Identification of M1 macrophage-related genes in rejection after kidney transplantation based on weighted gene co-expression network analysis / 器官移植

Objective To identify M1 macrophage-related genes in rejection after kidney transplantation and construct a risk prediction model for renal allograft survival. Methods GSE36059 and GSE21374 datasets after kidney transplantation were downloaded from Gene Expression Omnibus (GEO) database. GSE36059 dataset included the samples from the recipients with rejection and stable allografts. Using this dataset, weighted gene co-expression network analysis (WGCNA) and differential analysis were conducted to screen the M1 macrophage-related differentially expressed gene (M1-DEG). Then, GSE21374 dataset (including the follow-up data of graft loss) was divided into the training set and validation set according to a ratio of 7∶3. In the training set, a multivariate Cox's model was constructed using the variables screened by least absolute shrinkage and selection operator (LASSO), and the ability of this model to predict allograft survival was evaluated. CIBERSORT was employed to analyze the differences of infiltrated immune cells between the high-risk group and low-risk group, and the distribution of human leukocyte antigen (HLA)-related genes was analyzed between two groups. Gene set enrichment analysis (GSEA) was used to further clarify the biological process and pathway enrichment in the high-risk group. Finally, the database was employed to predict the microRNA (miRNA) interacting with the prognostic genes. Results In the GSE36059 dataset, 14 M1-DEG were screened. In the GSE21374 dataset, Toll-like receptor 8 (TLR8), Fc gamma receptor 1B (FCGR1B), BCL2 related protein A1 (BCL2A1), cathepsin S (CTSS), guanylate binding protein 2(GBP2) and caspase recruitment domain family member 16 (CARD16) were screened by LASSO-Cox regression analysis, and a multivariate Cox's model was constructed based on these 6 M1-DEG. The area under curve (AUC) of receiver operating characteristic of this model for predicting the 1- and 3-year graft survival was 0.918 and 0.877 in the training set, and 0.765 and 0.736 in the validation set, respectively. Immune cell infiltration analysis showed that the infiltration of rest and activated CD4+ memory T cells, γδT cells and M1 macrophages were increased in the high-risk group (all P < 0.05). The expression level of HLA I gene was up-regulated in the high-risk group. GSEA analysis suggested that immune response and graft rejection were enriched in the high-risk group. CTSS interacted with 8 miRNA, BCL2A1 and GBP2 interacted with 3 miRNA, and FCGR1B interacted with 1 miRNA. Conclusions The prognostic risk model based on 6 M1-DEG has high performance in predicting graft survival, which may provide evidence for early interventions for high-risk recipients.

Role of tertiary lymphoid structures in tumor immune microenvironment regulation and anti-tumor therapy / 国际肿瘤学杂志

Tertiary lymphoid structures (TLSs) is important channel for tumor immune cell infiltration. The existence of tumor TLSs is not only related to the prognosis of patients, but also to the efficacy of a variety of anti-tumor therapies. To explore the function and immunomodulatory mechanism of TLSs and its potential value as a tumor prognostic biomarker in comprehensive anti-tumor therapy will provide new ideas for follow-up research.

Evaluating criteria of immune risk stratification for kidney transplant recipients / 中华器官移植杂志

Objective:To establish risk stratifying criteria for acute rejection(AR)after kidney transplantation(KT)through analyzing the preoperative risk factors of KT recipients from deceased donor(DD).Methods:A retrospective study is conducted for 1 382 KT recipients of DD kidney at First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to December 2020.According to the presence or absence of AR within 1 year post-KT, they are divided into two groups of acute rejection(group AR, 115 cases)and non-rejection(group non-AR, 1 267 cases). Clinical data of two groups are examined by univariate and multivariate analyses for determining the risk factors of AR and a scoring standard is established on the basis of regression coefficients.They are divided into three groups of low-risk(907 cases), middle-risk(450 cases)and high-risk(25 cases)according to the scoring results and the incidence of AR is compared among different scoring groups.Results:Univariate analysis indicates that donor age(AR, 793 cases; non-AR, 474 cases, P=0.033), age difference between recipients and donors≥25 years(AR, 63 cases; non-AR; 315 cases; P<0.001), recipient panel-reactive antibodies(PRA)plus donor-specific antibody(DSA)(+ )(AR, 96 cases; non-AR, 1 169 cases, P=0.002), donor kidney cold ischemic time≥12h(AR, 81 cases; non-AR, 1 064 cases, P<0.001), donor/recipient HLA mismatch≥3(AR, 70 cases; non-AR, 984 cases, P<0.001)and expanded criteria donor(ECD)(AR, 50 cases; non-AR, 790 cases, P<0.001)are high risk factors for AR(all P<0.05). Variables with statistical significance during univariate analysis are included for multivariate analysis.Five variables are finally determined, including age difference between recipients and donors≥25 years(β=0.61, P=0.006), PRA+ DSA(+ )(β=0.74, P=0.008), donor kidney cold ischemic time≥12 h(β=0.74, P<0.001), HLA mismatch(≥3)(β=0.81, P<0.001)and ECD(β=0.82, P<0.001). Score for each risk factor is calculated according to the relevant regression coefficient and scoring standard formulate on the basis of the above five risk factors with a total score of 36.With an overall incidence of AR at 8.32%(115/1 382), the incidence of AR is 4.3%, 14.7% and 40.0% in low/middle/high-risk group and the difference is statistically significant.It hints that immune risk stratification can effectively determine the risk of postoperative AR for KT recipients.The incidence of AR is significantly higher in middle/high-risk group than that in low-risk group ( P<0.001). Conclusions:For recipients with middle/high immune risk, intensity and dose of immunosuppressants should be appropriately boosted during preoperative induction and maintenance period.And the occurrences of AR and infection should be dynamically monitored.

