Excess mortality in COVID-19-affected solid organ transplant recipients across the pandemic.

The excess mortality of coronavirus disease 2019 (COVID-19) solid organ transplant recipients (SOTRs) throughout the pandemic remains unclear. This prospective cohort study based on the Japanese nationwide registry included 1632 SOTRs diagnosed with COVID-19 between February 1, 2020, and July 31, 2022, categorized based on dominant phases of variants of concern (VOCs): Waves 1 to 3 (Beta), 4 (Alpha), 5 (Delta), 6 (Omicron BA.1/BA.2), and 7 (Omicron BA.5). Excess mortality of COVID-19-affected SOTRs was analyzed by calculating standardized mortality ratios (SMRs). Overall, 1632 COVID-19-confirmed SOTRs included 1170 kidney, 408 liver, 25 lung, 20 heart, 1 small intestine, and 8 multiorgan recipients. Although disease severity and all-cause mortality decreased as VOCs transitioned, SMRs of SOTRs were consistently higher than those of the general population throughout the pandemic, showing a U-shaped gap that peaked toward the Omicron BA.5 phase; SMR (95% CI): 6.2 (3.1-12.5), 4.0 (1.5-10.6), 3.0 (1.3-6.7), 8.8 (5.3-14.5), and 21.9 (5.5-87.6) for Waves 1 to 3 (Beta), Wave 4 (Alpha), Wave 5 (Delta), Wave 6 (Omicron BA.1/2), and Wave 7 (Omicron BA.5), respectively. In conclusion, COVID-19 SOTRs had greater SMRs than the general population across the pandemic. Vaccine boosters, immunosuppression optimization, and other protective measures, particularly for older SOTRs, are paramount.

Impact of COVID-19 on living donor liver and kidney transplantation programs in Japan in 2020.

BACKGROUND: Although many transplant programs have been forced to suspend living donor transplants due to the emergence of coronavirus disease (COVID-19), there are relatively few real-time databases to assess center-level transplant activities. We aimed to delineate the actual impact of COVID-19 on living donor transplant programs and the resumption process in Japan. METHODS: In a nationwide survey, questionnaires were sent to 32 liver transplant programs that had performed at least more than one case of living donor liver transplantation in 2019 and 132 kidney transplant programs that had performed more than one living donor kidney transplantation in 2018. RESULTS: Thirty-one (96.9%) and 125 (94.7%) liver and kidney transplant programs responded, respectively. In the early pandemic period, 67.7% (21/31) of liver programs and 29.8% (37/125) of kidney programs were able to maintain transplant activities similar to those during the pre-pandemic period. After temporal suspension, 58.1% of kidney programs resumed their transplant activity after the number of local COVID-19 cases peaked. Establishing institutional COVID-19 screening, triage, and therapeutic management protocols was mandatory to resume transplant activity for 64.5% and 67.7% of liver and kidney programs, respectively. In the future wave of COVID-19, 67.7% of liver programs would be affected by institutional COVID-19 intensive care unit-bound patient numbers, and 55.7% of kidney programs would stop if hospital-acquired severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection spreads. CONCLUSIONS: THIS NATIONWIDE SURVEY REVEALED FOR THE FIRST TIME HOW LIVING DONOR LIVER AND KIDNEY: transplant programs changed in response to the COVID-19 pandemic in a country where living donor transplantations are predominant.

National survey on deceased donor organ transplantation during the COVID-19 pandemic in Japan.

PURPOSE: We investigated the status of deceased organ donation and transplantation through a questionnaire distributed to transplant centers in Japan during the COVID-19 pandemic. METHODS: The questionnaire was distributed electronically to 206 transplant centers for heart (n = 11), lung (n = 10), liver (n = 25), kidney (n = 130), pancreas (n = 18), and small intestine (n = 12) transplantation. Organ donations and organ transplantation data were extracted from the Japan Organ Transplant Network website. RESULTS: We received questionnaire responses from 177 centers (response rate, 86%). In 2020, the number of brain-dead donors (BDDs) decreased to 68 (69% of the year-on-year average) and the number of donors after cardiac death (DCDs) decreased to 9 (32% of the year-on-year average). Eighty-five (48%) transplant centers (heart, n = 0; lung, n = 0; liver, n = 4; kidney, n = 78; pancreas, n = 22; and small intestine, n = 0) suspended transplant surgeries in response to the COVID-19 pandemic. Consequently, the number of organ transplantations from deceased donors was significantly lower in 2020 than in 2019. CONCLUSION: Although the COVID-19 pandemic has had less impact in Japan than in other countries, it has affected transplantation activity significantly, suspending transplantation surgeries in 48% of the transplantation centers, including 78% of the kidney transplantation centers, and reducing the number of organ donations to 61% of the year-on-year average.

