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Increased COVID-19-related morbidity and mortality have been reported in solid organ transplant recipients (SOTRs). Most studies are underpowered for rigorous matching. We report infections, hospitalization, ICU care, mortality from COVID-19, and pertinent vaccination data in Swedish SOTRs 2020–2021. We conducted a nationwide cohort study, encompassing all Swedish residents. SOTRs were identified with ICD-10 codes and immunosuppressant prescriptions. Comparison cohorts were weighted based on a propensity score built from potential confounders (age, sex, comorbidities, socioeconomic factors, and geography), which achieved a good balance between SOTRs and non-SOTR groups. We included 10,372,033 individuals, including 9073 SOTRs. Of the SARS-CoV-2 infected, 47.3% of SOTRs and 19% of weighted comparator individuals were hospitalized. ICU care was given to 8% of infected SOTRs and 2% of weighted comparators. The case fatality rate was 7.7% in SOTRs, 6.2% in the weighted comparison cohort, and 1.3% in the unweighted comparison cohort. SOTRs had an increased risk of contracting COVID-19 (HR = 1.15 p < 0.001), being hospitalized (HR = 2.89 p < 0.001), receiving ICU care (HR = 4.59 p < 0.001), and dying (HR = 1.42 p < 0.001). SOTRs had much higher morbidity and mortality than the general population during 2020–2021. Also compared with weighted comparators, SOTRs had an increased risk of contracting COVID-19, being hospitalized, receiving ICU care, and dying. In Sweden, SOTRs were vaccinated earlier than weighted comparators. Lung transplant recipients had the worst outcomes. Excess mortality among SOTRs was concentrated in the second half of 2021. [ABSTRACT FROM AUTHOR]

All chronic and treatment-resistant acute rejections are "difficult-to-treat" and lead to progressive loss of graft function in kidney transplant recipients (KTR), as no effective treatment exists for such rejections to date. We review our experience with a novel strategy to treat such rejections by adding everolimus as a "rescue" to conventional triple maintenance therapy with prednisolone, mycophenolate mofetil and calcineurin inhibitor. We retrospectively analysed data in 28 KTR who received everolimus-based quadruple therapy at our institution for biopsy-proven chronic active T cell-mediated or antibody-mediated rejection (n = 19) or treatment-resistant acute rejections (n = 9) between 2011–2017. The primary outcome was 5-year death-censored graft survival. Main secondary outcomes were response to treatment defined by stable or improved graft function, 5-year patient survival and discontinuation rate of treatment. The Kaplan–Meier estimate for 5-year death-censored graft survival was 79% in all patients, 90% for patients with chronic active T cell-mediated rejections, 78% for chronic active antibody-mediated rejection and 67% for acute rejections. Response to treatment was achieved in 43% and 5-year patient survival was 94%. Treatment was stopped in 12 (43%) patients due to adverse events. Everolimus-based maintenance quadruple therapy, despite high rate of everolimus discontinuation due to adverse events, may be a valid approach in a subset of kidney transplant recipients with such difficult-to-treat rejections, which otherwise would lead to a high rate of graft loss. [ABSTRACT FROM AUTHOR]

Background: Macrophages in renal transplants have been shown to participate in antibody‐mediated rejection and are associated with impaired renal function. We calculated the glomerular macrophage index (GMI) in a large transplant biopsy cohort, studied its quantity in different diagnostic groups, to clarify its possible impact on graft survival. Methods: GMI, defined as the mean number of macrophages in 10 glomeruli, was prospectively quantified in 1440 renal transplant biopsies over a 10‐year period. The main histopathological diagnoses were grouped into eight disease entities, and GMI was compared to normal transplant biopsies as the reference group. The impact of GMI on graft survival was analyzed. Results: GMI was highest in chronic (mean 9.4) and active (9.7) antibody mediated rejections (ABMR), mixed rejections (7.6), and recurrent or de novo glomerulonephritis (7.5) and differed significantly from normal transplants (1.3) in almost all diagnostic groups. Hazard ratios for graft loss were significantly increased for all biopsies with GMI ≥1.9 compared to GMI <.5 (reference group) in an adjusted Cox regression model and increased with higher GMI levels. Biopsies with GMI ≥ 4.6 had < 60% 10‐year graft‐survival, compared to > 80% with GMI ≤ 1.8. Conclusion: GMI levels were predictive of graft loss independent of histological diagnoses and may guide clinicians to decide follow‐up and therapy. [ABSTRACT FROM AUTHOR]

