TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway in mice.

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor that affects cellular phenotypes by modulating phagocytosis and metabolism, promoting cell survival, and counteracting inflammation. Its role in renal injury, in particular, unilateral ureteral obstruction (UUO) or ischemia-reperfusion injury (IRI)-induced renal injury remains unclear. In our study, WT and Trem2-/- mice were employed to evaluate the role of TREM2 in renal macrophage infiltration and tissue injury after UUO. Bone marrow-derived macrophages (BMDM) from both mouse genotypes were cultured and polarized for in vitro experiments. Next, the effects of TREM2 on renal injury and macrophage polarization in IRI mice were also explored. We found that TREM2 expression was upregulated in the obstructed kidneys. TREM2 deficiency exacerbated renal inflammation and fibrosis 3 and 7 days after UUO, in association with reduced macrophage infiltration. Trem2-/- BMDM exhibited increased apoptosis and poorer survival compared with WT BMDM. Meanwhile, TREM2 deficiency augmented M1 and M2 polarization after UUO. Consistent with the in vivo observations, TREM2 deficiency led to increased polarization of BMDM towards the M1 proinflammatory phenotype. Mechanistically, TREM2 deficiency promoted M1 and M2 polarization via the JAK-STAT pathway in the presence of TGF-ß1, thereby affecting cell survival by regulating mTOR signaling. Furthermore, cyclocreatine supplementation alleviated cell death caused by TREM2 deficiency. Additionally, we found that TREM2 deficiency promoted renal injury, fibrosis, and macrophage polarization in IRI mice. The current data suggest that TREM2 deficiency aggravates renal injury by promoting macrophage apoptosis and polarization via the JAK-STAT pathway. These findings have implications for the role of TREM2 in the regulation of renal injury that justify further evaluation.

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.

Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of MAPK and mammalian target of Rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro, blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg-1·day-1) and Rapamycin (0.1 mg·kg-1·day-1) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS: Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.

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.

Dietary vitamin intake and cancer risk in patients with chronic kidney disease: results from the National Health and Nutrition Examination Survey (2007-2018).

PURPOSE: The relationship between vitamin intake and cancer risk in the chronic kidney disease (CKD) population is unknown. For this reason, we investigated the relationship between dietary vitamin intake and cancer risk in CKD patients and looked for effective vitamin dietary patterns. METHODS: This study included 3518 CKD patients from 2007 to 2018 National Health and Nutrition Examination Survey database. All participants were categorized into four groups based on vitamin intake by K-mean clustering. The data were collected and analyzed from June 2023 to December 2023. RESULTS: A total of 3518 CKD patients with a mean age of (61.8 ± 16.3) years were included in the study. During a median follow-up of 7.3 years, 137 participants died of cancer. In the multivariate adjusted cox proportional hazards model for single vitamin intake, vitamin E Q4 intake (reference Q1) reduced cancer mortality (HR (95% CI) = 0.45 (0.24-0.87), P = 0.018). Further plotting of the restricted cubic spline curve revealed a linearly decreasing relationship between vitamin E intake and cancer mortality (Poverall = 0.010 Pnon-linear = 0.163). In the multivariate adjusted cox proportional hazards model for multivitamin co-intake, the vitamin C/K intake group reduced cancer mortality compared to the low vitamin intake group (HR (95% CI) = 0.42 (0.20-0.88), P = 0.022). CONCLUSION: Increased vitamin C intake was independently associated with reduced cancer risk in CKD patients, and a vitamin dietary pattern with high vitamin C/K intake was also effective in reducing cancer risk.

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.

Determination of Maximum Tolerable Cold Ischemia Time in a Mouse Model of Cervical Heterotopic Uterus Transplantation.

BACKGROUND: Uterus transplantation (UTx) is an emerging treatment for uterine factor infertility. Determining the maximum tolerable cold ischemia time is crucial for successful UTx. However, the limit for cold ischemia in the uterus is unclear. This study aimed to examine cold ischemia's effects on mouse uteri and identify the maximum cold ischemia duration that uteri can endure. METHODS: We systematically assessed the tolerance of mouse uteri to extended cold ischemia, 24 h, 36 h, and 48 h, using the cervical heterotopic UTx model. Multiple indicators were used to evaluate ischemia-reperfusion injury, including reperfusion duration, macroscopic examination, oxidative stress, inflammation, and histopathology. The function of transplants was evaluated through estrous cycle monitoring and embryo transfer. RESULTS: Mouse uteri subjected to 48 h of cold ischemia exhibited significant delays and insufficiencies in reperfusion, substantial tissue necrosis, and loss of the estrous cycle. Conversely, uteri that underwent cold ischemia within 36 h showed long survival, regular estrous cycles, and fertility. CONCLUSIONS: Our study demonstrated that mouse uteri can endure at least 36 h of cold ischemia, extending the known limits for cold ischemia and providing a pivotal reference for research on the prevention and treatment of cold ischemic injury in UTx.

