Post-transplant Allograft Research Articles

Prediction of allograft function in pre-transplant kidneys using sound touch elastography (STE): an ex vivo study

BackgroundThe purpose of the study was to evaluate renal quality and predict posttransplant graft function using ex vivo sound touch elastography (STE).MethodsIn this prospective study, 106 donor kidneys underwent ex vivo STE examination and biopsy from March 2022 to August 2023. The mean stiffness of the superficial cortex (STEsc), deep cortex (STEdc), and medulla (STEme) was obtained and synthesized into one index (STE) through the factor analysis method. Additionally, 100 recipients were followed up for 6 months. A random forest algorithm was employed to explore significant predictive factors associated with the Remuzzi score and allograft function. The performance of parameters was evaluated by using the area under the receiver operating characteristic curve (AUC).ResultsSTE had AUC values of 0.803 for diagnosing low Remuzzi and 0.943 for diagnosing high Remuzzi. Meanwhile, STE had an AUC of 0.723 for diagnosing moderate to severe ATI. Random forest algorithm identified STE and Remuzzi score as significant predictors for 6-month renal function. The AUC for STE in predicting postoperative allograft function was 0.717, which was comparable with that of the Remuzzi score (AUC = 0.756). Nevertheless, the specificity of STE was significantly higher than that of Remuzzi (0.913 vs 0.652, p < 0.001). Given these promising results, donor kidneys can be transplanted directly without the need for biopsy when STE ≤ 11.741.ConclusionsThe assessment of kidney quality using ex vivo STE demonstrated significant predictive value for the Remuzzi score and allograft function, which could help avoid unnecessary biopsy.Critical relevance statementPre-transplant kidney quality measured with ex vivo STE can be used to assess donor kidney quality and avoid unnecessary biopsy.Key PointsSTE has significant value for diagnosing low Remuzzi and high Remuzzi scores.STE achieved good performance in predicting posttransplant allograft function.Assessment of kidney quality using ex vivo STE could avoid unnecessary biopsies.Graphical

Unexpected and atypical clinical presentation of myocardial infarction in infants and children: complex pathogenesis of progressive and lethal disease.

Myocardial infarction is rare in children but frequently occurs unexpectedly with atypical presentation. It can cause a progressive lethal course unless prompt treatment is initiated. Paediatric cases of myocardial infarction diagnosed by the presence of ischaemic myocardial insults and symptomatic ventricular dysfunction were reviewed retrospectively. Eighteen patients (5 days to 14 years of age; median 3 months) with myocardial infarction were studied. The aetiology was variable, including congenital coronary anomalies: anomalous left coronary artery from pulmonary artery (five patients), pulmonary atresia with intact ventricular septum with right ventricle-dependent coronary circulation (four), anomalous aortic origin of left coronary artery (three), and Williams syndrome with supravalvar aortic stenosis (one). Two acquired coronary anomalies occurred in one patient with undiagnosed Kawasaki disease with complete thrombotic obstruction of the left coronary artery and another with post-transplant cardiac allograft microangiopathy. Three patients developed thromboembolic coronary artery incidents in normal coronary anatomy. Fourteen patients were less than 1 year of age (78%). Electrocardiographic abnormalities were noted in all patients. Four patients required extracorporeal membrane oxygenation support for severe ventricular dysfunction, none of whom survived. Five patients underwent heart transplant. Five patients died during the same hospitalisation, and one patient died after discharge (overall mortality 33%). Transplant-free survival was 39%. Most myocardial infarction occurred in infants who presented with abrupt onset of non-specific clinical manifestations with progressively deteriorating haemodynamic status resulting in poor transplant-free survival rate. Early diagnosis and treatment are essential to prevent catastrophic outcomes.

