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Renal ischemia-reperfusion injury (IRI) is an integral process in renal transplantation, which results in compromised graft survival. Macrophages play an important role in both the early inflammatory period and late fibrotic period in response to IRI. In this study, we investigated whether scutellarin (SCU) could protect against renal IRI by regulating macrophage polarization. Mice were given SCU (5-50 mg/kg) by gavage 1 h earlier, followed by a unilateral renal IRI. Renal function and pathological injury were assessed 24 h after reperfusion. The results showed that administration of 50 mg/kg SCU significantly improved renal function and renal pathology in IRI mice. In addition, SCU alleviated IRI-induced apoptosis. Meanwhile, it reduced macrophage infiltration and inhibited pro-inflammatory macrophage polarization. Moreover, in RAW 264.7 cells and primary bone marrow-derived macrophages (BMDMs) exposed to SCU, we found that 150 µM SCU inhibited these cells to polarize to an inflammatory phenotype induced by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). However, SCU has no influence on anti-inflammatory macrophage polarization in vivo and in vitro induced by in interleukin-4 (IL-4). Finally, we explored the effect of SCU on the activation of the mitogen-activated protein kinase (MAPK) pathway both in vivo and in vitro. We found that SCU suppressed the activation of the MAPK pathway, including the extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38. Our results demonstrated that SCU protects the kidney against IRI by inhibiting macrophage infiltration and polarization toward pro-inflammatory phenotype via the MAPK pathway, suggesting that SCU may be therapeutically important in treatment of IRI.
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Apigenina , Glucuronatos , Sistema de Señalización de MAP Quinasas , Macrófagos , Daño por Reperfusión , Animales , Masculino , Ratones , Apigenina/farmacología , Apoptosis/efectos de los fármacos , Glucuronatos/farmacología , Glucuronatos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/prevención & control , Inflamación/patología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos C57BL , Células RAW 264.7 , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismoRESUMEN
BACKGROUND: Delayed graft function (DGF) is an important complication after kidney transplantation surgery. The present study aimed to develop and validate a nomogram for preoperative prediction of DGF on the basis of clinical and histological risk factors. METHODS: The prediction model was constructed in a development cohort comprising 492 kidney transplant recipients from May 2018 to December 2019. Data regarding donor and recipient characteristics, pre-transplantation biopsy results, and machine perfusion parameters were collected, and univariate analysis was performed. The least absolute shrinkage and selection operator regression model was used for variable selection. The prediction model was developed by multivariate logistic regression analysis and presented as a nomogram. An external validation cohort comprising 105 transplantation cases from January 2020 to April 2020 was included in the analysis. RESULTS: 266 donors were included in the development cohort, 458 kidneys (93.1%) were preserved by hypothermic machine perfusion (HMP), 96 (19.51%) of 492 recipients developed DGF. Twenty-eight variables measured before transplantation surgery were included in the LASSO regression model. The nomogram consisted of 12 variables from donor characteristics, pre-transplantation biopsy results and machine perfusion parameters. Internal and external validation showed good discrimination and calibration of the nomogram, with Area Under Curve (AUC) 0.83 (95%CI, 0.78-0.88) and 0.87 (95%CI, 0.80-0.94). Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: A DGF predicting nomogram was developed that incorporated donor characteristics, pre-transplantation biopsy results, and machine perfusion parameters. This nomogram can be conveniently used for preoperative individualized prediction of DGF in kidney transplant recipients.