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).

Association between dietary vitamin E intake and chronic kidney disease events in US adults: a cross-sectional study from NHANES 2009-2016.

Background: The relationship between vitamin E supplementation and the prevalence of chronic kidney disease (CKD) is unclear. We discussed the relationship between vitamin E intake and CKD prevalence and further investigated the effect on different CKD risk strata. Methods: We ultimately included 20 295 participants from the National Health and Nutrition Examination Survey (NHANES) database from 2009 to 2016. Multiple logistic regression and restricted cubic splines (RCS) were applied to explore the relationship between vitamin E intake and CKD prevalence and risk stratification. Subgroup analysis was applied to assess the stability of the association between vitamin E intake and CKD. Results: In the CKD prevalence study, we found a negative association between high vitamin E intake and CKD prevalence through an adjusted multiple logistic regression model, the odds ratio (OR) was 0.86 [95% confidence interval (CI) 0.74-1.00; P for trend = .041] and RCS showed a nonlinear negative correlation (P-nonlinear = .0002, <.05). In the CKD risk stratification study, we found that in very high-risk patients, the OR was 0.51 (95% CI 0.32-0.84; P for trend = .006) and the RCS also showed a nonlinear negative correlation (P-nonlinear <.0001, <.05). Subgroup analysis demonstrated that the correlations were stable across populations (P-values >.01 for all interactions). Conclusion: Dietary vitamin E intake was negatively associated with the prevalence of CKD in US adults. Increased vitamin E intake was a protective factor across CKD risk strata, and as vitamin E intake increased, there was a non-linear downward trend in the proportion progressing to very high-risk CKD.

Homoharringtonine promotes heart allograft acceptance by enhancing regulatory T cells induction in a mouse model.

BACKGROUND: Homoharringtonine (HHT) is an effective anti-inflammatory, anti-viral, and anti-tumor protein synthesis inhibitor that has been applied clinically. Here, we explored the therapeutic effects of HHT in a mouse heart transplant model. METHODS: Healthy C57BL/6 mice were used to observe the toxicity of HHT in the liver, kidney, and hematology. A mouse heart transplantation model was constructed, and the potential mechanism of HHT prolonging allograft survival was evaluated using Kaplan-Meier analysis, immunostaining, and bulk RNA sequencing analysis. The HHT-T cell crosstalk was modeled ex vivo to further verify the molecular mechanism of HHT-induced regulatory T cells (Tregs) differentiation. RESULTS: HHT inhibited the activation and proliferation of T cells and promoted their apoptosis ex vivo. Treatment of 0.5 mg/kg HHT for 10 days significantly prolonged the mean graft survival time of the allografts from 7 days to 48 days (P <0.001) without non-immune toxicity. The allografts had long-term survival after continuous HHT treatment for 28 days. HHT significantly reduced lymphocyte infiltration in the graft, and interferon-γ-secreting CD4+ and CD8+ T cells in the spleen (P <0.01). HHT significantly increased the number of peripheral Tregs (about 20%, P <0.001) and serum interleukin (IL)-10 levels. HHT downregulated the expression of T cell receptor (TCR) signaling pathway-related genes (CD4, H2-Eb1, TRAT1, and CD74) and upregulated the expression of IL-10 and transforming growth factor (TGF)-ß pathway-related genes and Treg signature genes (CTLA4, Foxp3, CD74, and ICOS). HHT increased CD4+ Foxp3+ cells and Foxp3 expression ex vivo, and it enhanced the inhibitory function of inducible Tregs. CONCLUSIONS: HHT promotes Treg cell differentiation and enhances Treg suppressive function by attenuating the TCR signaling pathway and upregulating the expression of Treg signature genes and IL-10 levels, thereby promoting mouse heart allograft acceptance. These findings may have therapeutic implications for organ transplant recipients, particularly those with viral infections and malignancies, which require a more suitable anti-rejection medication.

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.

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.

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.

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.

Drug-induced Fanconi syndrome in patients with kidney allograft transplantation.

Background: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. Methods: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. Results: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. Conclusions: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

Utilization of HCV Viremic Kidneys with Genotyping/Subtyping-Free Sofosbuvir/Velpatasvir Treatment Strategy: Experience from China.

