Adjustment of Immunosuppressants to Facilitate Anti-COVID-19 Antibody Production after mRNA Vaccination in Liver Transplant Recipients.

Liver transplant recipients are immunocompromised and have low immunogenicity to produce antibodies in anti-COVID-19 vaccination. Whether immunosuppressant adjustment could facilitate anti-COVID-19 antibody production in anti-COVID-19 mRNA vaccination is undetermined. Our patients were informed to temporarily suspend mycophenolate mofetil (MMF) or everolimus (EVR) for 2 weeks during both the 1st and 2nd doses of Moderna mRNA-1273 vaccine. A total of 183 recipients receiving two doses of Moderna mRNA-1273 vaccine were enrolled and grouped into tacrolimus monotherapy (MT, n = 41), and dual therapy with non-adjustment (NA, n = 23), single suspension (SS, n = 19) and double suspension (DS, n = 100) of MMF/EVR in two-dose mRNA vaccination. A total of 155 (84.7%) patients had a humoral response to vaccines in this study. The humoral response rates were 60.9%, 89.5%, 91.0% and 80.5% in NA, SS, DS, and MT group patients, respectively (p = 0.003). Multivariate analysis showed that favorable factors for humoral response were temporary suspension of MMF/EVR and monotherapy, and unfavorable factors were deceased donor liver transplantation, WBC count < 4000/uL, lymphocyte < 20% and tacrolimus trough level ≥ 6.8 ng/mL. In conclusion, temporary two-week suspension of anti-proliferation immunosuppressants could create a window to facilitate antibody production during anti-COVID-19 mRNA vaccination. This concept may be applied to other vaccinations in liver transplant recipients.

Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil-containing Immunosuppressive Regimens.

BACKGROUND: Elderly kidney transplant recipients (KTRs) represent almost one third of the total kidney transplant population. These patients have a very high coronavirus disease 2019 (COVID-19)-related mortality, whereas their response to COVID-19 vaccination is impaired. Finding ways to improve the COVID-19 vaccination response in this vulnerable population is of uttermost importance. METHODS: In the OPTIMIZE trial, we randomly assign elderly KTRs to an immunosuppressive regimen with standard-exposure calcineurin inhibitor (CNI), mycophenolate mofetil, and prednisolone or an adapted regimen with low dose CNI, everolimus, and prednisolone. In this substudy, we measured the humoral response after 2 (N = 32) and 3 (N = 22) COVID-19 mRNA vaccinations and the cellular response (N = 15) after 2 vaccinations. RESULTS: . The seroconversion rates of elderly KTRs on a standard immunosuppressive regimen were only 13% and 38% after 2 and 3 vaccinations, respectively, whereas the response rates of KTRs on the everolimus regimen were significantly higher at 56% ( P = 0.009) and 100% ( P = 0.006). Levels of severe acute respiratory syndrome coronaVirus 2 IgG antibodies were significantly higher at both time points in the everolimus group ( P = 0.004 and P < 0.001). There were no differences in cellular response after vaccination. CONCLUSIONS: An immunosuppressive regimen without mycophenolate mofetil, a lower CNI dose, and usage of everolimus is associated with a higher humoral response rate after COVID-19 vaccination in elderly KTRs after transplantation. This encouraging finding should be investigated in larger cohorts, including transplant recipients of all ages.

Drug-drug interaction between remdesivir and immunosuppressant agents in a kidney transplant recipient.

A 60-year-old man was treated with a regimen of controlled-release tacrolimus (2 mg once daily), everolimus (0.5 mg twice daily), methylprednisolone (4 mg once daily), and mizoribine (100 mg twice daily) as an anti-rejection regimen following living-donor kidney transplantation. One year after transplantation, the recipient was admitted to Mie University Hospital (day X; admission date) to treat coronavirus disease 2019 pneumonia. The latest trough concentrations of tacrolimus and everolimus before admission (day X-65) were 4.5 ng/mL and 4.4 ng/mL, respectively. Since tacrolimus concentration was 4.2 ng/mL on day X+3, the dose was adjusted to 1.5 mg once daily to reach the target concentration of 3.0 ng/mL due to the introduction of remdesivir. After starting remdesivir on day X+4, the increased trough concentrations of tacrolimus on day X+6 (6.9 ng/mL) and everolimus on day X+7 (9.2 ng/mL) were observed, which resulted in dose reduction of tacrolimus (0.5 mg once daily) and discontinuation of everolimus. After discontinuation of remdesivir on day X+9, dose titration of controlled-release tacrolimus and restart of everolimus (0.5 mg twice daily) were performed from day X+15. The dose of controlled-release tacrolimus was titrated and fixed to 2 mg once daily at discharge (day X+21). There was no toxicity due to immunosuppressive agents during hospitalization. This case report indicated that remdesivir might interact with cytochrome P450 3A4 substrates, such as tacrolimus and everolimus, and elevate their blood concentrations under high inflammatory conditions.

Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS) - A phase II, randomized, double-blind, multi-center, placebo-controlled trial.

BACKGROUND: Activation of inflammatory pathways during acute myocardial infarction contributes to infarct size and left ventricular (LV) remodeling. The present prospective randomized clinical trial was designed to test the efficacy and safety of broad-spectrum anti-inflammatory therapy with a mammalian target of rapamycin (mTOR) inhibitor to reduce infarct size. DESIGN: Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS, clinicaltrials.gov NCT01529554) is a phase II randomized, double-blind, multi-center, placebo-controlled trial on the effects of a 5-day course of oral everolimus on infarct size, LV remodeling, and inflammation in patients with acute ST-elevation myocardial infarction (STEMI). Within 5 days of successful primary percutaneous coronary intervention (pPCI), patients are randomly assigned to everolimus (first 3 days: 7.5 mg every day; days 4 and 5: 5.0 mg every day) or placebo, respectively. The primary efficacy outcome is the change from baseline (defined as 12 hours to 5 days after pPCI) to 30-day follow-up in myocardial infarct size as measured by cardiac magnetic resonance imaging (CMRI). Secondary endpoints comprise corresponding changes in cardiac and inflammatory biomarkers as well as microvascular obstruction and LV volumes assessed by CMRI. Clinical events, laboratory parameters, and blood cell counts are reported as safety endpoints at 30 days. CONCLUSION: The CLEVER-ACS trial tests the hypothesis whether mTOR inhibition using everolimus at the time of an acute STEMI affects LV infarct size following successful pPCI.

Case Report of COVID-19 Infection After Kidney Transplant Treated With Casirivimab-Imdevimab and Mycophenolate Mofetil Changed to Everolimus.

BACKGROUND: Casirivimab-imdevimab is a cocktail of 2 monoclonal antibodies designed to prevent infection by SARS-CoV-2, the virus that causes COVID-19. Casirivimab-imdevimab has been approved in Japan for treating mild to moderate COVID-19; however, to our knowledge, there are no reports of its use after kidney transplant from a live donor. Everolimus, an antineoplastic chemotherapy drug, is expected to be effective in inhibiting the spread of SARS-CoV-2 and preventing its replication, which may facilitate treatment. Here, we report a case of COVID-19 infection after kidney transplant that was initially treated with casirivimab-imdevimab and mycophenolate mofetil but was later changed to everolimus. CASE REPORT: A 47-year-old man underwent living donor kidney transplant from his mother in 2017. Immunosuppression therapy was underway through the administration of tacrolimus, mycophenolate mofetil, and methylprednisolone. In early September 2021, he was diagnosed as having COVID-19 and was hospitalized on day 3. On hospitalization, mycophenolate mofetil was discontinued and casirivimab-imdevimab and heparin were started. The patient started an everolimus regimen on day 5. The clinical course was successful without rejection. There was no exacerbation of COVID-19; the patient's serum creatinine levels and renal function had otherwise remained stable. CONCLUSIONS: We could safely treat a patient with casirivimab-imdevimab after kidney transplant. It is suggested that casirivimab-imdevimab can prevent COVID-19 from becoming severe and can be administered without worsening renal function. In addition, everolimus may have inhibited the spread of the virus and prevented it from replicating.

COVID-19 associated with disseminated histoplasmosis in a kidney transplant patient.

