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.

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.

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.

Does Gut Microbiome have an Effect on Wilson's Disease Phenotype?

Wilson's Disease (WD), a genetic metabolic disorder, is characterized by the accumulation of copper in the liver and brain, resulting in a range of clinical symptoms. The clinical manifestations of WD vary widely. The present study introduces the distinctive features of intestinal microbiota in Chinese patients with WD, presenting diverse clinical symptoms. It shows a reduction in the diversity of gut microbiota among patients with hepatic symptoms associated with WD, particularly in the genus responsible for SCFAs production. It demonstrates an increase in the Haemophilus microorganism. This study may offer novel insights for further investigation into the mechanisms underlying the occurrence, development, and treatment of WD subtypes.

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).

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.

The transcription factor IRF4 determines the anti-tumor immunity of CD8+ T cells.

Understanding the factors that regulate T cell infiltration and functional states in solid tumors is crucial for advancing cancer immunotherapies. Here, we discovered that the expression of interferon regulatory factor 4 (IRF4) was a critical T cell intrinsic requirement for effective anti-tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced T cell tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic tumors and allowing the growth of allogeneic tumors. Additionally, engineered overexpression of IRF4 in anti-tumor CD8+ T cells that were adoptively transferred significantly promoted their tumor infiltration and transition from a naive/memory-like cell state into effector T cell states. As a result, IRF4-engineered anti-tumor T cells exhibited significantly improved anti-tumor efficacy, and inhibited tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of T cell infiltration and function in tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach.

Corrigendum to "The 100 top-cited articles in the field of Wilson's disease from 1990 to 2022: A bibliometric study" [Heliyon 9(7) (July 2023) e17785].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e17785.].

The 100 top-cited articles in the field of Wilson's disease from 1990 to 2022: A bibliometric study.

Objectives: To characterize the 100 most-cited articles in the field of Wilson's Disease (WD) to provide a general overview and reveal the historical developments classical studies, and new findings. Design: WD-related articles were searched on the Web of Science database. The 100 most-cited articles were retrieved and their descriptive statistics were analyzed. Data extraction and synthesis: The 100 most-cited articles in the field of WD were selected and several parameters, including citation count, citation density, first author, corresponding author, journal, country, institution, and keywords were extracted to assess the overall quality and impact of the articles. Results: Most of the selected 100 articles were published in the 1990s and 2000s, with the highest number of articles published in 2005. Citations per paper ranged from 100 to 1,631, with a mean number of citations of 199.03. The top 100 articles were published in 38 journals, and the majority were published in the Journal of Biological Chemistry. The most prominent research themes were clinical presentations, clinical trials, copper transport mechanisms, and dysregulation of copper metabolism. Prof. Svetlana Lutsenko, Prof. Peter Ferenci, Prof. George J. Brewer, and Prof. Diane W. Cox were among the most influential researchers in this field, while Euro-American countries were the most dominant in terms of research output. Keywords network analysis identified "Transporting ATPase," "ATP7B," and "Menkes disease" as the most influential keywords. Moreover, disease management, WD clinical phenotype, ATP7B function, and copper metabolism are potential hotspots in future WD research. Conclusions: This study reveals the most influential articles in the field of WD research. In addition, the major research themes and technological innovations in the field of WD worldwide are presented.

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.

Excellent clinical outcomes of renal transplant from pediatric deceased donors with acute kidney injury.

BACKGROUND: The use of kidneys from deceased donors with acute kidney injury (AKI) to expand the donor pool is an ongoing trend. Prior research on the utilization of AKI donor kidneys, especially from pediatric AKI donors, was limited and has been subject to small sample sizes. In this study, we aimed to evaluate the safety and effectiveness of early post-transplantation outcomes in pediatric deceased donors with AKI. METHODS: This retrospective study compared the clinical results (including delayed graft function [DGF], acute rejection, patient and death-censored graft survival rates and renal function post-transplant) of kidney transplantation from deceased donors who were categorized as pediatric donors and adult donors with or without AKI, as defined by the Kidney Disease: Improving Global Outcomes (KIDGO) criteria, at our center between January 2018 and December 2020. RESULTS: Of the 740 patients, 154 received kidneys from pediatric donors (with AKI group [n = 41]; without AKI group [n = 113]), and 586 received kidneys from adult donors (with AKI group [n = 218]; without AKI group [n = 368]). The baseline characteristics were similar in both cohorts. No significant difference was observed in 1-year patient survival, death-censored graft survival, or acute rejection between the AKI and non-AKI groups in both the pediatric and adult cohorts. However, compared with those transplanted with adult AKI kidneys, those transplanted with pediatric AKI kidneys showed a superior recovery of allograft function. In pediatric cohorts, no significant difference was found in serum creatinine/estimated glomerular filtration rate (SCr/eGFR) between the AKI and non-AKI groups, even in the first week post-transplant. In contrast, the post-transplant SCr/eGFR level of the AKI group recipients in adult cohorts did not recover to a level statistically similar to that of non-AKI recipients, even at 6-months post-transplant. Nonetheless, AKI kidney recipients were at an increased risk of DGF in both pediatric (34.1% vs. 16.8%) and adult (38.5% vs. 17.4%) cohorts. CONCLUSIONS: Kidney transplantation from deceased donors with AKI has short-term clinical outcomes comparable to those of non-AKI kidney transplantation. Pediatric AKI kidneys have a superior recovery of allograft function. The transplant community should utilize this donor pool to minimize waiting-list-related mortalities.