Summary: Although it is known that solid organ transplant recipients fare worse after COVID‐19 infection, data on the impact of COVID‐19 on clinical outcomes and allograft function in lung transplant (LTx) recipients are limited and based mainly on reports with short follow‐up. In this nationwide study, all LTx recipients with COVID‐19 diagnosed from 1 February 2020 to 30 April 2021 were included. The patients were followed until 1 August 2021 or death. We analysed demographics, clinical features, therapeutic management and outcomes, including lung function. Forty‐seven patients were identified: median age was 59 (10–78) years, 53.1% were male, and median follow‐up was 194 (23–509) days. COVID‐19 was asymptomatic or mild at presentation in 48.9%. Nine patients (19.1%) were vaccinated pre‐COVID infection. Two patients (4.3%) died within 28 days of testing positive, and the overall survival rate was 85.1%. The patients with asymptomatic or mild symptoms had a higher median % expected forced expiratory volume during the first second than the patients with worse symptoms (P = 0.004). LTx recipients develop the entire spectrum of COVID‐19, and in addition to previously acknowledged risk factors, lower pre‐COVID lung function was associated with more severe disease presentation. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) ranges from a mild illness to acute respiratory distress syndrome (ARDS), multiorgan dysfunction, and death. Transplant recipients are vulnerable due to comorbidities and immunosuppressants that render them susceptible to infections. The information on COVID-19 in kidney transplant recipients remains limited to small case series. A systematic literature search was conducted, and 12 case series totalling 204 kidney transplant recipients with COVID-19 were identified. Data were extracted, pooled and analysed. Most patients (74%) were men. The most frequent symptoms were fever (76%), cough (64%) and dyspnoea (43%). At admission, over 70% of the patients had abnormal radiological findings. Leukocyte counts were in the lower normal range. C-reactive protein, ferritin, and D-dimer were consistently increased. Treatments included lowering immunosuppression, hydroxychloroquine, antivirals, tocilizumab and intravenous immunoglobulins. Thirty-one percent of the patients were admitted to intensive care units (ICUs), and 16% required intubation. The overall mortality was 21.2%. Patients who died were significantly older than those who survived (61 ± 12 vs. 51 ± 15, p <.01). Logistic regression revealed that the odds for death increased by 4.3% for each additional year of age (odds ratio [OR] 1.043, 95% confidence interval [CI] 1.005–1.083, p value =.0265). No substantial conclusions could be drawn on the efficacy of any particular treatment. More rigorous patient stratification is needed when analysing and reporting data to facilitate future meta-analyses. [ABSTRACT FROM AUTHOR]

BK-virus (BKV) associated nephropathy (BKVAN) and BKV associated haemorrhagic cystitis (HC) are complications of BKV infection/reactivation in renal and allogeneic haematopoietic stem cell transplantation (HSCT) patients, respectively. The task of how to manage these diseases was given to the chair by the Swedish Reference Group for Antiviral Therapy (RAV). After individual contributions by members of the working group, consensus discussions were held in a meeting on 23 January 2018 arranged by RAV. Thereafter, the recommendations were published in Swedish on November 2018. The current translation to English has been approved by all co-authors. High BKV serum levels suggest an increased risk for BKVAN and potential graft failure. For detection of BKVAN, careful monitoring of BKV DNA levels in serum or plasma is recommended the first year after renal transplantation and when increased creatinine serum levels of unknown cause are observed. Notably, a renal biopsy is mandatory for diagnosis. To reduce the risk for progression of BKVAN, there is no specific treatment, and tailored individual decrease of immunosuppression is recommended. For BKV-HC, BKV monitoring is not recommended, since BK-viruria frequently occurs in HSCT patients and the predictive value of BKV in plasma/serum has not been determined. However, the risk for BKV-HC is higher for patients undergoing myeloablative conditioning, having an unrelated, HLA-mismatched, or a cord blood donor, and awareness of the increased risk and early intervention may benefit the patients. Also for BKV-HC, no specific therapy is available. Symptomatic treatment, e.g. forced diuresis and analgesics could be of use. [ABSTRACT FROM AUTHOR]

