DsbA-L deletion attenuates LPS-induced acute kidney injury by modulating macrophage polarization.

Disulfide bond A oxidoreductase-like protein (DsbA-L) drives acute kidney injury (AKI) by directly upregulating the expression of voltage-dependent anion-selective channels in proximal tubular cells. However, the role of DsbA-L in immune cells remains unclear. In this study, we used an LPS-induced AKI mouse model to assess the hypothesis that DsbA-L deletion attenuates LPS-induced AKI and explore the potential mechanism of DsbA-L action. After 24 hours of LPS exposure, the DsbA-L knockout group exhibited lower serum creatinine levels compared to the WT group. Furthermore, peripheral levels of the inflammatory cytokine IL-6 were decreased. Transcriptomic data analysis revealed a significant down-regulation in the IL-17 and tumor necrosis factor pathways in DsbA-L knockout mice following LPS induction. Metabolomic analysis suggested that arginine metabolism was significantly different between the WT and DsbA-L knockout groups after LPS treatment. Notably, the M1 polarization of macrophages in the kidneys of DsbA-L knockout AKI mice was significantly reduced. Expression of the transcription factors NF-κB and AP-1 was downregulated after DsbA-L knockout. Our results suggest that DsbA-L regulates LPS-mediated oxidative stress, promotes M1 polarization of macrophages, and induces expression of inflammatory factors via the NF-κB/AP-1 pathway.

A murine groin site cardiac transplantation model-applicable tool for studying roles of peripheral lymph nodes in transplantation.

The murine heterotopic cardiac transplantation model has been widely used to study antigen-specific immune responses or new immunosuppressive agents, which have a strong correlation with peripheral lymph nodes. Thus, a new organ transplantation model that is applicable to related studies is needed. Here, we describe a groin-site murine heart transplantation model using a cuff technique, in which the donor aorta and pulmonary artery are anastomosed to the truncated femoral vessels of the recipient. The mean survival time (MST) of the grafts in BALB/c-to-C57BL/6 allo-transplant group was 7.2 ± 0.3 days, and 1.9 ± 0.2 days in BALB/c-to-Sprague-Dawley (SD) rat xeno-transplant group. H&E results show that donor hearts from both groups demonstrate typical pathological features at the endpoint. Evans Blue tracing revealed that the popliteal lymph nodes of the grafted side hindlimb are larger than those of the contralateral side. Moreover, IHC staining for CD3, CD20 shows that the germinal center and cortex region of the grafted side of popliteal lymph nodes is apparently increased than that of the contralateral side. To sum up, this model may serve as an ideal model to study the role of peripheral lymph nodes in organ transplant rejection. In addition, extra-peritoneal grafting makes a step forward in animal welfare under the 3Rs' principle (Replacement, Reduction, Refinement).

The status and influencing factors of fatigue in kidney transplant recipients based on the theory of unpleasant symptoms: A cross-sectional study in China.

AIMS: This study describes the incidence of fatigue in kidney transplant recipients and analyses the relationship between physiological factors, psychological factors, situational factors and fatigue in kidney transplant recipients. BACKGROUND: Fatigue, as a common symptom after kidney transplantation, is affected by many factors, but the influence of some factors on the fatigue of kidney transplant recipients is still controversial. DESIGN: This cross-sectional study was designed based on the theory of unpleasant symptoms. METHODS: Our survey involved 307 participants attending the kidney transplant outpatient clinic of a tertiary Class A hospital (Changsha, Hunan, China). Data were collected between February and April 2021 using a structured questionnaire and electronic medical records. Data were analysed using IBM SPSS 25.0 (SPSS Inc.) RESULTS: It was found that the incidence of fatigue in kidney transplant recipients was 53.1%. According to the binary logistic regression analysis, sleep quality, hypokalemia, anxiety, depression and education level were independent risk factors for fatigue in kidney transplant recipients. CONCLUSION: The incidence of fatigue in kidney transplant recipients was high and was influenced by physical, psychological and situational factors. Clinical nurses should assess fatigue levels in a timely and multidimensional manner in clinical practice and provide effective and scientific guidance about fatigue self-coping and symptom management for kidney transplant recipients.

