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Little is known about the comparative differences between the Allosure (CareDx) and Prospera (Natera) donor-derived cell-free DNA (dd-cfDNA) assays following heart transplantation. We retrospectively analyzed 248 consecutive samples that had both dd-cfDNA assays simultaneously performed. Twenty-six biopsy specimens were available within 7 days from dd-cfDNA assays. Both dd-cfDNA assays were correctly suggestive of rejection when biopsy was available. However, discordant classifications were present in 23/248 samples when utilizing respective recommended cutoff values for each assay (0.12% for Allosure and 0.15% for Prospera). Discordance was due to increased classification as abnormal results with Allosure (McNemar’s p = 0.004). However, there were no significant differences between assays when identical thresholds of 0.12% or 0.15% were implemented for both assays (McNemar’s, p = non-significant). We conclude that both dd-cfDNA assays can be utilized interchangeably for surveillance of rejection following heart transplantation.

Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4+ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4+ T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR–HIF–1α pathway. Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c+ and CD4+ cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR–HIF–1α expression in the grafts; and CD4+ cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry. Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4+ and CD11c+ cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4+ T cells in vitro. Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4+ T cell responses. This process may be related to the inhibition of the mTOR–HIF–1α signaling pathway by OMT.

Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near‐infrared fluorescence signals to report cell‐mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros‐based urinalysis discriminates allograft rejection against other non‐alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions. [ABSTRACT FROM AUTHOR]

Although the treatment and prognosis of patients after heart transplantation have significantly improved, late graft dysfunction remains a critical problem. Two main subtypes of late graft dysfunction are currently described: acute allograft rejection and cardiac allograft vasculopathy, and microvascular dysfunction appears to be the first stage of both. Studies revealed that coronary microcirculation dysfunction, assessed by invasive methods in the early post-transplant period, correlates with a higher risk of late graft dysfunction and death during long-term follow-up. The index of microcirculatory resistance, measured early after heart transplantation, might identify the patients at higher risk of acute cellular rejection and major adverse cardiovascular events. It may also allow optimization and enhancement of post-transplantation management. Moreover, cardiac allograft vasculopathy is an independent prognostic factor for transplant rejection and survival rate. The studies showed that the index of microcirculatory resistance correlates with anatomic changes and reflects the deteriorating physiology of the epicardial arteries. In conclusion, invasive assessment of the coronary microcirculation, including the measurement of the microcirculatory resistance index, is a promising approach to predict graft dysfunction, especially the acute allograft rejection subtype, during the first year after heart transplantation. However, further advanced studies are needed to fully grasp the importance of microcirculatory dysfunction in patients after heart transplantation. [ABSTRACT FROM AUTHOR]

Abstract Background Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study. Methods C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay. Results Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients. Conclusion IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation.

Abstract Background α1-Antitrypsin (AAT) is an acute phase glycoprotein, a multifunctional protein with proteinase inhibitory, anti-inflammatory and cytoprotective properties. Both preclinical and clinical experiences show that the therapy with plasma purified AAT is beneficial for a broad spectrum of inflammatory conditions. The potential effects of AAT therapy have recently been highlighted in lung transplantation (LuTx) as well. Methods We used a murine fully mismatched orthotopic single LuTx model (BALB/CJ as donors and C57BL/6 as recipients). Human AAT preparations (5 mg, n = 10) or vehicle (n = 5) were injected to the recipients subcutaneously prior to and intraperitoneally immediately after the LuTx. No immune suppressive drugs were administered. Three days after the transplantation, the mice were sacrificed, and biological samples were assessed. Results Histological analysis revealed significantly more severe acute rejection in the transplanted lungs of controls than in AAT treated mice (p