Impact of donor-specific antibody with low mean fluorescence intensity on allograft outcomes in kidney transplant

BackgroundImmune-mediated rejection is the most common cause of allograft failure in kidney transplant (KT) patients. Exposure to alloantigen, including human leukocyte antigen (HLA), results in the production of donor-specific antibodies (DSA). There are limited data about low levels of mean fluorescence intensity (MFI) DSA, especially post-transplantation. This study evaluated allograft outcomes in KT patients with low MFI DSA. MethodsFrom January 2007 to December 2021, KT patients who were tested for post-transplant DSA at Ramathibodi Hospital, Bangkok, Thailand, with the DSA MFI ≤ 1000 were evaluated. These KT patients were categorized into two groups: very low DSA (VLL; MFI = 1–500) and low DSA (LL; MFI = 501–1000). All KT patients were evaluated for the primary outcomes, such as the incidence of acute rejection, serum creatinine levels at one and five years after transplantation as well as allograft and patient survivals. ResultsAmong 36 KT patients 25 were included as those with VLL and 11 as those with LL. The LL group had significantly higher T-cell mediated allograft rejection (TCMR) than the VLL group (45% vs. 12%, P = 0.04). In addition, 10 patients, 5 in the VLL group and 5 in the LL group developed antibody-mediated allograft rejection (ABMR). Both TCMR and ABMR were confirmed by biopsy results. There was a trend toward higher MFI in KT patients with ABMR than without ABMR (P = 0.22). At 5 post-transplant years, serum creatinine, allograft and patient survivals were comparable between these two groups. Furthermore, the univariate and multivariate analyzes revealed that the LL group was a high risk for rejection. ConclusionLow MFI DSA values after transplantation may be associated with a higher incidence of rejection, but this finding did not show differences in allograft and patient survival in this study's analysis.

Hepatitis C viremic lung transplantation to aviremic recipients: Comprehensive outcomes and post-transplant viremia.

Direct-acting antiviral (DAA) therapy has revolutionized solid organ transplantation by providing an opportunity to utilize organs from HCV-viremic donors. Though transplantation of HCV-viremic donor organs into aviremic recipients is safe in the short term, midterm data on survival and post-transplant complications is lacking. We provide a midterm assessment of complications of lung transplantation (LT) up to 2 years post-transplant, including patient and graft survival between HCV-viremic transplantation (D+) and HCV-aviremic transplantation (D-). This is a retrospective cohort study including 500 patients from 2018 to 2022 who underwent LT at our quaternary care institution. Outcomes of patients receiving D+ grafts were compared to those receiving D- grafts. Recipients of HCV antibody+ but PCR- grafts were treated as D- recipients. We identified 470 D- and 30 D+ patients meeting inclusion criteria. Crude mortality did not differ between groups (p=.43). Patient survival at years 1 and 2 did not differ between D+ and D- patients (p=.89, p=.87, respectively), and graft survival at years 1 and 2 did not differ between the two groups (p=.90, p=.88, respectively). No extrahepatic manifestations or fibrosing cholestatic hepatitis (FCH) occurred among D+ recipients. D+ and D- patients had similar rates of post-transplant chronic lung allograft rejection (CLAD) (p=6.7%vs. 12.8%, p=.3), acute cellular rejection (60.0%vs. 58.0%, p=.8) and antibody-mediated rejection (16.7%vs. 14.2%, p=.7). There is no difference in midterm patient or graft survival between D+ and D-LT. No extrahepatic manifestations of HCV occurred. No differences in any type of rejection including CLAD were observed, though follow-up for CLAD was limited. These results provide additional support for the use of HCV-viremic organs in selected recipients in LT.

Significance of Arterial Spin Labeling for Reducing Biopsies in Patients With Kidney Allograft Dysfunction.

