Recently published studies have found an impaired immune response after SARS-CoV-2 vaccination in solid organ recipients. However, most of these studies have not assessed immune cellular responses in liver and heart transplant recipients. We prospectively studied heart and liver transplant recipients eligible for SARS-CoV-2 vaccination. Patients with past history of SARS-CoV-2 infection or SARS-CoV-2 detectable antibodies (IgM or IgG) were excluded. We assessed IgM/IgG antibodies and ELISpot against the S protein 4 weeks after receiving the second dose of the mRNA-1273 (Moderna) vaccine. Side effects, troponin I, liver tests and anti-HLA donor-specific antibodies (DSA) were also assessed. A total of 58 liver and 46 heart recipients received two doses of mRNA-1273 vaccine. Median time from transplantation to vaccination was 5.4 years (IQR 0.3–27). Sixty-four percent of the patients developed SARS-CoV-2 IgM/IgG antibodies and 79% S-ELISpot positivity. Ninety percent of recipients developed either humoral or cellular response (87% in heart recipients and 93% in liver recipients). Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation. Local and systemic side effects were mild or moderate, and none presented DSA or graft dysfunction after vaccination. Ninety percent of our patients did develop humoral or cellular responses to mRNA-1273 vaccine. Factors associated with vaccine unresponsiveness were hypogammaglobulinemia and vaccination during the first year after transplantation, highlighting the need to further protect these patients.
Liver function is measured regularly in liver transplantation (LT) candidates. Currently, these previous disease development data are not used for survival prediction. By constructing and validating joint models (JMs), we aimed to predict the outcome based on all available data, using both disease severity and its rate of change over time. Adult LT candidates listed in Eurotransplant between 2007 and 2018 (n = 16 283) and UNOS between 2016 and 2019 (n = 30 533) were included. Patients with acute liver failure, exception points, or priority status were excluded. Longitudinal MELD(-Na) data were modeled using spline-based mixed effects. Waiting list survival was modeled with Cox proportional hazards models. The JMs combined the longitudinal and survival analysis. JM 90-day mortality prediction performance was compared to MELD(-Na) in the validation cohorts. MELD(-Na) score and its rate of change over time significantly influenced patient survival. The JMs significantly outperformed the MELD(-Na) score at baseline and during follow-up. At baseline, MELD-JM AUC and MELD AUC were 0.94 (0.92–0.95) and 0.87 (0.85–0.89), respectively. MELDNa-JM AUC was 0.91 (0.89–0.93) and MELD-Na AUC was 0.84 (0.81–0.87). The JMs were significantly (p < .001) more accurate than MELD(-Na). After 90 days, we ranked patients for LT based on their MELD-Na and MELDNa-JM survival rates, showing that MELDNa-JM-prioritized patients had three times higher waiting list mortality.
COVID-19 pandemic dramatically impacted transplantation landscape. Scientific societies recommend against the use of donors with active SARS-CoV-2 infection. Italian Transplant Authority recommended to test recipients/donors for SARS-CoV-2-RNA immediately before liver transplant (LT) and, starting from November 2020, grafts from deceased donors with active SARS-CoV-2 infection were allowed to be considered for urgent-need transplant candidates with active/resolved COVID-19. We present the results of the first 10 LTs with active COVID-19 donors within an Italian multicenter series. Only two recipients had a positive molecular test at LT and one of them remained positive up to 21 days post-LT. None of the other eight recipients was found to be SARS-CoV-2 positive during follow-up. IgG against SARS-CoV-2 at LT were positive in 80% (8/10) of recipients, and 71% (5/7) showed neutralizing antibodies, expression of protective immunity related to recent COVID-19. In addition, testing for SARS-CoV-2 RNA on donors’ liver biopsy at transplantation was negative in 100% (9/9), suggesting a very low risk of transmission with LT. Immunosuppression regimen remained unchanged, according to standard protocol. Despite the small number of cases, these data suggest that transplanting livers from donors with active COVID-19 in informed candidates with SARS-CoV-2 immunity, might contribute to safely increase the donor pool.
Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in post-transplant patients on immunosuppression regimens. Therefore, we studied rates of immunity against vaccine-preventable viruses in lung transplantation (LTx) candidates and their associations with underlying lung disease and clinical characteristics. We retrospectively studied 1025 consecutive adult patients who underwent first-time evaluation for LTx at a single center between January 2016 and October 2018. Viruses studied included varicella zoster (VZV), measles, and mumps. Young age (17–48 years old) was negatively associated with immunity for VZV (OR 4.54, p < .001), measles (OR 15.45, p < .001) and mumps (OR 3.1, p < .001), as compared to those 65+. Many LTx candidates with cystic fibrosis (CF) had undetectable virus-specific antibody titers including: 13.5% for VZV, 19.1% for measles, and 15.7% for mumps with significant odds of undetectable titers for VZV (OR 4.54, p < .001) and measles (OR 2.32, p = .010) as compared to those without CF. Therefore, a substantial number of patients undergoing LTx evaluation had undetectable virus-specific antibody titers. Our results emphasize the importance of screening for immunity to vaccine-preventable infections in this population and the need for revaccination in selected patients to boost their humoral immunity prior to transplantation.
Opportunities continue to be lost with a high rate of kidneys recovered for transplant but not utilized, particularly those considered less than ideal quality. The Organ Procurement and Transplantation Network (OPTN) Organ Center is tasked with allocating arguably the most difficult-to-place kidneys, and we hypothesized an accelerated placement pathway would increase utilization of kidneys placed by the Organ Center. The Kidney Accelerated Placement (KAP) project, implemented by the Organ Center from July 18, 2019 to July 15, 2020, aimed to offer kidneys with a high kidney donor profile index to programs that had a history of accepting such organs. We compared OPTN kidney match run, donor, and transplant recipient data during the project period and 1 year prior. There was no statistically significant change in the percentage of KAP-eligible donors accepted during the project period (16.4%) compared to the prior year (17.5%). Conversion from acceptance to transplant was higher under KAP (72.7% vs. 71.2%), though not significant. Waiting to accelerate placement after kidneys have been declined by multiple transplant programs locally and regionally is an intervention that may come too late to effectively increase utilization. Transplant rates of nationally shared and marginal kidneys remain a challenge, and future iterations of this project should be investigated.
A landmark 2002 study identified Black liver transplant (LT) recipients as having lower post-LT survival compared to other races. While persistent disparities exist, changes over time and mediating factors are understudied. Capturing LT recipients between 2002 and 2018 in UNOS, we used logistic regression and Cox proportional-hazard models to calculate differences in post-LT mortality among races. We examined interactions between transplant year and race. A mediation analysis assessed biologic and environmental factors potentially associated with race differences in post-LT survival. The cohort included 46,997 LT recipients (3898 Black;36,560 White;6539 Hispanic). In most years, Black (vs. White) LT recipients had a higher probability of age-adjusted mortality, not observed among Hispanics. In multivariable analysis, Blacks (vs. Whites) had higher (aHR = 1.15, 95% CI 1.07–1.24), whereas Hispanics had lower (aHR = 0.78, 95% CI 0.72–0.83) risk of mortality. Differences in post-LT mortality among Blacks (vs. Whites) narrowed between 2002 and 2009, were similar between 2010 and 2013, and may have worsened between 2014 and 2018. Race differences were larger for mortality beyond 1-year post-LT (vs. within 1-year), and among non-HCV (vs. HCV). Alcohol-associated liver disease (ALD) was the strongest mediator (13.9%, 95% CI 8.7–32.7%) of the Black–White disparity in 2010–2018. Our analyses suggest disparities may worsen with longer follow-up, as HCV recedes with elimination efforts, and with further increases in ALD.