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Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Funcionamiento Retardado del Injerto , Nomogramas , Supervivencia de Injerto , Riñón , Donantes de Tejidos , Biopsia/efectos adversos , Factores de RiesgoRESUMEN
Background and aims: Obesity and insulin resistance are well-known important risk factors for hypertension. This study aimed to investigate the mediating effect of the triglyceride-glucose index (TyG) in the association between Chinese visceral obesity index (CVAI) and hypertension among Chinese middle-aged and older adults. Methods: A total of 10,322 participants aged 45 years and older from CHARLS (2011-2018) were included. Baseline data were collected in 2011 and hypertension incidence data were gathered during follow-up in 2013, 2015 and 2018. Multivariate logistic regression models were constructed to investigate the association of CVAI and TyG with the incidence of hypertension. Additionally, mediation analyses were conducted to evaluate the mediating role of the TyG index in the relationship between CVAI and hypertension. Subgroup analysis was also performed. Results: A total of 2,802 participants developed hypertension during the follow-up period. CVAI and TyG index were independently and significantly associated with hypertension incidence. Increasing quartiles of CVAI and TyG index were associated with high hypertension incidence in middle-aged and older adults. The TyG index was identified as a mediator in the relationship between CVAI and hypertension incidence, with a mediation effect (95% confidence interval) was 12.38% (6.75, 31.81%). Conclusion: Our study found that CVAI and TyG were independently associated with hypertension incidence. TyG played a partial mediating effect in the positive association between CVAI and hypertension incidence.
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Hipertensión , Resistencia a la Insulina , Persona de Mediana Edad , Humanos , Anciano , Incidencia , Estudios Longitudinales , Jubilación , Obesidad/epidemiología , China/epidemiología , Glucosa , Hipertensión/epidemiología , TriglicéridosRESUMEN
INTRODUCTION: Both innate and adaptive immune system undergo evolution from low to high vertebrates. Due to the limitation of conventional approaches in identifying broader spectrum of immune cells and molecules from various vertebrates, it remains unclear how immune molecules evolve among vertebrates. OBJECTIVES: Here, we utilized carry out comparative transcriptome analysis in various immune cells across seven vertebrate species. METHODS: Single-cell RNA sequencing (scRNA-seq). RESULTS: We uncovered both conserved and species-specific profiling of gene expression in innate and adaptive immunity. Macrophages exhibited highly-diversified genes and developed sophisticated molecular signaling networks along with evolution, indicating effective and versatile functions in higher species. In contrast, B cells conservatively evolved with less differentially-expressed genes in analyzed species. Interestingly, T cells represented a dominant immune cell populations in all species and unique T cell populations were identified in zebrafish and pig. We also revealed compensatory TCR cascade components utilized by different species. Inter-species comparison of core gene programs demonstrated mouse species has the highest similarity in immune transcriptomes to human. CONCLUSIONS: Therefore, our comparative study reveals gene transcription characteristics across multiple vertebrate species during the evolution of immune system, providing insights for species-specific immunity as well as the translation of animal studies to human physiology and disease.
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Inmunidad Adaptativa , Inmunidad Innata , Transcriptoma , Animales , Humanos , Ratones , Inmunidad Adaptativa/genética , Macrófagos , Porcinos , Pez Cebra/genética , Inmunidad Innata/genéticaRESUMEN
Ischemia/reperfusion (I/R) injury causes excessive oxidative events and initiates destructive inflammatory responses, and it is an important promoter to the pathology of various pathema states. Ferroptosis is an iron-dependent type of nonapoptotic cell death accompanied by the accumulation of membrane lipid peroxide and consumption of polyunsaturated fatty acid, and it plays a key role in I/R injury diseases. Moreover, the excessive production of inflammatory cytokines contributes to the development of acute kidney injury. Here, we reported neutrophil membrane-coated copper-based nanoparticles (N-Cu5.4O@DFO NPs) for I/R kidney injury treatment. The highly biocompatible and stable N-Cu5.4O@DFO NPs showed excellent antioxidant and iron ion scavenging abilities in vitro. Our finding showed that the N-Cu5.4O@DFO NPs strategy could significantly accumulate in the inflammatory kidney, reduce oxidative damage events and inflammatory response, and finally achieve synergistic therapy against renal I/R injury. This work promotes the development of nanoantioxidant agents with multiple antioxidant properties for the therapy of other I/R injury diseases.
