Everolimus Alters the Bronchoalveolar Lavage and Endobronchial Biopsy Immunologic Profile Post-Human Lung Transplantation

Everolimus has recently shown promise in terms of short- and long-term clinical lung transplant outcomes. This study aims to determine the altered lung allograft cellular and cytokine mileau when everolimus is substituted for azathioprine (AZA). Twenty-three stable lung transplantation (LTx) recipients were randomized in a double-blinded study to receive everolimus (13) or AZA (10) plus standard cyclosporine/prednisolone. Bronchoalveolar lavage (BAL) and endobronchial biopsies (EBB) were performed on three occasions (T(0)-T(2)) to elucidate cellular and cytokine profiles via immunocytochemistry, immunohistology and enzyme-linked immunosorbent assay (ELISA) techniques. There were no group differences for demographics or clinical events throughout the study nor baseline cellular/cytokine differences. BAL lymphocyte percentage fell in the AZA group by T(2) (p = 0.05). BAL and EBB CD4 measures significantly declined in the everolimus group by T(2) (p < 0.05). EBB neutrophils rose significantly in the AZA group, with a fall in the everolimus group resulting in a significant difference at T(2) (p = 0.01). In conclusion, everolimus has contributed to potentially important differences in BAL and EBB cellular profiles.     

Everolimus Use in Lung Transplant Recipients

BackgroundMost lung transplantation centers prefer triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. However, to prevent complications and comorbidities caused by tacrolimus, replacing the drug with everolimus has been considered.MethodsThis is a retrospective observational study investigating everolimus switch for different reasons. The population was divided into 3 groups: chronic lung allograft dysfunction (CLAD), kidney impairment, and malignant neoplasm groups. We investigated whether we achieved the goal of the switch and the frequency of rejection, cytomegalovirus and fungal infections, and everolimus adverse effects.ResultsNineteen patients received everolimus therapy, and 5 of these were for CLAD, 7 for tacrolimus nephrotoxicity, and 7 for explant/de novo malignant neoplasm. The patients were followed up for a mean (SD) of 30 (16.7) months under the therapy. The number of acute cellular rejection, cytomegalovirus infection, and aspergillosis infection cases before switch were 7, 13, and 2, respectively, and 7, 2, and 3 after that. The mean values of creatinine and estimated glomerular filtration rate of the whole population after the switch improved with no statistical significance, whereas it was significant in tacrolimus nephrotoxicity group. Three patients in the CLAD group remained stable after switching, whereas 2 progressed. Only 1 of the 7 patients with malignant neoplasms had a recurrence during 31.1 (16.5) months of median follow-up. Eleven cases of everolimus adverse effects occurred in 9 patients (47.3%), with 2 (10.5%) withdrawal events. Kidney impairment (P = .02) and age (P = .05) stood out as significant risk factors for drug adverse effects.ConclusionsAfter lung transplant, everolimus can be a safe alternative for immunosuppression with acceptable adverse effects.     

Reduction in Size of Renal Angiomyolipoma After Treatment With Everolimus in Lung Transplantation Due to Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by abnormal proliferation of immature smooth muscle cells and cystic lung destruction, which determines the prognosis of the disease. The kidney angiomyolipomas are usually very common in this disease and are usually asymptomatic unless complications arise. In the absence of a curative treatment, recent publications show promising results in molecular therapy to prevent functional decline and to control the size of the angiomyolipomas. These therapies include mTOR complex inhibitors, especially sirolimus.We report a case of a patient diagnosed with LAM who underwent lung transplantation with reduction of renal angiomyolipoma size after treatment with the mTOR inhibitor everolimus.     

Renal Function Changes Under Everolimus Plus Cyclosporine or Everolimus Plus Tacrolimus After Heart Transplantation