COVID-19: clinical issues from the Japan Surgical Society.

In this unprecedented COVID-19 pandemic, several key issues must be addressed to ensure safe treatment and prevent rapid spread of the virus and a consequential medical crisis. Careful evaluation of a patient's condition is crucial for deciding the triage plan, based on the status of the disease and comorbidities. As functionality of the medical care system is greatly affected by the environmental situation, the treatment may differ according to the medical and infectious disease circumstances of the institution. Importantly, all medical staff must prevent nosocomial COVID-19 by minimizing the effects of aerosol spread and developing diagnostic and surgical procedures. Polymerase chain reaction (PCR) screening for COVID-19 infection, particularly in asymptomatic patients, should be encouraged as these patients are prone to postoperative respiratory failure. In this article, the Japan Surgical Society addresses the general principles of surgical treatment in relation to COVID-19 infection and advocates preventive measures against viral transmission during this unimaginable COVID-19 pandemic.

High-dose mizoribine combined with calcineurin inhibitor (cyclosporine or tacrolimus), basiliximab and corticosteroids for renal transplantation: A Japanese multicenter study.

OBJECTIVE: To evaluate the utility and safety of high-dose mizoribine combination therapy using cyclosporine and tacrolimus as calcineurin inhibitors in patients undergoing kidney transplant. METHODS: The present study enrolled 156 patients who received kidney transplants in 18 institutions between 2009 and 2013. ABO-incompatible and/or pre-sensitized recipients were excluded. Immunosuppression used cyclosporine (88) or tacrolimus (68) as a calcineurin inhibitor, and the dosage was adjusted based on blood concentrations. Mizoribine was started at 6 mg/kg/day, and the target trough level was 1-2 ng/mL. Primary efficacy end-points of this study were 2-year patient survival, 2-year graft survival and the acute rejection rate within 2 years after transplantation. RESULTS: The 2-year patient and graft survival rates in the cyclosporine group were 98.9% and 94.3%, respectively, whereas those in the tacrolimus group were 100% and 98.5%, respectively, with no significant difference between groups. Rates of onset of rejection during the observation period were also equivalent, at 22.7% in the cyclosporine group and 17.6% in the tacrolimus group. Furthermore, groups showed no significant differences in transplanted renal function. No notable differences in adverse events were observed between groups. CONCLUSIONS: A regimen of high-dose mizoribine in combination with calcineurin inhibitors basiliximab, and corticosteroids can provide effective immunosuppression while lowering the rate of cytomegalovirus infection in kidney transplant patients.

Inter-laboratory Variability of Current Immunoassay Methods for Tacrolimus among Japanese Hospitals.

The aim of this study was to assess inter-hospital laboratory variability (coefficient of variation; CV) of immunoassay methods for tacrolimus and the comparability of control samples and results obtained by immunoassay measurements. One hundred seven hospital laboratories routinely performing therapeutic drug monitoring (TDM) of tacrolimus participated in the study. Thirteen spiked samples with known tacrolimus concentrations in the range of 0-26.0 ng/mL were prepared. Each spiked sample was analyzed according to the manufacturer's instructions using an affinity column-mediated immunoassay (ACMIA) on a Dimension(®) analyzer, the enzyme multiplied immunoassay technique (EMIT) on a Viva-E(®) analyzer, a chemiluminescent enzyme immunoassay (CLIA) on the Architect(®) system, and the electro-chemiluminescence immunoassay (ECLIA) on a cobas(®) analyzer. The 20% coefficient of variation values for the CLIA, ACMIA, EMIT, and ECLIA assays in the hospital laboratories were 1.82, 5.36, 4.59, and 0.89 ng/mL, respectively. CLIA and ECLIA had positive biases at concentrations of tacrolimus above 12 ng/mL relative to the spiked concentration, whereas the assay bias for ACMIA tended to be more negative at concentrations of tacrolimus above 6 ng/mL. EMIT had positive biases over the wide concentration range of 0.0-26.0 ng/mL (mean of mean errors 1.224). CLIA and ECLIA provided adequate precision at the target tacrolimus concentration of 3.0 ng/mL, whereas ACMIA and EMIT were unable to respond to target concentrations between 3.0 and 5.0 ng/mL for renal transplant recipients. Appropriate assessment of tacrolimus concentration by an assay having higher sensitivity, precision, and accuracy is necessary to ensure long-term survival of transplant recipients receiving tacrolimus.

