Interstitial Lung Disease After Kidney Transplantation and the Role of Everolimus

Background. Kidney transplant recipients are at higher risk of developing pulmonary complications related to immunosuppression, and inhibitor of the mammalian target of rapamycin (mTORi) has been reported as a potential cause. Methods. Five hundred kidney-transplanted patients were retrospectively analyzed for pulmonary complications on the basis of clinical and instrumental data (chest radiography, high-resolution computed tomography, broncho-alveolar lavage, oximetry). Results. We found 26 interstitial lung diseases (ILD) (16%): 12 cases (46.2%) were from infections (42.8% by Pneumocystis jirovecii) and 14 cases of ILD (53.8%) resulted as drug induced ILD (DI-ILD). According to anti-rejection protocols, DI-ILD occurred in 8 patients (57%) while on triple regimen including steroids, everolimus (EVL), and cyclosporine (CyA) and in 6 patients on double regimen with steroids and mTORi: EVL or sirolimus (43%). In ILD+ patients, everolimus trough-concentration (EVLTLC) and cyclosporine (2nd-hour concentration: CyA(C2)) levels were higher than in patients in the same regimen but with ILD (EVLTLC [ng/mL] 9.84 versus 6.85; CyA(C2) [ng/mL] 303.97 versus 298.56). The formula that used the combined blood levels of both drugs (EVLTLC + CyA(C2)/100) resulted in a significant difference between groups of patients (12.88 +/- 1.61 versus 9.83 +/- 1.91). Applying receiver operator characteristic curve (ROC) analysis to detect risk of developing ILD when on combined protocol with EVL and CyA, we obtained an area under the curve of 0.8622 (P = .0081) and 0.9082 (P = .0028), respectively, when using EVLTLC or the combination formula with both drugs. Conclusions. In renal transplant patients, we obtained a relationship of ILD to specific drug concentration. On the basis of ROC analysis, patients on EVL and CyA combined protocol are at risk of ILD when EVLTLC is >9.03 ng/mL or >11.41 when a formula with summation of EVLTLC and CyA(C2) is used.