Background: Owing to the advent of pangenotypic direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) treatment, utilization of HCV-infected deceased donor kidneys with simplified genotyping/subtyping-free sofosbuvir/velpatasvir (SOF/VEL) treatment strategy is now becoming a promising strategy for expanding the organ donor pool. Methods: This retrospective, comparative, single-center study included HCV viremic donor kidneys that were transplanted to 9 HCV-positive (HCV Ab-positive) recipients (D+/R+ group) and 14 HCV-negative recipients (D+/R- group) from May 2018 to January 2021. Both groups received prophylaxis with SOF/VEL treatment within 1-week posttransplant devoid of HCV genotyping/subtyping. The primary outcomes were sustained virologic response 12 weeks after completion of therapy (SVR12) and graft survival at 1-year posttransplant. Results: Baseline characteristics were similar between the HCV D+/R- and D+/R+ groups. The mean age of all recipients was 39.09 ± 9.65 (SD) years, and 73.9% were male. A total of 92.9% (13 out of 14) recipients had pretreatment HCV viremia in the D+/R- group. The pretreatment HCV viral load in the D+/R+ group (5.98, log 10 IU/mL; IQR, 5.28-6.53) was significantly higher than that in the D+/R- group (3.61, log 10 IU/mL; IQR, 2.57-4.57). After SOF/VEL treatment, SVR12 was achieved in all recipients, with a 100% 1-year patient and graft survival rates. The D+/R+ group had a higher incidence of abnormal liver function (44.4% vs. 7.1%). No significant difference was observed between the two groups in terms of DGF, acute rejection, ALT, serum creatinine, and eGFR within 1-year posttransplant. No severe adverse events associated with either HCV viremia or SOF/VEL were observed. Conclusions: Using a simplified genotyping/subtyping-free SOF/VEL treatment strategy, kidneys from hepatitis C viremic donors for both infected and uninfected recipients presented with safe, excellent, and comparable 1-year outcomes, which can safely expand the donor pool. HCV-positive donor kidneys should be utilized regularly, regardless of the recipient's HCV status.

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.

Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation.

Xenotransplantation is a potential solution for the severe shortage of human donor organs and tissues. The generation of humanized animal models attenuates strong innate immune responses, such as complement-mediated hyperacute rejection. However, acute vascular rejection and cell mediated rejection remain primary barriers to xenotransplantation, which limits its clinical application. In this study, we systematically investigated the immunosuppressive effect of LEF using a rat-to-mouse heart xenotransplantation model. SD rat xenogeneic hearts were transplanted into C57BL/6 mice, and survived 34.5 days after LEF treatment. In contrast, BALB/c allogeneic hearts were transplanted into C57BL/6 mice, and survived 31 days after LEF treatment. Compared to normal saline treatment, LEF treatment decreased xenoreactive T cells and CD19+ B cells in recipient splenocytes. Most importantly, LEF treatment protected myocardial cells by decreasing xenoreactive T and B cell infiltration, inflammatory gene expression, and IgM deposition in grafts. In vivo assays revealed that LEF treatment eliminated xenoreactive and alloreactive T and B lymphocytes by suppressing the activation of the NF-κB signaling pathway. Taken together, these observations complement the evidence supporting the potential use of LEF in xenotransplantation.

Comparison of Outcomes of Kidney Transplantation From Extremely Low Body Weight ≤5kg Versus Larger Body Weight Pediatric Donors.

Background: Kidney transplantation from donors who weigh ≤5 kg is performed at only a few transplant centers owing to the high complication and low graft survival rates associated with this approach. Methods: We retrospectively compared the results of kidney transplantation at our center between January 2015 and December 2019 based on the following pediatric donor criteria: donor body weight ≤5 kg (n=32), 5 kg< donor weight ≤20 kg (n=143), and donor weight >20 kg (n=110). We also perform subgroup analysis of kidney transplantation outcomes from ≤5 kg donors, using conventional (dual separate and classic en-bloc KTx)/novel (en-bloc KTx with outflow tract) surgical methods and allocating to adult/pediatric recipients. Results: The death-censored graft survival rates from extremely low body weight ≤5kg at 1 month, and 1, 3, and 5 years were 90.6%, 80.9%, 77.5%, and 73.9%, respectively, which were significantly lower than that from larger body weight pediatric donors. However, the 3-, and 5-year post-transplantation eGFRs were not significantly different between the pediatric and adult recipient group. The thrombosis (18.8%) and urinary leakage (18.8%) rates were significantly higher in the donor weight ≤5 kg group. Compared with 5 kg< donor weight ≤20 kg group, donor weight ≤5kg group was at elevated risk of graft loss due to thrombosis (OR: 13.4) and acute rejection (OR: 6.7). No significant difference on the outcomes of extremely low body weight donor kidney transplantation was observed between adults and pediatric recipients. Urinary leakage rate is significantly lower in the novel operation (8.7%) than in the conventional operation group (44.4%). Conclusions: Although the outcomes of donor body weight ≤5kg kidney transplantation is inferior to that from donors with large body weight, it can be improved through technical improvement. Donors with body weight ≤5 kg can be considered as an useful source to expand the donor pool.