Bronchial artery aneurysm treated with video-assisted thoracoscopic surgery.

Bronchial artery aneurysms (BAA) are a rarely noted. Asymptomatic cases of BAA are very rare. Most patients are correctly diagnosed only after BAA ruptures. The conventional treatment includes aneurysm resection through thoracotomy or transcatheter arterial embolization. In the present report, we describe a case of an asymptomatic BAA treated using video-assisted thoracoscopic surgery and careful evaluation of the vessels by three-dimensional computed tomography.

Prediction of early graft function after living donor kidney transplantation by quantifying the "nephron mass" using CT-volumetric software.

Early renal function after living-donor kidney transplantation (LDKT) depends on the "nephron mass" in the renal graft. In this study, as a possible donor-recipient size mismatch parameter that directly reflects the "nephron mass," the cortex to recipient weight ratio (CRWR) was calculated by CT-volumetric software, and its ability to predict early graft function was examined. One hundred patients who underwent LDKT were enrolled. Patients were classified into a developmental cohort (n = 79) and a validation cohort (n = 21). Using the developmental cohort, the correlation coefficients between size mismatch parameters, including CRWR, and the posttransplantation estimated glomerular filtration rate (eGFR) were calculated. Multiple regression analysis was conducted to define a formula to predict eGFR 1-month posttransplantation. Using the validation cohort, the validity of the formula was examined. The correlation coefficient was the highest for CRWR (1-month r = 0.66, p < 0.001). By multiple regression analysis, eGFR at 1-month was predicted using the linear model: 0.23 × donor preoperative eGFR + 17.03 × CRWR + 8.96 × preemptive transplantation + 5.10 (adjusted coefficient of determination = 0.54). In most patients in the validation cohort, the observed eGFR was within a 10 ml/min/1.73 m2 margin of the predicted eGFR. CRWR was the strongest parameter to predict early graft function. Predicting renal function using this formula could be useful in clinical application to select proper donors and to avoid unnecessary postoperative medical interventions.

The Modified Chronic Kidney Disease Epidemiology Collaboration Equation for the Estimated Glomerular Filtration Rate Is Better Associated with Comorbidities than Other Equations in Living Kidney Donors in Japan.

Objective We studied three types of estimated glomerular filtration rate (eGFR) equations and evaluated which type was strongly associated with comorbidities in living kidney transplantation (LKT) donors. Methods We compared the Japanese modified eGFR, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations (Jm-eGFR, Jm-MDRD, and Jm-CKD-EPI, respectively) for Japanese LKT donors with respect to their relationships with obesity, hypertension, diabetes, cardiovascular disease, and stroke. Results Of the 8,176 enrolled Japanese LKT donors, the eGFR calculated using Jm-CKD-EPI (eGFR/Jm-CKD-EPI) detected significant differences in 4 of 5 comorbidities between the comorbidity-positive and comorbidity-negative groups, whereas the eGFR calculated using Jm-MDRD (eGFR/Jm-MDRD) and Jm-eGFR (eGFR/Jm-eGFR) detected only 3 and 1 comorbidities, respectively. The area under the receiver operating characteristic curve of Jm-CKD-EPI was larger than those of Jm-eGFR and Jm-MDRD for all five comorbidities. Conclusion We found that the eGFR/Jm-CKD-EPI correlated better with comorbidities than the eGFR/Jm-eGFR and eGFR/Jm-MDRD in Japanese LKT donors. We recommend using the eGFR/Jm-CKD-EPI for the initial assessment of the renal function in LKT donor candidates when evaluating the presence of associated comorbidities.

The Japanese Medical Science Federation COVID-19 Expert Opinion English Version.

In 2020, the COVID-19 pandemic has had unprecedented impacts on various aspects of the world. Each academic society has published a guide and/or guidelines on how to cope with COVID-19 separately. As the one and only nationwide association of academic societies that represent medical science in Japan, JMSF has decided to publish the expert opinion to help patients and care providers find specifically what they want. This expert opinion is a summary of recommendations by many academic societies and will be updated when necessary. Patients that each academic society targets differ even though they suffer from the same COVID-19, and recommendations can be different in a context-dependent manner. Readers are supposed to be flexible and adjustable when they use this expert opinion.

