Transplantology

Chronic liver injury and subsequent liver fibrosis are usually a slow process without any specific or no clinical signs, resulting in pathological conditions with a poor chance of improvement through medical and surgical treatment, which if not promptly recognized, often lead to a liver transplant as the only therapeutic option. On the other hand, screening and follow-up are hard to establish in large populations using regularly invasive methods such as biopsies and other expensive diagnostic tools due to cost and a lack of adequate specificity and sensibility. In the last few years, a large variety of serological and radiological tests have been proposed to assess liver fibrosis. In this review, we will consider the most commonly used scores to evaluate liver fibrosis, with a special focus on the NAFLD pathogenesis. We will try to answer the question: can we rely on them? Full article

Circulatory death donor (DCD) kidneys are increasingly used to enlarge the donor pool. These kidneys undergo ischemia-reperfusion injury, frequently leading to renal fibrosis. Transforming growth factor beta 1 (TGF-β1) and matrix metalloproteases have been identified as central mediators of fibrosis and inhibition of these targets could attenuate fibrosis. We studied whether galunisertib, doxycycline, taurine, and febuxostat alleviated fibrosis in precision-cut kidney slices (PCKS). PCKS were prepared from porcine kidneys that were exposed to 30 min of warm ischemia followed by 3 h of oxygenated hypothermic machine perfusion. We subsequently incubated PCKS for 48 h at 37 °C with the described compounds. To further elucidate the antifibrotic effects of galunisertib, we cultured PCKS with TGF-β1. We first screened the effects of the compounds without TGF-β1. Most significant effects were observed for galunisertib which lowered the expression of ACTA2, TGFB1, FN2, and SERPINE1. We then investigated the effects of galunisertib in fibrotic PCKS incubated with TGF-β1. TGF-β1 significantly increased expression of TGFB1, FN1, SERPINE1, and SERPINH1. Galunisertib, however, attenuated the expression of all fibrosis-related genes. Galunisertib appears to be a promising antifibrotic compound requiring further research in a preclinical model and may ultimately be administered during machine perfusion as an antifibrotic treatment in a transplant setting. Full article

Background: When a partial liver graft is transplanted into a recipient with portal hypertension, it is subject to sinusoidal shear stress, which, in good measure, is essential for regeneration. However, portal hyperperfusion which exceeds the capacity of the graft results in the small-for-size syndrome manifested by ascites, cholestasis and coagulopathy. This review discusses intraoperative hemodynamic variables that have been described in the literature, and inflow modulation strategies and their outcomes. Apart from using donor grafts which are of adequate size for the recipient weight, portal hemodynamics are an important consideration to prevent early allograft dysfunction, graft failure and mortality. Summary: Understanding normal portal hemodynamics, how they change with the progression of cirrhosis, portal hypertension and changes after the implantation of a partial liver graft is key to managing patients with living-donor liver transplantation. If the intraoperative measurement of portal flow or pressure suggests graft portal hyperperfusion, inflow modulation strategies can be adopted. Splenic artery ligation, splenectomy and hemiportocaval shunts are well described in the literature. The proper selection of a donor to match the recipient’s anatomic, metabolic and hemodynamic environment and deciding which modulation strategy to use in which patient is an exercise in sound clinical judgement. Key message: The intraoperative assessment of portal hemodynamics in living-donor liver transplant should be standard practice. Inflow modulation in properly selected patients offers a point-of-care solution to alter portal inflow to the graft with a view to improve recipient outcomes. In patients with small (anatomically/metabolically) grafts, using inflow modulation can result in outcomes equivalent to those in patients in whom larger grafts are used. Full article

