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Currently in the United States, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. Although early post-transplant care is delivered at the transplant center, the increasing number of kidney transplant recipients requires general nephrologists to actively participate in the long-term care of these patients. Serum creatinine and proteinuria are imperfect traditional biomarkers of allograft dysfunction and lag behind subclinical allograft injury. This manuscript reviews the various clinically available biomarkers in the field of kidney transplantation for a general nephrologist with a focus on the utility of donor-derived cell-free DNA, as a marker of early allograft injury. Blood gene expression profiling, initially studied in the context of early identification of subclinical rejection, awaits validation in larger multicentric trials. Urinary cellular messenger ribonucleic acid and chemokine CXCL10 hold promising potential for early diagnosis of both subclinical and acute rejection. Torque tenovirus, a ubiquitous DNA virus is emerging as a biomarker of immunosuppression exposure as peripheral blood torque tenovirus copy numbers might mirror the intensity of host immunosuppression. Although high-quality evidence is still being generated, evidence and recommendations are provided to aid the general nephrologist in implementation of novel biomarkers in their clinical practice.

BACKGROUND: The Sirtuins (SIRT) family plays a key role in the diagnosis and treatment of many renal diseases, but no studies have been reported in acute rejection of kidney transplantation. The aim of this study was to explore the diagnostic value of SIRT family change characteristics in acute rejection of kidney transplantation.
METHODS: We first explored the SIRT family expression profile in renal tissues using the HPA database; subsequently, we explored the potential biological functions and mechanistic changes during acute rejection of kidney transplantation by GSEA enrichment analysis. The Cibersort algorithm specifies the level of immune cell infiltration and explores the correlation between the SIRT family and immune cells using correlation analysis; Next, we constructed a diagnostic model using \"Logistic regression analysis\" and \"Nomogram model\", and evaluated the diagnostic model using calibration curves and ROC curves, and the decision curve (DCA) was used to evaluate the clinical diagnostic value of SIRT family changes; Finally, we constructed a model of acute rejection of rat kidney transplantation, and assessed rat kidney function by detecting the levels of urea nitrogen and creatinine in serum. Meanwhile, the expression level of SIRT family in kidney tissues was initially verified by transcriptome sequencing and RT-PCR.
RESULTS: We found that all seven SIRT family members were located and expressed in renal tissues. The results of enrichment analysis revealed that a large number of immune-related biological functions and pathways are activated during acute rejection of kidney transplantation, the difference was statistically significant (p < 0.05). The Cibersort algorithm revealed significant changes in the level of infiltration of 10 immune cells (p < 0.05), while correlation analysis revealed a strong link between the SIRT family and immune cells (p < 0.05). We constructed a diagnostic model for acute rejection using seven SIRT families, and the ROC curves(AUC = 0.71)and calibration curves proved their good diagnostic value, and the DCA curves also proved the role of SIRT families in clinical decision-making. Next, we again demonstrated the good diagnostic performance of the SIRT family in ABMR and TCMR, respectively(ROC curves:AUC = 0.64，AUC = 0.81). Finally, in a rat model of acute rejection of kidney transplantation, we found that renal function (BUN and creatinine) was significantly impaired in rats in the Allo group compared to rats in the Syn group (P < 0.05). Meanwhile, by transcriptome analysis and RT-PCR assay, we found that, except for SIRT1, the remaining SIRT family members were significantly changed in kidney tissues (P < 0.05).
CONCLUSIONS: The SIRT family has significant changes during acute rejection in kidney transplantation, and the SIRT family may be able to serve as a potential therapeutic target for alleviating acute rejection in kidney transplantation.

UNASSIGNED: Kidney transplantation significantly improves the lives of those with end-stage kidney disease, offering best alternative to dialysis. However, transplant success is threatened by the acute and chronic rejection mechanisms due to complex immune responses against the new organ.
UNASSIGNED: The ongoing research into biomarkers holds promise for revolutionizing the early detection and monitoring of the graft health. Liquid biopsy techniques offer a new avenue, with several diagnostic, predictive, and prognostic biomarkers showing promise in detecting and monitoring kidney diseases and an early and chronic allograft rejection.
UNASSIGNED: Evaluating the protein composition related to kidney transplant results could lead to identifying biomarkers that provide insights into the graft functionality. Non-invasive proteomic biomarkers can drastically enhance clinical outcomes and change the way how kidney transplants are evaluated for patients and physicians if they succeed in this transition. Hence, the advancement in proteomic technologies, leads toward a significant improvement in understanding of the protein markers and molecular mechanisms linked to the outcomes of kidney transplants. However, the road from discovery to the use of such proteins in clinical practice is long, with a need for continuous validation and beyond the singular research team with comprehensive infrastructure and across research groups collaboration.

