We investigated the impact of the presence of diabetes on each cause of mortality using national health insurance data in South Korea. Diabetes has a significant role in the death of patients with major organ diseases. Moreover, we identified that the presence of albuminuria significantly increased the risk of mortality irrespective of DKD stage. In particular, the presence of albuminuria adds to the reduced eGFR and synergistically increased mortality from all causes, endocrine and metabolic diseases, and circulatory diseases. Considering the different impacts of eGFR and albuminuria on each cause of mortality, these results could be a helpful guide for the focus of disease management.
Diabetes is a metabolic disorder that is characterized by hyperglycemia and glucose intolerance. Many complications begin with the chronic hyperglycemic status, and this is accompanied by high mortality and morbidity due to microvascular and macrovascular complications . These vascular complications ultimately involve overall major organ diseases, which might increase the risk of mortality irrespective of the site specificity. In this regard, diabetes is associated with not only cardiovascular death but also other substantial premature deaths from cancer, infectious diseases, external causes, and degenerative disorders [23, 24]. We found that these risks of mortality were incrementally increased according to kidney dysfunction among patients with diabetes. In addition, the presence of albuminuria has a more prominent impact on the increased risk of mortality irrespective of the cause of death.
Albuminuria is a significant early sign that indicates kidney damage in diabetes. In addition, it has also been recognized as a powerful risk factor for adverse clinical outcomes in various clinical settings, including cardiovascular disease [16, 17, 25]. Even a small increase in albuminuria or detection of albuminuria at a single visit significantly increased the risk of major cerebro-cardiovascular events such as cardiovascular death, ischemic stroke, and myocardial infarction . In addition to the presence of albuminuria, reduced eGFR is another independent risk factor for cardiovascular and renal outcomes, so these two variables are considered more suitable for risk assessment than other clinical risk factors in diabetic patients . Although there are limited data to represent the association between these factors and adverse outcomes other than cardiovascular outcome, this study showed a difference in the impact of albuminuria and reduced eGFR according to each cause of death.
The impact of diabetes on the development of cardiovascular disease and cardiovascular mortality has been extensively evaluated for decades [13, 16]. Likewise, similar results were obtained in this study. In particular, the synergistic effect of reduced eGFR and the presence of albuminuria was prominent in death due to circulatory diseases in this study. This finding could be related to the strong association between the severity of DKD and cardiovascular disease. Additionally, we found that subcategories of cardiovascular disease also showed a well-discriminated risk of mortality according to the presence of albuminuria and stage of DKD. Thus, additional attention to albuminuria is necessary for high-risk patients with cardiovascular disease.
In addition to cardiovascular mortality, death from endocrine and metabolic diseases also showed a synergistically increased risk of mortality according to the DKD stage and the presence of albuminuria. Diseases of the endocrine system include not only diabetes and thyroid diseases but also malnutrition, electrolyte imbalances, and acid-base disorder, which could be a common cause of death among patients with advanced kidney disease. However, because the death certificate is completed according to the ICD-10 code, this category could include overall death from diabetes, without evaluation for specific causes. Therefore, a more detailed evaluation of the cause of death in diabetic patients needs to be performed using a well-designed prospective cohort study to improve the accuracy of these vague results.
Interestingly, subjects with DKD stage 1 showed a higher risk of mortality than those with DKD stage 3 for all types of death. Moreover, even subjects with no DKD showed a higher risk of all-cause mortality, death from neoplasms, and death due to diseases of the digestive system than those with DKD stage 2. This could be related to the hazard effect of glomerular hyperfiltration as an independent risk factor for all-cause mortality . Moreover, this relationship was more prominent in diabetic patients, and the risk of mortality in subjects with hyperfiltration was reported to be similar to or even higher than that among subjects with an eGFR < 60 mL/min/1.73 m2 . However, in the separate analysis according to the presence of albuminuria, the impact of hyperfiltration was attenuated. The risk with DKD stage 1 was significantly higher than that with DKD stage 2 but not higher than that with DKD stage 3 for most causes of death except neoplasms. Based on the results of this study, we suggest that the presence of albuminuria synergistically increased the hazard effect of hyperfiltration for all types of death.
Among the indicators representing kidney dysfunction, in addition to the eGFR value, the presence of albuminuria, a kidney damage marker, showed a more prominent impact on the risk of mortality irrespective of specific causes. Moreover, these two markers showed different associations according to each cause of death. This significant finding, based on the nationwide population cohort, has not been commonly identified before. However, there were several limitations of this study to be discussed. First, this study is a retrospective cohort study. Second, we used only the ICD-10 code on the death certificate to determine the cause of mortality. This means that the exact clinical situation at the time of death could not be identified. Third, only qualitative results for albuminuria were used for analysis, and quantitative results were not available in this study. Fourth, despite the study targeting diabetic patients, there was no consideration of the severity of diabetes, disease duration, number of medications, usage of insulin, or presence of complications.
The mortality risk among patients with DM was incrementally increased according to the stage of DKD regardless of the cause of death. In addition to kidney function, the impact of albuminuria on mortality was prominent in all stages of DKD. Even for patients with a favorable eGFR, the presence of albuminuria should be considered a significant marker for mortality.