Kidney360 · 2026
Early Post-Transplant Hyperuricemia and Association with Histologic Fibrosis Progression and EMT-Related Changes in Proximal Tubular Cells.
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Kawabe Mayuko, Nakada Yasuyuki, Yamamoto Izumi, Kobayashi Akimitsu, Unagami Kohei, Hirai Toshihito, Omoto Kazuya, Shimizu Tomokazu, Yokoo Takashi, Takagi Toshio, Ishida Hideki
Аннотация
BACKGROUND: Hyperuricemia is common after kidney transplantation and frequently arises with calcineurin inhibitor exposure and reduced graft function. However, its role in development of interstitial fibrosis and tubular atrophy (IF/TA) remains unclear. This study examined the association between post-transplant hyperuricemia and histologic fibrosis progression using clinical and in vitro analyses.
METHODS: We retrospectively analyzed 138 non-diabetic kidney transplant recipients in the Japan Academic Consortium of Kidney Transplantation (JACK) who underwent baseline and follow-up allograft biopsies (mean interval, 4.2 ± 2.2 years). Hyperuricemia was defined as serum uric acid >7 mg/dL in men and >6 mg/dL in women at 6 months post-transplant. The primary outcome was fibrosis progression, defined as an increase of ≥2 Banff ci grades. In parallel, human proximal tubular epithelial (HK-2) cells were exposed to uric acid, and URAT1, α-smooth muscle actin (α-SMA), and E-cadherin expression was assessed.
RESULTS: Hyperuricemia at 6 months was significantly associated with IF/TA progression (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.16-3.77; p = 0.01) and remained significant after adjustment for serum creatinine and early T cell-mediated rejection (adjusted HR, 1.99; 95% CI, 1.05-3.77; p = 0.04). No association was observed with arteriolar hyalinosis progression. In HK-2 cells, uric acid induced dose-dependent α-SMA upregulation and E-cadherin downregulation, consistent with epithelial-mesenchymal transition(EMT).
CONCLUSIONS: Hyperuricemia within the first 6 months after kidney transplantation was independently associated with interstitial fibrosis progression. Experimental data demonstrated EMT-related changes in tubular epithelial cells exposed to uric acid, suggesting a biological link between hyperuricemia and chronic allograft remodeling.
METHODS: We retrospectively analyzed 138 non-diabetic kidney transplant recipients in the Japan Academic Consortium of Kidney Transplantation (JACK) who underwent baseline and follow-up allograft biopsies (mean interval, 4.2 ± 2.2 years). Hyperuricemia was defined as serum uric acid >7 mg/dL in men and >6 mg/dL in women at 6 months post-transplant. The primary outcome was fibrosis progression, defined as an increase of ≥2 Banff ci grades. In parallel, human proximal tubular epithelial (HK-2) cells were exposed to uric acid, and URAT1, α-smooth muscle actin (α-SMA), and E-cadherin expression was assessed.
RESULTS: Hyperuricemia at 6 months was significantly associated with IF/TA progression (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.16-3.77; p = 0.01) and remained significant after adjustment for serum creatinine and early T cell-mediated rejection (adjusted HR, 1.99; 95% CI, 1.05-3.77; p = 0.04). No association was observed with arteriolar hyalinosis progression. In HK-2 cells, uric acid induced dose-dependent α-SMA upregulation and E-cadherin downregulation, consistent with epithelial-mesenchymal transition(EMT).
CONCLUSIONS: Hyperuricemia within the first 6 months after kidney transplantation was independently associated with interstitial fibrosis progression. Experimental data demonstrated EMT-related changes in tubular epithelial cells exposed to uric acid, suggesting a biological link between hyperuricemia and chronic allograft remodeling.