Early Post-Transplant Urinary EGF as a Potential Predictor of Long-Term Allograft Loss in Kidney Transplant Recipients

Abstract

Improved biomarkers are needed to enhance prognostication in kidney transplantation. We evaluated urinary Epidermal Growth Factor (uEGF) as a predictor of long-term allograft loss. We conducted a prospective, single-center cohort study of 290 adult kidney transplant recipients with uEGF measured 3 months post-transplant. The primary outcome was allograft loss, defined as return to dialysis or pre-emptive re-transplantation. Multivariable cause-specific Cox models assessed the independent association between uEGF and allograft loss. Model performance was compared to the iBox prediction model using 7-year time-dependent AUC and Akaike Information Criterion (AIC), with internal validation via bootstrap resampling. Temporal validation was performed in an independent cohort of 203 patients. uEGF correlated with markers of chronic injury, including eGFR, donor age, and interstitial fibrosis. After a median 8.8-year follow-up, lower uEGF was independently associated with allograft loss (adjusted HR 0.19; 95% CI, 0.11-0.32). Adding uEGF to the iBox improved discrimination (AUC 0.72 vs. 0.63) and reduced AIC (383 vs. 394). While results were robust to internal validation, temporal validation did not show an independent association of uEGF with allograft loss. These findings suggest uEGF may provide independent prognostic value, but further studies in larger and more diverse cohorts are needed to confirm its clinical utility.

Keywords: allograft dysfunction; epidermal growth factor receptor; fibrosis; kidney transplant failure; survival analysis.

FIGURE 1

Flowchart.

FIGURE 2

Relationship between allograft loss, death, and uEGF at 3 months post-transplant in univariable survival analysis. (A) Cumulative incidence curves for allograft loss across tertiles of uEGF at 3 months; (B) Cumulative incidence curves for all-cause death across tertiles of uEGF at 3 months; (C) Time-dependent ROC curves for uEGF at 3 months in diagnosing allograft loss, evaluated every 400 days following transplantation. The statistical significance of differences in survival across uEGF tertiles is assessed using Gray’s test. uEGF, urinary Epidermal Growth Factor. ROC, receiver operating curve.

FIGURE 3

Covariates associated with uEGF levels at 3 months post-transplant. (A) Variable importance in explaining uEGF levels at 3 months post-transplant, measured by the total reduction in residual sum of squares in random forest regression analysis. Hyperparameters optimized by 10-fold cross validation were trees = 1,198, mtry = 19 and min_n = 20. Only the top 10 variables contributing most significantly to the model’s predictive performance are displayed. (B) Scatterplot of uEGF and eGFR distributions, with Sperman’s correlation coefficient. uEGF: urinary Epidermal Growth Factor. eGFR: estimated Glomerular Filtration Rate.

FIGURE 4

Cause-specific hazard ratios for allograft loss associated with uEGF levels at 3 months post-transplant. Models 1: uEGF alone. Models 2 and 3: step-forward variable selection. Variables were added sequentially based on significance starting from the null model. Model 2: uEGF and recipient sex. Model 3: uEGF, recipient sex and DSA immunodominant MFI at 3 months post-transplant. Models 4 to 6: variable selection based on random forest importance ranking. Variables identified as most associated with uEGF in the random forest analysis were included. Model 4: uEGF and eGFR. Model 5: uEGF, eGFR and donor age. Model 6: uEGF, eGFR, donor age and recipient age. Model 7: uEGF and iBox (see supplementary methods). uEGF: urinary Epidermal Growth Factor. eGFR: estimated Glomerular Filtration Rate. MFI: anti-HLA donor-specific antibody immunodominant mean fluorescence intensity.

FIGURE 5

Adjusted hazard ratios of allograft loss associated with uEGF levels. Adjusted on average iBox value. The shaded area corresponds to 95% confidence interval. uEGF: urinary Epidermal Growth Factor.

FIGURE 6

Optimism-corrected calibration plot at 7 years of the iBox + uEGF model. Average predicted (x-axis) and observed (y-axis) 7-year risks across quantiles of predicted risk. To reflect the original iBox publication, observed 7-year risks were estimated using the Kaplan-Meier method rather than the Aalen–Johansen estimator.