Background: Currently, there is no consensus among pediatric kidney transplant centers regarding the use and regimen for immunosuppressive induction therapy. Methods: In this single center, retrospective cohort study, pediatric kidney transplant recipients transplanted between 1 May 2013 and 1 May 2018 with rabbit antithymocyte globulin (rATG) induction were included. We stratified patients based on immunological risk, with high risk defined as those with repeat transplant, preformed donor specific antibody, current panel-reactive antibodies > 20%, 0 antigen match and/or African-American heritage. Outcome of interest was the incidence of biopsy proven acute rejection by 1 year. Results: A total of 166 patients met inclusion criteria. Age of patients was 12 years (11 mo-21 y), (median, range), 21.5% received a living donor transplant and 50.6% were female. Low-immunologic-risk patients were divided into 2 groups, those who received the lower cumulative rATG dose of ≤ 3.5 mg/kg (n = 52) versus the higher cumulative dose of > 3.5 mg/kg (n = 47). The median total dose in the lower dose group was 3.1 (IQR 0.3) and 4.4 (IQR 0.8) in the higher dose group, P < 0.001. Rejection rate did not differ significantly between the 2 treatment groups (7/52 vs. 6/47). None in the lower dose group developed BK nephropathy versus 3 in the higher dose group. Graft loss due to BK nephropathy occurred in 1 patient in the higher dose group. Graft loss in the whole cohort at 12 months was a rare event (n = 1) with 99.5% graft survival and 100% patient survival. Conclusions: Reduced rATG dosing (≤ 3.5 mg/kg) when compared to higher dosing (> 3.5 mg/kg) is safe and effective in low-risk pediatric kidney transplant recipients without increasing risk of rejection. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Administrative claims data could provide a unique opportunity to identify acute rejection (AR) events using specific antirejection medications and to validate rejected data reported to the Organ Procurement and Transplantation Network. This retrospective cohort study examined differences in registry-reported events and those identified using claims data among adult kidney transplant recipients from 2012 to 2017 using Standard Analysis Files from the US Renal Data System. Rejection rates, survival estimates, and center-level differences were assessed using each approach. Among 45 880 first-time kidney transplant recipients, we identified 3841 AR events within 12 months of transplant reported by centers in the registry; claims data yielded 2945 events. Of all events occurring within 12 months of transplant, 48.5% were reported using registry only, 32.9% were identified using claims only, and 18.6% were identified using both approaches. A 3-year death-censored graft survival probability was 90.0%, 88.4%, and 81.2% (P < .001) for ARs identified using registry only, claims data only, and both approaches, respectively. The large discordance between registry-reported and claims-based events suggests incomplete and potentially inaccurate reporting of events in the Organ Procurement Transplant Network registry. These findings have important implications for analyses that use AR data and underscore the need for improved capture of clinically meaningful events., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose, as described by the American Journal of Transplantation. S. Mohan receives grant funding from Kidney Transplant Collaborative and the National Institute of Health (NIH, Bethesda, MD), and personal fees from Sanofi, Kidney International Reports, and the Health Services Advisory Group outside of the submitted work. The other authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose Patients with end-stage heart failure who remain symptomatic even with exemplary medical and device therapy are treated with heart transplantation. Multitudes of endeavor have been contrived during the last decennium in the field of noninvasive tests to rule out heart transplant rejection (HTR). In spite of having supportive literature, noninvasive imaging techniques lack acceptable documentation of clinical robustness, and endomyocardial biopsy (EMB) still remains the gold standard. The aim of this review is to shed light on the existing noninvasive radiological modalities to detect rejection among heart transplant recipients.

Background: Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study. Methods: C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay. Results: Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients. Conclusion: IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation. [ABSTRACT FROM AUTHOR]

Background: We herein report the use of independent lung ventilation (ILV) for managing acute allograft rejection after single-lung transplantation (SLT) for end-stage emphysema. Case presentation: A 54-year-old woman was transferred to our hospital with severe hypoxemia and respiratory distress due to unilateral lung disease with diffuse alveolar damage in the right donor lung associated with acute allograft rejection and with hyperinflation of the left native lung due to emphysema. She was unresponsive to immunosuppressive medications and conventional ventilation strategies, so different ventilator settings for each lung were required. A double-lumen endotracheal tube (DLT) was inserted, and ILV was initiated. The right lung was ventilated with high positive end-expiratory pressure (PEEP), intended for lung recruitment, and the left lung was ventilated with lung protective strategies using a low tidal volume and low levels of PEEP to avoid hyperinflation. Two days later, her lung function was dramatically improved, and the DLT was replaced with a single-lumen endotracheal tube. Gas exchange was maintained, and she was successfully weaned from mechanical ventilation on intensive-care unit day 15. Conclusions: ILV appears to be effective and safe for managing acute allograft rejection after SLT for emphysema. J. Med. Invest. 69: 323-327, August, 2022. [ABSTRACT FROM AUTHOR]