Everolimus (EVR) can be used with calcineurin inhibitors to reduce the risk of renal dysfunction, with similar immunosuppressive effect. In this study, we compared renal function after heart transplantation (HT) under EVR with cyclosporine (CSA) or tacrolimus (TAC). Between 2004 and 2014, EVR with CSA or TAC was used in 117 HT at the National Taiwan University Hospital. After HT, all patients received corticosteroid, EVR (C0 target 3–8 ng/mL) and CSA (C0 blood level 100–200 ng/mL), or TAC (Co blood level 5–10 ng/mL). Renal function was evaluated before HT, every month after HT for up to 1 year, and then every 3 months for up to 2 years. Blood-drug levels of EVR, CSA, and TAC were also monitored simultaneously with renal function. The estimated mean glomerular filtration rate (eGFR) was 76.5 mL/min/1.73 m² before HT. After HT, the eGFR was 64 mL/min/1.73 m² at the third month, and 64 mL/min/1.73 m² at the end of first year. The difference was significant between pre-HT and post-HT (P?=?.00) during the first year. No significant differences were noted between the CSA and TAC groups. Careful monitoring of blood-drug level and renal function is crucial after heart transplantation. It is concluded that under close monitoring blood-drug level and renal function, it is possible to reach acceptable postoperative renal function with no difference of renal function between EVR plus CSA and EVR plus TAC.     

Indications and Management of Everolimus After Liver Transplantation

Objective

Our aim was to assess our experience with the use and management of everolimus after orthotopic liver transplantation (OLT).

Materials and Methods

Among the 759 patients who underwent transplantation from 1988 to 2008, 25 (3.2%) received immunosuppression with everolimus. Their mean age was 55.6 years. We analyzed indications for use, time between transplantation and introduction of everolimus, as well as its efficacy, side effects, and patient survival.

Results

The indications for everolimus treatment were: extended hepatocellular carcinoma (HCC) in the explanted liver (n = 6; 24%); HCC recurrence during follow-up (n = 4; 16%); de novo tumor (n = 6; 24%); refractory rejection (n = 3; 12%); side effects of calcineurin inhibitors (CNI; n = 3; 12%); and other causes (n = 3; 12%). Mean time between OLT and everolimus treatment was 40 ± 33 months (range, 10 days-178 months). Mean follow-up after conversion was 10 ± 9 months (range, 1.5-25 months). More than half of the patients resolved the event for which the drug was indicated: 75% of patients with refractory rejection; 60% of those with renal insufficiency; and 100% of those converted for neurotoxicity or hepatotoxicity. Two patients with recurrent HCC and 1 with extended HCC died at a mean time of 10.5 months. The 6 cases of de novo tumors were operated and are healthy. Side effects were dyslipidemia in 8 and infection in 2. Five patients (20%) discontinued the drug.

Conclusions

In the early posttransplantation period, everolimus is indicated for refractory rejection or as prophylaxis for recurrence of extended tumors. In any time but especially in the late period, everolimus is indicated for patients with serious side effects due to a CNI or to a de novo tumor.     

Lung Transplantation in Japan

The first successful living-donor lobar lung transplant (LDLLT) in Japan was performed at Okayama University in October 1998 after a long period of waiting for the legalization of thoracic organ transplantation. By May 2003, a further 41 lung transplants had been performed; 28 from living donors and 13 from cadaveric donors. The indications for a lung transplant are very specialized in Japan, the most common being primary pulmonary hypertension. Although the number of lung transplants is still small, survival in Japan, at 72% after 4 years, is better than the world average. Because the number of available cadaveric donors for lung transplantation is limited, at less than 5 per year, LDLLT is a realistic option for properly selected candidates.     

The Impact of Everolimus on Renal Function in Maintenance Liver Transplantation

We retrospectively investigated the impact on renal function (RF) of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) monotherapy in orthotopic liver transplant (OLT) recipients. Between January 2006 and July 2007, 70 deceased donor OLT recipients including 51 men and 19 women of overall mean age of 55.9 ± 11 years were enrolled into a program of conversion to EVL monotherapy at a mean interval of 45 ± 35.9 months from transplantation (range, 7-192 months). The indication for conversion was deteriorating RF in 64 (91.4%). Efficacy failure was defined as the persistence of CNI, EVL discontinuation, death, graft loss, loss to follow-up, or need for dialysis at 12 months. Twelve months after switching, 53 patients (75.7%) were on EVL monotherapy. Their mean change in creatinine clearance (CrCl) from baseline (day 1 before EVL introduction) to endpoint (12 months) was 5.8 ± 13.1 mL/min. On univariate and multivariate analyses, the clinical variable correlated with the greatest probability of improvement was the baseline CrCl (P < .0001). Conversion from CNI to EVL monotherapy was successful in 75.7% of cases with improvement in RF correlated with baseline CrCl. These data supported preemptive minimization of CNI in the posttransplant course, seeking to delay the decline in RF.