Novel Approaches to Immunomodulation for Solid Organ Transplantation.

Despite significant advances in the field of transplantation in the past two decades, current clinically available therapeutic options for immunomodulation remain fairly limited. The advent of calcineurin inhibitor-based immunosuppression has led to significant success in improving short-term graft survival; however, improvements in long-term graft survival have stalled. Solid organ transplantation provides a unique opportunity for immunomodulation of both the donor organ prior to implantation and the recipient post transplantation. Furthermore, therapies beyond targeting the adaptive immune system have the potential to ameliorate ischemic injury to the allograft and halt its aging process, augment its repair, and promote recipient immune tolerance. Other recent advances include expanding the donor pool by reducing organ discard, and bioengineering and genetically modifying organs from other species to generate transplantable organs. Therapies discussed here will likely be most impactful if individualized on the basis of specific donor and recipient considerations.

Overcoming barriers and stigma: new frontiers in solid organ transplantation for people with HIV.

There is a growing need for solid organ transplantation (SOT) for people living with human immunodeficiency virus (HIV). With the advent of antiretroviral therapy, people living with HIV are experiencing increased life expectancies and are, therefore, developing more comorbidities, including end-stage organ disease. In cases of advanced organ failure, SOT is often the best therapeutic option to improve quality of life and overall survival. As organ shortages persist, transplantation of organs from donors with HIV to recipients with HIV has become a potential therapeutic option. This article first reviews the current state of organ transplantation from donors without HIV to recipients with HIV (HIV D-/R+) by organ and discusses key lessons learned from these transplant trials, including those about drug-drug interactions, rejection, and opportunistic infections. It then explores transplantation from donors with HIV to recipients with HIV (HIV D+/R+), a new frontier. Finally, it investigates challenges of implementation, including public awareness and regulatory requirements, and explores future directions for SOT in people living with HIV.

Outcomes in solid organ transplant recipients with a pretransplant diagnosis of melanoma.

Melanoma causes significant morbidity in solid organ transplant recipients (SOTRs). Melanomas diagnosed before transplantation can recur with intensive immunosuppression, but outcomes have not been well studied. We evaluated 901 non-Hispanic White SOTRs with a pretransplant melanoma identified using linked transplant and cancer registry data in the United States. Most pretransplant melanomas were invasive (60.7%), and the median time from diagnosis to transplantation was 5.1 years. After transplantation, 41 SOTRs developed a new invasive melanoma, corresponding to 9-fold increased risk compared with the general population (standardized incidence ratio, 9.2; 95% confidence interval [CI], 6.6-12). Twenty-two SOTRs died from melanoma after transplantation, corresponding to 52-fold increased risk (standardized mortality ratio, 52; 95% CI, 33-79). Risk factors for posttransplant melanoma included age at transplantation (adjusted hazard ratio [HR], 2.86; 95% CI, 1.24-6.60; for age 55+ vs <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR, 2.53; 95% CI, 1.08-5.90). Melanoma mortality was strongly elevated after a posttransplant melanoma diagnosis (HR, 35.6; 95% CI, 14.0-90.4; adjusted for cyclosporine/azathioprine maintenance therapy and calendar year of transplantation). In conclusion, SOTRs with a pretransplant melanoma are at risk of adverse melanoma-related outcomes after transplantation. These findings support thorough dermatologic evaluation prior to transplantation and frequent posttransplant surveillance.

Adjunctive glucocorticoid therapy for Pneumocystis jirovecii pneumonia in solid organ transplant recipients: A multicenter cohort, 2015-2020.

Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.

The respiratory syncytial virus vaccines are here: Implications for solid organ transplantation.