• Recombinant human IL-37 can protect cardiac allografts; • Recombinant human IL-37 plays a protective role on cardiac allografts by regulating immunotolerant cells; • Recombinant human IL-37 inhibits CD4+ and CD11c+ cells associated with a reduction in p-mTOR expression in vivo and in vitro. Allograft rejection remains a major obstacle to long-term graft survival. Although previous studies have demonstrated that IL-37 exhibited significant immunomodulatory effects in various diseases, research on its role in solid organ transplantation has not been fully elucidated. In this study, the therapeutic effect of recombinant human IL-37 (rhIL-37) was evaluated in a mouse cardiac allotransplantation model. The C57BL/6 recipients mouse receiving BALB/c donor hearts were treated with rhIL-37. Graft pathological and immunohistology changes, immune cell populations, and cytokine profiles were analyzed on postoperative day (POD) 7. The proliferative capacities of Th1, Th17, and Treg subpopulations were assessed in vitro. Furthermore, the role of the p-mTOR pathway in rhIL-37-induced CD4+ cell inhibition was also elucidated. Compared to untreated groups, treatment of rhIL-37 achieved long-term cardiac allograft survival and effectively alleviated allograft rejection indicated by markedly reduced infiltration of CD4+ and CD11c+ cells and ameliorated graft pathological changes. rhIL-37 displayed significantly less splenic populations of Th1 and Th17 cells, as well as matured dendritic cells. The percentages of Tregs in splenocytes were significantly increased in the therapy group. Furthermore, rhIL-37 markedly decreased the levels of TNF-α and IFN-γ, but increased the level of IL-10 in the recipients. In addition, rhIL-37 inhibited the expression of p-mTOR in CD4+ cells of splenocytes. In vitro , similar to the in vivo experiments, rhIL-37 caused a decrease in the proportion of Th1 and Th17, as well as an increase in the proportion of Treg and a reduction in p-mTOR expression in CD4+ cells. We demonstrated that rhIL-37 effectively suppress acute rejection and induce long-term allograft acceptance. The results highlight that IL-37 could be novel and promising candidate for prevention of allograft rejection. [ABSTRACT FROM AUTHOR]

Background: Although antibody-mediated rejection (AMR) is described in other solid organ transplant populations, the literature describing the management following lung transplantation is limited. Objective: The purpose of this study is to evaluate the management strategies of AMR in lung transplant recipients. Methods: This single-center, retrospective study described the management of AMR in adult lung transplant recipients who received treatment with rabbit antithymocyte globulin, bortezomib, rituximab, intravenous immune globulin (IVIG), and/or plasmapheresis between September 2015 and June 2019. Results: A total of 270 medication orders for 55 patient admissions were included in the primary outcome analysis. The most commonly used regimen consisted of IVIG, plasmapheresis, and rituximab (49.1%; n = 27), followed by IVIG and plasmapheresis alone (27.3%, n = 15). A total of 51 patients (93%) received plasmapheresis as part of their AMR treatment, with a median of 4 [3, 5] sessions per encounter; 86% of patients with positive donor-specific antibodies (DSAs) had a reduction in DSAs following AMR treatment. Overall, 23.5% of patients had noted allograft failure or need for retransplantation. A total of 10 patients died during the AMR treatment hospital admission, and an additional 11 patients died within 1 year of the initial encounter. Conclusion and Relevance: This represents the largest report describing management strategies of AMR in lung transplant recipients. Although practice varied, the most commonly used regimen consisted of plasmapheresis, IVIG, and rituximab. [ABSTRACT FROM AUTHOR]

Background: α1-Antitrypsin (AAT) is an acute phase glycoprotein, a multifunctional protein with proteinase inhibitory, anti-inflammatory and cytoprotective properties. Both preclinical and clinical experiences show that the therapy with plasma purified AAT is beneficial for a broad spectrum of inflammatory conditions. The potential effects of AAT therapy have recently been highlighted in lung transplantation (LuTx) as well.Methods: We used a murine fully mismatched orthotopic single LuTx model (BALB/CJ as donors and C57BL/6 as recipients). Human AAT preparations (5 mg, n = 10) or vehicle (n = 5) were injected to the recipients subcutaneously prior to and intraperitoneally immediately after the LuTx. No immune suppressive drugs were administered. Three days after the transplantation, the mice were sacrificed, and biological samples were assessed.Results: Histological analysis revealed significantly more severe acute rejection in the transplanted lungs of controls than in AAT treated mice (p < 0.05). The proportion of neutrophil granulocytes, B cells and the total T helper cell populations did not differ between two groups. There was no significant difference in serum CXCL1 (KC) levels. However, when compared to controls, human AAT was detectable in the serum of mice treated with AAT and these mice had a higher serum anti-elastase activity, and significantly lower proportion of Th1 and Th17 among all Th cells. Cleaved caspase-3-positive cells were scarce but significantly less abundant in allografts from recipients treated with AAT as compared to those treated with vehicle.Conclusion: Therapy with AAT suppresses the acute rejection after LuTx in a mouse model. The beneficial effects seem to involve anti-protease and immunomodulatory activities of AAT. [ABSTRACT FROM AUTHOR]

