RESUMO
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).
Assuntos
Transplante de Coração , Ratos , Camundongos , Animais , Humanos , Transplante de Coração/métodos , Virilha , Ratos Sprague-Dawley , Transplante Heterólogo , Doadores de Tecidos , Linfonodos , Camundongos Endogâmicos C57BL , Rejeição de EnxertoRESUMO
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.
Assuntos
Transplante de Rim , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Animais , Camundongos , Transplante de Rim/métodos , Transplante de Rim/efeitos adversos , Masculino , Modelos AnimaisRESUMO
OBJECTIVES: Rejection remains the most important factor limiting the survival of transplanted kidneys. Although a pathological biopsy of the transplanted kidney is the gold standard for diagnosing rejection, its limitations prevent it from being used as a routine monitoring method. Recently, peripheral blood lymphocyte subpopulation testing has become an important means of assessing the body's immune system, however, its application value and strategy in the field of kidney transplantation need further exploration. Additionally, the development and utilization of routine test parameters are also important methods for exploring diagnostic strategies and predictive models for kidney transplant diseases. This study aims to explore the correlation between peripheral blood lymphocyte subpopulations and T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), as well as their diagnostic value, in conjunction with routine blood tests. METHODS: A total of 154 kidney transplant recipients, who met the inclusion and exclusion criteria and were treated at the Second Xiangya Hospital of Central South University from January to December, 2021, were selected as the study subjects. They were assigned into a stable group, a TCMR group, and an ABMR group, based on the occurrence and type of rejection. The basic and clinical data of these recipients were retrospectively analyzed and compared among the 3 groups. The transplant kidney function, routine blood tests, and peripheral blood lymphocyte subpopulation data of the TCMR group and the ABMR group before rejection treatment were compared with those of the stable group. RESULTS: The stable, TCMR group, and ABMR group showed no statistically significant differences in immunosuppressive maintenance regimens or sources of transplanted kidneys (all P>0.05). However, the post-transplant duration was significantly longer in the ABMR group compared with the stable group (P<0.001) and the TCMR group (P<0.05). Regarding kidney function, serum creatinine levels in the ABMR group were higher than in the stable group and the TCMR group (both P<0.01), with the TCMR group also showing higher levels than the stable group (P<0.01). Both TCMR and ABMR groups had significantly higher blood urea nitrogen levels than the stable group (P<0.01), with no statistically significant difference between TCMR and ABMR groups (P>0.05). The estimated glomerular filtration rate (eGFR) was lower in both TCMR and ABMR groups compared with the stable group (both P<0.01). In routine blood tests, the ABMR group had lower hemoglobin, red blood cell count, and platelet count than the stable group (all P<0.05). The TCMR group had higher neutrophil percentage (P<0.05) and count (P<0.05) than the stable group, and the ABMR group had a higher neutrophil percentage than the stable group (P<0.05). The eosinophil percentage and count in the TCMR group were lower than in the stable and ABMR groups (all P<0.05). Both TCMR and ABMR groups had lower basophil percentage and count, as well as lower lymphocyte percentage and count, compared with the stable group (all P<0.05). There were no significant differences in monocyte percentage and count among the 3 groups (all P>0.05). In lymphocyte subpopulations, the TCMR and ABMR groups had lower counts of CD45+ cells and T cells compared with the stable group (all P<0.05). The TCMR group also had lower counts of CD4+ T cells, NK cells, and B cells than the stable group (all P<0.05). There were no significant differences in the T cell percentage, CD4+ T cell percentage, CD8+ T cell percentage and their counts, CD4+/CD8+ T cell ratio, NK cell percentage, and B cell percentage among the stable, TCMR, and ABMR groups (all P>0.05). CONCLUSIONS: The occurrence of rejection leads to impaired transplant kidney function, accompanied by characteristic changes in some parameters of routine blood tests and peripheral blood lymphocyte subpopulations in kidney transplant recipients. The different characteristics of changes in some parameters of routine blood tests and peripheral blood lymphocyte subpopulations during TCMR and ABMR may help predict and diagnose rejection and differentiate between TCMR and ABMR.