[The Organ Transplantation Law].

The old Organ Transplantation Law was issued in 1997 and had never been revised for 12 years. Brain dead donors had to leave written consent to donate their own organs as well as their family consent. The organ donation from children under 15 years old was prohibited. The majority of the patients in need of organ transplantation died of organ shortages in Japan. Many patients especially children had to travel abroad to receive organs. The amendment bill for the Organ Transplantation Law was passed in the House of Councilors on July 13, 2009. The new Organ Transplantation Law permit organ donation from brain dead donors who had not refused to donate their organs, as long as there is family consent. Children under 15 years old can become donors. This article explains the old and the new Organ Transplantation Laws and the course of the amendment.

Development of the Asian Transplant Registry Under the Asian Society of Transplantation.

INTRODUCTION: In the Asian region, no international organ transplantation registry exists. Individual centers maintain their own database, or some countries developed a national registration system. To promote collaboration among Asian transplantation societies, the Asian Society of Transplantation (AST) has developed an international transplantation registry for the Asian countries that has been named as the Asian Society Transplant Registry (ASTREG). METHODS: In 2017, the AST council formed a registry committee to develop 2 kinds of databases: ASTREG-N (nationwide level), which collects yearly aggregated data of participating countries, and ASTREG-H (hospital level), which collects the data of transplant recipients and donors from individual centers. RESULTS: ASTREG-N collects each country's aggregate data of solid-organ transplantation, such as the total number of transplantations and deceased donors. ASTREG-H collects 5 transplant domains, namely recipient baseline characteristics, immunosuppression, post-transplant event, annual post-transplant evaluation, and donor traits. For the ASTREG-H project, South Korea, Philippines, Mongolia, and Myanmar are the current participants. A web-based secure data entry platform with real-time data visualization and automated data verification systems is currently available. Any participating centers can run this platform as their own data collection system. CONCLUSION: The ASTREG is a collaborative project that will be the representative solid-organ transplantation database in the Asian region. It can aid in the harmonization of transplantation data in the Asian region.

Transplantation in Asia during the coronavirus disease-19 (COVID-19) pandemic: briefs from member countries of the Asian Society of Transplantation.

The coronavirus disease-19 (COVID-19) pandemic has affected 1,029,968 people in Asia as of May 16, 2020. Although Asia was the first continent to be affected, many countries in the region continue to battle COVID-19, which challenges the way transplant programs provide their services. Given the diversity of healthcare systems in Asia, the countermeasures in response to COVID-19 are as potentially diverse. This review reports the experiences of transplant services in member countries of the Asian Society of Transplantation (AST) as well as provides a platform for sharing of best practices during the COVID-19 pandemic. AST invited member countries to provide a short description of their transplant experiences during the COVID-19 pandemic. Whenever information is available, countries were asked to provide information on COVID-19 related statistics, status of transplant programs, mitigation measures taken to prevent COVID-19, and other areas of transplant programs impacted by COVID-19. Ten countries responded to the invitation of which seven still have active transplant programs at varying levels of activity. All countries have protocols for donor/recipient screening and countermeasures to prevent COVID-19 infections in recipients and healthcare providers. Interestingly, these countries report only 16 transplant recipients with COVID-19 infection but no cases of donor-transmitted COVID-19 infection. Despite the diversity of healthcare systems in Asia, transplant centers in Asia have taken appropriate precautions to avoid COVID-19 infections, though the long-term impact of COVID-19 remains unclear.

A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis in Heart and Kidney Transplant Recipients in Japan.

