Acute Rejection In Kidney Transplantation Research Articles

Efficacy of Integrated Risk Score Using Omics-Based Biomarkers for the Prediction of Acute Rejection in Kidney Transplantation: A Randomized Prospective Pilot Study.

Acute rejection (AR) is critical for long-term graft survival in kidney transplant recipients (KTRs). This study aimed to evaluate the efficacy of the integrated risk score of omics-based biomarkers in predicting AR in KTRs. This prospective, randomized, controlled, multicenter, pilot study enrolled 40 patients who recently underwent high-immunologic-risk kidney transplantation (KT). Five omics biomarkers were measured, namely, blood mRNA (three-gene signature), urinary exosomal miRNA (three-gene signature), urinary mRNA (six-gene signature), and two urinary exosomal proteins (hemopexin and tetraspanin-1) at 2 weeks and every 4 weeks after KT for 1 year. An integrated risk score was generated by summing each biomarker up. The biomarker group was informed about the integrated risk scores and used to adjust immunosuppression, but not the control group. The outcomes were graft function and frequency of graft biopsy. Sixteen patients in the biomarker group and nineteen in the control group completed the study. The mean estimated glomerular filtration rate after KT did not differ between the groups. Graft biopsy was performed in two patients (12.5%) and nine (47.4%) in the biomarker and control groups, respectively, with the proportion being significantly lower in the biomarker group (p = 0.027). One patient (6.3%) in the biomarker group and two (10.5%) in the control group were diagnosed with AR, and the AR incidence did not differ between the groups. The tacrolimus trough level was significantly lower in the biomarker group than in the control group at 1 year after KT (p = 0.006). Integrated omics biomarker monitoring may help prevent unnecessary or high-complication-risk biopsy and enables tailored immunosuppression by predicting the risk of AR in KTRs.

Transcriptomics-based identification of TYROBP and TLR8 as novel macrophage-related biomarkers for the diagnosis of acute rejection after kidney transplantation

Macrophages play an important role in the development and progression of acute rejection after kidney transplantation. The study aims to investigate the biological role and significance of macrophage-associated genes (MAG) in acute rejection after kidney transplantation. We utilized transcriptome sequencing results from public databases related to acute rejection of kidney transplantation for comprehensive analysis and validation in animal experiments. We found that a large number of immune-related signaling pathways are activated in acute rejection. PPI protein interaction networks and machine learning were used to establish a Hub gene consisting of TYROBP and TLR8 for the diagnosis of acute rejection. The single-gene GSEA enrichment analysis and immune cell correlation analysis revealed a close correlation between the expression of Hub genes and immune-related biological pathways as well as the expression of multiple immune cells. In addition, the study of TF, miRNAs, and drugs provided a theoretical basis for regulating and treating the Hub genes in acute rejection. Finally, the animal experiments demonstrated once again that acute rejection can aggravate kidney tissue damage, apoptosis level, and increase the release of inflammatory factors. We established and validated a macrophage-associated diagnostic model for acute rejection after kidney transplantation, which can accurately diagnose the biological alterations in acute rejection after kidney transplantation.

Donor hepatitis C status is not associated with an increased risk of acute rejection in kidney transplantation