Assuntos
Rejeição de Enxerto , Transplante de Rim , Humanos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Estudos Retrospectivos , Feminino , Masculino , Subpopulações de Linfócitos/imunologia , Adulto , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
Thymic epithelial cells (TECs) are critical for the development and generation of functionally competent T cells. Until now, the mechanism that regulates the survival of TECs is poorly understood. In the current study, we found that Tsc1 controls the homeostasis of medullary TECs (mTECs) by inhibiting lysosomal-mediated apoptosis pathway in mice. TEC-specific deletion of Tsc1 predominately decreased the cell number of mTECs and, to a lesser content, affected the development cortical TECs. The defect of mTECs caused by Tsc1 deficiency in mice impaired thymocyte development and peripheral T cell homeostasis. Mechanistically, Tsc1 deficiency did not affect the cell proliferation of mTECs but increased the apoptosis of mTECs significantly. RNA-sequencing analysis showed that pathways involved in lysosomal biogenesis, cell metabolism, and apoptosis were remarkably elevated in Tsc1-deficient mTECs compared with their wild-type counterparts. Tsc1-deficient mTECs exhibited overproduction of reactive oxygen species and malfunction of lysosome, with lysosome membrane permeabilization and the release of cathepsin B and cathepsin L to the cytosol, which then lead to Bid cleaved into active truncated Bid and subsequently intrinsic apoptosis. Finally, we showed that the impaired development of mTECs could be partially reversed by decreasing mTORC1 activity via haploinsufficiency of Raptor Thus, Tsc1 is essential for the homeostasis of mTECs by inhibiting lysosomal-mediated apoptosis through mTORC1-dependent pathways.
Assuntos
Células Epiteliais/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Timo/citologia , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Células Epiteliais/citologia , Retroalimentação Fisiológica , Haploinsuficiência , Homeostase , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Proteína Regulatória Associada a mTOR/genética , Proteína 1 do Complexo Esclerose Tuberosa/genéticaRESUMO
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.
Assuntos
Transplante de Rim , Nefrite Lúpica , Linfo-Histiocitose Hemofagocítica , Viroses , Humanos , Criança , Feminino , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Transplante de Rim/efeitos adversos , Nefrite Lúpica/complicações , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Rim , Viroses/complicaçõesRESUMO
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.
Assuntos
Glomerulonefrite por IGA , Falência Renal Crônica , Transplante de Rim , Adulto , Humanos , Masculino , Adulto Jovem , Feminino , Glomerulonefrite por IGA/cirurgia , Estudos Retrospectivos , Rim , Falência Renal Crônica/cirurgiaRESUMO
BACKGROUND: Toxicity is a major concern related to the clinical use of polymyxin B, and available safety data for renal transplant patients are limited. AIMS: We investigated the safety of polymyxin B and toxicity risk factors in renal transplant patients. METHODS: A prospective study was performed on a group of renal transplant patients who received intravenous polymyxin B between January 2018 and August 2021. Polymyxin B treatment was monitored to evaluate toxicity and risk factors. RESULTS: A total of 235 courses of polymyxin B were administered to 213 patients. Of these, 121 (51.5%) developed skin hyperpigmentation (SH), 149 (63.4%) developed neurotoxicity and 10 (5.5%) developed acute kidney injury of which 80% was reversible. Risk factors for developing SH included a high total dose by weight (odds ration [OR] 1.31, 95% confidence interval [CI] 1.08-1.60, P = .008) and the presence of neurotoxicity (OR 2.86, 95% CI 1.56-5.26, P = .001). Neurotoxicity manifested during the first 2 days of treatment. Neurotoxicity occurred most commonly in women (OR 3.84, 95% CI 1.82-8.10, P < .0001), and the presence of SH (OR 1.98, 95% CI 1.13-3.46, P = .016) was also an independent risk factor. CONCLUSIONS: Neurotoxicity and SH are the two major adverse effects of polymyxin B in renal transplant patients, which may limit its clinical use.
