Dynamics of immunohistochemical markers of fibrogenesis and kidney functional status in experimental drug-induced nephropathy

Aim. To identify the patterns of drug-induced nephropathy development during prolonged administration of a combination of antibacterial drugs (ABDs) and to determine the role of immune cell infiltration and epithelial-mesenchymal transition (EMT) in its progression.

Materials and methods. The study was performed on 50 male white outbred rats divided into control and experimental groups. Animals in the experimental groups received daily a combination of ABDs used for the treatment of drug-resistant tuberculosis: kanamycin, bedaquiline, linezolid, cycloserine, levofloxacin, para-aminosalicylic acid (PAS), and prothionamide. Euthanasia was performed on days 60 and 120. Blood biochemical parameters – creatinine, urea, and estimated glomerular filtration rate (GFR) – were assessed. Immunohistochemical analysis of CD3, CD20, and vimentin expression in kidney tissue was conducted to evaluate cellular infiltration and fibrotic processes.

Results. By day 60, experimental animals showed statistically significant increases in creatinine (108.03 μmol/L vs. 57.0 μmol/L in controls, p < 0.01) and urea (8.88 mmol/L vs. 5.31 mmol/L, p < 0.01), along with reduced GFR (1.22 mL/min/100 g vs. 1.49 mL/min/100 g, p < 0.01). By day 120, renal function further deteriorated: creatinine rose to 172.91 μmol/L, urea to 11.08 mmol/L, and GFR declined to 1.11 mL/min/100 g (vs. control values of 56.48, 5.43, and 1.49, respectively). Interstitial infiltration by CD3+ and CD20+ cells progressively increased: by day 60–to 26.5 and 31.6 cells/HPF, and by day 120–to 29.6 and 36.5 cells/HPF (p < 0.05), compared to control values of 3.1 and 2.4, respectively. The proportion of vimentin-positive tubules rose from 38.6% on day 60 to 65.7% on day 120 (p < 0.01), indicating active EMT.

Conclusion. Prolonged ABD administration induces chronic kidney injury characterized by azotemia and reduced GFR. The pathogenesis involves immune-mediated inflammation (CD3+ and CD20+ infiltration) and epithelial–mesenchymal transition (vimentin expression). These findings support the need for nephroprotective agents targeting these specific mechanisms.

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