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Lesión Renal Aguda , Daño por Reperfusión , Humanos , Antioxidantes/farmacología , Cobre , Neutrófilos , Lesión Renal Aguda/tratamiento farmacológico , Riñón , Daño por Reperfusión/tratamiento farmacológico , Isquemia , Reperfusión , HierroRESUMEN
Renal fibrosis is a pathological feature of chronic kidney disease and its progression correlates with kidney function impairment. Since there are currently no specific therapies for renal fibrosis, we explored whether inducing local production of the anti-fibrotic molecule relaxin-2 in kidney cells has potential as a strategy for suppressing the development of renal fibrosis. Our study examined whether delivery of relaxin-2 mRNA to kidney cells in vitro and in vivo could inhibit mechanisms leading to renal fibrosis. Transfecting relaxin-2 mRNA into cultured kidney cells inhibited fibrotic responses to TGF-ß1 in an autocrine or paracrine manner by reducing fibrotic gene expression in kidney tubules, and reducing proliferation in kidney fibroblasts and mesangial cells. Similarly, cubosomes assisted delivery of relaxin-2 mRNA to mouse kidneys alleviated the fibrosis and inflammation associated with renal injury following unilateral ureter obstruction (UUO). Therefore, relaxin-2 mRNA exhibits potential as a novel therapy for inhibiting fibrosis and inflammation in chronic kidney disease.
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BACKGROUND: To explore the risk factors of ureteral stricture in transplant kidney and the clinical effects of different treatment methods. METHODS: The 62 patients with transplant kidney ureteral stenosis as the experimental group, and another group of recipients from the same donor as the control group (n = 59 cases). The risk factors for ureteral stricture and the survival rate of transplant kidney were analyzed and compared. The 62 patients were divided into open operation, luminal operation, and magnetic compression anastomosis (MCA) operation group. The effect of the operation and the survival rate of transplant kidney among the three groups were compared. RESULTS: In our study, we found that the above differences were statistically significant in clinical data such as gender, multiple donor renal arteries, history of infection, and delayed graft function (DGF) between the two groups (P < 0.05). Urinary tract infection and DGF history were the independent risk factors for the development of ureteral stricture. The open operation had the best treatment effect and the survival rate of the transplant kidney, followed by the MCA, the stricture recurrence rate in the luminal operation was the highest. CONCLUSION: The ureteral stricture has a negative correlation with the long-term survival rate of the transplant kidney, the curative rate and long-term effect of open surgery are the best, stricture recurrence rate of luminal surgery is high, and it may require multiple operations in the future, the MCA is a new breakthrough and innovation in the treatment of ureteral stricture.
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Trasplante de Riñón , Obstrucción Ureteral , Humanos , Constricción Patológica/etiología , Constricción Patológica/cirugía , Trasplante de Riñón/efectos adversos , Supervivencia de Injerto , Riñón , Obstrucción Ureteral/etiología , Obstrucción Ureteral/cirugía , Estudios RetrospectivosRESUMEN
BACKGROUND: The use of immature dendritic cells (imDCs) to induce donor-specific immunotolerance following in vivo stimulation is limited by their low rate of induction and their tendency to undergo maturation. We derived imDCs from bone marrow hematopoietic stem cells (HSCs-imDCs). We then tested the ability of naringenin (Nar) to impede the maturation of HSCs-imDCs for inducing transplantation immune tolerance. METHODS: HSCs derived from bone marrow were collected and induced to differentiate into imDCs by treating with Nar (Nar-HSCs-imDCs). Flow cytometry was used to evaluate DC surface markers, apoptosis, and endocytic ability. The ability of DCs to influence the in vitro proliferation of T cells and of regulatory T cells (Tregs) was analyzed by mixed lymphocyte reaction assays. Enzyme-linked immunoassays were used to quantify cytokine levels in supernatants from co-cultured DCs and Tregs, as well as in the serum of experimental animals. The level of immunotolerance induced by Nar-HSCs-imDCs was evaluated by skin grafting in recipient Balb/c mice, while the Kaplan-Meier method was used to statistically evaluate graft survival. RESULTS: Compared with HSC-imDCs, Nar-HSCs-imDCs showed higher expression of cluster of differentiation 11c (CD11c), but lower expression levels of CD80, CD86, and major histocompatibility complex class II. Nar-HSCs-imDCs also showed stronger inhibition of T cells and higher Treg cell proliferation. Interleukin 2 (IL-2) and interferon gamma levels were downregulated in Nar-HSCs-imDCs, whereas IL-4, IL-10, and transforming growth factor beta levels were upregulated. The rate of apoptosis and endocytic capacity of Nar-HSCs-DCs increased significantly after treatment with lipopolysaccharide. HSCs-imDCs or Nar-HSCs-imDCs were injected into Balb/c mice via the tail vein 7 days before skin grafting. Significantly reduced donor-specific CD4+ T cells and induced proliferation of CD4+CD25+FoxP3+ Treg cells were observed in the spleen of mice from the Nar-HSCs-imDCs group, especially at a dose of 106 Nar-HSCs-imDCs. The latter group also showed significantly prolonged survival of skin grafts. CONCLUSIONS: Nar-HSCs-imDCs markedly improved the acceptance of organ allografts, offering a potentially new strategy for inducing immune tolerance in transplantation.
