The Incidence, Mechanisms, and Clinical Impact of Tacrolimus-Associated Thrombotic Microangiopathy in Kidney Transplant Recipients: A Multicenter Retrospective Cohort Study

Background: Thrombotic microangiopathy (TMA) represents a critical and potentially devastating complication in kidney transplantation. Characterized by microvascular thrombosis, hemolytic anemia, and organ dysfunction, TMA poses significant risks to kidney transplant recipients. Among these patients, calcineurin inhibitors (CNIs) like tacrolimus have been implicated in TMA pathogenesis due to their ability to induce endothelial injury. This study aims to investigate the incidence of tacrolimus-related TMA and its clinical outcomes, hypothesizing that tacrolimus usage correlates with a higher incidence of TMA and poorer clinical outcomes compared to alternative immunosuppressive therapies. Methods: We conducted a multicenter retrospective analysis utilizing data from the TriNetX global health research network, examining 1252 kidney transplant recipients on tacrolimus and 290 on alternative immunosuppressive regimens. We assessed the incidence of TMA, rates of graft rejection and failure, and 5-year patient survival. Statistical analyses were performed, including adjusted relative risks (RR) and Kaplan-Meier survival curves. Results: The incidence of TMA was significantly higher in tacrolimus-treated patients (40.3%) compared to those on non-tacrolimus regimens (24.4%) (RR = 0.613, 95% CI = 0.495-0.760, P < .001). The 5-year survival rate was notably lower in the tacrolimus cohort (36.1%) compared to the non-tacrolimus group (77.3%) (RR = 0.379, 95% CI = 0.291-0.495, P < .001). Additionally, higher rates of graft rejection (43.1%) and graft failure (38.6%) were observed among tacrolimus recipients. Conclusion: Tacrolimus use in kidney transplant recipients was associated with a higher incidence of thrombotic microangiopathy, increased graft rejection and failure, and reduced 5-year survival. However, these findings are limited by the retrospective design, reliance on diagnosis codes, lack of detailed clinical and medication data, and absence of confounder adjustment. Prospective studies are needed to validate these associations and guide immunosuppressive strategies in high-risk patients.