Purpose Patients with end-stage heart failure who remain symptomatic even with exemplary medical and device therapy are treated with heart transplantation. Multitudes of endeavor have been contrived during the last decennium in the field of noninvasive tests to rule out heart transplant rejection (HTR). In spite of having supportive literature, noninvasive imaging techniques lack acceptable documentation of clinical robustness, and endomyocardial biopsy (EMB) still remains the gold standard. The aim of this review is to shed light on the existing noninvasive radiological modalities to detect rejection among heart transplant recipients. Methods A comprehensive search was conducted for this review article on the basis of literature available including scientific databases of PubMed, Embase, and Google Scholar, using keywords of "Heart transplantation," "Acute allograft rejection," "Arrhythmias," "Echocardiography," "Speckle tracking echocardiography," and "Cardiac magnetic resonance imaging" from inception until September 2020. Results After preliminary screening of the databases, details regarding existent noninvasive radiological modalities to detect HTR were gathered and compiled in this review article. Currently, deformation imaging using speckle tracking and T2 time using cardiac magnetic resonance imaging can serve as screening tools based on which further invasive investigations can be planned. Standardization of blood-based and imaging modalities as screening and possible diagnostic tools for rejection would have obvious clinical and financial benefits in the care of growing number of post heart transplant recipients in our country. Conclusion Diagnosis of allograft rejection in heart transplant recipients through noninvasive techniques is demanding. To unravel the potential of noninvasive radiological modalities that can serve as a standard-of-care test, a prospective multicentric study randomizing noninvasive modality as first strategy versus current EMB-based gold standard of care is the need of the hour. [ABSTRACT FROM AUTHOR]

Summary: Acute allografts rejection is the most important factor causing allograft disability for many patients undergoing organ transplantation. PJ34, which is a specific inhibitor of poly(ADP‐ribose) polymerase 1, is involved in immune regulation, may be effective in preventing acute cardiac rejection. We performed the models of abdominal heterotopic heart transplantation. PJ34 was injected intraperitoneally daily (20 mg/kg/day) starting the day after surgery. The severity of rejection was determined by histology. The mRNA expression levels of cytokines and transcription factors in the grafts were measured by quantitative polymerase chain reaction (qPCR). The proportion and number of T‐cell subpopulations in the spleens were analyzed by flow cytometry. In vitro, the effect of PJ34 on allogeneic responses was investigated. We found treatment with PJ34 prolonged allograft survival compared with normal saline treatment. Compared with the control group, PJ34 treatment reduced the proportion of CD4+IFN‐γ+ and CD4+IL‐17A+ cells and increased the percent of CD4+IL‐4+ and CD4+Foxp3+ cells in the spleens. In vitro, PJ34 treatment significantly inhibited the mRNA levels of IFN‐γ and IL‐17A and promoted the mRNA levels of TGF‐β and FOXP‐3 in activated CD4+ T cells. Modulating the CD4+ T lymphocyte response with PJ34 could attenuate acute allografts rejection after murine heart transplantation. These findings indicate that PARP1 may be a promising therapeutic target to attenuate acute cardiac allograft rejection. [ABSTRACT FROM AUTHOR]

Background and Aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4 + T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4 + T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR-HIF-1α pathway., Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c + and CD4 + cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR-HIF-1α expression in the grafts; and CD4 + cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry., Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4 + and CD11c + cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4 + T cells in vitro ., Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4 + T cell responses. This process may be related to the inhibition of the mTOR-HIF-1α signaling pathway by OMT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

Introduction: Thymoglobulin is a lymphocyte-depleting polyclonal antibody, administered for induction therapy at the time of kidney transplantation to reduce the risk of acute allograft rejection. The appropriate dosage and duration of therapy is controversial. The higher dosages are associated with infection and malignancy. Objectives: In this study efficacy and safety of lower dosage (in comparison with previous studies) of thymoglobulin in kidney transplant recipients was evaluated. Patients and Methods: In this clinical trial, 106 adult kidney transplant recipients, were randomized before transplantation in two groups (case and control). The case group (53 patients) were received induction therapy with thymoglobulin (1.5 mg/kg/d for 3 days) and the control group (53 patients) were received non-induction regiment. Delayed graft function (DGF), glomerular filtration rate (GFR), acute allograft rejection and thymoglobulin complications were evaluated during the first post-transplantation year. Results: Around 106 kidney transplant recipients were enrolled (71 or 66.98% deceased donor) to the study. No significant statistical differences were found in GFR at the time of discharge from hospital (P=0.399) and at 1 year (P=0.851) and acute allograft rejection (P= 0.304) between two groups. Graft survival (73.5% in case group versus 81.1% in control group, P=0.392) at month 12th was similar among groups. Additionally, no significant differences of acute allograft rejection in recipient from deceased or living donor between two groups were detected. There was a higher incidence of DGF in the control group (26.4%) than the thymoglobulin group (5.8%) and the difference was statistically significant (P= 0.004). Thrombocytopenia (17% versus 49.1%, P