Background. In organ transplanted patients, impaired renal function is of major prognostic importance and influences therapeutic decisions. Therefore, monitoring of renal function with glomerular filtration rate (GFR) is of importance, both before and after heart transplantation (HTx). The GFR can be measured directly (mGFR) or estimated (eGFR) with equations based on circulating creatinine or cystatin C levels. However, these equations have not been thoroughly validated in the HTx population. Methods. We investigated the correlation, agreement and accuracy between mGFR (using 51Cr-ethylenediaminetetraacetic acid or iohexol clearance) and three commonly used eGFR equations (Modification of Diet in Renal Disease, Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration) in a retrospective analysis of 416 HTx recipients followed between 1988 and 2012. Comparisons were performed prior to transplantation and at 1, 5 and 10 years of follow-up. Results. The correlations between eGFR and mGFR were only moderate, with r-values ranging from 0.55 preoperatively to 0.82 during follow-up. Most importantly, the level of agreement between eGFR and mGFR was very low for all three estimates, with percentage errors ranging from 93.3 to 157.3%. Also, the percentage of patients with eGFR within 30% of mGFR (P30) rarely reached the National Kidney Foundation recommended minimum level of 75%. Conclusion. We argue that the accuracy and the precision of the most commonly used estimation equations for assessment of kidney function are unacceptably low and we believe that mGFR should be used liberally as the basis for clinical decision-making both before and after HTx when eGFR is subnormal. [ABSTRACT FROM AUTHOR]

Objective. With improvements in long-term results after liver transplantation, chronic kidney disease (CKD) has become a highly relevant problem. The early measurement of the glomerular filtration rate (GFR) can identify those patients who are at risk of developing CKD years after liver transplantation. The aims of this study were to describe the prevalence of CKD 5 years after liver transplantation, to study the correlation between measured GFR early after transplantation and late renal function and to identify patients at risk of developing late CKD after liver transplantation. Material and methods. A total of 152 patients who were at least 5 years post-liver transplantation were studied. Measured GFR with Chromium EDTA or iohexol clearance was followed-up for 5 years (n=152) and 10 years (n=41). Results. The overall decrease in measured GFR was 36% after 5 years and 42% after 10 years. Eight patients (5%) required renal replacement therapy. GFR levels pretransplantation showed a poor correlation with later renal function (at 5 years). The GFR measured at 3 months and 1 year post-transplantation correlated well with measured GFR at 5 years post-transplantation. Multivariate analysis showed that measured GFR of less than 30 ml at 3 months post-transplantation was significantly associated with CKD at 5 years post-transplantation. Conclusions. GFR levels below 30 ml/min/1.73 m2 at 3 months post-liver transplantation are associated with the development of later CKD Stage 4-5 long after liver transplantation. The importance of this finding is the possibility of identifying at an early stage those individuals that may benefit from early implementation of calcineurin sparing or a withdrawal regimen with the goal of preserving long-term renal function. [ABSTRACT FROM AUTHOR]

Objectives To investigate whether measured glomerular filtration rate (mGFR) is a risk factor for death and/or end-stage renal disease (ESRD) after heart transplantation (HTx). Methods All adult patients (n = 416) who underwent HTx between 1988 and 2010 were included. mGFR was performed both preoperatively and postoperatively as annual follow-up. Eight patients received a concomitant kidney transplant (KTx), and 15 underwent late KTx due to chronic renal failure after HTx. Results The mean drop in mGFR compared with the preoperative value was 12% during the first year after HTx. Preoperative mGFR was not predictive of mortality or ESRD. Older or the use of a ventricular assist device (VAD) were preoperative predictors of death. Long-term survival was significantly worse in the patients who experienced a >25% decrease in mGFR during the first year after transplantation. The need for acute postoperative renal replacement therapy (RRT) was associated with impaired survival but did not predict ESRD among survivors. On multivariable analyses, previous heart surgery, preoperative VAD, and a lower mGFR were all predictors of RRT. In the most recent period, death without previous ESRD was lower, and the only preoperative factors associated with ESRD by multivariable analyses were mechanical ventilation and diabetes mellitus. Conclusions Pretransplantation mGFR was not predictive of mortality or ESRD after HTx, but necessitated simultaneous or late-stage KTx in this selected population of patients. However, patients with a decrease in >25% mGFR during the first year post-transplantation, as well as early postoperative dialysis-dependent acute renal dysfunction, had a poor prognosis. We suggest that patients with severely impaired kidney function, irrespective of pretransplantation renal function, still should be considered for HTx, but also encourage careful interpretation of our results given the selection bias involved in this population. [ABSTRACT FROM AUTHOR]

Background: Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS. Materials and Methods: Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated. Results: Donor- and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% ± 3.5% versus 24.8% ± 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 ± 5.0 versus 17.2 ± 8.1 μL/g, P = 0.004) and islet yield (1910 ± 980 versus 3150 ± 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets. Conclusions: Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage. [ABSTRACT FROM AUTHOR]