IntroductionIn renal transplantation, donor hepatitis C virus (HCV) status is crucial to consider when selecting a recipient given the high likelihood of transmission. We analyzed the effect of donor HCV status on post-renal transplant rejection and virologic infectious outcomes using electronic health record data from multiple US health care organizations. MethodsUsing real world data from electronic health records of renal transplant recipients, a propensity score-matched case-control study of one-year renal transplant outcomes was conducted on cohorts of HCV-negative recipients who received an organ from an HCV-positive donor (HCV D+/R-) versus from an HCV-negative donor (HCV D-/R-). Donor HCV positivity was defined as new recipient HCV positivity within 30 days post-transplant. Cohorts were matched by major risk factors for rejection including age, gender, race, etiologies of end-stage renal disease, dialysis dependence, donor type, induction immunosuppression, and virologic lab studies. The primary outcome was one-year incidence of rejection. Secondary outcomes included longitudinal measures of liver and kidney function, incidence of non-HCV viremia, and DAA treatment pathways and responses. ResultsData from 900 renal transplant recipients were analyzed, 450 subjects per group (D+/R-, D-/R-). Mean age at transplant was 57.1 ± 11.9 years, 60 % were male, and 38 % were African American. Kaplan-Meier analysis showed a significantly increased incidence of one-year rejection for HCV D-/R- compared to HCV D+/R- (16.6% vs 22.8 %, p = 0.02). This difference did not persist on a sub-analysis excluding subjects with delayed graft function (DGF) (16.3% vs 19.2 %, p = 0.25). Although mean eGFR was initially higher in HCV D+/R-, there were no significant differences in liver or kidney allograft function at 12 months. There was no significant difference for composite viremia (CMV/EBV/BK; 37.66% vs 31.60 %, p = 0.07). The most common DAA regimen was glecaprevir/pibrentasvir (52.8 %). DAA treatment responses were excellent, with most subjects having a negative viral load by 90 days (mean: 1.7 ± 1.9 log units/mL). ConclusionDonor HCV positivity did not negatively impact one-year rejection outcomes post-renal transplantation. Importantly, this effect was not biased by age. Anti-HCV treatment was effective and liver and kidney function were excellent at one-year post-transplant. These data support the continued expansion of the donor pool by utilizing organs from HCV-positive donors in the era of anti-HCV direct-acting antiviral therapies.

Screening of novel biomarkers for acute kidney transplant rejection using DIA-MS based proteomics.

Kidney transplantation is the preferred treatment for patients with end-stage renal disease. However, acute rejection poses a threat to the graft long-term survival. The aim of this study was to identify novel biomarkers to detect acute kidney transplant rejection. The serum proteomic profiling of kidney transplant patients with T cell-mediated acute rejection (TCMR) and stable allograft function (STA) was analyzed using data-independent acquisition mass spectrometry (DIA-MS). The differentially expressed proteins (DEPs) of interest were further verified by enzyme-linked immunosorbent assay (ELISA). A total of 131 DEPs were identified between STA and TCMR patients, 114 DEPs were identified between mild and severe TCMR patients. The verification results showed that remarkable higher concentrations of serum amyloid A protein 1 (SAA1) and insulin like growth factor binding protein 2 (IGFBP2), and lower fetuin-A (AHSG) concentration were found in TCMR patients when compared with STA patients. We also found higher SAA1 concentration in severe TCMR group when compared with mild TCMR group. The receiver operating characteristics (ROC) analysis further confirmed that combination of SAA1, AHSG, and IGFBP2 had excellent performance in the acute rejection diagnosis. Our data demonstrated that serum SAA1, AHSG, and IGFBP2 could be effective biomarkers for diagnosing acute rejection after kidney transplantation. DIA-MS has great potential in biomarker screening of kidney transplantation.

Impact of Preformed Donor-Specific Anti-HLA-Cw and Anti-HLA-DP Antibodies on Acute Antibody-Mediated Rejection in Kidney Transplantation.

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA.

The Impact of Recipient's Pre-Transplant Viral Status on Acute Kidney Transplant Rejection in the United States: A Retrospective Study

The Impact of Recipient's Pre-Transplant Viral Status on Acute Kidney Transplant Rejection in the United States: A Retrospective Study

Correlation of Urine Analysis Findings with Biopsy-Proven Acute Kidney Transplant Rejection

Correlation of Urine Analysis Findings with Biopsy-Proven Acute Kidney Transplant Rejection

Donor-Derived Cell-Free DNA at 1 Month after Kidney Transplantation Relates to HLA Class II Eplet Mismatch Load.

Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage.

P206 Impact of class I and II HLA antigenic, allelic, and epitopic mismatches on acute rejection in kidney transplantation

P206 Impact of class I and II HLA antigenic, allelic, and epitopic mismatches on acute rejection in kidney transplantation

Implantable bioelectronic systems for early detection of kidney transplant rejection.