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Médula Ósea , Células Madre Hematopoyéticas , Ratones , Animales , Células de la Médula Ósea , Ratones Endogámicos BALB C , Aloinjertos , Células Dendríticas/metabolismo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Donor-specific human leukocyte antigen (HLA) class II antibodies (HLA-II Abs) combined with allogeneic endothelial cells (ECs) mediate high-risk rejection in kidney transplant patients. Macrophage accumulation is a significant histological feature of antibody-mediated rejection (AMR) in kidney transplant patients. Here, we further investigated the effect of HLA-II Abs on macrophage phenotypes to provide theoretical basis for clinical treatment of AMR. METHODS: We prepared an experimental model containing HLA-II Ab-stimulated microvascular ECs and peripheral blood mononuclear cells (PBMCs) co-culture and explored the potential relationship of HLA-II Ab, ECs activation, and macrophage differentiation. Immune phenotype of macrophage subsets was analyzed and quantified by flow cytometry. HLA-II Ab activation of ECs induces M2 macrophage differentiation signal pathways which were investigated by qPCR and western blotting. RESULTS: The stimulation of ECs by F(ab')2 fragment of HLA-II Abs led to phosphorylation of PI3K, Akt, and mTOR, which mediated IL-10, ICAM-1, VCAM-1 secretion. The enhanced ICAM-1 and IL-10 promoted the migration of PBMCs and their differentiation into CD68+ and CD163+ (M2-type) macrophages, respectively, but not CD86+ macrophages. CONCLUSION: These findings revealed the PI3K/Akt/mTOR signal pathways activated by HLA-II Abs in ECs and the immune regulation ability of HLA-II Abs to induce PBMC differentiation.
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Células Endoteliales , Leucocitos Mononucleares , Humanos , Células Endoteliales/metabolismo , Interleucina-10/metabolismo , Interleucina-10/farmacología , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Antígenos HLA , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/farmacología , Macrófagos , Diferenciación Celular , Rechazo de InjertoRESUMEN
Vascular complications after renal transplantation are one of the serious surgical complications, which can affect the transplantation outcome and even endanger life if not treated properly. We performed a retrospective analysis of the 2,304 renal transplantations procedures completed between the period of Jan., 2015 and Jan., 2022, which consisted of 1,658 male patients and 646 female patients. Among the above cases, there were 54 cases of vascular complications after renal transplantation, the incidence of vascular complications in our study was 2.34% (54/2,304), the most common vascular complication was transplanted renal artery stenosis (TRAS, n = 36), followed by external iliac artery dissection (n = 5), renal artery rupture (n = 4), renal vein thrombosis (n = 3), renal artery thrombosis (n = 2), renal artery dissection (n = 1), renal artery pseudoaneurysm (n = 1), and internal iliac artery pseudoaneurysm (n = 1), and renal artery kinking (n = 1). 40 patients were treated by percutaneous transluminal angioplasty (PTA), including 3 balloon catheter dilatation and 37 endovascular stentings, and 14 underwent open surgery. Eventually, 9 patients had graft nephrectomy, resulting in an overall treatment rate of 81.5%. Most vascular complications can be treated satisfactorily with PTA. However, the overall treatment of renal artery rupture, thrombosis, renal artery kinking, and other complications is poor, and the rate of transplanted renal loss is high.