Association analysis of high level of BK virus viruria and HLA site after kidney transplantation / 中华器官移植杂志

Objective:To explore the temporal distribution of high level of BK virus(BKV) viruria after kidney transplantation(KT)and the association of high level of viruria with clinical factors and specific human leukocyte antigen(HLA)sites in donors and recipients.Methods:From January 1, 2017 to December 31, 2019, clinical data were retrospectively reviewed for 212 recipients of cadaveric KT.A high level of urinary BKV viruria was defined as urinary BKV-DNA quantification>10 7(copies/ml)after KT while 212 recipients with the same gender composition below the threshold during the same period were selected as low-level controls.Clinical data and HLA sites of two groups were statistically analyzed and risk factors for high level of viruria screened by univariate and multifactorial Logistic regressions. Results:The median time to initial high-level BKV infection in urine after RT was 125.5 days.Based upon univariate Logistic analysis, delayed graft function(DGF)and HLA-A24 of recipient were risk factors for high-level BKV infection in urine while HLA-DQ9 of donor acted as a protective factor.Through multivariate Logistic analysis, DGF( OR=2.18, 95% CI 1.18~4.01, P=0.012)and HLA-A24( OR=1.63, 95% CI 1.06~2.53, P=0.027)of recipient were independent risk factors for high-level BKV infection in urine.And HLA-DQ9 of donors( OR=0.58, 95% CI 0.36~0.91, P=0.019)was an independent protective factor. Conclusions:High level of BKV viruria after RT is associated with donor/recipient-specific HLA sites.Early risk factor stratification and protective factors of recipients can aid in tailoring postoperative immunosuppression and screening program and developing T cell-associated vaccines.

Clinical observations on acute rejection of elderly donor kidneys in kidney transplant recipients of different ages / 中华器官移植杂志

Objective:To explore the clinical data of acute rejection in kidney transplant recipients of different ages with elderly donor kidneys.Methods:During January 2012 and June 2020, a retrospective review was conducted for clinical data of 298 recipients undergoing kidney transplantation from elderly donors aged ≥60 years after citizen's death.According to the age, recipients were divided into group A(age<30 yr, 59 cases), group B(30~39 yr, 125 cases), group C(40~49 yr, 83 cases)and group D(age≥50 yr, 31 cases). The incidence of acute rejection(AR)was analyzed.Also based upon age difference between donors and recipients, they were divided into two groups of(30~39 yr)and (40~49 yr)and the occurrence of AR was recorded.Results:The incidence of AR within 1 year post-transplantation in groups A, B, C, and D were 15.3%(9/59), 8.8%(11/125), 7.2%(6/83) and 3.2%(1/31)respectively.The incidence of AR in age difference≥25 yr group(12.5%)and age difference <25 yr group(5.3%) had significant difference( P<0.05). The proportion and absolute value of peripheral blood lymphocytes in each group at 1 week/month post-transplantation had significant difference( P<0.05). No significant difference was observed in serum level of creatinine(SCr), the incidence of pulmonary infection and urinary tract infection or the survival rate of recipients and transplanted kidneys in each group within 1 year post-transplantation among four groups( P>0.05). Conclusions:Elderly donor kidneys can obtain better transplant outcomes in kidney transplant recipients of different ages.As the age of recipients decreases, AR shows an upward trend.Clinicians should pay more attention to the prevention and treatment of AR in recipients with large age difference between donors and recipients.

Serum concentrations of NSE and S100B in spinocerebellar ataxia type 3/Machado-Joseph disease / 中南大学学报(医学版)

Objective To determine the neuronal damage or loss and gliosis at the cellular level in spinocerebellar ataxia type 3/Machado-Joseph disease(SCA3/MJD), and evaluate the potential use of neuron-specific enolase (NSE) and protein S 100 B(S100B) serum concentrations as biochemical markers. Methods Serum concentrations of NSE and S100B were measured in 102 SCA3/MJD patients and 100 healthy subjects matched by sex and age. The correlations between both markers and age, age of onset, disease duration, CAG repeat size, scores of international cooperative ataxia rating scale(ICARS), and scale for the assessment and rating of ataxia(SARA) were analyzed. Results Compared with the healthy controls, patients with SCA3/MJD had higher NSE serum concentrations [(6.95±2.83)ng/mL vs (4.83±1.70) ng/mL, P<0.05] and higher S100B serum concentrations [(0.07±0.06) ng/mL vs (0.05±0.02) ng/mL, P<0.05]. In the SCA3/MJD patients group, NSE levels presented a positive correlation with age, disease duration, ICARS scores and SARA scores, whereas S100B levels did not correlate with age, age of onset, disease duration, ICARS scores and SARA scores. CAG repeat size did not correlate with the NSE levels and S100B levels in different age groups of SCA3/MJD patients. Conclusion Serum NSE might be a useful marker to monitor disease progression and represent the degree of severity of a certain disease. Elevated S100B serum concentrations in patients compared to healthy controls may suggest an application of this protein as a peripheral marker of brain impairment in SCA3/MJD.