Renal Allograft Rejection Research Articles

Artificial Urinary Biomarkers for Early Diagnosis of Acute Renal Allograft Rejection

AbstractAcute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near‐infrared fluorescence signals to report cell‐mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros‐based urinalysis discriminates allograft rejection against other non‐alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.

Artificial Urinary Biomarkers for Early Diagnosis of Acute Renal Allograft Rejection.

Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of artificial biomarker probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near-infrared fluorescence signals to report cell-mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros-based urinalysis discriminates allograft rejection against other non-alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.

Single-cell transcriptomic analysis of renal allograft rejection reveals insights into intragraft TCR clonality.

Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.

#6833 ARE KT RECIPIENTS TAKING THEIR IMMUNOSUPPRESSANT MEDICATION? PRELIMINARY EVIDENCE FROM A SUPER-SPECIALIZED TRANSPLANT CENTRE IN SUB-SAHARAN AFRICA

Abstract Background and Aims Immunosuppressant non-adherence is a leading cause of preventable renal allograft dysfunction, rejection and graft loss. The barriers to immunosuppressant adherence as well as associated risk factors of non-adherence vary across studies in different locations. This study aimed to investigate the prevalence of immunosuppressant non-adherence among adult kidney transplant recipients and identify barriers to adherence in a renal transplant cohort. Method A cross sectional survey was conducted using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS), the Immunosuppressant Therapy Barrier Scale and the Beliefs about Medicines Questionnaire. Adherence was defined according to the BAASIS, with barriers to adherence and beliefs about medicines compared between the two groups. Participants were recruited from the out-patient clinic at Zenith Medical and Kidney centre. An advert for the study was placed in consultation rooms and patients were approached to join the study when they attend appointments. IBM SPSS Statistics for Windows, Version 23 (Armonk, NY: IBM Corp) was used for data analysis. Results The rate of non-adherence was 50.7% out of 67 kidney transplant recipients attending outpatient clinic. There were statistically significant associations between non-adherence and occupation (P = 0.049). Participants who are on MMF were more adherent than those on sirolimus (97.0% vs 79.4% and 0.0% vs 8.8%) and this difference is statistically significant (P = .038). Also, participants who have had one or more post-transplant hospital admission are more non-adherent when compared with those that have never been admitted (P = .022) The only significant barrier to adherence was when patients travelled out of town (P < 0.005). Adherence was not associated with patients’ belief about their medicines. Conclusion Interventions aimed at ensuring constant access to immunosuppressant drugs and those based on habit forming may significantly improve adherence in this cohort.

#4743 OMNIGRAF (COMBINED GENE EXPRESSION AND DD-CF DNA) USE IN MONITORING RENAL ALLOGRAFT REJECTION IN MULTIORGAN TRANSPLANT RECIPIENTS

Abstract Background and Aims To date there is no clinically available non-invasive biomarker to monitor for renal allograft rejection in multiorgan transplant recipients. TruGraf (Gene expression profile) and TRAC (dd-cf DNA), as part of the biomarker panel OmniGraf, have shown to be reliable “rule out” tests for subclinical rejection in stable kidney transplant recipients. However, the validity and utility of these tests in monitoring for renal allograft rejections in the setting of multiorgan transplants has yet to be assessed. The aim of this study is to assess the feasibility of using the biomarkers individually, as well as together in the OmniGraf biomarker panel, to assist in making the decision to perform a renal allograft biopsy in multiorgan transplant recipients. Method This is an ongoing prospective, observational sample collection study in any multiorgan (kidney + non-renal organ) undergoing a renal allograft biopsy. Biopsies were considered positive if they showed rejection in the kidney based on Banff 2019 and included borderline changes as positive results. Copper-Pearson 95% CI were used for sensitivity, specificity, and accuracy; standard logit CIs were used for NPV and PPV. For TruGraf, (TX = negative result) and (not-TX = positive test). For TRAC, 0.7% was used as the threshold for all organs except for those that had a liver transplant, where a threshold of 15% was used to determine positive vs. negative. Results Paired renal allograft surveillance biopsies and biomarker samples were available for 20 patients. Of the 20, 9 (45%) were liver-kidney transplants, 6 (30%) were heart-kidney transplants, and 5 (25%) were kidney-pancreas transplants. Nine (45%) of the patients were male, 14 (70%) were White, 5 (25%) were Black, and 1 patient was Hispanic. The mean age was 50 ± 13 years. Average SrCr was 1.3 ± 0.5 mg/dL. Of the 20 paired biopsies and samples, 2 (10%) had only TruGraf results, while the other 18 (90%) had OmniGraf (TruGraf and TRAC). There were 2 rejections (borderline changes). Diagnostic performance is presented in tables 1–4. Both TruGraf and TRAC individually had NPV of 89% and 85%, respectively, and PPV of 65% and 73%, respectively. When analyzing the performance of the OmniGraf biomarker panel, OmniGraf +/+ showed a 100% PPV and OmniGraf -/- showed a 100% NPV. Conclusion In this analysis of renal allograft biopsies in a multiorgan transplant cohort, TruGraf, TRAC (when using organ-dependent thresholds) had reasonable diagnostic performance as a “rule out” test. When the tests are combined into OmniGraf, the PPV and NPV were 100% when both tests agreed with each other. These outcomes justify potential use and the need for continued analysis of the utility of the OmniGraf biomarker panel in monitoring renal allograft in multiorgan transplant recipients.

