. antibodies (odds ratio, 1.03; 95% CI, 1.01-1.06; = 0.005) were found to be associated with increased risk of de novo TMA. The risk of graft failure was higher in the TMA group at 5 y (hazard ratio [HR], 3.99; 95% CI, 2.04-7.84; 0.0001). Concomitant rejection significantly affected graft prognosis at 5 y (HR, 6.36; 95% CI, 2.92-13.87; 0.001). De novo TMA associated with the active antibody-mediated rejection was associated with higher risk of graft failure at 5 y (HR, 3.43; 95% CI, 1.69-6.98; 0.001) compared with other TMA. Conclusions. Longer cold ischemia and allosensitization play a role in de novo TMA development, whereas TMA as a part of active antibody-mediated rejection was associated with the highest risk for premature graft loss. INTRODUCTION Thrombotic microangiopathy (TMA) is a well-recognized complication affecting the long-term outcome in kidney transplantation.1 Although recurrent TMA in patients with atypical hemolyticCuremic syndrome is a rare event driven mainly by the recipients gene mutation of complement factors and regulatory proteins, de novo TMA is a much more frequent posttransplant pathology that Norverapamil hydrochloride negatively affects graft survival.1-6 The pathogenesis of de novo TMA remains poorly understood. Multiple triggers have been implicated, such as ischemia-reperfusion injury,7 immunosuppression with calcineurin inhibitors (CNIs) or the mechanistic target of rapamycin inhibitors,3, 4 severe antibody-mediated rejection (AMR),5, 8 and viral infections.7 The common pathophysiology of de novo TMA links severe endothelial injury and complement dysregulation.9 The aberrant complement regulation as a response to endothelial injury varies among individuals, which suggests hereditary susceptibility.10 Availability of an assessment of polymorphisms or mutations of genes associated with complement system is not realistic at the time of transplantation. Therefore, better understanding of TMA Norverapamil hydrochloride clinical phenotypes may be of aid to clinicians in therapy modification. Previous clinical descriptions of de novo TMA suffered from small sample sizes and ill-defined control groups. In this large, national, retrospective, multicenter, caseCcontrol study with paired kidney grafts, we evaluated the risk factors for de novo TMA and the outcomes of its clinical phenotypes. MATERIALS AND METHODS Study Cohorts We retrospectively evaluated histological reports of 4487 patients who had undergone kidney transplantation from 2000 to 2019, and we identified 122 biopsies with histologically proven posttransplant TMA (2.7%). To eliminate the effects of the donor-associated Norverapamil hydrochloride risk factors, a control group of paired kidney graft recipients was established. These kidney grafts had been transplanted in transplant centers all over the country. As we focused on donor-controlled recipient risks for de novo TMA, cases with recurrent TMA, donor-derived TMA, living donor transplants, and/or an incomplete data set from both kidney grafts were not included (Figure ?(Figure11). Open in a separate window FIGURE 1. Study flow diagram. TMA, thrombotic microangiopathy. Clinical data were collected from patients medical records, and survival data were collected from the transplant registry. Patient demographics are presented in Table ?Table11. TABLE 1. Demographics and outcomes test or Mann-Whitney U test was used for a simple comparison of groups in univariable analysis. Categorical variables were reported as proportions, and the McNemar test Rabbit polyclonal to BMPR2 was used to compare the groups in univariable analysis. Univariable conditional logistic regression was performed, and variables with value 0.05 was considered statistically significant. The study was approved by the institutional review board of the Institute for Clinical and Experimental Medicine, Prague, Czech Republic. The study is in accordance with the 1964 Helsinki Declaration and Norverapamil hydrochloride its later amendments. The clinical and research activities being reported are consistent with the Principles of the.