Mouse kidney transplantation model: Three novel methods. / å°é¼ è‚¾ç§»æ¤æ¨¡åž‹ï¼š3种创新术式（英文）.

OBJECTIVES: The mouse kidney transplantation model presents challenges in terms of surgical difficulty and low success rate, making it difficult to master. This study aims to provide a crucial model for transplantation immunology research by modifying and developing novel techniques for mouse kidney transplantation. METHODS: A total of 57 pairs of mice were used to establish and compare the modified and innovative surgical techniques for mouse kidney transplantation. Three different surgical models were established, including the abdominal suture technique for orthotopic kidney transplantation, the abdominal cuff technique for orthotopic kidney transplantation, and the cervical cuff technique for ectopic kidney transplantation. BALB/c or C57BL/6 male mice, aged 8 to 12 weeks and weighed 20 to 25 g with specified pathogen free-grade were served as the donor mice or the recipient mice. The surgical technique characteristics, key surgical times, complications, and pathological examination in the early postoperative period were summarized and compared. RESULTS: Three different surgical models of mouse kidney transplantation were successfully established. The comparison of warm ischemic time for the 3 groups of mice showed no statistical significance (P=0.510 4). The abdominal suture group had the shortest total operation time of the donor compared with the abdominal cuff group and the cervical cuff group [(18.3±3.6) min vs (26.2±4.7) min and (22.8±2.5) min; both P<0.000 1]. There was a significant difference in cold ischemia time among the 3 groups (all P<0.000 1), with (60.8±4.1) min in the cervical cuff group, (43.3±5.0) min in the abdominal suture group, and (88.8±6.7) min in the abdominal cuff group. Due to different anastomosis methods, the cervical cuff group had the shortest time [(17.6±2.7) min], whereas the abdominal cuff group had the longest time [(38.8±5.4) min]. The total operation time for the recipients showed significant differences (P<0.000 1), with the abdominal suture group having the shortest time [(44.0±6.9) min], followed by the cervical cuff group [(64.1±5.2) min], and the abdominal cuff group [(80.0±6.0) min] being the longest. In the 32 mice of the abdominal suture group, there were 6 with intraoperative bleeding, including 1 arterial intimal injury bleeding and 5 with bleeding after vessel opening. Six mice had ureteral complications, including ureteral bladder anastomotic stenosis, necrosis, and renal pelvis dilation. Two mice had postoperative abdominal infections. In the abdominal cuff group, there was no intraoperative bleeding, but 6 mice showed mild arterial stenosis and 5 showed venous stenosis, 4 arterial injury, 4 arterial thrombosis, and 2 ureteral complications. No postoperative infections occurred in the mice. In the cervical cuff group, no intraoperative bleeding, arterial intimal injury, arterial/venous stenosis, or thrombosis were found in 13 mice. Five mice had ureteral complications, including ureteral necrosis and infection, which were the main complications in the cervical cuff group. The renal function in mice of the 3 groups remained stable 7 days after surgery. Hematoxylin and eosin staining and periodic acid-Schiff staining showed no significant differences in terms of acute rejection among the 3 surgical methods (all P>0.05). CONCLUSIONS: All 3 surgical methods are able to successfully establish mouse kidney transplantation models, with no significant differences observed in the short-term graft survival and acute rejection. The modified abdominal suture technique and abdominal cuff technique have their respective advantages in research applications. The novel cervical cuff technique for ectopic kidney transplantation model is relatively simple to be prepared and causes less trauma to the mice, providing more options for studies involving xenotransplantation, secondary transplantation, and local lymphatic drainage. However, the difficulty in harvesting the donor kidney and the high incidence of ureteral infections need further validation in long-term survival. This study holds important reference value for choosing the type of mouse kidney transplantation model for different research needs.

TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation.