We report a case of disseminated histoplasmosis and COVID-19 infection in a renal transplant recipient in Argentina. The patient exhibited respiratory symptoms, and a chest computed tomography scan (CT) showed multiple bilateral centrilobular opacities with a tree-in-bud pattern in both lobes. The patient was initially treated as having bacterial community-acquired pneumonia, and then tuberculosis. A month later, histoplasmosis was diagnosed, and Histoplasma capsulatum LAmB clade was isolated from sputum, skin and oral lesions. The patient was hospitalized and treatment was started with intravenous liposomal amphotericin B. During the course of the antifungal therapy the respiratory symptoms worsened, a new chest CT showed a unilateral lesion with a ground glass appearance and SARS-CoV-2 was detected in a new nasopharyngeal sample. In addition, plasma therapy was administered, and the immunosuppressive regimen was adjusted (everolimus was interrupted, mycophenolate mofetil reduced, and meprednisone increased). Finally, the patient's progress was favorable and was discharged after five days on oral itraconazole treatment for histoplasmosis.

Can We Use mTOR Inhibitors for COVID-19 Therapy?

Infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes acute inflammation due to extensive replication of the virus in the epithelial cells of the upper and lower respiratory system. The mammalian target of rapamycin (mTOR) is a l signalling protein with critical functions in cell growth, metabolism, and proliferation. It is known for its regulatory functions in protein synthesis and angiogenesis cascades. The structure of mTOR consists of two distinct complexes (mTORC1 and mTORC2) with diverse functions at different levels of the signalling pathway. By activating mRNA translation, the mTORC1 plays a key role in regulating protein synthesis and cellular growth. On the other hand, the functions of mTORC2 are mainly associated with cell proliferation and survival. By using an appropriate inhibitor at the right time, mTOR modulation could provide immunosuppressive opportunities as antirejection regimens in organ transplantation as well as in the treatment of autoimmune diseases and solid tumours. The mTOR also has an important role in the inflammatory process. Inhibitors of mTOR might indeed be promising agents in the treatment of viral infections. They have further been successfully used in patients with severe influenza A/H1N1 pneumonia and acute respiratory failure. The officially accepted mTOR inhibitors that have undergone clinical testing are sirolimus, everolimus, temsirolimus, and tacrolimus. Thus, further studies on mTOR inhibitors for SARS-CoV-2 infection or COVID-19 therapy are well merited.

[Interdisciplinary recommendations for the treatment of advanced renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des fortgeschrittenen Nierenzellkarzinoms.

In the treatment of advanced renal cell carcinoma, anti-VEGFR tyrosine kinase inhibitors (TKI) have been replaced mostly by immunotherapy combinations with checkpoint inhibitors (CPI), especially in first line therapy. Due to these novel therapies, the prognosis of patients has been improved further. In pivotal studies a median overall survival of 3-4 years has been achieved. TKI monotherapy remains important for patients with low risk, a contraindication against immunotherapy and with regard to the SARS-CoV-2 pandemic.Selection of the correct first line therapy is difficult to answer because there are two CPI-TKI combinations and one CPI-combination. Temsirolimus and the combination bevacizumab + interferon alfa have become less important. In second line therapy, nivolumab and cabozantinib have demonstrated superior overall survival compared to everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second line and further settings. TKI are an option as well, but they have lower supporting evidence. Everolimus has been replaced in the second line setting by these new options. Biomarkers are not available. The German S3 guideline has been updated recently to give better orientation in clinical practice.The question of the optimal sequence is still unanswered. Most second line options were evaluated after failure of anti-VEGF-TKI, but these are only applicable for a minority of patients.The purpose of an interdisciplinary expert meeting in november 2020 was to debate which criteria should influence the therapy. The members discussed several aspects of treating patients with advanced or metastatic RCC, including the SARS-CoV-2 pandemic. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.

New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration.

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 µM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 µM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.

Complete recovery from COVID-19 of a kidney-pancreas transplant recipient: potential benefit from everolimus?

We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.