In 2023, the Food and Drug Administration approved 2 recombinant subunit respiratory syncytial virus (RSV) vaccines based on prefusion RSV F glycoproteins for the prevention of RSV-associated lower respiratory tract disease. These vaccines were subsequently recommended for individuals ≥60 years of age using shared clinical decision-making by the Center for Disease Control and Prevention's Advisory Committee on Immunization Practices. The development, deployment, and uptake of respiratory virus vaccines are of particular importance for solid organ recipients who are at higher risk of infectious complications and poor clinical outcomes, including from RSV-associated lower respiratory tract disease, compared to patients without immunocompromise. This review aims to summarize what is currently known about the burden of RSV disease in solid organ transplantation, to describe the currently available tools to mitigate the risk, and to highlight considerations regarding the implementation of these vaccines before and after transplantation. We also explore areas of unmet need for organ transplant recipients including questions of RSV vaccine effectiveness and safety, inequities in disease and vaccine access based on race and socioeconomic status, and expansion of coverage to immunocompromised individuals below the age of 60 years.

Consequences of low estimated glomerular filtration rate either before or early after kidney donation.

In the general population, decreases in glomerular filtration rate (GFR) are associated with subsequent development of chronic kidney disease (CKD), cardiovascular disease (CVD), and death. It is unknown if low estimated GFR (eGFR) before or early after kidney donation was also associated with these risks. One thousand six hundred ninety-nine living donors who had both predonation and early (4-10 weeks) postdonation eGFR were included. We studied the relationships between eGFR, age at donation, and the time to sustained eGFR<45 (CKD stage 3b) and <30 mL/min/1.73m2 (CKD stage 4), hypertension, diabetes mellitus (DM), CVD, and death. Median follow-up was 12 (interquartile range, 6-21) years. Twenty-year event rates were 5.8% eGFR<45 mL/min/1.73m2; 1.2% eGFR<30 mL/min/1.73m2; 29.0% hypertension; 7.8% DM; 8.0% CVD; and 5.2% death. The median time to eGFR<45 mL/min/1.73m2 (N = 79) was 17 years, and eGFR<30 mL/min/1.73m2 (N = 22) was 25 years. Both low predonation and early postdonation eGFR were associated with eGFR<45 mL/min/1.73m2 (P < .0001) and eGFR<30 mL/min/1.73m2 (P < .006); however, the primary driver of risk for all ages was low postdonation (rather than predonation) eGFR. Predonation and postdonation eGFR were not associated with hypertension, DM, CVD, or death. Low predonation and early postdonation eGFR are risk factors for developing eGFR<45 mL/min/1.73m2 (CKD stage 3b) and <30 mL/min/1.73m2 (CKD stage 4), but not CVD, hypertension, DM, or death.

Severe Presentation of Mpox With Skin, Lung and Pleural Involvement in a Non-HIV-Infected Kidney Transplant Recipient.

Monkeypox (mpox) is an orthopoxviral zoonotic disease with a similar but less severe clinical presentation as smallpox. However, immunocompromised patients such as solid organ transplant recipients are at higher risk of developing severe forms of the disease. Herein, we describe the case of a 43-year-old female kidney transplant recipient that manifested severe skin ulcers alongside nodular lung opacities and pleural effusion attributed directly to the monkeypox virus. Notwithstanding the initiation of early treatment with tecovirimat, a satisfactory response was not achieved until a reduction in immunosuppression to everolimus monotherapy, coupled with the transition to cidofovir for antiviral treatment. In conclusion, mpox has the potential to produce a severe form of systemic infection in individuals who have undergone solid organ transplantation, demanding a meticulous approach involving sequential antiviral treatment and modifications to immunosuppressive regimens in order to achieve complete healing.

Primary central nervous system lymphomas in immunocompromised patients require specific response criteria.

