Early Post-Transplant Hyperuricemia and Association with Histologic Fibrosis Progression and EMT-Related Changes in Proximal Tubular Cells.

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.