Early-stage organ transplant rejection can be difficult to detect. Percutaneous biopsies occur infrequently and are risky, and measuring biomarker levels in blood can lead to false-negative and -positive outcomes. We developed an implantable bioelectronic system capable of continuous, real-time, long-term monitoring of the local temperature and thermal conductivity of a kidney for detecting inflammatory processes associated with graft rejection, as demonstrated in rat models. The system detects ultradian rhythms, disruption of the circadian cycle, and/or a rise in kidney temperature. These provide warning signs of acute kidney transplant rejection that precede changes in blood serum creatinine/urea nitrogen by 2 to 3 weeks and approximately 3 days for cases of discontinued and absent administration of immunosuppressive therapy, respectively.

Évaluation post-transplantation précoce de la dysfonction aiguë du greffon rénal

AbstractKidney transplantation is the best option in the treatment of end-stage kidney disease. Early acute kidney transplant dysfunction is a common complication that corresponds to acute renal failure (AKI) postoperatively after renal transplantation. When it occurs, it favors acute rejection and chronic dysfunction of kidney transplant. Incidence of this complication is constantly rising due to the increased use of grafts from extended criteria donors and from donors after circulatory death. This acute renal failure clinically results in a persistent elevation of serum creatinine and possibly a decrease in diuresis and the need for dialysis during the first postoperative week. However, these signs of renal damage are mostly inefficient and lead to a late diagnosis, limiting treatment efficiency. Therefore, it is essential to develop and use new methods for evaluating acute renal damage early after kidney transplantation. This review explores the various established or developing diagnostic modalities for early AKI after kidney transplantation, whether glomerular filtration rate (GFR) assessment methods or other approaches.

#5509 LOW DOSE THYMOGLOBULIN-BASILIXIMAB INDUCTION PROTOCOL ON INCIDENCE OF ACUTE REJECTION AND POSTTRANSPLANT NEOPLASIA: AN OBSERVATIONAL RETROSPECTIVE STUDY

Abstract Background and Aims Induction therapy plays a key role in the prevention of 1-year acute rejection in kidney transplantation. Several studies suggest that depleting drugs, including thymoglobulin (ATG), are superior to anti-CD25 antibodies in reducing the incidence of acute rejection. However, large retrospective investigations demonstrate a close and significant association between the use of depleting agents and the development of post-transplant neoplasia, in particular post-transplant lymphoproliferative disease. Thus, in the attempt to improve the risk/benefit profile of antibody therapy, we implemented an induction protocol based on low-dose ATG and anti-CD25 blocker basiliximab (Bas). The aim of the present study was to evaluate the efficacy and safety of this approach compared to standard dose ATG alone and basiliximab alone. Method This is a an observational, retrospective, single center study including 957 patients receiving a single kidney transplant the Gemelli kidney transplant center from January 2000 to February 2022 The primary efficacy outcome was biopsy proven acute rejection and the primary safety outcome was the development of post-transplant neoplasia. Patients in the ATG group received a cumulative dose of 7mg/kg in the first week after transplantation; patients in the Bas group were administered the anti-CD25 antibody at a dose of 20 mg before surgery and 20 mg 4 days after transplantation. Finally, patients in the ATG-Bas group received ATG at a cumulative concentration of 3mg/kg over the first 6 days after transplantation and Bas at a dose of 20 mg before surgery and 20 mg 4 days after transplantation. Results In our study population we evaluated 154 patients in the standard ATG group, 492 patients in the low AATG-Bas group and 311 patients in the Bas group. No statistical difference for age, mismatches, donor type, donor age, pre-transplant PRA was observed among groups. Use of mTOR inhibitors was more frequent in the standard ATG and low ATG-Bas groups compared to Bas group (80/154, 155/492, 76/311, respectively, p<0.001). We did not observe any significant difference in the use of other maintenance immunosuppressive drugs. Multivariate analysis (Cox model, including number of mismatches, presence of DSA at transplantation and use of mTOR inhibitors) demonstrated that only low ATG-Bas treatment (HR 0.509 95%CI 0.344-0.754, p<0.001), but not standard ATG (HR 0,819 95%CI 0.472-1.423, p = 0.5), was able to reduce the risk for acute rejection compared to Bas alone. On the other hand, multivariate analysis (Cox model including acute rejection, age, use of mTOR inhibitors) demonstrated that standard ATG induction (HR 1.677 95%CI 1.035-2.717, p = 0.03), but not low ATG-Bas (HR 1,324 95%CI 0,930-1,884, p = 0.1), significantly increased the risk for the development of post-transplant neoplasia compared to Bas alone. Conclusion In this retrospective analysis we demonstrated that low ATG-Bas protocol was the most effective treatment in preventing biopsy-proven acute rejection. In addition, on the contrary of standard ATG dose protocol it did not increase the risk of post-transplant neoplasia compared to Bas alone induction therapy.