Long-term survival after lung transplantation is limited by chronic allograft dysfunction. The aim of this study was to investigate the effect of locally augmented immunosuppression with liposomal cyclosporine A for inhalation (L-CsA-i) for the prevention of bronchiolitis obliterans syndrome (BOS). In a randomized, double-blind, placebo-controlled, multi-center Phase 3 study, 180 LT recipients in BOS grade 0 were planned to receive L-CsA-i or placebo in addition to triple-drug immunosuppression. L-CsA-i was administered twice daily via an Investigational eFlow nebulizer to recipients of single (SLT) and bilateral lung transplants (BLT) within 6–32 weeks posttransplant, and continued for 2 years. The primary endpoint was BOS-free survival. 130 patients were enrolled before the study was prematurely terminated for business reasons. Despite a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA-i in the overall study population, the primary endpoint was not met (p = .243). The pre-defined per protocol analysis of SLT recipients (n = 24) resulted in a treatment difference of 58.2% (p = .053). No difference was observed in the BLT (n = 48) subpopulation (p = .973). L-CsA-i inhalation was well tolerated. Although this study failed to meet its primary endpoint, the results warrant additional investigation of L-CsA-i in lung transplant recipients.
Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.
Despite prevention strategies, cytomegalovirus (CMV) remains a common infection in pediatric solid organ transplant recipients (SOTR). We sought to determine the frequency, associations with, and long-term outcomes of CMV DNAemia in pediatric SOTR. We performed a single-center retrospective cohort study, including 687 first time SOTR ≤21 years receiving universal prophylaxis from 2011 to 2018. Overall, 159 (23%) developed CMV DNAemia, the majority occurring after completing primary prophylaxis. CMV disease occurred in 33 (5%) SOTR, 25 (4%) with CMV syndrome and 10 (1%) with proven/probable tissue-invasive disease. CMV contributed to the death of three (0.4%) patients (all lung). High-risk (OR 6.86 [95% CI, 3.6–12.9]) and intermediate-risk (4.36 [2.3–8.2]) CMV status and lung transplantation (4.63 [2.33–9.2]) were associated with DNAemia on multivariable analysis. DNAemia was associated with rejection in liver transplant recipients (p < .01). DNAemia was not associated with an increase in graft failure, all-cause mortality, or other organ-specific poor outcomes. We report one of the lowest rates of CMV disease after SOTR, showing that universal prophylaxis is effective and should be continued. However, we observed CMV morbidity and mortality in a subset of patients, highlighting the need for research on optimal prevention strategies. This study was IRB approved.
Immunosuppression and comorbidities might place solid organ transplant (SOT) recipients at higher risk from COVID-19, as suggested by recent case series. We compared 45 SOT vs. 2427 non-SOT patients who were admitted with COVID-19 to our health-care system (March 1, 2020 - August 21, 2020), evaluating hospital length-of-stay and inpatient mortality using competing-risks regression. We compared trajectories of WHO COVID-19 severity scale using mixed-effects ordinal logistic regression, adjusting for severity score at admission. SOT and non-SOT patients had comparable age, sex, and race, but SOT recipients were more likely to have diabetes (60% vs. 34%, p < .001), hypertension (69% vs. 44%, p = .001), HIV (7% vs. 1.4%, p = .024), and peripheral vascular disorders (19% vs. 8%, p = .018). There were no statistically significant differences between SOT and non-SOT in maximum illness severity score (p = .13), length-of-stay (sHR: 0.91.11.4, p = .5), or mortality (sHR: 0.10.41.6, p = .19), although the severity score on admission was slightly lower for SOT (median [IQR] 3 [3, 4]) than for non-SOT (median [IQR] 4 [3–4]) (p = .042) Despite a higher risk profile, SOT recipients had a faster decline in disease severity over time (OR = 0.760.810.86, p < .001) compared with non-SOT patients. These findings have implications for transplant decision-making during the COVID-19 pandemic, and insights about the impact of SARS-CoV-2 on immunosuppressed patients.
Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020–June 19, 2020) and late 2020 (June 20, 2020–December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46–0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.