Although biopsy is often entailed for managing patients with kidney allograft dysfunction, it is associated with potential complications of severe hemorrhage. Arterial spin labeling (ASL) is a non-invasive technique that assesses tissue perfusion. To assess the utility of ASL for the discrimination of patients with post-transplant allograft dysfunction who do not need biopsy from those who need. Prospective. Forty-six patients (34 males/12 females, aged 38.8 ± 9.5 years) with kidney allograft dysfunction, including 31 in which biopsy directly lead to changes in management (NECESSARY group) and 15 in which clinical management did not alter after biopsy (UNNECESSARY group). 3.0 T and 3D fast-spin echo sequence. All patients underwent both ASL scan and biopsies. The serum creatinine, proteinuria, pathologic results, and cortical ASL readings were obtained and compared between the two groups. Chi-square test, independent student t-test, Mann-Whitney U test, receiver-operating characteristic curve. A two-tailed P < 0.05 denoted statistical significance. The NECESSARY group presented with significantly elevated serum creatinine as compared with the UNNECESSARY group (1.87 ± 0.56 mg/dL vs. 1.31 ± 0.37 mg/dL). The acute composite score was significantly higher in the NECESSARY group than that in the UNNECESSARY group (7 [4-8] vs. 1 [0-2]). Cortical ASL in the NECESSARY group was significantly decreased as compared with the UNNECESSARY group (108.06 [69.96-134.92] mL/min/100 g vs. 153.48 [113.19-160.37] mL/min/100 g). Serum creatinine differentiated UNNCESSARY group from the NECESSARY group with an area under the curve (AUC) and specificity of 0.79 and 54.84%, respectively. By comparison, the cortical ASL yielded an AUC of 0.75 and a specificity of 70.97%. Notably, the specificity was increased to 90.30% by combined use of serum creatinine and cortical ASL. The combined use of ASL and serum creatinine yielded a high specificity for selecting patients who may not need allograft biopsy. 2 TECHNICAL EFFICACY: Stage 3.

Evaluation of Donor Lungs for Transplantation: The Efficacy of Screening Bronchoscopy for Detecting Donor Aspiration and Its Relationship to the Resulting Allograft Function in Corresponding Recipients

Potential organ donors often have suffered anoxic and/or traumatic brain injury during which they may have experienced aspiration of gastric material (AGM). Evaluation of such donors typically includes a screening bronchoscopic examination during which determinations of aspiration are made. The efficacy of this visual screening and its relationship to post-transplant allograft function are unknown. Before procurement, bronchoscopy was performed on donors in which both bronchoalveolar lavage fluid (BALF) was collected and a visual inspection made. As a marker of AGM, BALF specimens were analyzed for the presence of bile salts. Data collected on the corresponding recipients included primary graft dysfunction (PGD) score, post-transplant spirometry, acute rejection scores (ARS), and overall survival. Of 31 donors evaluated, bronchoscopies revealed only 2 with visual evidence of AGM, whereas BALF analysis for bile salts indicated AGM in 14. As such, screening bronchoscopy had a sensitivity of only 7.1%. Visual detection of AGM via bronchoscopy was not associated with any resulting grade of PGD (χ2=2.96, P=.23); however, AGM defined by detection of bile salts was associated (χ2=7.56, P=.02). Over the first post-transplant year, the corresponding recipients experienced a similar improvement in allograft function (χ2=1.63, P=.69), ARS (P=.69), and survival (P=.24). Visual inspection during a single bronchoscopic examination of lung donors underestimates the prevalence of AGM. The detection of bile salts in donor BALF is associated with early allograft dysfunction in the corresponding recipients but not with later allograft proficiency, acute rejection responses, or 1-year post-transplant survival.

Pathological Approach to Kidney Allograft Infection.

Infectious agents can pose a significant challenge in kidney transplantation, as they have the potential to cause direct infections in the transplanted kidney. These infections can lead to a decline in kidney function and reduce the longevity of the transplanted kidney. Common post-transplant allograft infections include bacterial pyelonephritis and the BK virus infection, while adenovirus, JC virus, and cytomegalovirus are less frequent but can also lead to significant allograft dysfunctions. The histopathological features of these infections are characterized by the infiltration of inflammatory cells in the kidney interstitial area and the presence of viral nuclear inclusions or cytopathic changes in the renal tubular epithelial cells. The confirmation of causative organisms can be achieved by immunohistochemical staining or the visualization of viral particles using electron microscopic examination. However, these methods typically require a longer turnaround time and are not readily available in developing countries, unlike standard hematoxylin-eosin staining. Notably, the differential diagnosis of interstitial inflammation in kidney allografts almost always includes T cell-mediated rejection, which has a different treatment approach than allograft infections. The aim of this review was to prompt clinicians to identify diverse pathological alterations as observed in kidney allograft biopsies, thereby facilitating further investigations and the management of suspected kidney allograft infections.