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BACKGROUND: Immature dendritic cells (imDCs) play an important role in the induction of donor-specific transplant immunotolerance. However, these cells have limitations, such as rapid maturation and a short lifespan in vivo. In previous studies, induced pluripotent stem cells (iPSCs) differentiated into imDCs, and sinomenine (SN) was used to inhibit the maturation of imDCs. AIM: To study the capacity of SN to maintain iPSC-derived imDCs (SN-iPSCs-imDCs) in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance. METHODS: In this study, mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN (iPSCs-imDCs and SN-iPSCs-imDCs). The imDC-related surface markers, endocytotic capacity of fluorescein isothiocyanate-Dextran and apoptosis were analyzed by flow cytometry. The effects of iPSCs-imDCs and SN-iPSCs-imDCs on T-cell stimulatory function, and regulatory T (Treg) cell proliferative function in vitro were analyzed by mixed lymphocyte reaction. Cytokine expression was detected by ELISA. The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting. The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice. Statistical evaluation of graft survival was performed using Kaplan-Meier curves. RESULTS: Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained, and their biological characteristics and ability to induce immunotolerance were compared. SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs. Reduced major histocompatibility complex II expression, worse T-cell stimulatory function, higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs (P < 0.05). The levels of interleukin (IL)-2, IL-12, interferon-γ in SN-iPSCs-imDCs were lower than those in iPSCs-imDCs, whereas IL-10 and transforming growth factor-ß levels were higher (P < 0.05). The apoptosis rate of these cells was significantly higher (P < 0.05), and the expression levels of cleaved caspase3, Bax and cleaved poly(ADP-ribose) polymerase were higher after treatment with lipopolysaccharides, but Bcl-2 was reduced. In Balb/c mice recipients immunized with iPSCs-imDCs or SN-iPSCs-imDCs 7 d before skin grafting, the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+ T-cell proliferation (P < 0.05) and a higher capacity to induce CD4+CD25+FoxP3+ Treg cell proliferation in the spleen (P < 0.05). The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern. CONCLUSION: This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.
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BACKGROUND: Recently, early graft loss has become very rare in living-related kidney transplantation (LKT) as a result of decreased risk of hyperacute rejection and improvements in immunosuppressive regimens. Post-transplant acute thrombotic microangiopathy (TMA) is a rare, multi-factorial disease that often occurs shortly after kidney transplantation and is usually resistant to treatment with dismal renal outcomes. The complement genetic variants may accelerate the development of TMA. However, the complement genetic test was seldom performed in unknown native kidney disease recipients scheduled for LKT. CASE PRESENTATION: We reported three cases of unknown native kidney diseases who had fulminant TMA in the allograft shortly after LKT. Both the donors and the recipients were noted to carry complement genetic variants, which were identified by genetic testing after transplantation. However, all recipients were refractory to treatment and had allograft loss within 3 months after LKT. CONCLUSION: This case series highlights the suggestion to screen complement gene variants in both the donors and the recipients with unknown native kidney diseases scheduled for LKT.