BACKGROUND: Recently, chronic hepatitis E has been reported in solid organ transplant (SOT) recipients in European countries. Previously, we clarified the prevalence of hepatitis E virus (HEV) infection in Japanese liver transplant recipients and identified 2 chronic hepatitis E patients infected by blood transfusion. However, the rate of HEV infection in recipients of SOTs other than liver in Japan remains unclear, so we conducted a nationwide survey to clarify the prevalence of chronic HEV infection in Japanese heart and kidney transplant recipients. METHODS: A total of 99 heart and 2526 kidney transplant recipients in 17 hospitals in Japan were examined for the presence of the IgG class of anti-HEV antibodies as well as for serum HEV RNA. RESULTS: The prevalence of anti-HEV IgG among heart and kidney transplant recipients was 7.07% (7/99) and 4.08% (103/2526), respectively. One heart transplant patient (1.01%) and 11 kidney transplant patients (0.44%) were found to be positive for HEV RNA. The HEV isolates from all viremic patients were typed as genotype 3. Four patients developed chronic hepatitis E after transplantation. Three patients were treated with ribavirin; their liver enzymes normalized, and HEV RNA became negative immediately. Sustained virologic response was achieved in all cases. CONCLUSIONS: This is the first nationwide survey of HEV infection in Japanese heart and kidney transplant recipients. The prevalence of anti-HEV IgG and HEV RNA in heart and kidney transplant recipients in Japan was lower than that in European countries. Of note, 42% of viremic transplant patients developed chronic hepatitis.

Sarcopenia in Resected NSCLC: Effect on Postoperative Outcomes.

INTRODUCTION: Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with NSCLC after surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer. METHODS: This retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm2/m2). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm2/m2 for males and 3.92 cm2/m2 for females, based on PMI values from "healthy" subjects. RESULTS: The median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p < 0.001), being male (p < 0.001), smoking habit (p < 0.001), lower body mass index (p < 0.001), and postoperative major complication (Clavien-Dindo grade ≥3, p = 0.036). The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females older than 70 years. The 5-year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p = 0.019). CONCLUSIONS: Sarcopenia as determined using preoperative computed tomography could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management.

APC0576: a novel small molecule, immunosuppressive agent effective in primate models.

BACKGROUND: APC0576, 5-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine is a novel synthetic compound with an inhibitory activity on NF-kappaB-dependent gene activation and chemokine synthesis in human endothelial cells. This article describes the effect of APC0576 on T-cell-dependent immune functions in vitro and in vivo in primate models, because NF-kappaB is known to be one of the potent mediators in T-cell activation. METHODS: The effects of APC0576 on interleukin-2 production and proliferative responses in human peripheral blood mononuclear cells were studied under various stimuli with in vitro culture assay. Next, female rhesus monkeys were immunized with tetanus toxoid (TTx), and APC0576 was orally administered for 4 weeks. Serum-specific antibody for TTx was monitored weekly using an enzyme-linked immunosorbent assay, and delayed-type hypersensitivity reaction was examined after 4 weeks of APC0576 treatment. To evaluate the immunosuppressive activity, APC0576 was orally administered for 32 days to rhesus monkeys that received transplants of allogeneic kidney. RESULTS: APC0576 effectively suppressed interleukin-2 production and proliferation in activated human peripheral blood mononuclear cells. Both delayed-type hypersensitivity reaction and specific antibody formation evoked by TTx was significantly and dose-dependently attenuated by 4 weeks treatment of APC0576 without any serious toxicologic signs. Allogeneic kidneys grafted in rhesus monkeys were not rejected and fully functioned during the 32 days of APC0576 treatment, although they were rapidly rejected after the withdrawal of the drug. CONCLUSIONS: A novel, orally available immunosuppressive agent, APC0576, effectively inhibited T-cell-based immune responses both in vitro and in vivo. APC0576 may have potential for a therapeutic agent in clinical organ transplantation and various cytokine-mediated diseases.

Auxiliary partial orthotopic liver transplantation for fulminant hepatitis: regeneration of the diseased native liver in a pig model.

BACKGROUND: This study was performed to develop a clinically relevant porcine model of auxiliary partial orthotopic liver transplantation (APOLT) for fulminant hepatic failure. METHODS: FHF was induced by intraportal administration of alpha-amanitin and lipopolysaccharide. Thereafter, pigs were divided into four groups. Group 1 was an untreated, control group. In group 2, pigs underwent only a left hemihepatectomy. Pigs in groups 3 and 4 received APOLT after hemihepatectomy. Tacrolimus was administered to pigs in group 4, but not to those in group 3. RESULTS: Two-week survival rates were 0%, 20%, 40%, and 100% for groups 1, 2, 3, and 4, respectively. In group 4, after abolishing the graft function at 1 week, pigs survived for more than 2 weeks, and regeneration of the native liver was confirmed histologically. CONCLUSIONS: Pigs suffering from fulminant hepatic failure could achieve long survival and liver regeneration with a temporary support of the auxiliary graft.