ABSTRACT
Background: Long-term survival of kidney allografts is limited by either inadequately controlled rejection and/or by side effects of long-term immunosuppression (drug toxicity, infections and neoplasia). Induction of donor-specific tolerance would resolve most, if not all of these limitations. Here, we report on 6 patients included in the first European trial of combined kidney and hematopoietic stem cell transplantation (HSCT;swisstolerance. CH). Methods or Case description: Six patients (3 female / 3 male) underwent combined kidney and hematopoietic stem cell transplantation from their HLA-identical living siblings between 2016 and 2022. Conditioning therapy for HSCT and immunosuppression was performed according to the Stanford protocol including total lymphoid irradiation, anti-thymocyte globulin followed by corticosteroids (3 days), mycophenolate (1 months) and cyclosporine for 6-15 months. After 9-15 months all immunosuppression was withdrawn. Results or Learning points: Five out of six patients were completely withdrawn from all immunosuppression (follow-up between 6 years and 4 months). No rejection or graft-versus-host disease episodes and no relevant infections occurred. Initial donor chimerism was seen in all patients. However, in 5/6 patients the chimerism level was declining, whereas one patient remained a stable mixed chimera. Specificity of tolerance was tested by molecular microscope analysis (absence of rejection signature) and by successful SARS CoV2 vaccination in some of the patients. One patient experienced a relapse of her primary glomerulonephritis in the allograft. She developed proteinuria, but renal function remained normal so far. Conclusion(s): Combined HSCT and kidney transplantation from the same living donor provides tolerance to a kidney allograft. This tolerance is donor-specific, as shown by protective immune responses against a SARS-CoV2-specific vaccine and absence of "molecular rejection".
ABSTRACT
INTRODUCTION: Ventilatory ratio (VR) is a simple bedside index of carbon dioxide removal. VR correlates well with physiologic dead space fraction (VD/VT) and clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that high VR would identify COVID-19 ARDS patients with higher risk for death and organ failure. METHOD(S): We conducted a retrospective cohort study of patients admitted to a single hospital in New York, NY, USA from March-July 2020 who had PCR-confirmed SARS-CoV-2 infection, met the Berlin criteria for ARDS, and required tracheostomy for prolonged invasive mechanical ventilation (MV). MV parameters were collected 2-8 hours after intubation. Based on prior studies, a VR>2 was considered to be abnormally elevated. Comparisons were performed using the Wilcoxon rank-sum test or z-test for difference in proportions with alpha=0.05. The primary outcome was 30- day mortality and the secondary outcome was a composite endpoint of death or organ failure defined as requiring renal replacement or extracorporeal membrane oxygenation (ECMO) during the hospitalization. RESULT(S): Of 139 subjects enrolled, 67 (48.2%) had a VR>2. Low and high VR groups had similar baseline characteristics, including age (mean 58 years, SD +/-15.2), body mass index (30.1+/-6.69 kg/m2), simplified acute physiology score II (35.4+/-12.4), sequential organ failure assessment (SOFA) score (5.7+/-2.5), and a 19-point review of systemic disease history. High VR was not significantly associated with mortality (OR 0.92, p=0.827). However, high VR was associated with increased risk for the composite endpoint (OR 1.96, p=0.049) and independently identified patients with a higher risk of organ failure (OR 2.03, p=0.047). High VR was also associated with longer hospital length-of-stay for subjects who survived to discharge (52 vs. 43, p=0.035), more MV-free days within the 30 days after intubation (3.2 vs. 1.8, p=0.029), and higher SOFA score at 10+/-4 days post-intubation (6.2 vs. 4.8, p=0.024). CONCLUSION(S): Ventilatory ratio identifies COVID-ARDS ventilated patients with increased risk for organ failure requiring advanced intervention, as well as patients who may require prolonged mechanical ventilation and hospitalization.
ABSTRACT
Background: Immunocompromised patients, including Kidney Transplant Recipients (KTRs) and lupus nephritis (LN) patients, are at increased risk for prolonged SARS-CoV-2 infection and developing COVID-19-related complications. Recently, we reported that voclosporin, a novel calcineurin inhibitor (CNI), demonstrated in vitro a more potent inhibitory effect on SARS-CoV-2 replication than other CNIs (tacrolimus and ciclosporin). Additionally the AURORA-2 study, where 216 LN patients were treated with voclosporin or placebo on top of standard of care, SARS-CoV-2 infection was detected in 12/100 placebo-treated patients (12%) compared to 7/116 voclosporin treated patients (6%) and more patients died due to COVID-19 in the placebo arm versus voclosporin arm (3% vs 0%). In this proof-of-concept study we assessed whether voclosporin demonstrated an added antiviral benefit in SARS-CoV-2 positive immunocompromised patients. Method(s): We performed a prospective, randomised, open-label, single-center, exploratory, proof of concept study in 20 KTRs with mild to moderate symptoms from a COVID-19 infection comparing time to viral clearance of SARS-CoV-2 between patients on standard immunosuppressive therapy with tacrolimus versus voclosporin (the VOCOVID study). Result(s): In the VOCOVID study no difference in time to viral clearance or time to clinical recovery was found between both treatment arms. Pharmacokinetic analysis demonstrated that adequate trough levels of voclosporin were reached from day 4-8 after randomization. Looking at specific timepoint in a post-hoc analysis, indeed a significantly better viral clearance of SARS-CoV-2 was observed in voclosporin treated patients at day 4-8. No safety concerns were raised. Conclusion(s): The present study provides evidence that voclosporin has a favorable benefit-risk profile for immunocompromised kidney disease patients who contract a SARS-CoV-2 infection while requiring the continuation of their immunosuppressants.
ABSTRACT
Corona virus disease 2019 (COVID-19) is an emerging pandemic of highly contagious caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2). Understanding the infectivity of various clinical samples and its transmission routes have been the main focus of current researches since the causative pathogens was identified. In this comprehensive review, we discuss the viral shedding from different clinical samples and reveal that infectious virus may be mainly discharged through respiratory and digestive systems. Also, SARS-CoV-2 showed a potential tropism for eyes, kidney, testis, placenta and other extrapulmonary tissues and high viral loads correlated with severe conditions. A better understanding of viral shedding may help the studies on pathogenesis and transmission of SARS-CoV-2 and provide suggestions for the disease control.