It has been reported that deletion of tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2, TIPE2) facilitates the activation of T-cell receptors. However, the role of TIPE2 in T-cell-mediated acute transplant rejection remains unclear. To illustrate the underlying cellular mechanisms, we transplanted BALB/c hearts into C57BL/6 wild-type (WT) or C57BL/6 mice deficient for TIPE2 (TIPE2-/-) and found that TIPE2-/- recipient mice showed significantly prolonged survival of heart allografts and suppressed maturation of CD11c+ dendritic cells (DCs), which largely abolished the activation and proliferation of alloreactive T cells and their cytotoxic activity. TIPE2-/- DCs increased CD4+CD25+Foxp3+CD127- regulatory T cells (Tregs)generation, likely by inhibiting DCs maturation and CD80 and CD86 expression. Administration of anti-CD25 abolished the allograft survival induced by TIPE2 deficiency. Moreover, TIPE2 deficiency increased IL-10 production in T cells and in recipient serum and allografts. Mechanistic studies revealed that TIPE2-/- restrained the maturation of DCs via inhibition of PI3K/AKT phosphorylation during alloantigen stimulation. Taken together, TIPE2 deficiency in recipient mice inhibited acute rejection by increasing Tregs generated by immature DCs. Thus, TIPE2 could be a therapeutic target for suppressing rejection in organ transplantation.

Hemophagocytic lymphohistiocytosis secondary to virus infection and followed by lupus nephritis recurrence in a renal transplantation pediatric recipient: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder characterized by systemic inflammation and organ failure as a result of dysregulated immune cell activation. HLH can be induced by a variety of factors including infection, tumours and autoimmune disease and can also occur in patients following solid organ transplantation. Occurrence of HLH and lupus nephritis (LN) successively within a short period of time after renal transplantation is uncommon. CASE PRESENTATION: We described an 11-year-old female post-transplant patient who presented with hemocytopenia, fever, elevated serum ferritin, splenomegaly, hyperlipidemia, and hypofibrinemia, and was clinically diagnosed with HLH. After comprehensive treatment with corticosteroids, intravenous immunoglobulin (IVIG), and reducing immunosuppressants, her condition improved, but then hematuria ensued. The transplant kidney biopsy showed LN. She was treated with hydroxychloroquine and methylprednisolone while intensive immunosuppressive agents were given. She has remained in remission for two years until now. CONCLUSIONS: The main inducing factors of HLH should be identified as early as possible, and accurate treatment plans should be taken. The long-course IVIG regimen may be one of the effective treatments for virus-induced HLH. After remission of HLH, we need to be alert to the recurrence of autoimmune diseases in patients with underlying diseases, and timely increase immunosuppressants.

Clinical outcomes for kidney transplantation in 81 adults with IgA nephropathy. / 81例成人IgAè‚¾ç— è‚¾ç§»æ¤çš„ä¸´åºŠç–—æ•ˆï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Immunoglobulin A nephropathy (IgAN) is one of the most common types of kidney disease, and kidney transplantation is the most effective treatment for end-stage renal disease. This study aims to analyze the clinical curative effect of renal transplantation for adults with IgAN and to discuss the efficacy and safety of kidney transplantation for IgAN at the perioperative period and medium- and long-term follow-up. METHODS: This retrospective study included the clinical and follow-up data of 81 adult patients with IgAN who underwent kidney transplantation at the Second Xiangya Hospital, Central South University from January 2018 to January 2022. Of the 81 patients whose age at (34.1±9.9) years old, 47 (58.0%) were male. The body mass index was (20.8±3.2) kg/m2, and the human leukocyte antigen (HLA) mismatch number was 3.5±1.2. The estimated glomerular filtration rate (eGFR) and daily 24-hour urine output for the recipients on the 1st, 5th, and 7th day after kidney transplantation and when they were discharged were analyzed. The recovery of the transplanted kidney and occurrence of complications were comprehensively evaluated. The eGFR, urinary protein, and occult blood were evaluated at the 6th, 12th, 24th, 36th, and 48th month and at the last follow-up. RESULTS: The follow-up time was (25.7±15.8) months. No primary non-function occurred in any patient during the perioperative period time. Fifty-one (63.0%) patients had immediate graft function recovery, and 16 (19.8%) patients had slow graft function recovery. Delayed recovery of graft function was observed in 14 (17.3%) patients. A total of 19 perioperative complications occurred, including 9 patients with acute rejection, 5 patients with urinary fistula, 1 thrombosis in both lower limbs, and 4 lymphatic fistula. The eGFR at 6th, 12th, 24th, 36th, and 48th month of follow-up were (65.3±22.9), (67.6±23.0), (64.3±21.8), (65.9±24.7), and (68.7±31.2) mL/(min·1.73 m2), respectively. The eGFR remained high during the medium- and long-term follow-ups. At the longest follow-up of 56 months, eGFR fluctuation was still mild, and the positive rate of urine protein and occult blood was low. IgAN recurred in 4 transplanted kidneys, accounting for 4.94% of the total patients, without severe renal insufficiency. Three patients had kidney dysfunction due to severe pneumonia, rejection, and stone in the transplanted kidney. The overall survival rate of the transplanted kidney was higher than 95%, and the survival rate of all patients was 100% till Januray 2022. CONCLUSIONS: Renal transplantation for adults with IgAN had a remarkable short-term effect. The recipients can be beneficial significantly to favorable midium- and long-term outcomes. IgAN recurrence is infrequent and rarely causes severe renal function damage.