#2970 CYTOMEGALOVIRUS INFECTION AND RISK OF NEW-ONSET DIABETES AFTER TRANSPLANTATION: A RETROSPECTIVE STUDY

Abstract Background and Aims New-onset diabetes after transplantation (NODAT) is one of the common complications reported in patients with kidney transplant and is associated with risk of infection, poor allograft and patient survival. There is conflicting research literature regarding the role of cytomegalovirus (CMV) infection in increasing the risk of NODAT development. Aim To assess the risk of development of NODAT in kidney transplant patients with CMV infection Method A total of 59 kidney transplant patients were studied from March 2017 to February 2019. NODAT was defined as two readings of fasting plasma glucose of ≥126 mg/dL at three months post-transplant. CMV viral load was also documented. The 12 months post-transplant allograft and patient survival outcomes were also measured. Results Mean age was 43.4 ± 6.2 years. Nearly one-fourth, 14 (23.7%), of the patients had NODAT. CMV viral load and viremia were high in NODAT group; however, the result did not reach statistical significance. CMV DNA replication was statistically high during 1-6 months post-transplant for NODAT group (P&amp;lt;0.001). Only 7 (11.9%) recipients advanced to symptomatic CMV infection. Also, we found that high CMV viremia load was associated with poor kidney allograft function at 12 months. Conclusion In summary, this study showed that infection with CMV may not be a risk factor to develop NODAT in patients transplanted with kidney. An elevated CMV viral load may decrease the post-transplant allograft function at 12 months. The prompt diagnosis and timely 2 management of CMV infection could substantially lessen the risk to develop NODAT subsequent worsening of allograft and patient survival.

Organ Preservation in the 2020s: XVIVO Heart Box (Part 2)

The XVIVO Heart Box (XHB) is an emerging technology in cardiac transplantation that protects the donor heart via non-ischaemic heart preservation (NIHP). A first-in-human trial utilising XHB demonstrated its safe use in human cardiac transplantation [ [1] Nilsson J, Jernryd V, Qin G, Paskevicius A, Metzsch C, Sjöberg T, et al. A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation. Nat Commun. 2020;11:2976. Google Scholar ]. In response, an Australian and New Zealand multicentre trial of extended (6–8 hours) NIHP of donor hearts for transplantation utilising XHB is underway. The current study is an open-labelled, single-arm, multicentre clinical trial. It aims to investigate the effect of NIHP on donor hearts with extended ischaemic time (6–8 hours) with respect to immediate and long-term post-transplant heart allograft function.

Isolated arterial mucoid intimal thickening lesion in early post-transplant kidney allograft biopsies.

Thrombotic microangiopathy (TMA) on kidney biopsy shows a variable combination of features: arterial mucoid intimal thickening, acellular closure of glomerular capillary loops, fragmented red blood cells, fibrin thrombi, and arterial fibrinoid necrosis. However, some early post-transplant kidney biopsies show only arterial mucoid intimal thickening. We aimed to elucidate the importance of this finding. We identified 19 biopsies showing isolated arterial mucoid intimal thickening and compared them with 22 bona fide TMA biopsies identified based on the pathological findings (excluding rejection) (2011-2020). Additionally, delayed graft function (DGF) (n=237), and no DGF (control, n=1314) groups were included for survival analysis. Seven of 19 cases with isolated arterial mucoid intimal thickening showed peripheral blood schistocytes but no other systemic features of TMA. Eight patients underwent adjustments in maintenance immunosuppression (mainly calcineurin inhibitors). None of the cases progressed to full-blown TMA on consecutive biopsies. The overall and death-censored graft survival rates in this group were comparable to the DGF group, but significantly better than the TMA group (P=.005 and .04, respectively). Isolated arterial mucoid intimal thickening in early post-transplant biopsies may be an early/mild form of TMA, probably requiring adjustment in immunosuppressive regimen. Careful exclusion of known causes of TMA, and donor-derived arterial injury are important.