PURPOSE: Immunosuppression is a well-established risk factor for primary central nervous system lymphomas (PCNSLs), which present in this context distinct radiological characteristics. Our aim was to describe the radiological evolution of treated PCNSL in immunocompromised patients and suggest adapted MRI response criteria. METHODS: We conducted a multicenter retrospective study of patients from the French LOC, K-Virogref and CANCERVIH network databases and enrolled adult immunocompromised patients with newly diagnosed PCNSL. RESULTS: We evaluated the baseline, intermediate, end-of-treatment and follow-up MRI data of 31 patients (9 living with HIV, 16 with solid organ transplantation and 6 with an autoimmune disease under chronic immunosuppressive therapy). At baseline, 23/30 (77%) patients had necrotic lesions with ring enhancement and 28% of the lesions were hemorrhagic. At the end of the first-line treatment, 12/28 (43%) patients could not be classified according to the IPCG criteria. Thirteen of 28 (46%) patients still harbored contrast enhancement, and 11/28 (39%) patients had persistent large necrotic lesions with a median diameter of 15 mm. These aspects were not associated with a pejorative outcome and progressively diminished during follow-up. Six patients relapsed; however, we failed to identify any neuroimaging risk factors on the end-of-treatment MRI. CONCLUSION: In immunocompromised patients, PCNSLs often harbor alarming features on end-of-treatment MRI, with persistent contrast-enhanced lesions frequently observed. However, these aspects seemed to be related to the necrotic and hemorrhagic nature of the lesions and were not predictive of a pejorative outcome. Specific response criteria for this population are thereby proposed.

An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management.

OBJECTIVE: Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS: Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS: PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION: The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.

Challenges for the improvement of valganciclovir prophylaxis in solid organ transplantation and the possible role of therapeutic drug monitoring in adults.

Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the development of valganciclovir prophylaxis has lowered the incidence of CMV infection and its complications in immunosuppressed solid organ transplant recipients. However, breakthrough infections during valganciclovir prophylaxis and late CMV infection after cessation of valganciclovir prophylaxis still occur with the current prophylactic strategy. Additionally, valganciclovir resistance has emerged among CMV strains, which complicates the treatment of CMV infections. Furthermore, the use of valganciclovir is associated with myelotoxicity, which can lead to the premature withdrawal of prophylaxis. It is important to address these current issues in order to improve the standard care after solid organ transplantation. This paper will therefore discuss the clinical practice of valganciclovir prophylaxis, elaborate on its issues and suggest how to improve the current prophylactic strategy with a possible role for therapeutic drug monitoring.

The potential for therapeutic drug monitoring of belatacept and other biologicals in solid organ transplantation.

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody-mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model-informed precision dosing. Biologicals are used for off-label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof-of-concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.

Diabetes mellitus and blood glucose variability increases the 30-day readmission rate after kidney transplantation.

INTRODUCTION: Inpatient hyperglycemia is an established independent risk factor among several patient cohorts for hospital readmission. This has not been studied after kidney transplantation. Nearly one-third of patients who have undergone a kidney transplant reportedly experience 30-day readmission. METHODS: Data on first-time solitary kidney transplantations were retrieved between September 2015 and December 2018. Information was linked to the electronic health records to determine diagnosis of diabetes mellitus and extract glucometric and insulin therapy data. Univariate logistic regression analysis and the XGBoost algorithm were used to predict 30-day readmission. We report the average performance of the models on the testing set on bootstrapped partitions of the data to ensure statistical significance. RESULTS: The cohort included 1036 patients who received kidney transplantation; 224 (22%) experienced 30-day readmission. The machine learning algorithm was able to predict 30-day readmission with an average area under the receiver operator curve (AUC) of 78% with (76.1%, 79.9%) 95% confidence interval (CI). We observed statistically significant differences in the presence of pretransplant diabetes, inpatient-hyperglycemia, inpatient-hypoglycemia, minimum and maximum glucose values among those with higher 30-day readmission rates. The XGBoost model identified the index admission length of stay, presence of hyper- and hypoglycemia, the recipient and donor body mass index (BMI) values, presence of delayed graft function, and African American race as the most predictive risk factors of 30-day readmission. Additionally, significant variations in the therapeutic management of blood glucose by providers were observed. CONCLUSIONS: Suboptimal glucose metrics during hospitalization after kidney transplantation are associated with an increased risk for 30-day hospital readmission. Optimizing hospital blood glucose management, a modifiable factor, after kidney transplantation may reduce the risk of 30-day readmission.