Novel immunosuppressive effect of FK506 by upregulation of PD-L1 via FKBP51 in heart transplantation.

The calcineurin inhibitor-FK506-is a first-line immunosuppressant that regulates T cell secretion of IL-2 and other cytokines. However, the mechanism of its protective effect on target cells and its role on tumour recurrence and interaction with anti-tumour immune checkpoint inhibitors, such as PD-L1 blocking, are still unclear. Here, in a murine heart transplantation model, we observed the upregulation of programmed death-ligand 1 (PD-L1) expression by FK506 in both dendritic cells (DCs) and allografts. Blocking PD-L1 during FK506 treatment increased IFN-γ and TNF-α expression, enhanced CD4+ and CD8+ T cell proliferation, and suppressed Treg differentiation. Moreover, PD-L1 decreased T cell infiltration and induced T cell apoptosis in both the spleen and graft. PD-L1 was not only required in FK506-mediated immunosuppression but also upregulated by FK506. Treatment with SAFit2, a FKBP51 selective inhibitor, reduced the expression of PD-L1 on DCs and the grafts and interfered with the immunosuppressive effect of FK506, suggesting that the mechanism depends on FK506-binding protein (FKBP) 51 expression. Overall, our results add new insights into the role of FK506, not only on T cell cytokine secretion but also on co-inhibitory molecular regulation and target cell immune privilege.

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5-10 × 106 cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD-L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and "cross-dressing" of host DCs in blood and lymph nodes. PD-L1 co-localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T-bethi Eomeshi memory CD8+ T cells decreased, whereas regulatory (CD25hi CD127- Foxp3+ ): T-bethi Eomeshi CD8+ T cell ratios increased. Thus, donor-derived DCreg infusion may induce systemic changes in host antigen-presenting cells and T cells potentially conducive to modulated anti-donor immune reactivity at the time of transplant.

Assessing health-related quality of life of living kidney donors using the 36-item medical outcomes Short-Form-36 questionnaire: a meta-analysis.

The purpose of this meta-analysis was to assess the health-related quality of life (HRQoL) of living kidney donors using the 36-item Medical Outcomes Short-Form-36 questionnaire (SF-36). A systematic search of the Web of Science, PubMed, Embase, Elsevier/ScienceDirect, Wanfang, Weipu, and China National Knowledge Infrastructure databases for studies that used the SF-36 to evaluate the HRQoL of living kidney donors up to April 2020 was performed. Stata version 12.0 (StataCorp LLC, College Station, TX, USA) was used for meta-analysis. In all, nine studies comprising 802 living kidney donors were included in this meta-analysis. The research revealed that living kidney donors were inferior in physical health to the general population with regard to bodily pain (BP), superior to the general population in terms of general health (GH), and exhibited no significant difference from the general population in physical function (PF) and role-physical (RP). In the case of psychological health, living kidney donation had a positive impact on well-screened living kidney donors. Based on our results, clinicians can inform potential kidney donors that there is a low risk in donating a kidney, which contributes to provide guidance to design counseling interventions for both kidney recipients and donors.