Chicken or Egg: Tricuspid Regurgitation-The Cause or the Consequence of Post-Heart Transplant Allograft Dysfunction.

Tricuspid regurgitation (TR) is the most common valvular abnormality in cardiac transplant recipients.1 The causes of posttransplant TR are often obscure and can be multifactorial.2,3 The prognostic significance of posttransplant TR and the clinical implications of the severity of TR remain unclear and undefined.4-6 To clarify these questions, Bart et al7 conducted a retrospective study of their heart transplant patients over a 6-y period, examining transthoracic echocardiograms in 163 patients. Of these patients, 142 had a transthoracic echocardiograms before their first posttransplant endomyocardial biopsy (EMB). At month 0 posttransplant, 127 patients (78%) had no or mild TR before their first EMB, whereas 36 patients (22%) had moderate–severe TR.7 In patients with no or mild TR, 9 (7%) progressed to moderate–severe TR by 6 mo and 1 underwent tricuspid valve (TV) surgery.7 Of the patients with moderate–severe TR before the first biopsy, by 2 y, 3 had undergone TV surgery. Furthermore, in the moderate–severe TR before first biopsy group, postoperative extracorporeal membrane oxygenation (ECMO) use was significantly more common (78%; P < 0.05), as was rejection frequency (P = 0.02).7 Patients with late progressive moderate–severe TR had a significantly higher 2-y mortality than those who had moderate–severe TR immediately.7 Severe TR post–heart transplant is associated with a worse outcome8 although the clinical outcomes are otherwise variable.4 The consequences of severe TR can result in right ventricular dilatation with hepatic and renal congestion and subsequent dysfunction. Major causes of posttransplant TR include damage to the TV from the EMB and perioperative complications such as primary graft dysfunction (PGD), which often requires ECMO. This would explain the association of ECMO with moderate–severe TR. Additionally, rejection frequency was associated with greater severity of TR. This may be because of injury to the allograft from rejection as well as performing more EMB to make the diagnosis of rejection with concomitant damage to the TV. There has been some evidence that bicaval heart transplants are less likely to develop severe TR as opposed to the older biatrial transplant technique.9,10 However, the current study did not observe a difference. This retrospective study has significant limitations, which are clearly delineated by the authors. A retrospective, single-center study is likely not able to determine if there are specific factors that have causality in the development of TR, its severity, and its progression. The predominant use of the biatrial approach among this study’s patients would limit the ability to distinguish one surgical approach from another in terms of causality of TR. The increasing use of the bicaval approach may reduce the likelihood of developing TR or severe TR. The correlation of ECMO with the development of moderate–severe TR and worse prognoses would suggest that the presence of moderate–severe TR would be a consequence of severe allograft dysfunction posttransplant, necessitating resorting to ECMO for postoperative support. These patients would have worse prognoses on the basis of having PGD, and the severity of TR would, in essence, be an epiphenomenon and a surrogate marker of severe allograft dysfunction posttransplant, given the increased likelihood of developing hepatic and renal congestion and subsequent end-organ dysfunction with severe TR. We can conclude from the results of the current study that TR severity and progression are unsurprisingly associated with severe posttransplant allograft dysfunction with damage to the valve and allograft function. This and the concomitant TV valve damage would adversely affect posttransplant outcomes. The association of rejection frequency with TV severity could be associated with EMB-induced TR, which is also not surprising. What is missing from this study is a more prospective assessment of the relationship of pretransplant and posttransplant pulmonary hemodynamics and volume status to the development of and the severity of TR as well as the relationship with risk factors of PGD. This article serves as a starting point for future investigations. Ultimately, to resolve the questions raised by this article and to better understand the causes and risk factors of TR and prognostic factors of TR development and severity, a larger, prospective, multicenter study collecting echocardiographic information of TR severity, relationship of TR with type of transplant surgery performed, correlation of pulmonary hemodynamics with severity of TR, and prognosis and correlation of number of biopsies and rejection episodes with severity of TR should be performed. The care of transplant patients has changed with greater reliance on noninvasive biomarkers to assess the need for performing EMB, thus reducing the numbers of EMB. This may reduce the incidence and severity of TR. Given the large number of heart transplant programs in the United States that have switched to a biomarker-guided posttransplant strategy (donor-derived cell-free DNA, gene expression profiling) with biopsy minimization, it may be difficult to compare this approach with the more traditional biopsy-guided approach in terms of the impact on TR.

