Markers of inflammation, fibrosis, endothelial dysfunction, and podocytopathy in patients with long-term type 1 diabetes mellitus

BACKGROUND: A comprehensive assessment of biomarkers involved in the development of systemic inflammation in patients with long-term type 1 diabetes mellitus (T1D), accompanied by the development and progression of cardiac and renal pathology, may allow stratification of patients according to specific inflammatory activity and help in the search for new therapeutic prevention and treatment options.

AIM: To evaluate markers of inflammation, fibrosis, endothelial dysfunction, and podocytopathy in patients with prolonged course of T1D (≥ 20 years).

MATERIALS AND METHODS: The study consisted of 2 stages. In the first stage, a single-center, cross-sectional study of 133 patients was conducted. Of these, 87 patients with 10-year data available were included in the second stage of the study with dynamic assessment of parameters. All patients were examined and treated at the Endocrinology Research Centre of the Ministry of Health of Russia from 2011 to 2024. Patients were divided into several groups: without chronic kidney disease (CKD) and with CKD at different stages. In addition to standard laboratory parameters, the levels of matrix metalloproteinase-9 (MMP-9), brain natriuretic hormone (NT-proBNP), transforming growth factor beta-1 (TGF-β1), asymmetric dimethylarginine (ADMA), monocyte chemotactic factor-1 (MCP-1), osteopontin, and tumor necrosis factor receptors type 1 (TNFRSF1A) and type 2 (TNFRSF1B), cystatin C in blood, nephrin, podocin in urine were studied using commercial kits in accordance with manufacturers’ recommendations. Based on the values of the regression coefficients, the estimated glomerular filtration rate (eGFR) showed an inverse relationship with the development of chronic heart failure (CHF), while podocin exhibited a positive relationship with acute kidney injury (AKI). The risk of CHF decreased with every 1 mL/min/1.73 m² increase in eGFR, OR=1.12 (95% CI: 1.02–1.22, P=0.015). The risk of AKI increased with every 1 ng/mL increase in podocin level, OR = 1.43 (95% CI: 1.01–2.03, P=0.047).

RESULTS: According to the criteria of CKD, preserved kidney function was observed in 43.2% of patients (n=54), the rest were at various stages of CKD. The prevalence of late complications of diabetes among the examined patients was high and increased as renal dysfunction progressed. Individuals with CKD showed increased levels of ADMA (P<0.005), TNFRSF1A and TNFRSF1B (P<0.001) and decreased levels of TGF-β1 (P<0.006) compared with those without CKD. In the dynamic control group (n=87), statistically significant increases in the levels of TGF-β1, nephrin, podocin, a decrease in the estimated glomerular filtration rate (eGFR) (P<0.001), and a statistical trend towards an increase in cystatin C during the follow-up period against the background of progression of renal and cardiovascular pathology were detected. In the same group, an inverse correlation (strong and noticeable) was determined between eGFR and TNFRSF1A and TNFRSF1B, ADMA.

CONCLUSION: In individuals with a long history of T1D, a significant role of factors of endothelial dysfunction, inflammation and fibrosis, podocytopathy in the development and progression of CKD with involvement of the cardiovascular system in the pathological process has been determined.

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