Enhancing pressure consistency and transferability of structure-based coarse-graining.

Coarse-graining, which models molecules with coarse-grained (CG) beads, allows molecular dynamics simulations to be applied to systems with large length and time scales while preserving the essential molecular structure. However, CG models generally have insufficient representability and transferability. A commonly used method to resolve this problem is multi-state iterative Boltzmann inversion (MS-IBI) with pressure correction, which matches both the structural properties and pressures at different thermodynamic states between CG and all-atom (AA) simulations. Nevertheless, this method is usually effective only in a narrow pressure range. In this paper, we propose a modified CG scheme to overcome this limitation. We find that the fundamental reason for this limitation is that CG beads at close distances are ellipsoids rather than isotropically compressed spheres, as described in conventional CG models. Hence, we propose a method to compensate for such differences by slightly modifying the radial distribution functions (RDFs) derived from AA simulations and using the modified RDFs as references for pressure-corrected MS-IBI. We also propose a method to determine the initial non-bonded potential using both the target RDF and pressure. Using n-dodecane as a case study, we demonstrate that the CG model developed using our scheme reproduces the RDFs and pressures over a wide range of pressure states, including three reference low-pressure states and two test high-pressure states. The proposed scheme allows for accurate CG simulations of systems in which pressure or density varies with time and/or position.

Short-term outcome of kidney transplantation from deceased donors with nephrolithiasis. / 尸体供肾结石对肾移植短期疗效的影响（英文）.

OBJECTIVES: Shortage of kidney allografts is a major barrier to end-stage renal disease patients receiving kidney transplantation, and it is necessary to enlarge the donor pool and find better ways of using available allografts. The global incidence of nephrolithiasis is increasing, nephrolithiasis affects approximately 10% of adults worldwide, and it also affects the kidney donors. However, there is little information about the use of cadaveric kidney allografts with nephrolithiasis. This study aims to evaluate the safety and outcome of kidney transplantation with allografts from the deceased donors with nephrolithiasis. METHODS: A total of 520 deceased donors who was at least 10 years old, and 945 adult recipients with single kidney transplantation at the Department of Kidney Transplantation, the Second Xiangya Hospital from 2016 to 2020 were included in this study. The donors were divided into 2 groups according to nephrolithiasis diagnoses: The donors with nephrolithiasis (D + ) and the donors without nephrolithiasis (D - ). The recipients were assigned into 3 groups according to their donors and the allografts they received: The allografts from donors without nephrolithiasis (D - K - ), the allografts without nephrolithiasis from donors with nephrolithiasis (D + K - ), and the allografts with nephrolithiasis (D + K + ). The demographic and clinical data of enrolled subjects were retrospectively analyzed. The allograft discard ratio between different donors were analyzed. The one-year survival of allografts and recipients, as well as the allograft function and the complications of kidney transplantation were compared. RESULTS: Fifty out of 520 donors had nephrolithiasis, and the nephrolithiasis incidence was 9.6%. We recovered 1 040 kidneys, and total discard rate was 4.4% (46/1 040). The D + group had a rate of 7% discard. The donors with kidney discard accounted for 12% in the D + group, and this was higher than that of donors in the D - group (5.1%, P <0.05). The total incidence of delayed graft function (DGF) was 7.5%, and there were no significant differences in the incidence of DGF in recipients among the D - K - , D + K - , and D + K + group (7.5% vs 6.5% vs 8.2%, P> 0.05). During the one-year follow-up, 8 allografts lost function and 19 recipients died with a functional allograft. Recipients in the D - K - , D + K - ,and D + K + groups also had no significant difference between a one-year allograft and patient survival rate ( P >0.05). However, recipients in the D + K + group had a higher level of serum creatinine [(139.2±62.46) µmol/L vs (117.19±51.22) µmol/L, P <0.05] and lower estimated glomerular filtration rate [eGFR; (56.67±23.31) mL/(min·1.73 m -2 ) vs (66.86±21.90) mL/(min·1.73 m -2 ), P <0.05] compared with recipients in the D - K - group at 12 months after transplantation. During the first year after transplantation, 4 recipients developed urolithiasis, and recipients who received allografts from the D + group donors had a higher incidence of urolithiasis than those who received allografts from the D - group donors (2.2% vs 0.2%, P <0.05). There were no significant differences in the incidence of urinary tract infections and ureteral strictures at 1 year between recipients of D + and D - donors (both P >0.05). CONCLUSIONS: The cadaveric kidney allografts with nephrolithiasis could be safely used for transplantation, and the short-term outcome is acceptable. However, nephrolithiasis in donors may increase the rate of kidney discard, disturb the short-term function of allografts, and increase the risk of urolithiasis in recipients. Further research with a long-term study is needed to verify the long-term outcome of kidney transplantation using cadaveric kidney allografts with nephrolithiasis.