Early posttransplant reductions in club cell secretory protein associate with future risk for chronic allograft dysfunction in lung recipients: results from a multicenter study

Chronic lung allograft dysfunction (CLAD) increases morbidity and mortality for lung transplant recipients. Club cell secretory protein (CCSP), produced by airway club cells, is reduced in the bronchoalveolar lavage fluid (BALF) of lung recipients with CLAD. We sought to understand the relationship between BALF CCSP and early posttransplant allograft injury and determine if early posttransplant BALF CCSP reductions indicate later CLAD risk. We quantified CCSP and total protein in 1606 BALF samples collected over the first posttransplant year from 392 adult lung recipients at 5 centers. Generalized estimating equation models were used to examine the correlation of allograft histology or infection events with protein-normalized BALF CCSP. We performed multivariable Cox regression to determine the association between a time-dependent binary indicator of normalized BALF CCSP level below the median in the first posttransplant year and development of probable CLAD. Normalized BALF CCSP concentrations were 19% to 48% lower among samples corresponding to histological allograft injury as compared with healthy samples. Patients who experienced any occurrence of a normalized BALF CCSP level below the median over the first posttransplant year had a significant increase in probable CLAD risk independent of other factors previously linked to CLAD (adjusted hazard ratio 1.95; p=0.035). We discovered a threshold for reduced BALF CCSP to discriminate future CLAD risk; supporting the utility of BALF CCSP as a tool for early posttransplant risk stratification. Additionally, our finding that low CCSP associates with future CLAD underscores a role for club cell injury in CLAD pathobiology.

Assessment of Cytokines as Potential Biomarkers to Predict Allograft Rejection in Kidney Transplant Recipients

Objectives: Allograft rejection is the most common event that occurs posttransplant and the current diagnostic tools like the measurement of serum creatinine or core kidney biopsy could not serve as a predictive tool and have certain drawbacks. Thus, our target was to find potential, non-invasive, and predictive biomarkers which could identify recipients at the risk of post-transplant allograft rejection. Methods: It is a prospective longitudinal cohort study comprising of 40 live-related kidney transplant recipients whose peripheral blood was collected at three time points viz pre, one and threemonths post-transplant to assess the plasma cytokine levels of FOXP3, IL- 6, IL-17 and TGF-b using Enzyme linked immunosorbent assay (ELISA). The patients were clinically followed for period of two years to determine their posttransplant outcome. Findings: 13 of our recipients had biopsy proven allograft rejection at the end of follow-up period. The pre-transplant concentration of FOXP3 were less in the rejection group whereas the concentration of IL-6, IL- 17 and TGF- b were more in the rejection group (p<0.05). The classification accuracy of the markers FOXP3, TGF- b , IL-17 and IL-6 were assessed and they had an AUC of 1.0, 1.0, 0.96 and 0.84 respectively with high sensitivity, specificity, and statistical significance. Novelty: Pre-transplant levels of plasma cytokines were able to predict recipients at the risk of allograft rejection. Thus, our study confirms the predictive power of our cytokine biomarkers FOXP3, IL- 6, IL-17 and TGF-b and further paves way for personalized immunosuppressive regimen. Keywords: Predictive Biomarkers; Allograft Rejection; FOXP3; IL6; IL17; TGFb

Portal vein thrombosis, hepatic decompensation, and survival in patients with porto-sinusoidal vascular disease and portal hypertension.