Assuntos
Hiperpigmentação , Transplante de Rim , Síndromes Neurotóxicas , Antibacterianos/efeitos adversos , Feminino , Humanos , Hiperpigmentação/induzido quimicamente , Hiperpigmentação/epidemiologia , Incidência , Transplante de Rim/efeitos adversos , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/etiologia , Polimixina B/efeitos adversos , Estudos ProspectivosRESUMO
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.
Assuntos
Cálculos Renais , Transplante de Rim , Adulto , Humanos , Criança , Sobrevivência de Enxerto , Estudos Retrospectivos , Doadores de Tecidos , CadáverRESUMO
OBJECTIVES: To summarize the emergency management of the kidney transplantation for a large tertiary first-class hospital in response to the epidemic of coronavirus disease 2019 (COVID-19). METHODS: The clinical data of inpatients in the Department of Kidney Transplantation from January 24, 2020 to February 29, 2020 were retrospectively analyzed. Since the outbreak of COVID-19, we conducted telephone, Wechat follow-up, and online education for kidney transplant recipients and patients on waiting-list for kidney transplantation one by one. We also strictly screened for COVID-19 in outpatients. To guarantee the security of medical staff and recipients and to reduce the transmission risk of COVID-19, we have made detailed approaches to prevent COVID-19, which mainly included 6 aspects of preventive approaches, such as kidney transplant clinic, kidney transplant ward, patients on waiting-list for kidney transplantation, kidney transplant operation, medical staff self-protection, and postoperative follow-up of kidney transplant recipients. RESULTS: There were altogether 47 inpatients which included 20 recipients who had just received kidney transplantation in the meantime, 2 577 kidney transplant recipients, 1 689 patients on waiting-list for kidney transplantation, and 794 outpatients in our hospital. No case of COVID-19 occurred in this period. CONCLUSIONS: Through strictly implementing proactive and preventive approaches, we avoid the occurrence of COVID-19 in carrying out kidney transplantation in the epidemic period.
Assuntos
Infecções por Coronavirus/epidemiologia , Transplante de Rim , Pneumonia Viral/epidemiologia , Betacoronavirus , COVID-19 , Infecções por Coronavirus/prevenção & controle , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Estudos Retrospectivos , SARS-CoV-2 , Centros de Atenção Terciária , Transplantados , Listas de EsperaRESUMO
AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l·h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections.
Assuntos
Antifúngicos/farmacocinética , Citocromo P-450 CYP2C19/genética , Modelos Biológicos , Voriconazol/farmacocinética , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Disponibilidade Biológica , Variação Biológica da População/fisiologia , Peso Corporal , Citocromo P-450 CYP2C19/metabolismo , Relação Dose-Resposta a Droga , Feminino , Genótipo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Absorção Intestinal , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/imunologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Período Pós-Operatório , Estudos Prospectivos , Fatores de Tempo , Transplantados , Voriconazol/administração & dosagem , Voriconazol/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: NDUFA4L2 is overexpressed in VHL-deficient cell lines and neuroblastoma. The clinical significance of NDUFA4L2 in clear cell renal cell carcinoma (ccRCC) has not been well studied. Therefore, we evaluated the prognostic value of NDUFA4L2 in ccRCC patients. METHODS: In our study, NDUFA4L2 expression in 86 cases of ccRCC and adjacent normal tissues was monitored by immunohistochemistry, semi-quantitative RT-PCR, and Western blot analyses. The relationship between NDUFA4L2 expression and the clinical features of ccRCC was assessed. RESULTS: The results showed that NDUFA4L2 protein expression was found to be higher in ccRCC tissues 81.4% (70/86) than in normal tissues 26.7% (23/86) (p = 0.021). The average level of NDUFA4L2 mRNA expression was found to be 122.23 ± 6.018 and 21.34 ± 1.036 in ccRCC tissue and adjacent normal tissue (p < 0.001). NDUFA4L2 expression levels were correlated with some clinical features of ccRCC. Multivariate analysis showed NDUFA4L2 expression was an independent prognostic factor for ccRCC patients. CONCLUSIONS: Our study has provided the significant clinical relevance of NDUFA4L2 in ccRCC and suggested that ccRCC patients with NDUFA4L2 overexpression may be suitable as a potential therapeutic target for ccRCC patients.
