Everolimus,Cyclosporine, and Thrombotic Microangiopathy: Clinical Role and Preventive Tools in Renal Transplantation

Introduction

Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation.

Objective

The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy.

Patients and Methods

From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC + (cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC + (C2/100) was performed for patients exposed to mTORi.

Results

Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n = 19) and drug-related TMA (n = 17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P = .006).

Conclusions

Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)] >12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.     

Bilocular pericardial cyst in an aberrant location

Pericardial cysts classically are found in the right or left cardiophrenic angle and rarely are located outside of this location. An 82-year-old man presented with an asymptomatic cystic mass on chest CT-scan located in the upper right mediastinum and measuring 7 x 6 x 4 cm. A follow-up chest CT-scan 12 months later showed that the cyst had increased in size to where it now measured 10 x 9 x 8 cm and was noted to be dislocating and compressing the superior vena cava. The patient underwent surgical excision because of the uncertain diagnosis and the compression of contiguous organs. Two cystic masses were able to be completely excised intact. A definitive diagnosis of double pericardial cyst was histopathologically confirmed. Radiological findings of a pericardial cyst in the upper mediastinum are extremely rare. In particular there have been no reports of bilocular or double pericardial cysts.     

Transection of the popliteal artery caused by exostosis

Two cases of post-traumatic transection of the popliteal artery in patients with exostosis of the lower extremities are reported. This complication does not seem to have been previously described in the literature. The pathogenetic, clinical, diagnostic and therapeutic aspects are analysed.     

Aminophylline treatment of preterm labor

Prevention of neonatal mortality linked to prematurity may be achieved by treating preterm labor, thus allowing fetal lungs to spontaneously develop, or by administering drugs able to enhance pulmonary maturation. The methylxantine derivative aminophylline has been reported to reduce uterine contractility and increase the concentrations of saturated phosphatidylcholine in fetal lungs. Its effectiveness in treating preterm labor and preventing respiratory distress syndrome (RDS) has been evaluated in comparison to the widely used drug ritodrine. In 39 pregnant women with preterm labor the efficacy of aminophylline and ritodrine in delaying the delivery seemed similar. However, while two of the babies born from ritodrine treated mothers died because of RDS, all babies born from aminophylline-treated mothers survived. These data might then confirm the effectiveness of aminophylline treatment to prevent RDS.