Porto-sinusoidal vascular disease (PSVD) is a novel nomenclature to describe non-cirrhotic portal hypertension and characteristic histology without portal vein thrombosis (PVT). It is a more inclusive definition than the previously well-recognized entity idiopathic non-cirrhotic portal hypertension. There is a paucity of data on PSVD patients. A total of 33 patients diagnosed with PSVD and portal hypertension (PH) between 2005 and 2021 were included. Data were retrieved from electronic medical record system and analyzed. Of the 33 patients, 6 (18%) occurred in post-transplant allograft liver. After a median follow-up of 96months (interquartile range, IQR [52, 139]), 14 deaths occurred (42%), 4 directly related to decompensated liver disease. The Kaplan-Meier survival estimates at 1, 5, and 10years were 94%, 87% and 58%. PVT occurred in 10 patients (30%). The Nelson-Aalen cumulative risk estimate for PVT at 1, 5 and 10years were 16%, 25% and 48%. The median model for end-stage liver disease and Child-Pugh score at initial presentation were 8 (IQR [7-12]) and 5 [5-6], and increased to 13 [8, 18] and 7 [5, 8], respectively, at the end of follow-up. Of the 11 patients who presented with splenomegaly and no specific sign of PH, 7 (64%) developed varices and 3 (27%) ascites at a median follow-up of 100months. PSVD with PH is not a benign entity. Mortality, PVT and hepatic decompensation are common. Patients with PSVD must be closely monitored, including those who only have non-specific clinical signs (e.g., splenomegaly) of PH.

Outcomes of Patients Receiving a Kidney Transplant or Remaining on the Transplant Waiting List at the Epicentre of the COVID-19 Pandemic in Europe: An Observational Comparative Study.

Since the declaration of the COVID-19 pandemic, the number of kidney transplants (KT) performed worldwide has plummeted. Besides the generalised healthcare crisis, this unprecedented drop has multiple explanations such as the risk of viral transmission through the allograft, the perceived increase in SARS-CoV-2-related morbidity and mortality in immunocompromised hosts, and the virtual “safety” of dialysis while awaiting effective antiviral prophylaxis or treatment. Our institution, operating at the epicentre of the COVID-19 pandemic in Italy, has continued the KT programme without pre-set limitations. In this single-centre retrospective observational study with one-year follow-up, we assessed the outcomes of patients who had undergone KT (KTR) or remained on the transplant waiting list (TWL), before (Pre-COV) or during (COV) the pandemic. The main demographic and clinical characteristics of the patients on the TWL or receiving a KT were very similar in the two periods. The pandemic did not affect post-transplant recipient and allograft loss rates. On the contrary, there was a trend toward higher mortality among COV-TWL patients compared to Pre-COV-TWL subjects. Such a discrepancy was primarily due to SARS-CoV-2 infections. Chronic exposure to immunosuppression, incidence of delayed allograft function, and rejection rates were comparable. However, after one year, COV-KTR showed significantly higher median serum creatinine than Pre-COV-KTR. Our data confirm that KT practice could be safely maintained during the COVID-19 pandemic, with excellent patient- and allograft-related outcomes. Strict infection control strategies, aggressive follow-up monitoring, and preservation of dedicated personnel and resources are key factors for the optimisation of the results in case of future pandemics.

How useful is the machine perfusion in liver transplantation? An answer from a national survey.

Machine perfusion (MP) has been shown worldwide to offer many advantages in liver transplantation, but it still has some gray areas. The purpose of the study is to evaluate the donor risk factors of grafts, perfused with any MP, that might predict an ineffective MP setting and those would trigger post-transplant early allograft dysfunction (EAD). Data from donors of all MP-perfused grafts at six liver transplant centers have been analyzed, whether implanted or discarded after perfusion. The first endpoint was the negative events after perfusion (NegE), which is the number of grafts discarded plus those that were implanted but lost after the transplant. A risk factor analysis for NegE was performed and marginal grafts for MP were identified. Finally, the risk of EAD was analyzed, considering only implanted grafts. From 2015 to September 2019, 158 grafts were perfused with MP: 151 grafts were implanted and 7 were discarded after the MP phase because they did not reach viability criteria. Of 151, 15 grafts were lost after transplant, so the NegE group consisted of 22 donors. In univariate analysis, the donor risk index >1.7, the presence of hypertension in the medical history, static cold ischemia time, and the moderate or severe macrovesicular steatosis were the significant factors for NegE. Multivariate analysis confirmed that macrosteatosis >30% was an independent risk factor for NegE (odd ratio 5.643, p = 0.023, 95% confidence interval, 1.27–24.98). Of 151 transplanted patients, 34% experienced EAD and had worse 1- and 3-year-survival, compared with those who did not face EAD (NoEAD), 96% and 96% for EAD vs. 89% and 71% for NoEAD, respectively (p = 0.03). None of the donor/graft characteristics was associated with EAD even if the graft was moderately steatotic or fibrotic or from an aged donor. For the first time, this study shows that macrovesicular steatosis >30% might be a warning factor involved in the risk of graft loss or a cause of graft discard after the MP treatment. On the other hand, the MP seems to be useful in reducing the donor and graft weight in the development of EAD.

