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Project description:Background: T-cell mediated rejection (TCMR) remains a significant challenge after kidney transplantation and is associated with reduced allograft outcome. Previous research highlighted the critical role of TCMR-induced renal epithelial injury. Yet, the detailed cellular origin of these injury responses and the associated clinical implications remain poorly understood. Methods: To induce acute TCMR, we used mouse models of allogeneic (C57BL/6 to BALB/c and BALB/c to C57BL/6) kidney transplantation and syngeneic controls (C57BL/6 to C57BL/6 and BALB/c to BALB/c). Molecular changes were analyzed 7 days post-transplant using single-nucleus RNA sequencing and spatial transcriptomics. Results were compared with snRNA-seq data from three human TCMR biopsies and three stable allografts without rejection. The clinical impact of TCMR-induced epithelial injury was evaluated using marker gene sets on bulk transcriptomic data from 1292 kidney allografts, including 95 TCMR samples, with allograft outcome. Results: Mouse kidneys from allogeneic transplants exhibited all hallmark histological features of TCMR. Single-nucleus RNA sequencing revealed TCMR-induced injured cell states and significant gene expression changes particularly in proximal tubules (PT) and thick ascending limbs (TAL). Spatial transcriptomics showed a heterogeneous spatial distribution of these injured cell states and proximity to leukocytes. Cross-species analysis confirmed similar injured PT and TAL cell states in human TCMR. Signatures of a severely injured TCMR-induced TAL cell state correlated strongly with allograft survival in a large kidney transplant cohort specifically after TCMR. Conclusion: This is the first study showing kidney allograft outcome with distinct injured epithelial cell states. We found a particularly strong correlation between kidney allograft survival and TAL injury in TCMR, which occurred with reduced proximity to leukocytes, suggesting potential epithelial injury driven by non-immune mechanisms.
2025-11-21 | GSE284715 | GEO
Project description:Background: T-cell mediated rejection (TCMR) remains a significant challenge after kidney transplantation and is associated with reduced allograft outcome. Previous research highlighted the critical role of TCMR-induced renal epithelial injury. Yet, the detailed cellular origin of these injury responses and the associated clinical implications remain poorly understood. Methods: To induce acute TCMR, we used mouse models of allogeneic (C57BL/6 to BALB/c and BALB/c to C57BL/6) kidney transplantation and syngeneic controls (C57BL/6 to C57BL/6 and BALB/c to BALB/c). Molecular changes were analyzed 7 days post-transplant using single-nucleus RNA sequencing and spatial transcriptomics. Results were compared with snRNA-seq data from three human TCMR biopsies and three stable allografts without rejection. The clinical impact of TCMR-induced epithelial injury was evaluated using marker gene sets on bulk transcriptomic data from 1292 kidney allografts, including 95 TCMR samples, with allograft outcome. Results: Mouse kidneys from allogeneic transplants exhibited all hallmark histological features of TCMR. Single-nucleus RNA sequencing revealed TCMR-induced injured cell states and significant gene expression changes particularly in proximal tubules (PT) and thick ascending limbs (TAL). Spatial transcriptomics showed a heterogeneous spatial distribution of these injured cell states and proximity to leukocytes. Cross-species analysis confirmed similar injured PT and TAL cell states in human TCMR. Signatures of a severely injured TCMR-induced TAL cell state correlated strongly with allograft survival in a large kidney transplant cohort specifically after TCMR. Conclusion: This is the first study showing kidney allograft outcome with distinct injured epithelial cell states. We found a particularly strong correlation between kidney allograft survival and TAL injury in TCMR, which occurred with reduced proximity to leukocytes, suggesting potential epithelial injury driven by non-immune mechanisms.
