Rapid and reversible endothelial glycocalyx injury during tyrosine kinase inhibitor therapy in locally advanced or metastatic renal cell carcinoma.

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Background: Endothelial glycocalyx, which coats the luminal surface of vascular endothelial cells, plays a pivotal role in maintaining vascular homeostasis by regulating thrombogenicity, modulating inflammatory responses, and preserving endothelial barrier integrity. Tyrosine kinase inhibitors (TKIs) are associated with vascular toxicities, yet their impact on endothelial glycocalyx integrity remains unclear. Because glycocalyx disruption is an early event in endothelial dysfunction, we investigated whether TKI therapy induces endothelial glycocalyx injury in patients with locally advanced or metastatic renal cell carcinoma (mRCC). Methods: In this retrospective study, 25 patients initiating and 24 patients discontinuing TKIs (axitinib, cabozantinib, lenvatinib, or pazopanib) due to adverse events were analyzed. Plasma hyaluronan levels, a validated biomarker of endothelial glycocalyx injury, were measured before and 1 month after TKI initiation or discontinuation using enzyme-linked immunosorbent assay. Paired comparisons were performed using the Wilcoxon signed-rank test. Differences among agents were evaluated using the Kruskal–Wallis test. Results: Among patients initiating TKIs, plasma hyaluronan levels significantly increased at 1 month (median 117 vs. 218 ng/mL; +75%; P <0.001). No significant differences were observed among the four agents ( P = 0.922). Conversely, in patients discontinuing TKIs due to adverse events, plasma hyaluronan levels significantly decreased (median 221 vs. 135 ng/mL; −37%; P <0.001), without inter-agent differences ( P = 0.865). Conclusions: TKI therapy is associated with rapid and reversible endothelial glycocalyx injury in patients with locally advanced or mRCC. These findings suggest a potential mechanistic link between TKI exposure and vascular toxicity across agents.