Background: Solid organ transplant (SOT) recipients may be more vulnerable to coronavirus disease 2019 (COVID-19). Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the optimal management strategy for these patients is yet unclear., Methods: We present 53 SOT recipients (31 kidney transplant recipients, 8 liver transplant recipients, 5 heart transplant recipients, 5 lung transplant recipients, 3 liver-kidney transplant recipients, and 1 kidney-after-heart transplant recipient), transplanted at a Swedish high-volume transplant center and each diagnosed with COVID-19 between February 21, 2020 and June 22, 2020. Demographic, clinical, and treatment data were extracted from the electronic patient files., Results: Patients reported fever (61%), cough (43%), diarrhea (31%), and upper respiratory symptoms (29%). The median age was 56 years, and 57% were male. According to severity, 55% had mild, 13% had moderate, 19% had severe, and 13% had critical disease. Thirty-seven patients (70%) were hospitalized, with 8 requiring intensive care. Thirteen of the 37 patients were initially managed as outpatients but later hospitalized. One patient received hydroxychloroquine, and no patients received antivirals. Antimetabolites and calcineurin inhibitors were held or reduced in two-thirds. Twenty-seven of 37 hospitalized patients (73%) received low-molecular-weight heparin. Five (13.5%) hospitalized patients died. Overall survival for the entire cohort was 90.5%. No rejection episodes were noted., Conclusions: Hospitalization, lowering of immunosuppression, and prophylactic anticoagulation were the most common therapeutic interventions for SOT recipients with COVID-19. A significant proportion of patients could be managed on an outpatient basis, while keeping a low threshold for admission. Mild and moderate disease forms seem to have a good outcome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The procedure of human islet isolation needs further optimization and standardization. Here, we describe techniques to enhance enzymatic digestion and minimize mechanical forces during the digestion process. The isolation protocol has also been modified to meet current GMP (cGMP) standards. Moreover, the impact of donor- and process-related factors was correlated to the use of islets for clinical transplantation., Methods: One hundred twelve standardized consecutive islet isolations were evaluated. Metyltioninklorid and indermil (topical tissue adhesive) were applied to detect leakage of collagenase injected and to repair the damaged pancreatic glands. The effects of dye and glue were evaluated in terms of islet yield, islet function using the perifusion assay, and success rate of the isolation. To analyze key factors for successful isolations, both univariate and multivariate regression analysis were performed., Results: Both Metyltioninklorid and Indermil were effective to prevent leakage of enzyme solutions from the pancreatic glands. Both islet yield and success rate were higher when these tools were applied (4,516.1+/-543.0 vs. 3,447.7+/-323.5, P=0.02; 50.0% vs. 21.3%, P=0.02, respectively). No adverse effects on islet function or collagenase activity were observed. Multivariate regression analysis identified the maximal recorded amylase >100 U/L (P=0.026), BMI (P=0.03), and the use of catecholamine (P=0.04) as crucial donor-related factors. In addition, cold ischemia time (P=0.005), the dissection procedure using whole glands with duodenum (P=0.02), and the local procurement team (P=0.03) were identified as crucial isolation-related variables., Conclusions: A standardized technique of islet isolation is presented applying novel means to improve enzymatic digestion and to meet cGMP standards.

Background: Islet-produced tissue factor (TF) triggers an adverse clotting reaction, the instant blood-mediated inflammatory reaction (IBMIR), providing a likely explanation for the need of tissue from multiple donors in clinical islet transplantation. In this study, the authors investigated whether compounds previously shown to affect TF and macrophage chemoattractant protein (MCP)-1 expression in monocytes and endothelial cells have the same effect in human islet cells., Methods: Islets were cultured in the presence of l-arginine, cyclosporine A, enalapril, or nicotinamide for 48 hr, after which the TF content and MCP-1 expression were assessed. The effect of nicotinamide on IBMIR was evaluated by exposing the treated islets to fresh human ABO-compatible blood in an in vitro loop model., Results: Nicotinamide was the only compound that significantly reduced both TF and MCP-1. This reduction was dose-dependent. The level of MCP-1 was strongly correlated with TF expression (r2=0.98). In addition, the level of TF was also correlated with the ability of the islets to initiate IBMIR (r2=0.94)., Conclusions: TF and MCP-1 expression in human islets can be decreased by adding nicotinamide to the culture medium. These observations indicate that the adverse effects of IBMIR in clinical islet transplantation could be reduced without endangering the recipient using antithrombotic drugs.