BACKGROUND: Kidney transplant Chronic Allograft Dysfunction (CAD), a major cause of long-term graft failure, is currently diagnosed at a late and irreversible stage by graft biopsies. Our goal was to identify predictive urinary biomarkers of CAD before renal lesions appeared by analysis of the urine proteomic profile. METHODS/METHODS: Twenty-nine urinary samples withdrawn three months post-transplant were analyzed by SELDI-TOF technology. CAD development was evaluated by serum creatinine level and confirmed by allograft biopsy one year after transplantation. Comparison of protein profile of both groups revealed 18 biomarkers predictive of CAD occurrence. RESULTS: The biomarker demonstrating the highest diagnostic performance was a protein of 8860 Da that predicted CAD with a sensitivity of 93% and a specificity of 65%. Moreover combination of these biomarkers in two multivariate analyses improved the diagnostic potential of CAD. Relevance of these individual biomarkers and a decisional algorithm constituted of 3 proteins was confirmed in an independent cohort of patients with undetermined CAD status one year post-transplant. CONCLUSIONS: These non invasive biomarkers, detected as soon as three months post-grafting, allowed identification of patients who would develop CAD as late as 4 years after graft. Systematic measurement of these biomarkers would greatly improve the management of immunosuppressive therapy of kidney grafted patients.