Allogeneic kidney transplantation is the optimal approach for the treatment of patients with terminal stage of chronic kidney disease. Moreover, post-transplant monitoring and optimization of immunosuppressive therapy with early non-invasive molecular-biological markers can significantly improve the long-term outcome of transplantation. As markers of damage to the kidney transplant, it is proposed to use micro-RNAs that play a fundamental role in the regulation of the activity of various genes. The level of expression of micro-RNA in different tissues can correlate with certain pathological conditions. In this review, the literature data on the study of the perspectives for the use of micro-RNA as biomarkers of the post-transplantation period in kidney transplant recipients are considered.

Abstract Background Solid organ transplant recipients show heterogeneity in the occurrence and timing of acute rejection episodes. Understanding the factors responsible for such variability in patient outcomes may lead to improved diagnostic and therapeutic approaches. Rejection kinetics of transplanted organs mainly depends on the extent of genetic disparities between donor and recipient, but a role for environmental factors is emerging. We have recently shown that major alterations of the microbiota following broad-spectrum antibiotics, or use of germ-free animals, promoted longer skin graft survival in mice. Here, we tested whether spontaneous differences in microbial colonization between genetically similar individuals can contribute to variability in graft rejection kinetics. Results We compared rejection kinetics of minor mismatched skin grafts in C57BL/6 mice from Jackson Laboratory (Jax) and Taconic Farms (Tac), genetically similar animals colonized by different commensal microbes. Female Tac mice rejected skin grafts from vendor-matched males more quickly than Jax mice. We observed prolonged graft survival in Tac mice when they were exposed to Jax mice microbiome through co-housing or fecal microbiota transplantation (FMT) by gastric gavage. In contrast, exposure to Tac mice did not change graft rejection kinetics in Jax mice, suggesting a dominant suppressive effect of Jax microbiota. High-throughput sequencing of 16S rRNA gene amplicons from Jax and Tac mice fecal samples confirmed a convergence of microbiota composition after cohousing or fecal transfer. Our analysis of amplicon data associated members of a single bacterial genus, Alistipes, with prolonged graft survival. Consistent with this finding, members of the genus Alistipes were absent in a separate Tac cohort, in which fecal transfer from Jax mice failed to prolong graft survival. Conclusions These results demonstrate that differences in resident microbiome in healthy individuals may translate into distinct kinetics of graft rejection, and contribute to interpersonal variability in graft outcomes. The association between Alistipes and prolonged skin graft survival in mice suggests that members of this genus might affect host physiology, including at sites distal to the gastrointestinal tract. Overall, these findings allude to a potential therapeutic role for specific gut microbes to promote graft survival through the administration of probiotics, or FMT.

Immune processes in liver transplantation remain poorly understood. Acute allograft rejection in liver transplantation is a kind of T cell–mediated inflammatory disease accompanied by inflammatory cell infiltration. However, the effect of acute allograft rejection on the immunological characteristics of TCRs in peripheral blood mononuclear cell is unknown. In this study, we characterized the pattern of the human T cell receptor beta chain (TRB) and immunoglobulin heavy chain (IGH) complementarity‐determining region 3 (CDR3) repertoires via high‐throughput sequencing in 11 acute allograft rejection (AG) cases, 23 patients with stable allograft liver function (ST) who had liver transplantation performed and 20 healthy controls (HC). The diversity of TRB‐CDR3 was significantly reduced in the AG group compared with the ST group and healthy controls (HC). The CDR3 and N‐addition length distribution were not significantly different between the AG and ST groups. However, N‐addition length distribution was significantly changed compared to HC. It seemed that AG used more short N‐additions and healthy people used more long N‐additions in TRB‐CDR3 repertoire. Our findings suggested that the TRB‐CDR3 region of AG had distinctive V gene use compared with that of HC. The characteristics of ST seemed to be in between those of AG and HC although the difference is not significant. Cluster analysis showed that the TRB repertoire could not effectively distinguish AG from ST. This research might give to a better understanding of the immune process of liver transplantation. [ABSTRACT FROM AUTHOR]