BACKGROUND: Oxidative stress is an unavoidable process in kidney transplantation and is closely related to the development of acute rejection after kidney transplantation. This study aimed to investigate the biomarkers associated with oxidative stress and their potential biological functions during acute rejection of kidney transplants.
METHODS: We identified Hub genes using five machine learning algorithms based on differentially expressed genes (DEGs) in the kidney transplant acute rejection dataset GSE50058 and oxidative stress-related genes (OS) obtained from the MSigDB database, and validated them with the datasets GSE1563 and GSE9493, as well as with animal experiments; Subsequently, we explored the potential biological functions of Hub genes using single-gene GSEA enrichment analysis; The Cibersort algorithm was used to explore the altered levels of infiltration of 22 immune cells during acute rejection of renal transplantation, and a correlation analysis between Hub genes and immune cells was performed; Finally, we also explored transcription factors (TFs), miRNAs, and potential drugs that regulate Hub genes.
RESULTS: We obtained a total of 57 genes, which we defined as oxidative stress-associated differential genes (DEOSGs), after intersecting DEGs during acute rejection of kidney transplants with OSs obtained from the MSigDB database; The results of enrichment analysis revealed that DEOSGs were mainly enriched in response to oxidative stress, response to reactive oxygen species, and regulation of oxidative stress and reactive oxygen species; Subsequently, we identified one Hub gene as APOD using five machine learning algorithms, which were validated by validation sets and animal experiments; The results of single-gene GSEA enrichment analysis revealed that APOD was closely associated with the regulation of immune signaling pathways during acute rejection of kidney transplants; The Cibersort algorithm found that the infiltration levels of a total of 10 immune cells were altered in acute rejection, while APOD was found to correlate with the expression of multiple immune cells; Finally, we also identified 154 TFs, 12 miRNAs, and 12 drugs or compounds associated with APOD regulation.
CONCLUSIONS: In this study, APOD was identified as a biomarker associated with oxidative stress during acute rejection of kidney transplants using multiple machine learning algorithms, which provides a potential therapeutic target for mitigating oxidative stress injury and reducing the incidence of acute rejection in kidney transplantation.

Isolated v-lesion presents diagnostic stratification and clinical challenges. We characterized allograft outcomes for this entity based on posttransplant time (early: ≤1 month vs late: >1 month) and compared its molecular phenotype with other v+ rejection forms. Using the NanoString B-HOT panel, we analyzed 92 archival formalin-fixed paraffin-embedded tissue kidney biopsies from 3 centers: isolated v-lesion (n = 23), antibody-mediated rejection (ABMR) v+ (n = 26), T cell-mediated rejection (TCMR) v+ (n = 10), mixed rejection v+ (n = 23), and normal tissue (n = 10). Six gene sets (ABMR, DSAST, ENDAT, TCMR, early/acute injury, late injury) were assessed. Early isolated v-lesions had the poorest 1-year death-censored graft survival compared with late isolated v-lesions or other rejections (P = .034). Gene set analysis showed lower TCMR-related gene expression in isolated v+ groups than TCMR and mixed rejection (P < .001). Both early- and late isolated v-lesions had lower ABMR-related gene expression than ABMR, mixed rejection, and TCMR (P ≤ .022). Late isolated v-lesions showed reduced DSAST and ENDAT gene expression versus ABMR (P ≤ .046) and decreased early/acute injury gene expression than early isolated v+, ABMR, TCMR, and mixed rejection (P ≤ .026). In conclusion, isolated v-lesions exhibit distinct gene expression patterns versus other rejection v+ forms. Early isolated v+ is associated with poorer prognosis and increased early/acute injury gene expression than late isolated v+, suggesting distinct etiologies.