Background: Serotherapy with anti-T lymphocyte globulin (ATLG, Grafalon, formerly ATG-Fresenius) is established for the prevention of severe graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). The evidence from prospective studies is predominantly derived from a setting where methotrexate (MTX) and a calcineurin inhibitor (CNI) are used as the backbone of GVHD prophylaxis. The efficacy of ATLG in combination with CNI and mycophenolate mofetil (MMF) has not been investigated as much, particularly in terms of a direct comparison with its effects when combined with CNI/MTX. A total of 401 HSCTs from two Austrian transplant centers were retrospectively evaluated. We included peripheral blood transplants from early- or intermediate-stage (excluding advanced/refractory) hematological diseases from matched siblings or 10/10 or 9/10 matched unrelated donors with CNI/MTX or CNI/MMF prophylaxis, either without (n = 219) or with ATLG (n = 182). Overall, ATLG significantly reduced the risk for all-cause mortality by multivariate Cox analysis (HR 0.53; p = 0.002). Stratification by postgrafting prophylaxis type revealed a significant survival advantage for ATLG in the CNI/MMF cohort (HR 0.49; p = 0.001; n = 193), while its effect on survival in the CNI/MTX cohort was not significant (HR 0.87; p = 0.56; n = 208). In unrelated HSCT with CNI/MMF prophylaxis, ATLG exhibited its greatest survival benefit (HR 0.34; p = 0.001; n = 104). In the context of CNI/MMF, ATLG may provide even greater benefits than in the setting of CNI/MTX for post-grafting immunosuppression. Future prospective studies on ATLG should therefore focus on CNI/MMF-based transplants, which are widely performed in elderly or comorbid patients not expected to tolerate a standard course of MTX. Full article

Background: Kidney allografts with the presence of diffuse glomerular fibrin thrombi are typically rejected by most centers due to concern for poor allograft outcomes in the recipients. The aim of this study was to report our single center experience in the use of such deceased donor allografts. Methods: Retrospective single-center cohort study of kidney transplant recipients who received deceased donor allografts with moderate-to-severe diffuse glomerular fibrin microthrombi on the pre-implantation biopsy. Results: Three adult recipients received deceased donor kidney transplantation from donation after circulatory death donors. One patient was pre-emptive to dialysis at the time of transplant. The donors had moderate-to-severe diffuse glomerular fibrin thrombi on preimplantation biopsies with no evidence of cortical necrosis. Mean follow-up period was 196 days. None of the recipients developed delayed allograft function. The mean 3-month and 6-month creatinine were 1.6 and 1.5 mg/dL, respectively, with corresponding mean eGFRs (estimated glomerular filtration rates) of 45.7 and 47.3 mL/min/1.73m². Conclusions: After excluding significant cortical necrosis by experienced transplant renal pathologist, otherwise transplantable kidney allografts with diffuse fibrin thrombi may be successfully transplanted in renal transplant recipients with good renal outcomes. Full article

Laparoscopic donor nephrectomy (LDN) is the current gold standard in kidney donation. Mini-incision open donor nephrectomy (MINI) techniques have been used extensively but have become less popular. The aim of the present study was to compare the results and safety of a non-muscle-splitting MINI technique with the current gold standard of LDN. A single center retrospective cohort study of all living donor nephrectomies between 2011 and 2019 was used for the study. The primary outcome of this study was short term (<30 days) with Clavien–Dindo grade complications. Secondary outcomes included multivariable regression analysis of perioperative data. No differences in complication rates were observed between MINI and LDN and also after correction for known confounders. As expected, the operative time and first warm ischemia were significantly shorter in the MINI group and less blood loss was observed in the LDN group. Complications and conversion rate (LDN to open) among the LDN patients were in line with recent published meta-analyses. This study confirms the perioperative safety of living kidney donation in modern practice. Complication rates of both MINI and LDN procedures are limited and not different between procedures. In specific circumstances, the MINI procedure can still be considered a safe and feasible alternative for living kidney donation. Full article

I should highlight that this manuscript is not a formal review on the topic, but a report from an ESOT meeting held on 22 June 2022. The assumption of immunosuppressants exposes kidney transplant recipients to the risk of infections, including COVID-19 infection. A transplant patient having COVID-19 infection raises several questions, including whether the immunosuppressive therapy should be reduced with the consequent risk of favoring acute rejections. Patient vaccination before transplantation is probably the gold standard to avoid the risk of COVID-19 infection after transplantation. In the case of transplant patients, three measures may be undertaken: vaccination, use of monoclonal antibodies and use of therapeutic antiviral small molecules. Concerning vaccination, it is still debated which one is the best and how many doses should be administered, particularly considering the new variants of the virus. The onset of virus variants has stimulated researchers to find new active vaccines. In addition, not all transplant patients develop antibodies. An alternative prophylactic measure to be principally used for patients that do not develop antibodies after vaccination is the use of monoclonal antibodies. These drugs may be administered as prophylaxis or in the early stage of the disease. Finally, the small antiviral molecules may be used again as prophylaxis or treatment. Their major drawbacks are their interference with immunosuppressive drugs and the fact that some of them cannot be administered to patients with low eGFR. Full article

