Alejandro Campos-Murguia

Long-term success after liver transplantation (LT) is often hindered by side effects from lifelong immunosuppression (IS). Standard liver enzyme tests are poor indicators of graft inflammation or fibrosis. To address this, a program of surveillance liver biopsy (svLbx)-guided personalized IS has been implemented to inform decisions on IS minimization. This study, spanning from 2018 to 2024, extends previous short-term observations to assess the long-term impact of biopsy-guided Calcineurin Inhibitor (CNI) reduction in LT recipients, including follow-up biopsies. Patients’ IS was adjusted based on svLbx findings, donor-specific antibodies, liver function, and comorbidities. Analyzing 242 LT recipients, the study compared outcomes in those whose CNI dosage was reduced (n=89) versus those whose dosage was maintained or increased (n=83). CNI reduction proved safe, with no increase in rejection, graft loss or death. Crucially, it significantly preserved kidney function (ΔeGFR: +0.5 vs. −6.5 mL/min) over a median follow-up of 47 months, even when controlling for baseline kidney function, CNI score, graft injury and time post-LT. Sequential biopsies revealed no worsening of fibrosis or inflammation, and non-invasive measures corroborated these findings. In conclusion, svLbx-guided CNI reduction safely maintains kidney function and prevents graft injury late after LT, making it a viable strategy for long-term IS minimization.

Background and Aims: The European Reference Network on Hepatological Diseases (ERN RARE‐LIVER) launched the prospective, multicentre, quality‐controlled R‐LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment.Methods: Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow‐up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels.Results: A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid‐free CBR within the first year.Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01–1.05]; p = .007), severe fibrosis (OR .38 [95% .16–.89], p = .026) and change of treatment within the first 6 months (OR .40 [95% CI .2–.86]; p = .018) were associated with a lesser chance of ALT normalization at 12 months follow‐up.Conclusion: The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids.

Background&Aims: The role of antibody-mediated rejection (ABMR) after liver transplantation (LT) remains controversial. Chronic ABMR (cABMR) is often subclinical and potentially missed without surveillance biopsies (svLbx). Transcriptome analysis previously characterized molecular changes in T cell-mediated rejection (TCMR) after solid organ transplantation. We aimed to identify molecular cABMR signatures after LT. Methods: Indication and svLbx from two prospective institutional biorepositories were screened. We performed RNA-sequencing on liver biopsies (discovery cohort: n=71; Hannover validation cohort: n=58; Barcelona validation cohort: n=29). Downstream analyses explored the molecular features of cABMR, clinical (clinTCMR), subclinical TCMR (subTCMR) and chronic ductopenic rejection compared to no histological rejection (NHR). Results: Nineteen percent of LT recipients with donor-specific antibodies had cABMR in the training cohort. Fifty seven percent of cABMR patients had normal/near normal liver enzymes, recognized only by svLbx. CABMR was associated with subsequent cirrhosis development in 40-50% and displayed differentially expressed genes (DEGs) uniquely enriched in fibrogenesis-, complement activation- and TNFα-signaling-related pathways. ClinTCMR showed no such recurrent cirrhosis and DEGs uniquely enriched in antigen presentation-, interferon-signaling-, and T cell receptor-signaling-related pathways. SubTCMR was molecularly almost indistinguishable from NHR. There was a high degree of correlation in the DEGs between the training and two independent validation cohorts. Conclusions: We report transcriptome features of cABMR that is a unique molecular identity associated with inflammation and fibrogenesis as described in other solid organ transplantations and being linked to a high rate of liver graft failure. Impact and Implications: - Chronic antibody-mediated rejection (ABMR) is a recognized relevant cause of graft injury and unfavorable patient outcomes after kidney, heart and lung transplantation but the role of chronic ABMR after liver transplantation (LT) remains controversial, despite a recurrent cirrhosis rate of 40-50% in the present study. Therefore, we aimed to characterize rejection phenotypes after LT on a molecular basis, as done in other solids organ transplants, to identify unique features of chronic ABMR. - Our findings highlight chronic ABMR to be a molecularly distinct clinical phenotype of rejection after LT that often presents with normal liver enzymes validated in three independent cohorts. - Therefore, our work emphasizes the usage of surveillance graft biopsies for the detection of a fibrosis associated phenotype of chronic ABMR. The molecular signature may be used in the future by researchers and clinicians to discriminate chronic ABMR from graft injury of other causes.

La enfermedad granulomatosa crónica (EGC) es un error innato de la inmunidad causado por un defecto en uno de los componentes del complejo NADPH oxidasa, responsable de generar especies reactivas de oxígeno (ERO) durante el estallido respiratorio en los fagocitos. La ausencia de ERO producidos por la NADPH oxidasa en los neutrófilos y en los macrófagos produce mayor susceptibilidad a infecciones bacterianas y fúngicas, además de manifestaciones inflamatorias por una respuesta inflamatoria desregulada, lo que sugiere que la capacidad para regular adecuadamente la señalización inflamatoria depende de las ERO derivadas de la NADPH oxidasa. Los pacientes con EGC ligada al cromosoma X tienen un curso de enfermedad más grave con infecciones invasivas recurrentes, a diferencia de los pacientes con EGC no clásica, quienes no presentan infecciones bacterianas o fúngicas invasivas, pero con manifestaciones inflamatorias más prominentes. Las manifestaciones gastrointestinales más frecuentes son estomatitis, gingivitis, diarrea crónica, abscesos hepáticos, similares a las de la enfermedad inflamatoria intestinal (EII) y granulomas, que pueden provocar obstrucción o estenosis en esófago, estómago o intestino. Se ha observado que la deficiencia de p40phox y EROS (EGC no clásica) se asocia a mayor susceptibilidad a colitis y al desarrollo de inflamación severa, por lo que se plantea que estas proteínas participan en la resolución de la inflamación. En general, los hallazgos inflamatorios en la EGC, incluyendo los gastrointestinales, han sido poco descritos. En las cohortes internacionales se reportan manifestaciones similares a EII hasta en 58 % de los pacientes con EGC; en cambio, en la única cohorte mexicana se describe su hallazgo solo en cuatro de 93 pacientes (4.3 %). En esta revisión resumimos los hallazgos clínicos gastrointestinales de la EGC, incluidas las manifestaciones infecciosas e inflamatorias, con énfasis en las últimas.