BACKGROUND: Outcomes of deceased donor kidney transplant (DDKT) recipients from the same donor with donor-recipient sex discordance have been studied with inconsistent results.
METHODS: Adult DDKT where both kidneys from the same donor occurred at our center in two different recipients of different sexes were included. Outcomes were analyzed separately for male and female donors, based on the concordance or discordance between donor-recipient sex: Male-male (M-m) versus Male to female (M-f) or vice versa, F-f versus F-m. Acute rejection (AR) and uncensored graft failure were primary outcomes of interest. The univariate and multivariate risks for AR and graft failure were conducted using the Cox proportional hazards model and log-rank tests.
RESULTS: A total of 130 donors, 84 male and 46 female fulfilled our selection criteria and were transplanted in 260 recipients. With respect to the concordant groups (M-m or F-f), sex discordance was not significantly associated with the risk of rejection in multivariate analysis (M-f vs. M-m HR 1.15 [0.53-2.53, P = 0.72]; F-m vs. F-f HR 1.77 [0.71-4.39, P = 0.23]). Sex discordance was also not significantly associated with graft failure in multivariate analysis. Interestingly, risk factors for AR differed among male donors and female donors. The higher calculated panel reactive antibodies (cPRA) and nonwhite recipients were at increased risk for AR in F-m, but not in M-f.
CONCLUSIONS: Donor-recipient sex discordance was not significantly associated with AR or graft failure. Risk factors for AR may differ across male and female donors.

BACKGROUND: There seems to be a close link between the changing levels of selenoproteins, which are important for maintaining redox homeostasis in the body, and acute rejection of kidney transplants. The aim of this study was to explore the diagnostic value of selenoprotein change characteristics in renal tissues for acute rejection of kidney transplantation.
METHODS: We first explored the potential biological functions of 25 selenoproteins in the human body by enrichment analysis and used the HPA database to clarify the expression levels of selenoproteins in kidney tissues; We then constructed a diagnostic model using \"Logistic regression analysis\" and \"Nomogram model\"; Calibration curves and ROC curves were used to evaluate the diagnostic models, and clinical decision curves (DCA) were used to assess the diagnostic value of selenoprotein changes to the clinic; Single-gene GSEA enrichment analysis to further explore the potential regulatory mechanisms of selenoproteins; The Cibersort algorithm explores the level of immune cell infiltration and uses correlation analysis to clarify the correlation between selenoproteins and immune cells; We further assessed the diagnostic value of selenoproteins in kidney transplantation ABMR and TCMR, respectively. Finally, we validated the expression level of selenoproteins in kidney tissues by constructing a rat model of acute rejection of kidney transplantation using transcriptome sequencing.
RESULTS: Our enrichment analysis revealed that selenoproteins are mainly closely associated with biological functions such as oxidative stress, inflammation, and immune regulation (P<0.05); The HPA database suggests that a total of 23 selenoproteins can be expressed in kidney tissue. We constructed a diagnostic model using these 23 selenoproteins, and both calibration curves and ROC curves proved that their change levels have good diagnostic value for acute rejection of kidney transplantation, and DCA curves proved the role of selenoproteins in clinical decision-making; Single-gene GSEA enrichment analysis revealed that selenoproteins are closely associated with immune regulation-related pathways (P<0.05); The Cibersort algorithm identified 10 immune cell infiltration levels that were significantly altered during acute rejection of kidney transplantation (P<0.05), while correlation analyses indicated that selenoproteins correlate with multiple immune cell infiltrations; In ABMR and TCMR, we again verified the diagnostic value of selenoprotein changes in acute rejection of kidney transplantation. Finally, we found significant differences in the expression levels of nine selenoproteins in a rat model of acute rejection of kidney transplantation (P<0.05).
CONCLUSIONS: Changes in selenoproteins in renal tissues have good diagnostic value for acute rejection of kidneyl transplantation, and selenoproteins may be able to be a potential target for alleviating acute rejection of kidney transplantation.

Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed.

UNASSIGNED: [18F]FDG PET/CT noninvasively disproves acute kidney allograft rejection (AR) in kidney transplant recipients (KTRs) with suspected AR. However, the correlation of biopsy-based Banff vs. PET/CT-based scores of acute inflammation remains unknown, as does the prognostic performance of [18F]FDG PET/CT at one year post suspected AR.
UNASSIGNED: From 2012 to 2019, 114 [18F]FDG-PET/CTs were prospectively performed in 105 adult KTRs who underwent per cause transplant biopsies. Ordinal logistic regression assessed the correlation between the extent of histological inflammation and the mean standardized [18F]FDG uptake values (mSUVmean). Functional outcomes of kidney allografts were evaluated at one year post per cause biopsy and correlated to mSUVmean.
UNASSIGNED: A significant correlation between mSUVmean and acute Banff score was found, with an adjusted R 2 of 0.25. The mSUVmean was significantly different between subgroups of \"total i\", with 2.30 ± 0.71 in score 3 vs. 1.68 ± 0.24 in score 0. Neither the function nor the survival of the graft at one year was statistically related to mSUVmean.
UNASSIGNED: [18F]FDG-PET/CT may help noninvasively assess the severity of kidney allograft inflammation in KTRs with suspected AR, but it does not predict graft outcomes at one year.