coronary lesions (39
). Such standardized exercise testing and/or coronary imaging was not feasible in a large study such as FinnDiane. Consequently, the true contribution of underlying macrovascular disease to the observed changes in mortality cannot be ascertained in this study. Nonetheless, a reliance on clinical history is potentially more representative of the true clinical setting. Changes in medications and risk factor control during follow-up cannot be controlled for. Finally, it is possible that our results were biased by residual confounding by factors not measured in the study but potentially related to cardiovascular disease/mortality in type 1 diabetes, including silent cardiovascular disease, lipoprotein subclasses (40
), oxidative stress (41
), and endothelial (31
) and autonomic dysfunction (42
In conclusion, results from our study clearly demonstrate that chronic kidney disease is the dominant contributor to excess mortality in type 1 diabetes. Consequently, if you have type 1 diabetes, prevention of chronic kidney disease is currently the best way to reduce your risk of a premature death. Modern multifactorial therapeutic approaches, such as those detailed in American Diabetes Association guidelines, are effective in preventing the development of kidney disease. For those with established chronic kidney disease, more intensive multifactorial interventions are also valuable in reducing the progression of chronic kidney disease, and, with it, mortality.