Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) in the United States and one of the most common complications of diabetes mellitus, increasing the risk of cardiovascular disease in individuals with diabetes. Risk factors for developing diabetes-related kidney disease include poor glycemic control, hypertension, older age, dyslipidemia, and genetic factors, among others (1). Jia Xin Huang, MD, et al. (2) recently published an article about the role of acute kidney injury (AKI) and diabetic ketoacidosis (DKA) in the development of proteinuria in children with diabetes.
The study is a well-designed retrospective chart review of 2345 children with type 1 diabetes mellitus (T1DM), cared for in two academic tertiary care children's hospitals in the United States. Children were included if they were diagnosed with T1DM for at least 1 year and had at least one urine microalbumin measurement. The study reports DKA episodes in 41% of the cohort with 560 unique episodes of AKI. A total of 183 children (7.8%) developed microalbuminuria. Similar to previous studies (3), older age at the time of diagnosis of T1DM and higher mean hemoglobin A1c were associated with a higher hazard rate for development of microalbuminuria. Uniquely, the study found that each AKI induced by DKA increased the hazard rate of developing microalbuminuria by a ratio of 1.56 (95% confidence interval, 1.3−1.87). Furthermore, the hazard rate of microalbuminuria increased with the number of AKI-associated DKA episodes, increasing by >3-fold for patients with two AKI episodes and >5-fold for those with four or more AKI episodes. Although the hazard rate increased for moderate or severe DKA episodes, as well as more severe AKI, DKA episodes without AKI were not associated with an increased hazard rate of microalbuminuria.
Despite what is known about AKI episodes increasing the risk of kidney function decline in children with CKD (4, 5), there have been no studies that addressed this matter in children with T1DM. Other strong points about this study are that it included a relatively large number of children with T1DM and a long duration of follow-up (mean of 6.5 ± 3 years), which allow for detection of early microalbuminuria. In the statistical analysis, the authors distinguished between possible and confirmed microalbuminuria, with the latter being based on two abnormal morning urine samples or abnormal 24-hour urine albumin. Such distinction is essential in distinguishing abnormal random urine albumin levels that later normalize on further testing and do not represent true positive screens.
The study had some limitations, primarily related to the retrospective study design. Classification of AKI severity assumed a normal baseline kidney function in all children before the AKI episode. Height measurements used in the Schwartz formula were also estimated in some of the calculations. Furthermore, some DKA episodes might have been missed due to their occurrence in institutions outside of the centers where the study was held. Another limitation to the study was the lack of differentiation between prerenal etiology (as often seen in DKA-induced AKI) and intrinsic AKI. In such cases, checking specific urinary biomarkers (such as neutrophil gelatinase-associated lipocalin) may help differentiate between the causes.
In current clinical practice, urine albumin excretion is used as the primary screening method to detect the onset of diabetic nephropathy. However, several other biochemical markers have been identified that represent different mechanistic factors in diabetes-related kidney disease. Some such markers have been shown to appear much earlier than microalbuminuria (6, 7). With this consideration in mind and combined with the fact that DKA episodes without AKI were not associated with higher risk for microalbuminuria, it should be studied further whether it is the background of diabetes-related kidney disease that increases the risk of AKI in some children in the context of DKA.
AKI has been recognized as a predictor of CKD in both adults and children (8). Although the pathophysiology of this progression remains unclear, it is suspected that AKI in the context of DKA can have the same consequence in individuals with diabetes. Knowing that kidney damage in diabetes is a process that may start as early as the first few years after diagnosis (9), the inflammation, oxidative stress, hypoperfusion, and endothelial dysfunction associated with DKA and/or AKI episodes might accelerate the progression of diabetes-related kidney damage. The study discussed highlights and confirms this association between AKI and microalbuminuria as a sign of diabetic nephropathy. Findings from this study are of substantial importance and are expected to lead to further research exploring the progression of diabetes-related kidney disease and its relation to acute diabetes complications.
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