Introduction: Thymoglobulin is a lymphocyte-depleting polyclonal antibody, administered for induction therapy at the time of kidney transplantation to reduce the risk of acute allograft rejection. The appropriate dosage and duration of therapy is controversial. The higher dosages are associated with infection and malignancy. Objectives: In this study efficacy and safety of lower dosage (in comparison with previous studies) of thymoglobulin in kidney transplant recipients was evaluated. Patients and Methods: In this clinical trial, 106 adult kidney transplant recipients, were randomized before transplantation in two groups (case and control). The case group (53 patients) were received induction therapy with thymoglobulin (1.5 mg/kg/d for 3 days) and the control group (53 patients) were received non-induction regiment. Delayed graft function (DGF), glomerular filtration rate (GFR), acute allograft rejection and thymoglobulin complications were evaluated during the first post-transplantation year. Results: Around 106 kidney transplant recipients were enrolled (71 or 66.98% deceased donor) to the study. No significant statistical differences were found in GFR at the time of discharge from hospital (P = 0.399) and at 1 year (P = 0.851) and acute allograft rejection (P = 0.304) between two groups. Graft survival (73.5% in case group versus 81.1% in control group, P = 0.392) at month 12th was similar among groups. Additionally, no significant differences of acute allograft rejection in recipient from deceased or living donor between two groups were detected. There was a higher incidence of DGF in the control group (26.4%) than the thymoglobulin group (5.8%) and the difference was statistically significant (P = 0.004). Thrombocytopenia (17% versus 49.1%, P < 0.001) and leukopenia (11.3% versus 50.9%, P < 0.001) were also significantly higher in the case group. Conclusion: While the incidence of DGF was reduced in thymoglobulin group, the short-term acute allograft rejection rate was not reduced compared to the control group. However, our results require further consideration with larger samples. [ABSTRACT FROM AUTHOR]

Background: Thymoglobulin is a lymphocyte-depleting polyclonal antibody, administered for induction therapy at the time of kidney transplantation to reduce the risk of acute allograft rejection. The appropriate dosage and duration of therapy is controversial. The higher dosages are associated with infection and malignancy. Objectives: In this study efficacy and safety of lower dosage (in comparison with previous studies) of thymoglobulin in kidney transplant recipients was evaluated. Patients and Methods: In this clinical trial, 106 adult kidney transplant recipients, were randomized before transplantation in two groups (case and control). The case group (53 patients) were received induction therapy with thymoglobulin (1.5 mg/kg/d for 3 days) and the control group (53 patients) were received non-induction regiment. Delayed graft function (DGF), glomerular filtration rate (GFR), acute allograft rejection and thymoglobulin complications were evaluated during the first post-transplantation year. Results: Around 106 kidney transplant recipients were enrolled (71 or 66.98% deceased donor) to the study. No significant statistical differences were found in GFR at the time of discharge from hospital (P = 0.399) and at 1 year (P = 0.851) and acute allograft rejection (P = 0.504) between two groups. Graft survival (73.5% in case group versus 81.1% in control group, P = 0.721) at month 12th was similar among groups. Additionally, no significant differences of acute allograft rejection in recipient from deceased or living donor between two groups were detected. There was a higher incidence of DGF in the control group (26.4%) than the thymoglobulin group (5.8%) and the difference was statistically significant (P = 0.004). Thrombocytopenia (17% versus 49.1%, P < 0.001) and leukopenia (11.3% versus 50.9%, P < 0.001) were also significantly higher in the case group. Conclusions: While the incidence of DGF was reduced in thymoglobulin group, the short-term acute allograft rejection rate was not reduced compared to the control group. However, our results require further consideration with larger samples. [ABSTRACT FROM AUTHOR]

