Background <p>In end-stage renal disease, kidney transplantation reduces mortality risk and is more cost-effective than dialysis. Despite advances in transplantation techniques, long-term graft failure remains a significant issue. This study aims to investigate the simultaneous effect of three longitudinal biomarkers—serum creatinine, Blood Urea Nitrogen (BUN), and hematocrit—on kidney transplant failure in Iranian kidney transplant patients, and across different subgroups.</p> Methods <p>This retrospective cohort study included 731 kidney transplant patients from multiple hospitals in Mashhad, the capital of a northeastern Iranian province, between 2000 and 2015. After applying the inclusion criteria, data from 558 patients were extracted from medical records. Univariate and multivariate joint models were used to evaluate the impact of longitudinal biomarkers on the risk of kidney graft failure. All statistical analyses were performed at a significance level of 0.05.</p> Results <p>The multivariate joint model revealed the association between the three longitudinal biomarkers and the risk of transplant failure. The hazard of kidney graft failure increased with higher log-serum creatinine (mg/dL) levels (HR = 1.373, 95% CI: 1.183–1.682) and higher log-BUN (mg/dL) levels (HR = 1.134, 95% CI: 0.948–1.322), while it decreased with higher hematocrit (%) levels (HR = 0.907, 95% CI: 0.813–0.987).</p> Conclusions <p>The results of this study underscore the importance of multivariate joint modeling for investigating the simultaneous effects of longitudinal biomarkers on the risk of kidney graft failure. This model revealed a simultaneous association between three longitudinal biomarkers—serum creatinine, BUN, and hematocrit—and the risk of graft failure in the study’s population. Regular monitoring of these biomarkers may help identify patients at higher risk of graft failure, enabling closer clinical follow-up and timely intervention to preserve graft function.</p>