Assuntos
Carcinoma de Células Renais/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Neoplasias Renais/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/patologia , China , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , RNA Mensageiro/genéticaRESUMO
OBJECTIVE: To gain an insight into the transplantation with donor kidneys from extended criterion donation after cardiac death (DCD) and to improve the management during and after renal transplantation METHODS: Renal transplantation in 2 patients who used organs from small pediatric donors (<3 years) was performed. The graft kidneys were procured from 1 donor aged 11 months and the other 1 year and 7 months. The 2 donors were diagnosed as brain death caused by serious infantile hepatitis syndrome and severe craniocerebral injury, respectively. After the cardiac death, en bloc organ resection was performed. En bloc kidneys were transplanted to 2 adult recipients who were 37 and 41 years old, respectively. RESULTS: The recipients were followed-up for 6 months. Both of them developed large volume of bloody drainage in the early post-operational period and relieved after relevant treatment. The kidney grafts functioned well and no other surgical complications or acute rejections happened during the follow-up. CONCLUSION: Based on modified peri-operative techniques, it is safe to perform renal transplantation with kidneys procured from cardiac death donors who are younger than 3 years old, an important source to increase the number of organs available for transplantation, yet the vascular complications require attention.
Assuntos
Sobrevivência de Enxerto , Transplante de Rim , Doadores de Tecidos , Adulto , Humanos , Lactente , Rim , Período Pós-OperatórioRESUMO
OBJECTIVES: SARS-CoV-2 pneumonia poses significant challenges to health systems worldwide, particularly, in severe and critical cases. Immunosuppressed renal transplant recipients appear to be at a particularly high risk for severe or critical COVID-19 illness. However, few studies elucidated the risk factors of SARS-CoV-2 pneumonia in renal transplant recipients with COVID-19. METHODS: A postinfection cross-sectional survey was conducted in 312 renal transplant recipients and 503 age- and sex-matched controls to explore risk factors for SARS-CoV-2 pneumonia in immunosuppressed renal transplant recipients. RESULTS: The results showed that renal transplant recipients had a much higher incidence of SARS-CoV-2 pneumonia (48.1%) after infection with the SARS-CoV-2 Omicron variant than controls (5.6%). The multivariate binary logistic regression analysis identified older age, lower creatinine clearance before infection, and higher dose of prednisone before infection as risk factors for SARS-CoV-2 pneumonia in renal transplant recipients. Preexisting renal dysfunction was a major risk factor for SARS-CoV-2 pneumonia, with an odds ratio of 3.27 (1.01-10.61). CONCLUSIONS: Preexisting renal graft dysfunction was a major risk factor for SARS-CoV-2 Omicron variant pneumonia. It is suggested that high-risk renal transplant recipients should undergo computed tomography scanning within 14 days after infection with SARS-CoV-2.
Assuntos
COVID-19 , Transplante de Rim , Pneumonia , Humanos , Transplante de Rim/efeitos adversos , SARS-CoV-2 , Estudos Transversais , COVID-19/complicações , COVID-19/epidemiologia , Fatores de Risco , TransplantadosRESUMO
Poor skin wound healing, which is common in patients with diabetes, is related to imbalanced macrophage polarization. Here, we find that nutrition sensor GCN2 (general control nonderepressible 2) and its downstream are significantly upregulated in human skin wound tissue and mouse skin wound macrophages, but skin wound-related GCN2 expression and activity are significantly downregulated by diabetes and hyperglycemia. Using wound healing models of GCN2-deleted mice, bone marrow chimeric mice, and monocyte-transferred mice, we show that GCN2 deletion in macrophages significantly delays skin wound healing compared with wild-type mice by altering M1 and M2a/M2c polarization. Mechanistically, GCN2 inhibits M1 macrophages via OXPHOS-ROS-NF-κB pathway and promotes tissue-repairing M2a/M2c macrophages through eukaryotic translation initiation factor 2 (eIF2α)-hypoxia-inducible factor 1α (HIF1α)-glycolysis pathway. Importantly, local supplementation of GCN2 activator halofuginone efficiently restores wound healing in diabetic mice with re-balancing M1 and M2a/2c polarization. Thus, the decreased macrophage GCN2 expression and activity contribute to poor wound healing in diabetes and targeting GCN2 improves wound healing in diabetes.