Pneumocysis jirovecii pneumonia (PJP) is a type of pneumonia originating from the fungus Pneumocystis jiroveci and is a major cause of serious pneumonia in immunocompromised conditions. PJP typically appears as bilateral diffuse pulmonary infiltrates. Granulomatous PJP is an uncommon form of pneumocystis infection, occurring in only 3% to 5% of patients. Calcification is exceptional. We present a 9-month-old boy affected by Severe Combined Immunodeficiency (SCID) that has been diagnosed at the age of 7 months following a lung Pneumocystis jirovecii infection. He underwent a routine total-body magnetic resonance imaging (MRI) prior to an allogeneic hematopoietic stem cell transplantation (HSCT). The MRI showed significant alterations of the pulmonary parenchyma; hence, a computer tomography of the lung was performed showing the presence of 11 calcified granulomatous nodules. We report a unique case of calcified granulomatous PJP in a toddler affected by SCID. Awareness of this rare yet possible presentation in patients with SCID is important given the potential clinical implications when managing a patient undergoing HSCT and it further enhances the importance of advanced radiologic imaging prior to HSCT. Full article

Introduction: We report on characteristics and lung function outcomes among lung transplant recipients (LTRs) after COVID-19 with infections occurring in the first year of the coronavirus pandemic prior to introduction of the vaccines. Methods: This was a retrospective study of 18 LTRs who tested positive for SARS-CoV-2 between 1 February 2020 and 1 March 2021. The mean age was 49.9 (22–68) years; 12 patients (67%) were male. Two patients died due to severe COVID-19. Results: During the study period, there were 18 lung transplant recipients with a community-acquired SARS-CoV-2 infection. In this cohort, seven had mild, nine had moderate, and two had severe COVID-19. All patients with mild and moderate COVID-19 survived, but the two patients with severe COVID-19 died in the intensive care unit while intubated and on mechanical ventilation. Most patients with moderate COVID-19 showed a permanent lung function decrease that did not improve after 12 months. Conclusion: A majority of LTRs in the current cohort did not experience an alteration in the trajectory of FEV1 evolution after developing SARS-CoV-2 infection. However, in the patients with moderate COVID-19, most patients had a decline in the FEV1 that was present after 1 month after recovery and did not improve or even deteriorated further after 12 months. In LTRs, COVID-19 can have long-lasting effects on pulmonary function. Treatment strategies that influence this trajectory are needed. Full article

Basiliximab (BAS) is an interleukin-2 monoclonal antibody initially used as induction therapy after liver and kidney transplantation. BAS use after lung transplantation (LTx) has supplanted antithymocyte globulin (ATG) as the main induction immunosuppression over the years, but few studies have compared them. In this study, we aimed to compare the efficacy and safety between BAS and ATG in LTx. We performed a retrospective analysis of all LTx done in Portugal between January 2016 and December 2019. Three groups were made according to the initial induction status: BAS, ATG or no induction (NI). The occurrences of cytomegalovirus (CMV) infection, pneumonia, side effects, primary graft dysfunction (PGD), acute rejection, chronic allograft disfunction (CLAD) and death episodes were assessed during two years after LTx. A total of 124 patients were divided in 3 groups: 61 (49.2%) BAS; 43 (34.7%) ATG; 20 (16.1%) NI. The incidences of pneumonia and CMV were similar between induction groups. Additionally, there was no difference between the induction groups in PGD, acute rejection, CLAD, deaths and two-year survival. Side effects were reported only in ATG group (n = 20; 46.5%). In our study, BAS had a better safety profile than ATG in LTx with a similar efficacy. Full article