Clinical course of COVID-19 disease in immunosuppressed renal transplant patients

Background/aim: We aimed to identify clinical settings of renal transplant patients with COVID-19. Materials and methods: In this retrospective study, we included kidney transplant inpatients with laboratory confirmed COVID-19 who had been discharged or had died by October 1st, 2020. Characteristics of the patients, including basal and last outpatient biochemical parameters were recorded. Discontinuation or dosage reduction of immunosuppressives and other treatment information was documented. Results: Twenty patients were included in this study, of whom 18 were discharged and 2 died in hospital. The mean duration of hospitalization and follow-up were 9.7 ± 6.4 days and 4.5 ± 2.0 months, respectively. Fourteen patients (70%) were male and mean age was 48.0 ± 10.3 years. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/ day (50%) or dexamethasone (50%). Tacrolimus/m-TOR inhibitors were reduced by 50% and all antimetabolites were discontinued. Hemodialysis was needed for 10% of patients. Acute kidney injury was detected in 25% of the patients. With respect to hospitalization time and complications, there was no significant difference between patients who used dexamethasone and those who did not (P > 0.05). The discontinued immunosuppressives were resumed within 2 to 4 weeks after discharge according to the severity of disease. No rehospitalization or acute rejection was detected during the follow-up of the patients. Conclusion: Renal transplant patients are considered a high risk group for COVID-19. It can be said that discontinuation or reducing dosages of immunosuppressives may be effective and safe in kidney transplant patients.

Treating diabetic all-comers with contemporary drug-eluting stents: Prespecified comparisons from the BIO-RESORT and the BIONYX randomized trials.

BACKGROUND: Patients with diabetes have more extensive coronary disease, resulting in higher risks of adverse clinical events following stenting. In all-comer patients, contemporary DES have shown excellent safety and efficacy, but data on diabetic patients are scarce. Separately for the BIO-RESORT and BIONYX trials, we assessed the 2-year clinical outcomes of diabetic patients, treated with various contemporary drug-eluting stents (DES). METHODS: We performed two prespecified secondary analyses of two randomized DES trials, which both stratified for diabetes. The main endpoint was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization. Follow-up was finished before the COVID-19 pandemic. RESULTS: In BIO-RESORT, 624/3514 (17.8%) had diabetes: 211 received Orsiro sirolimus-eluting stents (SES), 203 Synergy everolimus-eluting stents (EES), and 210 Resolute Integrity zotarolimus-eluting stents (RI-ZES). TVF did not differ between SES (10.2%) and EES (10.0%) versus RI-ZES (12.7%) (SES vs. RI-ZES HR:0.78, 95%-CI [0.44-1.40]; p = 0.40, EES vs. RI-ZES HR:0.79, 95%-CI [0.44-1.40]; p = 0.42). In BIONYX, 510/2488 (20.5%) patients had diabetes: 250 received SES and 260 Resolute Onyx zotarolimus-eluting stents (RO-ZES). There was no difference in TVF between SES (10.7%) versus RO-ZES (12.2%) (HR:0.88, 95%-CI [0.52-1.48]; p = 0.63). CONCLUSIONS: There was no difference in 2-year clinical outcome among patients with diabetes, who were treated with SES, or EES, versus RI-ZES. In addition there was no difference in clinical outcome in diabetic patients, who were treated with SES versus RO-ZES. These findings may be considered as a signal of safety and efficacy of the studied DES in patients with diabetes.

Liver transplant immunosuppression during the covid-19 pandemic. / Inmunosupresión en el trasplante hepático en la era covid-19.

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.

Severe COVID-19 in a renal transplant recipient: A focus on pharmacokinetics.

The current coronavirus disease 2019 (COVID-19) pandemic requires extra attention for immunocompromised patients, including solid organ transplant recipients. We report on a case of a 35-year-old renal transplant recipient who suffered from a severe COVID-19 pneumonia. The clinical course was complicated by extreme overexposure to the mammalian target of rapamycin inhibitor everolimus, following coadministration of chloroquine and lopinavir/ritonavir therapy. The case is illustrative for dilemmas that transplant professionals may face in the absence of evidence-based COVID-19 therapy and concurrent pressure for exploration of experimental pharmacological treatment options. However, the risk-benefit balance of experimental or off-label therapy may be weighed differently in organ transplant recipients than in otherwise healthy COVID-19 patients, owing to their immunocompromised status and potential drug interactions with immunosuppressive therapy. With this case report, we aimed to achieve increased awareness and improved management of drug-drug interactions associated with the various treatment options for COVID-19 in renal transplant patients.