Assuntos
Diabetes Mellitus Experimental , Animais , Humanos , Camundongos , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo , Macrófagos/metabolismo , Pele , CicatrizaçãoRESUMO
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.
Assuntos
Dieta , Neoplasias , Inquéritos Nutricionais , Insuficiência Renal Crônica , Vitaminas , Humanos , Insuficiência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias/epidemiologia , Vitaminas/administração & dosagem , Idoso , Medição de Risco , Adulto , Estados Unidos/epidemiologia , Fatores de TempoRESUMO
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.
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Renal fibrosis is the common final pathway of progressive renal diseases, in which the macrophages play an important role. ELISA was used to detect CD5 antigen-like (CD5L) in serum samples from end-stage renal disease (ESRD), as well as in mice serum with unilateral ureteral occlusion (UUO). Recombinant CD5L was injected into UUO mice to assess renal injury, fibrosis, and macrophage infiltration. The expression of CD5L was significantly upregulated in the serum of patients with ESRD and UUO mice. Histological analysis showed that rCD5L-treated UUO mice had more severe renal injury and fibrosis. Furthermore, rCD5L promoted the phenotypic transfer of monocytes from Ly6Chigh to LyC6low. RCD5L promoted TGF-ß signaling pathway activation by promoting Smad2/3 phosphorylation. We used Co-IP to identify HSPA5 interact with CD5L on cell membrane could inhibit the formation of the Cripto/HSPA5 complex, and promote the activation of the TGF-ß signaling pathway. The CD5L antibody could reduce the degree of renal fibrosis in UUO mice.
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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.
Assuntos
Apoptose , Macrófagos , Glicoproteínas de Membrana , Camundongos Endogâmicos C57BL , Receptores Imunológicos , Fatores de Transcrição STAT , Transdução de Sinais , Animais , Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Fatores de Transcrição STAT/metabolismo , Janus Quinases/metabolismo , Rim/patologia , Rim/metabolismo , Camundongos Knockout , Masculino , Fibrose , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/genética , Obstrução Ureteral/patologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/complicações , Polaridade Celular , Serina-Treonina Quinases TOR/metabolismo , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/genéticaRESUMO
OBJECTIVE: To better understand the pre-operation evaluation of donor kidneys from extended criteria donation after cardiac death and to improve the management during and after renal transplantation. METHODS: Both of the donor kidneys were from the donor who underwent liver transplantation 5 years ago in the Center of Organ Transplantation of Central South University. The donor was admitted because of liver function deterioration which led to hepatic coma, brain death, hepatorenal syndrome and cardiac death sequentially. Deceased donor score (DDS) and "zero point" kidney biopsy were applied to evaluate the donor kidney. After thorough examination of the donor and the renal function, renal transplantation was performed on 2 recipients. RESULTS: The recipients were followed up by 6 months, both of whom developed pulmonary infection and relieved after treatments. The kidney grafts functioned well and no surgical complication and no acute rejection occurred during the follow-up. CONCLUSION: Proper evaluation of the donor organs ensures the safety of renal transplantation with kidneys from cardiac death donors who underwent liver transplantation, which is an important way to increase the number of organs for transplantation, yet the long-term effects need further observation.
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Parada Cardíaca , Transplante de Rim , Transplante de Fígado , Doadores de Tecidos , Obtenção de Tecidos e Órgãos/métodos , Adulto , Morte , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.