DNAX Activating Protein of 12 kDa/Triggering Receptor Expressed on Myeloid Cells 2 Expression by Mouse and Human Liver Dendritic Cells: Functional Implications and Regulation of Liver Ischemia-Reperfusion Injury.

Liver interstitial dendritic cells (DCs) have been implicated in the control of ischemia-reperfusion injury (IRI) and host immune responses following liver transplantation. Mechanisms underlying these regulatory functions of hepatic DCs remain unclear. We have shown recently that the transmembrane immunoadaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulates mouse liver DC maturation and proinflammatory and immune stimulatory functions. Here, we used PCR analysis and flow cytometry to characterize expression of DAP12 and its associated triggering receptor, triggering receptor expressed on myeloid cells 2 (TREM2), by mouse and human liver DCs and other immune cells compared with DCs in other tissues. We also examined the roles of DAP12 and TREM2 and their expression by liver DCs in the regulation of liver IRI. Injury was induced in DAP12-/- , TREM2-/- , or wild-type (WT) mice by 1 hour of 70% clamping and quantified following 6 hours of reperfusion. Both DAP12 and TREM2 were coexpressed at comparatively high levels by liver DCs. Mouse liver DCs lacking DAP12 or TREM2 displayed enhanced levels of nuclear factor κB and costimulatory molecule expression. Unlike normal WT liver DCs, DAP12-/- liver DC failed to inhibit proliferative responses of activated T cells. In vivo, DAP12-/- and TREM2-/- mice exhibited enhanced IRI accompanied by augmented liver DC activation. Elevated alanine aminotransferase levels and tissue injury were markedly reduced by infusion of WT but not DAP12-/- DC. Conclusion: Our data reveal a close association between DAP12 and TREM2 expression by liver DC and suggest that, by negatively regulating liver DC stimulatory function, DAP12 promotes their control of hepatic inflammatory responses; the DAP12/TREM2 signaling complex may represent a therapeutic target for control of acute liver injury/liver inflammatory disorders.

Predictors and one-year outcomes of patients with delayed graft function after deceased donor kidney transplantation.

BACKGROUND: Delayed graft function (DGF) is closely associated with the use of marginal donated kidneys due to deficits during transplantation and in recipients. We aimed to predict the incidence of DGF and evaluate its effect on graft survival. METHODS: This retrospective study on kidney transplantation was conducted from January 1, 2018, to December 31, 2019, at the Second Xiangya Hospital of Central South University. We classified recipients whose operations were performed in different years into training and validation cohorts and used data from the training cohort to analyze predictors of DGF. A nomogram was then constructed to predict the likelihood of DGF based on these predictors. RESULTS: The incidence rate of DGF was 16.92%. Binary logistic regression analysis showed correlations between the incidence of DGF and cold ischemic time (CIT), warm ischemic time (WIT), terminal serum creatine (Scr) concentration, duration of pretransplant dialysis, primary cause of donor death, and usage of LifePort. The internal accuracy of the nomogram was 83.12%. One-year graft survival rates were 93.59 and 99.74%, respectively, for the groups with and without DGF (P < 0.05). CONCLUSION: The nomogram established in this study showed good accuracy in predicting DGF after deceased donor kidney transplantation; additionally, DGF decreased one-year graft survival.

The "other" mTOR complex: New insights into mTORC2 immunobiology and their implications.

A central role of the mechanistic target of rapamycin (mTOR) in regulation of fundamental cell processes is well recognized. mTOR functions in two distinct complexes: rapamycin-sensitive mTOR complex (C) 1 and rapamycin-insensitive mTORC2. While the role of mTORC1 in shaping immune responses, including transplant rejection, and the influence of its antagonism in promoting allograft tolerance have been studied extensively using rapamycin, lack of selective small molecule inhibitors has limited understanding of mTORC2 biology. Within the past few years, however, intracellular localization of mTORC2, its contribution to mitochondrial fitness, cell metabolism, cytoskeletal modeling and cell migration, and its role in differentiation and function of immune cells have been described. Studies in mTORC2 knockdown/knockout mouse models and a new class of dual mTORC1/2 inhibitors, have shed light on the immune regulatory functions of mTORC2. These include regulation of antigen-presenting cell, NK cell, T cell subset, and B cell differentiation and function. mTORC2 has been implicated in regulation of ischemia/reperfusion injury and graft rejection. Potential therapeutic benefits of antagonizing mTORC2 to inhibit chronic rejection have also been described, while selective in vivo targeting strategies using nanotechnology have been developed. We briefly review and discuss these developments and their implications.

mTORC2 deficiency in cutaneous dendritic cells potentiates CD8+ effector T cell responses and accelerates skin graft rejection.

Mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 regulate the differentiation and function of immune cells. While inhibition of mTORC1 antagonizes dendritic cell (DC) differentiation and suppresses graft rejection, the role of mTORC2 in DCs in determining host responses to transplanted tissue remains undefined. Using a mouse model in which mTORC2 was deleted specifically in CD11c+ DCs (TORC2DC-/- ), we show that the transplant of minor histocompatibility Ag (HY)-mismatched skin grafts from TORC2DC-/- donors into wild-type recipients results in accelerated rejection characterized by enhanced CD8+ T cell responses in the graft and regional lymphoid tissue [Correction added on January 9, 2019, after first online publication: in the previous sentence, major was changed to minor]. Similar enhancement of CD8+ effector T cell responses was observed in MHC-mismatched recipients of TORC2DC-/- grafts. Augmented CD8+ T cell responses were also observed in a delayed-type hypersensitivity model in which mTORC2 was absent in cutaneous DCs. These elevated responses could be ascribed to an increased T cell stimulatory phenotype of TORC2DC-/- and not to enhanced lymph node homing of the cells. In contrast, rejection of ovalbumin transgenic skin grafts in TORC2DC-/- recipients was unaffected. These findings suggest that mTORC2 in skin DCs restrains effector CD8+ T cell responses and have implications for understanding of the influence of mTOR inhibitors that target mTORC2 in transplant.

Graft-infiltrating PD-L1hi cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance.

Although a key role of cross-dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. We investigated the role of intragraft dendritic cells (DCs) and cross-dressing in mouse major histocompatibility complex (MHC)-mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. Although donor interstitial DCs diminished rapidly after transplantation, they were replaced in the liver by host DCs that peaked on postoperative day (POD) 7 and persisted indefinitely. Approximately 60% of these recipient DCs displayed donor MHC class I, indicating cross-dressing. By contrast, only a very minor fraction (0%-2%) of cross-dressed DCs (CD-DCs) was evident in the spleen. CD-DCs sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD-L1) and high levels of interleukin-10 compared with non-CD-DCs (nCD-DCs) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD-1)hi T cell immunoglobulin and mucin domain containing 3 (TIM-3)+ exhausted graft-infiltrating CD8+ T cells were observed. Unlike nCD-DCs, the CD-DCs failed to stimulate proliferation of allogeneic T cells but markedly suppressed antidonor host T cell proliferation. CD-DCs were much less evident in allografts from DNAX-activating protein of 12 kDa (DAP12)-/- donors that were rejected acutely. CONCLUSION: These findings suggest that graft-infiltrating PD-L1hi CD-DCs may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. (Hepatology 2018;67:1499-1515).

Rictor deficiency in dendritic cells exacerbates acute kidney injury.