The association between anti-AT1Rabs and microvascular injury observed in antibody-mediated rejection has been described in kidney graft Biopsies (KGBx). We herein describe the histopathologic findings of KGBx performed during the first year of transplantation (Tx) in 134 patients tested for pre-Tx anti-AT1Rabs in cryopreserved sera (04/2009 to 09/2013). Protocol KGBx before implantation (time-zero), 1 year after Tx and for cause KGBx were included. 21/134 Tx patients were anti-AT1Rab positive (≥17 U/mL); 7/21 experienced acute rejection. For comparison a control group with anti-AT1Rabs <17 U/mL, with (n = 16) and without (n = 31) acute rejection was included. Preimplantation KGBx showed no differences in inflammatory and chronic findings, nor in subintimal fibrosis (25 vs 12.8%, p =.42) between patients with anti-AT1Rabs ≥17 U/mL and those with <17 U/mL. Follow-up KGBx revealed a significantly greater proportion of arterial sub-intimal fibrosis (52.3 vs. 27.6%, p =.049) and extension (15.7 vs. 5.3, p =.015) in anti-AT1Rabs ≥17 U/mL compared to anti-AT1Rabs <17 U/mL KGBx. No differences were observed in microcirculation inflammation, nor in interstitial fibrosis or tubular atrophy between groups. Also, anti-AT1Rabs ≥17 U/mL (β 10.1, 2.3 to 17.8, p =.012) and more importantly anti-AT1Rabs ≥ 30 U/mL (β12.1, 3.1 to 20.9, p <.01), were independent risk factors associated with vascular occlusion resulting from sub-intimal fibrosis. Our study findings have shown that anti-AT1Rab values ≥17 U/mL are significantly associated to sub-intimal fibrosis and a greater percentage of vessel occlusion in kidney graft biopsies obtained during the first year posttransplant, particularly in coexistence with inflammation and de novo DSA. • Patients with anti-AT1Rabs ≥17 U/mL had greater arterial sub-intimal fibrosis • Anti-AT1Rabs ≥17 U/mL and ≥ 30 U/mL are associated with vascular occlusion • Anti-AT1Rabs ≥17 U/mL is not associated to microcirculation inflammation • Anti-AT1Rabs ≥17 U/mL is not related to interstitial fibrosis or tubular atrophy [ABSTRACT FROM AUTHOR]

Heart transplantation has been increasingly performed for patients with end-stage heart failure most commonly related to ischemic and non-ischemic cardiomyopathies. The major complications are procedure-related complications, infection, acute rejection, cardiac allograft vasculopathy, and malignancy. Radiologists have an important role in the evaluation of transplant candidates and early detection of postoperative complications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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Background T cell immunoglobulin and mucin domain 3 (TIM-3) is involved in alloimmune and autoimmune responses, as well as tolerance induction in kidney transplantation. Kidney injury molecule-1 (KIM-1) is highly expressed in epithelial cells of the injured proximal tubule. In this study, we have investigated both urinary and blood TIM-3 mRNA expressions, urinary KIM-1 mRNA expression, and urinary and serum KIM-1 proteins in renal allograft recipients diagnosed with acute allograft rejection (AR) and chronic allograft dysfunction (CAD), as well as those with well-functioning transplants (WFG). Methods We divided 85 patients into the following groups: AR (n = 24), CAD (n = 19), and WFG (n = 42). TIM-3 and KIM-1 mRNA expressions were quantified using real-time reverse-transcription TaqMan probe polymerase chain reaction (RT-PCR). An ELISA test was used to measure the amount of KIM-1 protein in serum and urine samples. Results AR and CAD patients had significantly greater urinary and blood TIM-3 mRNA expressions, urinary KIM-1 mRNA expression, and urinary and serum KIM-1 proteins compared to WFG patients. Receiver operating characteristic (ROC) analysis showed that these molecules discriminated Allograft rejections from WFG. Conclusion Quantification of TIM-3 and KIM-1 mRNA expressions, along with KIM-1 protein measurements in urine and blood could be employed as promising tools for noninvasive diagnosis of allograft dysfunction. [ABSTRACT FROM AUTHOR]

Noninvasive biomarkers of acute allograft rejection (AAR) following orthotopic heart transplantation (OHT) are needed. The aim of this study was to investigate the accuracy of echocardiographic (ECHO) right ventricular (RV) global functional and resistance indices in the detection of AAR. This retrospective chart review included children with biopsy-proven AAR (grade ≥ 2R cellular or CD4 + antibody-mediated rejection) following OHT and an ECHO within 12 h of the biopsy. ECHO measures: (a) ratio of systolic to diastolic duration (S/D), (b) RV myocardial performance index (MPI) and (c) tricuspid regurgitant gradient to RV outflow tract velocity time integral ratio (TRG/VTI), were derived at baseline, during AAR and at two follow-ups. Sixteen patients [56% male, mean (SD) age at OHT 3.5 (4.3) years] had 16 AAR episodes. S/D (1.15 vs. 1.60, p < 0.01), RV MPI (0.19 vs. 0.39, p < 0.01) and TRG/VTI (1.05 vs. 1.7, p = 0.01) deteriorated during AAR and, except for diastolic duration, improved significantly at first follow-up. The negative predictive values for S/D, RV MPI and TRG/VTI at cutoffs of 1.3, 0.31 and 1.3 were 97, 97 and 87%, respectively. RV S/D, MPI and TRG/VTI deteriorated during AAR. Their excellent negative predictive values suggest that their incorporation in surveillance may obviate the need for routine biopsies. [ABSTRACT FROM AUTHOR]

The article focuses on the results of the investigation of peripheral blood lymphocyte morphofunctional status in healthy volunteers and renal allograft recipients for early postoperative period. Working out noninvasive tests for diagnosis of acute renal allograft rejection based on the measuring of cell morphometric parameters by method of coherent phase microscopy (CPM). It was found out that the lymphocyte phase height was proportional cell image density and its geometrical thickness. Our results showed that the variations of immunocompetent cell morphometric indicants can be in advance the dynamics of blood creatine increasing and answer for early criteria of acute renal allograft rejection.

