Role of Matrix Metalloproteinase-9 During Diabetic Ketoacidosis: Results From the Diabetic Kidney Alarm (DKA) Study

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Background: Matrix metalloproteinases (MMPs) are involved in the pathophysiology of acute and chronic kidney disease. However, their role in acute kidney injury (AKI) and proximal tubular dysfunction, a common complication of diabetic ketoacidosis (DKA), is unknown. We examined changes in MMP-9 during and 3 months after episodes of DKA in youth with known or new onset type 1 diabetes (T1D). Methods: Serum samples were collected from youth with DKA at 2 time points: 0-8 hours after starting an insulin infusion and 3 months after hospital discharge. Mixedeffects models evaluated the changes in serum MMP9 and associations with serum copeptin and uric acid and adjustments were made for estimated glomerular filtration rate (eGFR) calculated by serum creatinine and cystatin C. Data are reported as mean and standard deviation (SD) or standard error (SE), or β-estimates and SE for mixed-effects models. Results: We enrolled 40 youth (52% boys, age [mean±SD] 11±4 years, venous pH 7.2±0.1, blood glucose 451±163 mg/dL). 17% of participants (n= 7) met criteria for AKI. Concentrations of MMP-9 were significantly higher during episodes of DKA compared to 3 months follow-up (mean±SE: 1504.6±137 vs. 668.7±159 ng/mL, p=0.0003). At 0-8 hours, participants with AKI had significantly higher MMP-9 (2256.9±310.1 vs. 1344.7±143.5 ng/mL, p=0.01). Higher serum MMP9 was associated with higher serum copeptin, a surrogate marker of vasopressin, (β±SE: 12.4±3.6 per 1 pmol/L increment in copeptin) and higher uric acid (β±SE: 123.9±42.2 per 1 mg/dL increment in uric acid). Conclusions: In our study, DKA and accompanying AKI associated with elevated concentrations of serum MMP-9, a marker of oxidative stress and remodeling, potentially highlighting the underlying mechanisms of kidney injury during DKA. Funding: Other NIH Support - NIH CTSA Grant UL1 TR002535, Private Foundation Support

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