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Trasplante de Riñón , Microangiopatías Trombóticas , Humanos , Inmunosupresores , Trasplante de Riñón/efectos adversos , Microangiopatías Trombóticas/genética , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Objective: We aimed to identify feature immune-related genes that correlated with graft rejection and to develop a prognostic model based on immune-related genes in kidney transplantation. Methods: Gene expression profiles were obtained from the GEO database. The GSE36059 dataset was used as a discovery cohort. Then, differential expression analysis and a machine learning method were performed to select feature immune-related genes. After that, univariate and multivariate Cox regression analyses were used to identify prognosis-related genes. A novel Riskscore model was built based on the results of multivariate regression. The levels of these feature genes were also confirmed in an independent single-cell dataset and other GEO datasets. Results: 15 immune-related genes were expressed differently between non-rejection and rejection kidney allografts. Those differentially expressed immune-related genes (DE-IRGs) were mainly associated with immune-related biological processes and pathways. Subsequently, a 5-immune-gene signature was constructed and showed favorable predictive results in the GSE21374 dataset. Recipients were divided into the high-risk and low-risk groups according to the median value of RiskScore. The GO and KEGG analysis indicated that the differentially expressed genes (DEGs) between high-risk and low-risk groups were mainly involved in inflammatory pathways, chemokine-related pathways, and rejection-related pathways. Immune infiltration analysis demonstrated that RiskScore was potentially related to immune infiltration. Kaplan-Meier survival analysis suggested that recipients in the high-risk group had poor graft survival. AUC values of 1- and 3-year graft survival were 0.804 and 0.793, respectively. Conclusion: Our data suggest that this immune-related prognostic model had good sensitivity and specificity in predicting the 1- and 3-year kidney graft survival and might act as a useful tool for predicting kidney graft loss.
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Regulación Neoplásica de la Expresión Génica , Trasplante de Riñón , Biomarcadores de Tumor/genética , Humanos , Riñón , Trasplante de Riñón/efectos adversos , PronósticoRESUMEN
The polydopamine nanoparticles (PDA NPs) as a self-polymerized form of dopamine have occurred with growing interest in biomedical applications in late years. Its natural-inspired feature as a conjugated polymer endows excellent inactivating capability for radical species to PDA-based nanoparticles that provide a theoretical foundation for applications in preventing inflammation-mediated acute kidney injury (AKI) from ROS. Here, we develop a polydopamine wrapped manganese ferrite nanoparticles (PDA@MF NPs) strategy for acute kidney injury therapy by synergistically scavenging ROS and producing O2, which further regulates macrophages amounts by decreasing M1-type and increasing M2-type. Water-soluble PDA@MF NPs were prepared in one step after the oxidative and self-polymerized process of the dopamine monomer. Here, the biodegradable PDA NPs were applied to scavenge ROS. MF NPs undertake continuous O2 production in an H2O2-based hypoxic environment. Based on this system, we aim to relieve the hypoxia, pathological symptoms, and inflammation via scavenging ROS during the O2 production process, and effective polarization to M2-type macrophages. PDA@MF NPs in this study were verified could significantly attenuate oxidative stress in vivo, reduce inflammatory events in renal, and improve renal function, which might be a potential treatment to inhibit oxidative damages and inflammatory events in renal AKI disease.
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Lesión Renal Aguda/genética , Indoles/metabolismo , Inflamación/genética , Nanopartículas/metabolismo , Estrés Oxidativo/genética , Polímeros/metabolismo , Lesión Renal Aguda/patología , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
BACKGROUND: Delayed graft function (DGF) is the main cause of renal function failure after kidney transplantation. This study aims at investigating the value of hypothermic machine perfusion (HMP) parameters combined with perfusate biomarkers on predicting DGF and the time of renal function recovery after deceased donor (DD) kidney transplantation. METHODS: HMP parameters, perfusate biomarkers and baseline characteristics of 113 DD kidney transplantations from January 1, 2019 to August 31, 2019 in the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively analyzed using univariate and multivariate logistic regression analysis. RESULTS: In this study, the DGF incidence was 17.7% (20/113); The multivariate logistic regression results showed that terminal resistance (OR: 1.879, 95% CI 1.145-3.56) and glutathione S-transferase (GST)(ORâ=â1.62, 95% CI 1.23-2.46) were risk factors for DGF; The Cox model analysis indicated that terminal resistance was an independent hazard factor for renal function recovery time (HRâ=â0.823, 95% CI 0.735-0.981). The model combining terminal resistance and GST (AUCâ=â0.888, 95% CI: 0.842-0.933) significantly improved the DGF predictability compared with the use of terminal resistance (AUCâ=â0.756, 95% CI 0.693-0.818) or GST alone (AUCâ=â0.729, 95% CI 0.591-0.806). CONCLUSION: According to the factors analyzed in this study, the combination of HMP parameters and perfusate biomarkers displays a potent DGF predictive value.
