Evaluation of acute kidney i̇njury in children with diabetic ketoacidosis

Type 1 Diabetes Mellitus (Type 1 DM) is characterized by hyperglycemia due to deficiency of insulin secretion; It is a chronic heterogeneous group of metabolic diseases that cause disorders of carbohydrate, protein, fat metabolism and cause microvascular (nephropathy, neuropathy and retinopathy) and macrovascular (coronary artery disease, peripheral and cerebral vascular diseases) complications and is among the most common chronic diseases of childhood ( 1-3). Diabetic kidney injury is a serious microvascular complication that causes death in Type 1 DM patients (4). The rapid increase in the frequency of DM in recent years indicates that the number of patients who need dialysis treatment and kidney transplantation will increase day by day. For this reason, it is very important to recognize the development of kidney damage as early as possible and to prevent the disease with necessary treatments and to slow its progression (5). Diabetic ketoacidosis (DKA) is the leading cause of hospitalization, morbidity and mortality in children with Type 1 DM (6,7). Despite advances in the diagnosis and treatment of type 1 DM; Approximately 30-50% of children with type 1 DM are diagnosed with DKA at the first presentation (8,9). The risk of renal involvement is high in children with type 1 DM and DKA (10-14). Osmotic diuresis induced by hyperglycemia leads to dehydration, hypovolemia, and renal hypoperfusion, which will cause tubular damage. Decreased renal perfusion causes a decrease in renal reabsorption, and vasoconstriction that develops to compensate for the decreased reabsorption causes a significant decrease in GFR (10,11,15). When type 1 DM is complicated by DKA, acidosis can lead to further worsening of tubular damage with further adverse effects on renal perfusion (10). Most children presenting with severe DKA have fluid loss and dehydration resulting in acute tubular necrosis (ATN). In addition to fluid loss, hyperglycemia can cause tubular damage and inflammation in the kidney (12). Acute kidney injury (AKI); It is a clinical syndrome that occurs with various etiologies, in which the ability of the kidney to maintain fluid-electrolyte and acid-base homeostasis rapidly and suddenly decreases with a decrease in the glomerular filtration rate (GFR), in which serum urea and creatinine concentrations increase (16). AKI develops in 1/5 of patients with type 1 DM and 2/3 of patients with DKA (10,11). This rate increases in recurrent DKA attacks (15,17). Hyperglycemia is known to cause tubule damage. Although both AKI and tubular damage are reversible, they have been associated with an increased risk of future chronic kidney disease (CKD) (11). Therefore, many studies have been conducted to determine the incidence of AKI in DKA in children, to determine risk factors, and to improve outcomes (15,17,18,19). Increased expression of the protein NGAL (Neutrophil Gelatinase-associated Lipocalin) has been shown in damaged renal tubules. It increases earlier than serum creatinine in the detection of AKI (20,21). The fact that NGAL is a tubuloprotein, that it is elevated in the urine at the onset of tubulopathy before glomerular damage begins, and that it is an appropriate marker in the diagnosis of AKI suggested that it may be a marker of renal involvement in children with the diagnosis of DKA. In this study, it is aimed to evaluate the development of AKI and renal tubule functions together with NGAL, which is an early marker of AKI, in children followed up with the diagnosis of DKA. Patients and Methods: 44 patients admitted to the study with DKA [M/F: 19/25; mean age 11.4 ± 4.84 years, median duration of DM 0.9 years (0.45 – 8.64)], 33 patients with Type 1 DM, who were followed up with a diagnosis of Type 1 DM, with appropriate age and gender as the control group, with no diagnosis of chronic disease except DM [M/F: 16/17; mean age 12.1 ± 3.56 years, median DM duration 2.12 (0.89 - 4.18) years] and 33 healthy children [M/F: 14/19; mean age 10.35 ± 4.45 years] were included. Demographic characteristics, clinic, admission serum and urine laboratory values, urinary NGAL values and NGAL/creatinine ratios of the patient and control groups, in patients followed up with the diagnosis of DKA; Urinary NGAL values, serum and urine laboratory values at the time of admission, 12th hour, 24th hour and discharge were evaluated in patients with and without AKI, patients with new and old DM diagnosis, and patients presenting with mild, moderate and severe DKA. Results: Adjusted sodium, serum uric acid, BUN, creatinine, magnesium, hematocrit values and serum osmolarity values were higher in the DKA patient group compared to the control groups. Serum sodium and chlorine levels were lower. Calculated fractional sodium, potassium, magnesium, phosphorus, uric acid, urea excretion values were above and higher than normal, tubular phosphorus reabsorption values were below and lower than normal. There was no significant difference between urinary NGAL and NGAL/creatinine values. A new diagnosis of DM was made in 24 (54.5%) patients with DKA. The mean age, body weight and BMI of patients with newly diagnosed DM were lower than patients with a previous diagnosis of DM. Serum creatinine values were lower. Their estimated GFRs were similar. There was no significant difference between urinary NGAL and NGAL/creatinine values, but they were higher in patients newly diagnosed with DM. 16 (57.1%) of newly diagnosed with Type 1DM children developed AKI. Mild acidosis was seen in 10 (22.7%) patients with DKA, moderate acidosis in 16 (36.4%) and severe acidosis in 18 (40.9%) patients. Admission serum creatinine, BUN, BUN/creatinine ratio values were similar between the groups. Urine protein, microalbumin values, calculated fractional sodium, potassium, phosphorus excretion values and serum osmolarity were higher in the severe acidosis group. There was no significant difference between urinary NGAL and NGAL/creatinine values. AKI developed in 4 (40%) patients with mild DKA, 8 (50%) patients with moderate DKA, and 16 (88.9%) patients with severe DKA. A statistical difference was found between the development of AKI and the degree of acidosis. AKI developed in 63.6% (n=28) of patients with DKA according to the KDIGO (Kidney Disease Improving Global Outcomes) criteria. 16 (57.1%) of the patients had Stage-1, 10 (35.7%) Stage-2, 2 (7.1%) Stage-3 AKI. Serum glucose, creatinine, base deficit, phosphorus, magnesium and calculated fractional potassium excretion values were higher in patients with AKI than in patients without AKI. pH, bicarbonate and estimated GFR values were lower. Between the admission urine NGAL and NGAL/creatinine values, 24-hour urine NGAL values were significantly higher in the AKI group. No risk factor predicting AKI was detected. According to the pediatric modified RIFLE criteria, 57.1% (n=16) of the patients were evaluated as 'risk' and 42.9% (n=12) as 'injury'. There was no difference between the groups in terms of baseline, 12th hour, 24th hour and discharge urinary NGAL values. The initial urine NGAL/creatinine ratio was significantly lower in the group evaluated as injury compared to the patients who did not develop AKI. ROC analysis was performed to determine the role of NGAL/creatinine ratio in the diagnosis of AKI. When the cutoff value of the NGAL/creatinine ratio was taken as 5, the sensitivity was found to be 68% and the specificity as 60%. (Area under curve: 0.741, p: 0.008 , 95% CI 0.58-0.897) Conclusion: It was found that renal tubule function tests were impaired and urinary NGAL and urinary NGAL/creatinine ratios were increased in patients with DKA who developed AKI. The return of kidney damage caused by DKA to normal values within 24 hours with fluid and insulin treatment shows that the renal tubular damage is reversible, but more extensive studies are needed. Keywords: Type 1 DM, DKA, diabetic ketoacidosis, AKI, acute kidney injury, neutrophil gelatinase-associated lipocalin, NGAL.