2025-11-21 | GSE284717 | GEO
Project description:BackgroundT cell-mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy, and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival.MethodsWe developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility, and allograft survival.Results18S rRNA normalized levels of mRNA for FOXP3 (P = 0.01, Kruskal-Wallis test), CD25 (P = 0.01), CD3E (P < 0.0001), and perforin (P < 0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC = 0.764; 95% confidence interval, 0.611-0.917; P = 0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781-0.997; P < 0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P = 0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P = 0.047) but not after controlling for TCMR reversal (P = 0.477).ConclusionsUrinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.
| S-EPMC8024419 | biostudies-literature
Project description:Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .
| S-EPMC11333280 | biostudies-literature
Project description:The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.
| S-EPMC9299170 | biostudies-literature
Project description:T cell-mediated rejection (TCMR) remains a challenge in kidney transplantation. Based on a histopathological biopsy examination, patients can be classified into groups defining their kidney’s status, i.e. no rejection (NR), borderline rejection (BR) and acute rejection (AR). Yet, this classification is not perfect, since for the borderline cases, a number of patients may or may not require further clinical intervention. Although in other studies, detection of early signs of rejection in the urine proteome was already attempted, these results failed to be replicated. Thus, a robust method of classification by biopsy proteome profiling may provide a possible solution. Unlike for urine or small extracellular vesicle’s analysis, biopsy proteome directly reflects the subclinical changes leading to allograft loss. Kidney tissue biopsies from patients classified into NR, BR and AR groups based on the current Banff guidelines were subjected to a mass spectrometry based proteomic profiling. Using qualitative, quantitative, profile and ROC analysis, a set of four proteins (i.e., GNB4, PDK1, AGXT and CD73) was chosen for further validation using immunohistochemical (IHC) methods. Proteomic analysis identified 2547 proteins across all groups with their abundance profiles showing high degree of similarity between the BR and AR datasets. In a quantitative comparison, GNB4 and AGXT emerged as the proteins significantly differentiating the groups with the highest fold change. Moreover, AGXT was indicated as a potential biomarker candidate following a ROC analysis. Morover, PDK1 and CD73 were found to best classify the samples in a binary fashion. These candidate biomarkers were validated using an IHC approach, where only upregulation of GNB4 in immune cells and PDK1 in macrophages could be confirmed, with no significant changes in the tubular epithelium. Based on these results, GNB4 and PDK1 presence in the immune cells and macrophages has been identified as an interesting target for further extensive studies. If their relevance was to be confirmed in a large patient cohort, their analysis could potentially serve an extension of the already established histopathological classification in the context of kidney transplant rejection. This retrospective study was approved by the Bioethics Committee of the Medical University of Gdańsk no. NKBBN/201/2021.
2025-10-27 | PXD064523 | Pride
Project description:No tool is available for the early assessment of response to antibody-mediated rejection (ABMR) therapies in kidney allograft recipients. This study was designed to define a dynamic composite prognostic ABMR score to predict kidney allograft survival, integrating the disease characteristics at diagnosis and the response to treatment. Among 1978 kidney recipients who underwent transplant between 2008 and 2014, we included 278 patients diagnosed with active ABMR and receiving standard treatment, including plasma exchange, intravenous Ig, and rituximab. Patients were prospectively assessed at diagnosis and after treatment for clinical data, histologic characteristics (allograft biopsy specimen), and donor-specific anti-HLA antibodies (DSA). The dynamic ABMR prediction model included GFR (P<0.001) and presence of interstitial fibrosis/tubular atrophy (P=0.003) at diagnosis and changes in GFR (P<0.001), peritubular capillaritis Banff score (P=0.002), and DSA mean fluorescence intensity (P<0.001) after treatment. Overall, this model showed good calibration and discrimination (C-statistic=0.84). The ABMR prognostic score derived from the prediction model identified three risk strata with 6-year kidney allograft survival rates of 6.0% (high-risk group, n=40), 44.9% (intermediate-risk group, n=36), and 84.4% (low-risk group, n=202), and it provided greater net clinical benefit to patients than did considering them all to have the same level of risk of allograft loss. The performance of the ABMR prognostic score was validated in an independent cohort of 202 kidney recipients with ABMR (C-statistic=0.79). The ABMR prognostic score could be used to inform therapeutic decisions in clinical practice and for the design of clinical trials.
| S-EPMC5791064 | biostudies-literature
Project description:Fc gamma receptors (Fc?Rs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 Fc?Rs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37-9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08-3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.
| S-EPMC6582937 | biostudies-literature
Project description:In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete antitumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living-unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of antitumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple antitumor and anti-allograft immunity.
| S-EPMC7395855 | biostudies-literature
Project description:C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.
| S-EPMC6418012 | biostudies-literature