Background: Early reports of COVID-19 in lung transplant recipients (LTRs) showed high hospitalization and mortality rates. However, the outcomes of COVID-19 in LTRs since the advent of newer therapies and vaccines have been poorly defined. Methods: We evaluated the risks for SARS-CoV-2-related hospitalization and mortality in a cohort of LTRs at the Henry Ford Lung Transplant Program in Detroit, Michigan during the study period March 2020–March 2022. Univariate logistic regression, followed by multivariable modeling were performed to estimate the odds ratio (OR) with 95% confident intervals (CI). Results: Sixty-four laboratory-confirmed SARS-CoV-2 infections were identified in 59 patients. For the primary analysis of the hospitalization and mortality risks, we included these 59 patients with symptomatic COVID-19. SARS-CoV-2 infections were confirmed with real-time polymerase chain reaction (RT-PCR) from a nasopharynx swab. The mean age (±STD) was 61 (±12), 63% were males, 27% were African Americans, and the time from lung transplant to COVID-19 was 5.5 (±4.8) years. Thirty-four (57.6%) patients were hospitalized, and the inpatient mortality rate was 24% (8/34). A multivariable analysis showed that patients with a higher baseline forced expiratory volume (FEV1) were less likely to be hospitalized (OR = 0.91 and 95% CI 0.87–0.98, p = 0.02). Seventy-five percent (75%; 6/8) of patients on invasive mechanical ventilation died, compared with only 8% mortality rate in those without mechanical ventilation (OR = 36.0 and 95% CI 4.2–310.4, p < 0.01). Although a trend toward a higher risk of death was observed in those infected during the Alpha (p = 0.17) and Delta (p = 0.22) waves, no significant risk was detected after adjusting for other covariates. Five LTRs were diagnosed with COVID-19 twice. Thirty of the sixty-four COVID-19 cases (46.8%) occurred in LTRs that had received at least two doses of any of the available mRNA vaccines at a median of 123 days (IQR 98–164 days) after vaccination. Twelve of the thirty (40%) were hospitalized, and four patients (33%) died during their hospitalizations. Conclusions: In our LTR population, the hospitalization and mortality rates associated with COVID-19 were high despite the increased use of new therapies. Vaccine-breakthrough infections were common and were associated with poor outcomes. Studies are needed to determine optimal prevention and therapeutic strategies to improve COVID-19 outcomes in LTRs. Full article

The three most common modalities of graft surveillance in pediatric heart transplant (HT) recipients include echocardiography, coronary angiography, and endomyocardial biopsy (EMB). The survival outcomes after HT in children have improved considerably in recent years. However, allograft rejection and cardiac allograft vasculopathy remain the leading cause of death or re-transplantation. The routine surveillance by EMB and coronary angiography are invasive and risky. Newer noninvasive echocardiographic techniques, including tissue Doppler imaging (TDI), 2-D speckle tracking echocardiography, CT coronary angiography (CTCA), cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) and invasive techniques such as intravascular ultrasound (IVUS), functional flow reserve (CFR) of coronary arteries, optical coherence tomography (OCT), have emerged as powerful tools which may help early recognition of sub-clinical rejection, response to treatment, early detection, and progression of CAV. The multimodality imaging approach, including noninvasive and invasive tests, is the future for the transplanted heart to detect dysfunction, rejections, and early CAV. This review illustrates noninvasive and invasive imaging techniques currently used or could be considered for clinical use in detecting heart transplant rejection, dysfunction, and CAV in children. Full article

COVID-19 can be associated with lung fibrosis. Although lung fibrosis after COVID-19 is a relatively rare finding, the mere fact that globally a very large number of patients have had COVID-19 leads to a significant burden of disease. However, patients with COVID-19-associated lung fibrosis have different clinical and radiological features. The aim of this review is to define the different phenotypes of COVID-19-associated lung fibrosis, based on the medical literature. We found that two phenotypes have emerged. One phenotype is COVID-19-related acute respiratory distress syndrome (CARDS); the other phenotype is post-COVID-19 pulmonary fibrosis (PCPF). Both phenotypes have different risk factors, clinical, and radiological features, and differ in their pathophysiological mechanisms and prognoses. A long-term follow-up of patients with pulmonary complications after COVID-19 is warranted, even in patients with only discrete fibrosis. Further studies are needed to determine the optimal treatment because currently the literature is scarce, and evidence is only based on small case series or case reports. Full article