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Trasplante de Riñón , Biomarcadores , Funcionamiento Retardado del Injerto , Supervivencia de Injerto , Humanos , Riñón/fisiología , Trasplante de Riñón/efectos adversos , Preservación de Órganos , Perfusión , Estudios Retrospectivos , Donantes de TejidosRESUMEN
INTRODUCTION: Acute renal rejection usually fails to be diagnosed before the increase in the serum creatinine levels, and the resultant damage to the renal tissues occur in varying degrees. We hypothesized that the combined detection of human leucocyte antigen-G (HLA-G) 14-bp insertion/deletion genotypes and kidney injury molecule-1 (KIM-1) and osteopontin (OPN) levels in serum might facilitate the prediction of acute renal allograft rejections in kidney transplant recipients. METHODS: HLA-G 14-bp insertion/deletion genotypes and the serum KIM-1 and OPN levels of 77 kidney transplant recipients were determined and compared before operation and on days 1, 4, and 7 after the operation (32 in acute rejection [AR] group and 45 in stable allograft function [STA] group). These 3 indicators were combined to establish a model for the early prediction of AR. RESULTS: The KIM-1 levels in the serum of patients were significantly higher in the AR group than in the STA group. The area under the receiver operator characteristics (ROC) curve (AUC) of KIM-1 for the prediction of rejection was maximized on the1st day after operation, with a sensitivity of 84.4% and a specificity of 86.7%. The OPN levels in the serum of patients were significantly higher in the AR group than in the STA group only before operation and on the 7th day after operation. The AUC of OPN for the prediction of rejection was maximized on 7th day after operation, with a sensitivity of 68.8% and a specificity of 88.9%. The HLA-G + 14-bp allele frequency was also significantly higher in the AR group than in the STA group. The results of these three indicators were converted into a qualitative method. If any two of the three indicators show as positive, it was diagnosed as acute rejection, and it has the highest ability to predict acute rejection with a sensitivity and specificity of 84.38% and 91.11%, respectively. CONCLUSIONS: The HLA-G 14-bp insertion/deletion genotype and KIM-1 and OPN levels in the patients' serum were significantly different between the AR and STA groups. The power of predicting acute renal allograft rejection could be improved by combined these three biomarkers.
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Antígenos HLA-G , Trasplante de Riñón , Aloinjertos , Genotipo , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/genética , Antígenos HLA-G/genética , Humanos , Riñón , Osteopontina/genéticaRESUMEN
Tubular epithelial cells (TECs) represent the primary site of renal ischemia/reperfusion injury (RIRI). However, whether the damage of TECs could drive the initiation of inflammation was unclear. Here we investigated the role of the TECs and macrophages during RIRI. Increased expression of inflammation response and activated M1 macrophage were determined in the mice model of RIRI. Moreover, we demonstrated global miRNA expression profiling of renal exosomes, and miR-374b-5p was most upregulated in these exosomes in vivo. Inhibition of miR-374b-5p in the mice upon RIR operation would alleviate the kidney injury via decreasing the production of proinflammatory cytokines and suppressing the macrophage activation. Similar results were also identified in the hypoxia-induced cell model where exosomal miR-374b-5p was dramatically upregulated. Uptake of exosomes derived from the hypoxic TECs by macrophages would trigger M1 polarization via transferring miR-374b-5p. Besides, we confirmed that miR-374b-5p could directly bind to Socs1 using a dual-luciferase reporter assay. Notably, when we injected the miR-374b-5p-enriched exosomes into mice, a high-level inflammatory response and M1 macrophage activation were performed. Our studies demonstrated that exosomal miR-374b-5p played an essential role in the communication between injured TECs and macrophages, resulting in the M1 macrophage activation during RIRI. The blockage of the release of such exosomes may serve as a new therapeutic strategy for RIRI.