A Digital Approach to Improve Infection Screening Among Solid Organ Transplant Candidates.

BACKGROUND: Pretransplant infection screening (IS) of potential organ recipients is essential to optimal outcome of solid organ transplantation (SOT). METHODS: A pre-post study was performed during 2020-2023 to investigate the impact of the STREAM (Solid organ TRansplant stEwArdship and Multidisciplinary approach) intervention to improve IS in SOT. The intervention, performed in 2022, included the implementation of IS through educational meetings, local guidelines, and the availability of a digital screening tool. The objective of the study was the assessment of IS completion, including a list of 17 laboratory tests and the investigation of vaccination status. The reduction of unnecessary tests was also analyzed. The test of proportions and a multilevel multivariate Poisson regression model were used to compare IS completion before and after STREAM. infectious diseases (ID) consultation and urgent evaluation were investigated as predictors of IS completion. RESULTS: A total of 171 patients were enrolled, including liver (44%), heart (32%), and kidney (24%) transplant candidates. Mean age was 56 ± 11 years, and most patients (77%) were males. Ninety-five (56%) patients were included before the intervention and 76 (44%) after STREAM. IS completion increased after STREAM (IRR 1.41, p < 0.001) with significant improvement recorded for seven (39%) IS items. Unnecessary tests decreased by 43% after the intervention. ID consultation (IRR 1.13, p = 0.02) and urgent evaluation (p = 0.68, p < 0.001) were predictors of IS improvement. CONCLUSIONS: STREAM was successful in improving IS completion. Further research is needed to investigate the impact of this intervention on posttransplant infections.

Recipient donor sex combinations in solid organ transplantation and impact on clinical outcome: A scoping review.

INTRODUCTION: Solid organ transplantation (SOT) is a lifesaving treatment for end-stage organ failure. Although many factors affect the success of organ transplantation, recipient and donor sex are important biological factors influencing transplant outcome. However, the impact of the four possible recipient and donor sex combinations (RDSC) on transplant outcome remains largely unclear. METHODS: A scoping review was carried out focusing on studies examining the association between RDSC and outcomes (mortality, graft rejection, and infection) after heart, lung, liver, and kidney transplantation. All studies up to February 2023 were included. RESULTS: Multiple studies published between 1998 and 2022 show that RDSC is an important factor affecting the outcome after organ transplantation. Male recipients of SOT have a higher risk of mortality and graft failure than female recipients. Differences regarding the causes of death are observed. Female recipients on the other hand are more susceptible to infections after SOT. CONCLUSION: Differences in underlying illnesses as well as age, immunosuppressive therapy and underlying biological mechanisms among male and female SOT recipients affect the post-transplant outcome. However, the precise mechanisms influencing the interaction between RDSC and post-transplant outcome remain largely unclear. A better understanding of how to identify and modulate these factors may improve outcome, which is particularly important in light of the worldwide organ shortage. An analysis for differences of etiology and causes of graft loss or mortality, respectively, is warranted across the RDSC groups. PRACTITIONER POINTS: Recipient and donor sex combinations affect outcome after solid organ transplantation. While female recipients are more susceptible to infections after solid organ transplantation, they have higher overall survival following SOT, with causes of death differing from male recipients. Sex-differences should be taken into account in the post-transplant management.

Potassium-lowering effects of sodium zirconium cyclosilicate in the early post-transplant period.