Multiple case series of kidney transplant recipients with COVID-19 have shown increased mortality compared to nontransplant patients. To date, we do not have high-level evidence to inform immunosuppression minimization strategies in infected transplant recipients. Most centers, however, have adopted an early antimetabolite withdrawal in addition to other interventions. The epidemiological problem concerns also dialysis patients and waitlisted patients who have a higher COVID-19 infection diffusion with respect to kidney transplant recipients. Several factors influence mortality among kidney transplant recipients. Among these factors are the age, race, and comorbidity factors, such as hypertension, diabetes mellitus, obesity, and previous respiratory problems. Treatment is still limited. The only effective antiviral drug is remdesivir that should be administered before the development of the cytokine storm. Vaccination seems to be useful, but due to the concomitant immunosuppression limiting its efficacy, at least three or four doses should be administered. Full article

The use of novel oral anticoagulants in patients with impaired renal function or undergoing immunosuppressive therapy is limited due to the risk of drug-to-drug interactions and anticoagulation-related adverse events. This article aims to assess the current data on the safety of direct-acting oral anticoagulant-based therapy in the population of kidney transplant recipients and patients with impaired renal function. The most important factors affecting the safety of treatment are the incidence of bleeding events, thromboembolic events, deaths and drug-to-drug interactions. The available data were compared to the findings on warfarin-based anticoagulation. Findings on the use of novel oral anticoagulants in kidney transplant recipients are limited yet promising in terms of safety and efficacy of use. However, current recommendations state that the co-administration of non-vitamin K antagonist oral anticoagulants with several immunosuppressive agents is contraindicated. Full article

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) was declared a pandemic in March 2020. Its reported impact on solid-organ-transplant-recipient morbidity and mortality has varied. The aim of this study was to present the effect of transplant status, patient comorbidities and immunosuppression modality on the survival of solid-organ-transplant recipients who contracted SAR-CoV-2 during the pre-vaccination era, at a single academic transplant center. Patients (n = 103) were assessed for 90-day mortality. A univariate analysis identified an age of over 60 years (HR = 10, p = 0.0034), Belatacept (HR = 6.1, p = 0.022), and Cyclosporine (HR = 6.1, p = 0.0089) as significant mortality risk factors; Tacrolimus was protective (HR = 0.23, p = 0.022). Common metabolic comorbidities (hypertension, diabetes, obesity) did not stand out as risk factors in our patient cohort. This study on the unvaccinated is expected to facilitate a paired comparison of outcomes in transplanted patients who contracted SARS-CoV-2 during the latter period of the pandemic, when broad SARS-CoV-2 vaccination and novel antibody treatments became broadly available. Full article

Dyslipidemia is a frequent complication after kidney transplantation (KT) and is an important risk factor for cardiovascular disease (CVD). Renal transplant recipients (RTRs) are considered at high, or very high, risk of CVD, which is a leading cause of death in this patient group. Despite many factors of post-transplant dyslipidemia, the immunosuppressive treatment has the biggest influence on a lipid profile. There are no strict dyslipidemia treatment guidelines for RTRs, but the ones proposing an individual approach regarding CVD risk seem most suitable. Proper diet and physical activity are the main general measures to manage dyslipidemia and should be introduced initially in every patient after KT. In the case of an insufficient correction of lipemia, statins are the basis for hypolipidemic treatment. Statins should be introduced with caution to avoid serious side-effects (e.g., myopathy) or drug-drug interactions, especially with immunosuppressants. To lower the incidence of adverse effects, and improve medication adherence, ezetimibe in combination with statins is recommended. Fibrates and bile sequestrants are not recommended due to their side-effects and variable efficacy. However, several new lipid-lowering drugs like Proprotein convertase subtilisin/Kexin type9 (PCSK9) inhibitors may have promising effects in RTRs, but further research assessing efficacy and safety is yet to be carried out. Full article