Nanotherapeutics for solid organ transplantation: new kid onthe block.

Nanotherapeutics for solid organ transplantation: new kid onthe block.

Multidrug resistant 1 (MDR1) C3435T and G2677T gene polymorphism: impact on the risk of acute rejection in pediatric kidney transplant recipients

BackgroundTacrolimus is the backbone drug in kidney transplantation. Single nucleotide polymorphism of Multidrug resistant 1 gene can affect tacrolimus metabolism consequently it can affect tacrolimus trough level and incidence of acute rejection. The aim of this study is to investigate the impact of Multidrug resistant 1 gene, C3435T and G2677T Single nucleotide polymorphisms on tacrolimus pharmacokinetics and on the risk of acute rejection in pediatric kidney transplant recipients.MethodsTyping of Multidrug resistant 1 gene, C3435T and G2677T gene polymorphism was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 83 pediatric kidney transplant recipients and 80 matched healthy controls.ResultsIn Multidrug resistant 1 gene (C3435T), CC, CT genotypes and C allele were significantly associated with risk of acute rejection when compared to none acute rejection group (P = 0.008, 0.001 and 0.01 respectively). The required tacrolimus doses to achieve trough level were significantly higher among CC than CT than TT genotypes through the 1st 6 months after kidney transplantation. While, in Multidrug resistant 1 gene (G2677T), GT, TT genotypes and T allele were associated with acute rejection when compared to none acute rejection (P = 0.023, 0.033 and 0.028 respectively). The required tacrolimus doses to achieve trough level were significantly higher among TT than GT than GG genotypes through the 1st 6 months after kidney transplantation.ConclusionThe C allele, CC and CT genotypes of Multidrug resistant 1 gene (C3435T) and the T allele, GT and TT genotypes of Multidrug resistant 1 gene (G2677T) gene polymorphism may be risk factors for acute rejection and this can be attributed to their effect on tacrolimus pharmacokinetics. Tacrolimus therapy may be tailored according to the recipient genotype for better outcome.

COVID-19 as a cause of acute kidney transplant rejection: clinical and morphological analysis of a fatal case report

COVID-19 against the background of the respiratory system damage often causes changes in the morpho-functional state of the kidneys, accelerates the progression and development of complications of chronic kidney disease, and is the cause of a high mortality rate in kidney transplant recipients. In the article, the authors conduct a detailed clinical and morphological analysis of a fatal case report of acute kidney transplant rejection of antibody-mediated and cell-mediated genesis, the development of which was determined by the presence of COVID-19 in the patient. The authors emphasize that the morphological study is crucial for the diagnosis of renal transplant rejection. This clinical and morphological analysis of a case report shows the need for an individual approach to this category of patients for the purpose of timely diagnosis, treatment and prevention of COVID-19.

401 Successful Treatment of Thrombotic Microangiopathy Due to Acute Antibody Mediated Rejection of Kidney Transplant

401 Successful Treatment of Thrombotic Microangiopathy Due to Acute Antibody Mediated Rejection of Kidney Transplant

Changes and Significance of Interleukin 17 Expression in Patients After Renal Transplantation