PROBLEM: Hyperkalemia is a serious condition among intra-abdominal transplant recipients, and the safety and efficacy of sodium zirconium cyclosilicate (SZC) for its management during the early post-transplant period are not well-established. METHODS: Adults who received at least one 10-g dose of SZC within 14 days after an intra-abdominal transplant between January 2020 and July 2022 were included in our study. The primary outcome was the change in potassium (K+) levels following the first SZC dose. Other analyses explored adjunctive potassium-lowering therapies, potential gastrointestinal complications, and patient subgroups based on therapy and transplant type. RESULTS: Among the recipients (n = 46), 11 were kidney recipients, 26 were liver recipients, seven were simultaneous liver/kidney recipients, and two were simultaneous pancreas/kidney recipients. The mean time to first dose post-transplant was 7.6 (±4) days, and the mean change in serum K+ after the initial SZC dose was -.27 mEq (p = .001). No gastrointestinal complications were observed following the SZC dose. The mean increase in serum bicarbonate was .58 mEq (p = .41) following the first dose of SZC. Four kidney recipients required dialysis following the SZC dose. CONCLUSION: This study represents the largest investigation on the use of SZC in transplant recipients. A single 10-g dose of SZC reduced serum K+ levels in all subgroups, while the use of adjunctive K+-lowering therapies did not provide additional reduction beyond the effects of SZC. Importantly, no gastrointestinal complications were observed. These findings suggest that SZC may be a safe and promising therapeutic option for hyperkalemia management following solid organ transplantation.

Torque teno virus load as marker of rejection and infection in solid organ transplantation - A systematic review and meta-analysis.

Balancing immunosuppression to prevent rejection in solid organ transplant (SOT) recipients remains challenging. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as marker of functional immunity: higher loads correspond to over-immunosuppression, and lower loads to under-immunosuppression. This review offers an overview of the current evidence of the association between TTV-load and infection and rejection after SOT. A systematic literature search strategy, deposited in the PROSPERO registry, resulted in 548 records. After screening, 23 original and peer-reviewed articles were assessed investigating the association between TTV-load, infection and/or rejection in SOT. The Quality in Prognostic Studies (QUIPS)-tool was used to assess the risk of bias. Meta-analysis with random-effects was performed on results with similar outcomes and exposure measures. Most of the included studies involved retrospective cohorts in which the TTV-load was measured longitudinally, within the first 2 years post-transplantation. Infection outcomes differed between studies and included viral, bacterial, parasitic and fungal infections. Rejection was defined by biopsy confirmation or initiation of rejection treatment. Twelve out of 16 studies reported an association between high TTV-load and infections, whereas 13 out of 15 reported an association between low TTV-load and rejection. Meta-analysis showed an increased risk of infection (OR: 1.16, 95% CI: 1.03-1.32; HR: 1.05, 95% CI: 0.97-1.14) and a decreased risk of rejection (OR: 0.90, 95% CI: 0.87-0.94; HR: 0.74, 95% CI: 0.71-0.76) per 1 log TTV-load increase. The qualitative assessment showed varying risks of bias in the included studies. This systematic review and meta-analysis indicates that blood TTV-load measured within the first 2 years after SOT is associated with the risk of infection or allograft rejection, although substantial risk of bias in the studies included warrant cautious interpretation. The results in this review provide a rationale for larger, prospective, studies into TTV as marker of infection and rejection after SOT.

Can the pan-immune-inflammation value predict gram negative bloodstream infection-related 30-day mortality in solid organ transplant patients?