Food-safety measures are recommended to solid organ transplant (SOT) recipients. However, the burden of foodborne infections in SOT recipients has not been established. We describe the epidemiology and outcomes of bacterial foodborne infections in a nationwide cohort including 4405 SOT recipients in Switzerland between 2008 and 2018. Participants were prospectively followed for a median of 4.2 years with systematic collection of data on infections, and patient and graft-related outcomes. We identified 151 episodes of microbiologically confirmed bacterial foodborne infections occurring in median 1.6 years (IQR 0.58–3.40) after transplantation (131 [88%] Campylobacter spp. and 15 [10%] non-typhoidal Salmonella). The cumulative incidence of bacterial foodborne infections was 4% (95% CI 3.4–4.8). Standardized incidence rates were 7.4 (95% CI 6.2–8.7) and 4.6 (95% CI 2.6–7.5) for Campylobacter and Salmonella infections, respectively. Invasive infection was more common with Salmonella (33.3% [5/15]) compared to Campylobacter (3.2% [4/125]; p = .001). Hospital and ICU admission rates were 47.7% (69/145) and 4.1% (6/145), respectively. A composite endpoint of acute rejection, graft loss, or death occurred within 30 days in 3.3% (5/151) of cases. In conclusion, in our cohort bacterial foodborne infections were late post-transplant infections and were associated with significant morbidity, supporting the need for implementation of food-safety recommendations.
Pediatric en bloc kidney transplants (EBKs) from small deceased pediatric donors are associated with increased early graft loss and morbidity. Yet, urologic complications post‐EBK and their potential impact on graft survival have not been systematically studied. We retrospectively studied urological complications requiring intervention for 225 EBKs performed at our center January 2005 to September 2017 from donors ≤20 kg into recipients ≥18 years. Overall ureteral complication incidence after EBK was 9.8% (n = 22) (12% vs 2% for EBK donors 10 vs 10 kg, respectively [P = .031]). The most common post‐EBK urologic complication was a stricture (55%), followed by urine leak (41%). In all, 95% of all urologic complications occurred early within 5 months posttransplant (median, 138 days). Urologic complications could be successfully managed nonoperatively in 50% of all cases and had no impact on graft or patient survival. In summary, urologic complications after EBK were common, associated with lower donor weights, occurred early posttransplant, and were often amenable to nonoperative treatment, without adversely affecting survival. We conclude that the higher urologic complication rate after EBK (1) should not prevent increased utilization of small pediatric donor en bloc kidneys for properly selected recipients, and (2) warrants specific discussion with EBK recipients during the preoperative consent process. 相似文献
The Australian estimated post-transplant survival (EPTS-AU) prediction score was developed by re-fitting the United States of America EPTS, without diabetes, to the Australian and New Zealand kidney transplant population over 2002–2013. The EPTS-AU score incorporates age, previous transplantation and time on dialysis. Diabetes was excluded from the score, as this was not previously recorded in the Australian allocation system. In May 2021, the EPTS-AU prediction score was incorporated into the Australian kidney allocation algorithm to optimize utility for recipients (maximized benefit). We aimed to temporally validate the EPTS-AU prediction score to ensure it can be used for this purpose.
Methods
Using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, we included adult recipients of deceased donor kidney-only transplants between 2014 and 2021. We constructed Cox models for patient survival. We assessed validation using measures of model fit (Akaike information criterion and misspecification), discrimination (Harrell's C statistic and Kaplan–Meier curves), and calibration (observed vs. predicted survival).
Results
Six thousand four hundred and two recipients were included in the analysis. The EPTS-AU had moderate discrimination with a C statistic of 0.69 (95% CI 0.67, 0.71), and clear delineation between Kaplan–Meier's survival curves of EPTS-AU. The EPTS was well calibrated with the predicted survivals equating with the observed survival outcomes for all prognostic groups.
Conclusions
The EPTS-AU performs reasonably well in choosing between recipients (discrimination) and to predict a recipient's survival (calibration). Reassuringly, the score is functioning as intended to predict post-transplant survival for recipients as part of the national allocation algorithm.