The purpose of this study was to investigate the expression and significance of interleukin (IL)-17 in acute rejection after renal transplantation. From September 2019 to December 2021, patients and healthy volunteers who underwent renal allograft transplantation and renal biopsy in our hospital were selected and divided into 4 groups: the stable group (stable) showed no obvious abnormality in renal transplantation pathology; the pathologic diagnosis of acute rejection was the rejection group; the pathologic diagnosis of renal transplantation was immunosuppressive poisoning in the drug group; and the normal group (control) was healthy volunteers. The expression of IL-17 was detected by reverse transcription-polymerase chain reaction, quantitative enzyme-linked immunosorbent assay, and immunohistochemistry. Analysis of the area under the curve and sensitivity and specificity of IL-17 for the diagnosis of acute rejection after raw transplantation was done using receiver operating characteristic curves. Compared with those in the normal group and the stable group, the expression of IL-17 DNA in the blood, the value of IL-17 in the blood, and the integrated optical density value of IL-17 in the transplanted kidney were significantly higher in the rejection group (P < .05). There were no statistically significant differences in the expression of blood IL-17 DNA, the value of blood IL-17, or the integrated optical density value of transplanted kidney IL-17 between the normal group and the stable group (P > .05). IL-17 is involved in acute rejection after renal transplantation. Increased expression of IL-17 is seen in the blood and kidneys of patients with acute rejection after renal transplantation. The detection of IL-17 may provide a theoretical basis for diagnosing and treating acute rejection in human kidney transplantation.

Role of Biomarkers in Detecting Acute Rejection in Kidney Transplantation

Medicine has evolved from the so-called experience-based medicine to evidence-based medicine, which is now evolving into precision-based medicine [...]

Identification of PDCD1 as a potential biomarker in acute rejection after kidney transplantation via comprehensive bioinformatic analysis.

Acute rejection is a determinant of prognosis following kidney transplantation. It is essential to search for novel noninvasive biomarkers for early diagnosis and prompt treatment. Gene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the intersected differentially expressed genes (DEGs) was calculated. We conducted the DEGs with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Distribution of immune cell infiltration was calculated by CIBERSORT. A hub gene marker was identified by intersecting the rejection-related genes from WGCNA and a selected KEGG pathway-T cell receptor signaling pathway (hsa04660), and building a protein-protein interaction network using the STRING database and Cytoscape software. We performed flow-cytometry analysis to validate the hub gene. A total of 1450 integrated DEGs were obtained from five datasets (GSE1563, GSE174020, GSE98320, GSE36059, GSE25902). The GO, KEGG and immune infiltration analysis results showed that AR was mainly associated with T cell activation and various T-cell related pathways. Other immune cells, such as B cells, Macrophage and Dendritic cells were also associated with the progress. After utilizing the WGCNA and PPI network, PDCD1 was identified as the hub gene. The flow-cytometry analysis demonstrated that both in CD4+ and CD8+ T cells, PD1+CD57-, an exhausted T cell phenotype, were downregulated in the acute rejection whole blood samples. Our study illustrated that PDCD1 may be a candidate diagnostic biomarker for acute kidney transplant rejection via integrative bioinformatic analysis.

Application of plasma donor-derived cell free DNA for lung allograft rejection diagnosis in lung transplant recipients

BackgroundDonor-derived cell-free DNA (dd-cfDNA) has been applied to monitor acute rejection (AR) in kidney and heart transplantation. This study was aimed to investigate the application of dd-cfDNA levels in the diagnosis of AR and chronic lung allograft dysfunction (CLAD) among the lung transplantation recipients (LTRs).MethodsOne hundred and seventy LTRs were enrolled at the First Affiliated Hospital of Guangzhou Medical University between 1 June 2015 and 30 March 2021. Patients were divided into 4 groups: stable group, AR group, infection group and CLAD group. The level of dd-cfDNA was analyzed using target region sequencing and the performance characteristics of dd-cfDNA for diagnosis of AR and CLAD were determined, respectively.ResultsKruskal–Wallis test showed that there were some significant differences in the level of dd-cfDNA (%) among the 4 groups, with p < 0.001. Among them, the level of dd-cfDNA (%) was highest (median 2.17, IQR [1.40–3.82]) in AR group, and higher in CLAD group (median 1.07, IQR [0.98–1.31]), but lower in infection group (median 0.71, IQR [0.57–1.07]) and lowest in stable group (median 0.71, IQR [0.61–0.84]). AUC-ROC curve analysis showed that the threshold of dd-cfDNA for AR was 1.17%, with sensitivity being 89.19% and specificity being 86.47%, and the optimal threshold of 0.89% was determined of CLAD, with sensitivity being 95.00% and specificity of 76.99%.ConclusionsPlasma dd-cfDNA could be a useful tool for the assessment of lung allograft rejection, including AR and CLAD, and holds promise as a noninvasive biomarker for “allograft injury” in both acute and chronic rejection following lung transplantation.