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.

Adsorption Behavior of TEMPO-Based Organic Friction Modifiers during Sliding between Iron Oxide Surfaces: A Molecular Dynamics Study.

Organic friction modifiers (OFMs) added to lubricating oils to reduce friction and wear are crucial for reducing energy loss and CO2 emissions. In our previous studies, we have developed N-(2,2,6,6-tetramethyl-1-oxyl-4-piperidinyl)dodecaneamide, referred to as C12TEMPO, as a new type of OFM and experimentally demonstrated its superior performance to conventional OFMs of stearic acid and glycerol monooleate. However, the behavior of C12TEMPO adsorbing onto solid surfaces from base oil during sliding, which largely dictates the lubrication performance, is yet to be elucidated. Here, we performed molecular dynamics simulations for confined shear of a C12TEMPO solution in poly-α-olefin between hematite surfaces. Unlike conventional OFMs, which typically have one functional group or multiple functional groups of the same type, C12TEMPO features two functional groups of different types: one amide and one terminal free oxygen radical. The results showed that adsorbed boundary films with a double-layer structure form stably during sliding, owing to double- or single-site surface adsorption and interlayer hydrogen bonding via the two functional groups. Additionally, some molecules in each of the first and second layers also form intralayer hydrogen bonding. Such multitype adsorption is unique and favorable for enhancing the strength of boundary films to withstand heavily loaded and prolonged sliding. The velocity distribution indicates that the first and second layers are solid- and liquid-like, respectively. The second layer could act as a buffer for the first layer, which is the last barrier to prevent solid-solid contact, against shear. We also found that the second layer can act as a reservoir to rapidly repair the once depleted region in the first layer because of the interlayer hydrogen bonding. The combination of the high strength and self-repair ability of the C12TEMPO boundary films can rationally explain the experimentally observed properties of high load-carrying capacity, excellent antiwear effect, and high stability of friction over time.

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.

The Role of Regulatory B cells in Kidney Diseases.

B cells, commonly regarded as proinflammatory antibody-producing cells, are detrimental to individuals with autoimmune diseases. However, in recent years, several studies have shown that regulatory B (Breg) cells, an immunosuppressive subset of B cells, may exert protective effects against autoimmune diseases by secretion of inhibitory cytokines such as IL-10. In practice, Breg cells are identified by their production of immune-regulatory cytokines, such as IL-10, TGF-ß, and IL-35, however, no specific marker or Breg cell-specific transcription factor has been identified. Multiple phenotypes of Breg cells have been found, whose functions vary according to their phenotype. This review summarizes the discovery, phenotypes, development, and function of Breg cells and highlights their potential therapeutic value in kidney diseases.

Solid Organ Transplantation During the COVID-19 Pandemic.

Since December 2019, the ongoing coronavirus disease 2019 (COVID-19) pandemic has significantly affected solid organ transplantation (SOT) worldwide and has become a threat to the lives of SOT recipients. Here, we have reviewed, condensed, and organized the available information on COVID-19 to provide recommendations to transplant healthcare workers. Our review of reported cases shows that the symptoms of SOT patients with COVID-19 are similar to those of the normal population, but their severity and outcomes are worse. Thus far, there is no evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly causes permanent damage to kidney, liver, or heart allografts.