Dendritic cells (DCs) are critical initiators of innate immunity in the kidney and orchestrate inflammation following ischemia-reperfusion injury. The role of the mammalian/mechanistic target of rapamycin (mTOR) in the pathophysiology of renal ischemia-reperfusion injury has been characterized. However, the influence of DC-based alterations in mTOR signaling is unknown. To address this, bone marrow-derived mTORC2-deficient (Rictor-/-) DCs underwent hypoxia-reoxygenation and then analysis by flow cytometry. Adoptive transfer of wild-type or Rictor-/- DC to C57BL/6 mice followed by unilateral or bilateral renal ischemia-reperfusion injury (20 min ischemia) was used to assess their in vivo migratory capacity and influence on tissue injury. Age-matched male DC-specific Rictor-/- mice or littermate controls underwent bilateral renal ischemia-reperfusion, followed by assessment of renal function, histopathology, and biomolecular and cell infiltration analysis. Rictor-/- DCs expressed more costimulatory CD80/CD86 but less coinhibitory programmed death ligand 1 (PDL1), a pattern that was enhanced by hypoxia-reoxygenation. They also demonstrated enhanced migration to the injured kidney and induced greater tissue damage. Following ischemia-reperfusion, Rictor-/- DC mice developed higher serum creatinine levels, more severe histological damage, and greater proinflammatory cytokine production compared to littermate controls. Additionally, a greater influx of both neutrophils and T cells was seen in Rictor-/- DC mice, along with CD11c+MHCII+CD11bhiF4/80+ renal DC, that expressed more CD86 but less PDL1. Thus, DC-targeted elimination of Rictor enhances inflammation and migratory responses to the injured kidney, highlighting the regulatory roles of both DCs and Rictor in the pathophysiology of acute kidney injury.

A novel technique for en bloc kidney transplantation from infant donors with extremely low body weight by using the distal abdominal aorta as an outflow tract.

Pediatric kidney donors remain underutilized due to the high risk of postoperative thrombosis. To address this problem, we developed a novel en bloc kidney transplantation technique using donor thoracic aorta and the distal abdominal aorta as inflow and outflow tracts, respectively. Briefly, eight kidneys from deceased infant donors under five months old and with low body weight (1.9-4.9 kg) were transplanted en bloc into four pediatric and four adult patients. The donor's common iliac artery or external iliac artery was anastomosed to the recipient's distal external iliac artery or inferior epigastric artery, respectively, as an outflow tract. Recipients received basiliximab or antithymocyte globulin as induction therapy followed by tacrolimus, mycophenolate mofetil, and prednisone but without prophylactic anticoagulation. Delayed graft function was observed in one patient but was reversed at 90 days posttransplant. Two patients had urine leakage, which was cured by conservative treatment. Two recipients developed lung infections that eventually cleared. No patients experienced posttransplant vascular thrombosis. After 1-1.5 years of follow-up, all patients are well and have normal serum creatinine levels. In conclusion, this novel en bloc kidney transplantation technique using a modified arterial inflow and outflow tract can prevent vascular thrombosis and provide adequate graft function.

Long-term atorvastatin-ezetimibe-probucol triple therapy for homozygous familial hypercholesterolaemia from early childhood.

In this observational case report, we share our experience of achieving >40% LDL cholesterol reduction in four Chinese homozygous familial hypercholesterolaemia children below 8 years of age with a triple combination of atorvastatin, probucol, and ezetimibe for >6 years. Within a follow-up duration of 6-13 years, this triple therapy achieved significant reduction of LDL cholesterol as well as an impressive regression of xanthomas in all paediatric cases. All the children remained free from treatment-related adverse responses and cardiovascular events throughout follow-up.

Transplantation of en bloc kidneys from cardiac deceased small pediatric donors: 2 case reports and literature review.

OBJECTIVE: To gain an insight into the transplantation with donor kidneys from extended criterion donation after cardiac death (DCD) and to improve the management during and after renal transplantation METHODS: Renal transplantation in 2 patients who used organs from small pediatric donors (<3 years) was performed. The graft kidneys were procured from 1 donor aged 11 months and the other 1 year and 7 months. The 2 donors were diagnosed as brain death caused by serious infantile hepatitis syndrome and severe craniocerebral injury, respectively. After the cardiac death, en bloc organ resection was performed. En bloc kidneys were transplanted to 2 adult recipients who were 37 and 41 years old, respectively. RESULTS: The recipients were followed-up for 6 months. Both of them developed large volume of bloody drainage in the early post-operational period and relieved after relevant treatment. The kidney grafts functioned well and no other surgical complications or acute rejections happened during the follow-up. CONCLUSION: Based on modified peri-operative techniques, it is safe to perform renal transplantation with kidneys procured from cardiac death donors who are younger than 3 years old, an important source to increase the number of organs available for transplantation, yet the vascular complications require attention.

Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target.

ABSTRACT: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.