Background: Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer. Case presentation: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient's immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response. Conclusions: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis. [ABSTRACT FROM AUTHOR]

Background: Some studies have reported causal associations between bacteremia and mortality or allograft loss in kidney transplant recipients (KTR). However, few studies have assessed the clinical course of kidney function and the risk of acute allograft rejection after bacteremia. Methods: We retrospectively reviewed 902 kidney transplants performed at Nagoya Daini Red Cross Hospital between January 1, 2002 and March 31, 2014. Forty-five living donor kidney transplant recipients with single bacteremia were included. We analyzed death, change in kidney function, and development of acute allograft rejection 12 months after bacteremia according to the following groups: primary source of bacteremia (urinary tract or other sources), site of acquisition (community acquired or nosocomial), severity (not meeting the systemic inflammatory response syndrome criteria and sepsis or severe sepsis and septic shock), empiric antibiotic use (appropriate or inappropriate), and baseline kidney function (estimated glomerular filtration rate ≤44.7 or ≥44.8 ml/min). Results: Urinary tract infection (UTI) was the leading cause of bacteremia (68.9 %), and Escherichia coli was the most common pathogen. Three cases (6.7 %) died of infection that caused bacteremia within 12 months. Pneumonia accounted for two-thirds. Kidney function declined 1 week after bacteremia ( P < 0.05), particularly in severe cases. Thereafter, kidney function was comparable to baseline level in each group ( P ≥ 0.05). Severe UTI was associated with subsequent acute allograft rejection ( P = 0.03). Conclusions: Pneumonia in KTR should be managed with caution. Kidney function generally returned to baseline level after bacteremia. However, severe UTI may be associated with subsequent acute allograft rejection. [ABSTRACT FROM AUTHOR]

After lung transplantation, early detection of acute allograft rejection is important not only for timely and optimal treatment, but also for the prediction of chronic rejection which is a major cause of late death. Many biological and immunological approaches have been developed to detect acute rejection; however, it is not well known whether lung mechanics correlate with disease severity, especially with pathological rejection grade. In this study, we examined the relationship between lung mechanics and rejection grade development in a rat acute rejection model using the forced oscillation technique, which provides noninvasive assessment of lung function. To this end, we assessed lung resistance and elastance ( RL and EL) from implanted left lung of these animals. The perivascular/interstitial component of rejection severity grade (A-grade) was also quantified from histological images using tissue fraction ( TF; tissue + cell infiltration area/total area). We found that TF, RL, and EL increased according to A-grade. There was a strong positive correlation between EL at the lowest frequency ( Elow; EL at 0.5 Hz) and TF ( r2 = 0.930). Furthermore, the absolute difference between maximum value of EL ( Emax) and Elow ( Ehet; Emax − Elow) showed the strong relationship with standard deviation of TF ( r2 = 0.709), and A-grade (Spearman's correlation coefficients; r s = 0.964, P < 0.0001). Our results suggest that the dynamic elastance as well as its frequency dependence have the ability to predict A-grade. These indexes should prove useful for noninvasive detection and monitoring the progression of disease in acute rejection. [ABSTRACT FROM AUTHOR]

Complement-mediated cytotoxic antibodies in conventional cross match, often result in misappropriation of true positives and borderline positives which are detrimental to allograft survival. Flow cross matches (FCXM) are sensitive to capture even non comple-ment fixing cytotoxic antibodies. This retrospective study evaluates the utility of FCXM in effectively predicting acute allograft rejection. A total of 17 cases were processed for FCXM (T and B cell) of whom seven had no rejection episodes, while the remaining 11 had acute rejection despite negative cross match and panel reacting antibodies being ne-gative (less than 20%). The sensitivity and specificity of the FCXM outcome demons-trated that positive B-cell FCXM has potential to be a good tool in pre-transplant scree-ning. The current analysis proposes the possible utility of B-cell positive FCXM as a more sensitive parameter in predicting acute allograft rejection prior to transplantation.