BACKGROUND: The recently used pan-immune-inflammation value (PIV) has not been adequately studied as a predictive marker for mortality in immunosuppressed patients. The aim of this study was to evaluate the usefulness of baseline PIV level as a predictor of 30-day mortality in solid organ transplant (SOT) recipients with gram negative bloodstream infections (GN-BSI). METHODS: This retrospective, cross-sectional study was conducted between January 1, 2019, and December 31, 2022, in 1104 SOT recipients. During the study period, 118 GN-BSI were recorded in 113 patients. Clinical, epidemiological, and laboratory data were collected, and mortality rates (30-day and all-cause) were recorded. RESULTS: The 113 recipients had a median age of 50 years [interquartile range (IQR) 37.5-61.5 years] with a male predominance (n = 72, 63.7%). The three most common microorganisms were as follows: 46 isolates (38.9%) of Escherichia coli, 41 (34.7%) of Klebsiella pneumoniae, and 12 (10.2%) of Acinetobacter baumannii. In 44.9% and 35.6% of the isolates, production of extended-spectrum beta-lactamases and carbapenem resistance were detected, respectively. The incidence of carbapenem-resistant GN-BSI was higher in liver recipients than in renal recipients (n = 27, 69.2% vs n = 13, 17.6%, p < 0.001). All-cause and 30-day mortality rates after GN-BSI were 26.5% (n = 30), and 16.8% (n = 19), respectively. In the group with GN-BSI-related 30-day mortality, the median PIV level was significantly lower (327.3, IQR 64.8-795.4 vs. 1049.6, IQR 338.6-2177.1; p = 0.002). The binary logistic regression analysis identified low PIV level [hazard ratio (HR) = 0.93, 95% confidence interval (CI) 0.86-0.99; p = 0.04], and increased age (HR = 1.05, 95% CI 1.01-1.09; p = 0.002) as factors associated with 30-day mortality. The receiver operating characteristic analysis revealed that PIV could determine the GN-BSI-related 30-day mortality with area under curve (AUC): 0.723, 95% CI 0.597-0.848, p = 0.0005. CONCLUSIONS: PIV is a simple and inexpensive biomarker that can be used to estimate mortality in immunosuppressed patients, but the results need to be interpreted carefully.

Harnessing Immune Cell Metabolism to Modulate Alloresponse in Transplantation.

Immune cell metabolism plays a pivotal role in shaping and modulating immune responses. The metabolic state of immune cells influences their development, activation, differentiation, and overall function, impacting both innate and adaptive immunity. While glycolysis is crucial for activation and effector function of CD8 T cells, regulatory T cells mainly use oxidative phosphorylation and fatty acid oxidation, highlighting how different metabolic programs shape immune cells. Modification of cell metabolism may provide new therapeutic approaches to prevent rejection and avoid immunosuppressive toxicities. In particular, the distinct metabolic patterns of effector and suppressive cell subsets offer promising opportunities to target metabolic pathways that influence immune responses and graft outcomes. Herein, we review the main metabolic pathways used by immune cells, the techniques available to assay immune metabolism, and evidence supporting the possibility of shifting the immune response towards a tolerogenic profile by modifying energetic metabolism.

Solid Organ Transplant Litigation at One of Europe's Largest University Hospitals.

Due to its intrinsic complexity and the principle of collective solidarity that governs it, solid organ transplantation (SOT) seems to have been spared from the increase in litigation related to medical activity. Litigation relating to solid organ transplantation that took place in the 29 units of the Assistance Publique-Hôpitaux de Paris and was the subject of a judicial decision between 2015 and 2022 was studied. A total of 52 cases of SOT were recorded, all in adults, representing 1.1% of all cases and increasing from 0.71% to 1.5% over 7 years. The organs transplanted were 25 kidneys (48%), 19 livers (37%), 5 hearts (9%) and 3 lungs (6%). For kidney transplants, 11 complaints (44%) were related to living donor procedures and 6 to donors. The main causes of complaints were early post-operative complications in 31 cases (60%) and late complications in 13 cases (25%). The verdicts were in favour of the institution in 41 cases (79%). Solid organ transplants are increasingly the subject of litigation. Although the medical institution was not held liable in almost 80% of cases, this study makes a strong case for patients, living donors and their relatives to be better informed about SOT.

In Vitro Profiling of Commonly Used Post-transplant Immunosuppressants Reveals Distinct Impact on Antiviral T-cell Immunity Towards CMV.

Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.