Radiomic analysis of liver grafts from brain-dead donors can predict early allograft dysfunction following transplantation: a proof-of-concept study.

Selection of liver grafts suitable for transplantation (LT) mainly depends on a surgeon's subjective assessment. This study aimed to investigate the role of radiomic analysis of donor-liver CTs after brain death (DBD) to predict the occurrence of early posttransplant allograft dysfunction (EAD). We retrospectively extracted and analyzed the left lobe radiomic features from CT scans of DBD livers in training and validation cohorts. Multivariate analysis was performed to identify predictors of EAD. From 126 LTs included in the study in the training cohort, 27 (21.4%) had an EAD. For each patient, 279 radiomic features were extracted of which 5 were associated with EAD (AUC=0.81) (95% CI 0.72-0.89). Among donor and recipient clinical characteristics, cardiac arrest, steatosis on donor's CT, cold ischemic time and age of recipient were also identified as independent risk factors for EAD. Combined radiomic signature and clinical risk factors showed a strong predictive performance for EAD with a C-index of 0.90 (95% CI 0.84-0.96). A validation cohort of 23 patients confirmed these results. Radiomic signatures extracted from donor CT scan, independently or combined with clinical risk factors is an objective and accurate biomarker for prediction of EAD after LT.

Pretransplant characteristics of kidney transplant recipients that predict posttransplant outcome.

Better characterization of the potential kidney transplant recipient using novel biomarkers, for example, pretransplant plasma endotrophin, will lead to improved outcome after transplantation. This mini-review will focus on current knowledge about pretransplant recipients’ characteristics, biomarkers, and immunology. Clinical characteristics of recipients including age, obesity, blood pressure, comorbidities, and estimated survival scores have been introduced for prediction of recipient and allograft survival. The pretransplant immunologic risk assessment include histocompatibility leukocyte antigens (HLAs), anti-HLA donor-specific antibodies, HLA-DQ mismatch, and non-HLA antibodies. Recently, there has been the hope that pretransplant determination of markers can further improve the prediction of posttransplant complications, both short-term and long-term outcomes including rejections, allograft loss, and mortality. Higher pretransplant plasma endotrophin levels were independently associated with posttransplant acute allograft injury in three prospective European cohorts. Elevated numbers of non-synonymous single-nucleotide polymorphism mismatch have been associated with increased allograft loss in a multivariable analysis. It is concluded that there is a need for integration of clinical characteristics and novel molecular and immunological markers to improve future transplant medicine to reach better diagnostic decisions tailored to the individual patient.

The Edge of Unknown: Postoperative Critical Care in Liver Transplantation.

Perioperative care of patients undergoing liver transplantation (LT) is very complex. Metabolic derangements, hypothermia, coagulopathy and thromboses, severe infections, and graft dysfunction can affect outcomes. In this manuscript, we discuss several perioperative problems that can be encountered in LT recipients. The authors present the most up-to-date information regarding predicting and treating hemodynamic instability, coagulation monitoring and management, postoperative ventilation strategies and early extubation, management of infections, and ESLD-related pulmonary complications. In addition, early post-transplant allograft dysfunction will be discussed.

Antibody-suppressor CXCR5+CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice

CCR5KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5KO recipient mice, which can be rescued with ACT.