Laparoscopy provides extensive data for the decannulation of a peritoneal dialysis catheter and is being increasingly used to diagnose encapsulating peritoneal sclerosis. However, there are few reports on the methods of decannulation of peritoneal dialysis catheters. In this study, we examined the laparoscopic findings and postoperative complications of patients undergoing peritoneal dialysis catheter removal. A total of 119 laparoscopic decannulations of peritoneal dialysis catheters were performed between 2003 and 2018 at the Juntendo University Hospital and Juntendo University Nerima Hospital. Laparoscopy was performed during peritoneal dialysis catheter removal by a gastrointestinal surgeon. Patient characteristics such as age, sex, duration of peritoneal dialysis, history of peritonitis and age at the time of peritoneal dialysis termination were assessed. Of these 119 cases, 19 (16.0%) showed adhesion between the peritoneal dialysis catheter and intraperitoneal organs. There were 13 (10.9%) cases involving a tangled omentum, 4 (3.4%) cases involving the small intestine and 2 (1.7%) cases of adhesions extending from the bowels to the abdominal wall. No postoperative complications were associated with the laparoscopic surgery. In these cases, blind decannulation of the peritoneal dialysis catheter may result in injury to the gastrointestinal tract in patients with adhesions. Therefore, we need to pay attention to adhesions between peritoneal dialysis catheters and intraperitoneal organs, and laparoscopy could be a valuable tool in detecting such adhesions and ensuring patient safety.
The cover image is based on the Original Article The application of the Limberg flap repair technique in the surgical treatment of pilonidal sinus disease by Yaoyao Song et al., https://doi.org/10.1111/iwj.14105 .
The low bath bicarbonate concentration ([]) used by a nephrology group in Japan (25.5 mEq/L), coupled with a bath [acetate] of 8 mEq/L, provided an opportunity to study the acid-base events occurring during hemodialysis when flux is from the patient to the bath. We used an analytic tool that allows calculation of delivery during hemodialysis and the physiological response to it in 17 Japanese outpatients with an average pre-dialysis blood [] of 25 mEq/L. Our analysis demonstrates that addition is markedly reduced and that all of it comes from acetate metabolism. The added to the extracellular fluid during treatment (19.5 mEq) was completely consumed by H+ mobilization from body buffers. In contrast to patients dialyzing with higher bath [] values in the US and Europe, organic acid production was suppressed rather than stimulated. Dietary analysis indicates that these patients are in acid balance due to the alkaline nature of their diet. In a larger group of patients using the same bath solution, pre-dialysis blood [] was lower, 22.2 mEq/L, but still in an acceptable range. Our studies indicate that a low bath [] is well tolerated and can prevent stimulation of organic acid production. 相似文献
Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disorder and a rare cause of urolithiasis due to mutations in APRT (OMIM #102600). APRT deficiency results in increased urinary excretion of 2,8-dihydroxyadenine (DHA) which can cause urolithiasis and kidney failure. However, with prompt diagnosis, patients with APRT deficiency can be treated with xanthine oxidoreductase inhibitors which decrease urinary DHA excretion and improve outcomes. We report a pair of siblings, an 11-year-old brother and his 14-year-old sister with compound heterozygous variants c.270del (p.Lys91Serfs*46) and c.484_486del (p.Leu162del) in APRT with variable clinical presentation of APRT deficiency. The brother presented at 17 months of age with urolithiasis and severe acute kidney injury. His elder sister remained well and asymptomatic with normal kidney function and did not develop renal calculi. Brownish disk or sphere-like crystals with both concentric and radial markings were reported on urine microscopy in the sister on screening. The sister's diagnosis was confirmed with further laboratory evidence of absent red cell lysate APRT activity with corresponding elevated levels of urinary DHA. In conclusion, we identified a novel mutation in the APRT gene in a pair of siblings with greater phenotypic severity in the male.