#5189 THE ASSOCIATION BETWEEN CD86 +1057G>A POLYMORPHISM AND ACUTE KIDNEY ALLOGRAFT REJECTION AMONG EGYPTIAN PATIENTS

Abstract Background and Aims T-cell mediated immune response is crucial in kidney transplantation and plays an important role in allograft rejection. . CD86 is a costimulatory molecule that participates in the regulation of T-cell lymphocytes activation. Single nucleotide polymorphisms (SNPs) located in this gene have been studied with inconsistent results. The aim of the study was to examine the association between (rs1129055:G/A) polymorphism in the CD86 gene and the development of acute renal allograft rejection among Egyptian patients. Method In this non- concurrent cohort study, we included a group of 50 kidney transplant recipients diagnosed by acute allograft rejection (AR) (which was defined by clinical diagnosis, elevated serum creatinine >30% of basal line in the absence of other pathology including infection, urinary tract obstruction, allograft artery stenosis or calcineurin toxicity and responded to treatment by immunosuppression and was confirmed by positive biopsy that was graded according to BANFF classification) and another matched group of 50 kidney transplant recipients without AR and all of the 100 patients were genotyped by direct sequencing for CD 86 polymorphism (rs1129055:G/A) by TaqMan genotyping assay. Results The genotypic frequencies of CD 86 rs1129055 SNP in the acute rejection group were 72% GG, 28% AG and 0% AA while in the no rejection group it were 66% GG, 30% AG and 4% AA. The AA genotype and A allele at position +1057 in the CD86 gene were more frequent in patients without AR (4% and 23.4%, respectively) compared with those showing an AR (0% and 16.2%, respectively). The odds of acute rejection weren`t statistically significant either in dominant or recessive model (P = 0.665 and 0.475 respectively). Conclusion These results suggest that AA genotype and A allele of CD86 +1057G>A polymorphism may provide a nonsignificant protection against acute kidney allograft rejection among Egyptian patients.

Autoantibodies against DNA topoisomerase I promote renal allograft rejection by increasing alloreactive T cell responses

Antibodies reactive to self-antigens are an important component of posttransplant immune responses. The generation requirements and functions of autoantibodies, as well as the mechanisms of their influence on alloimmune responses, still remain to be determined. Our study investigated the contribution of autoimmunity during rejection of renal allografts. We have previously characterized a mouse model in which the acute rejection of a life-supporting kidney allograft is mediated by antibodies. At rejection, recipient sera screening against >4000 potential autoantigens revealed DNA topoisomerase I peptide 205-219 (TI-I205-219) as the most prominent epitope. Subsequent analysis showed TI-I205-219-reactive autoantibodies are induced in nonsensitized recipients of major histocompatibility complex–mismatched kidney allografts in a T cell–dependent manner. Immunization with TI-I205-219 broke self-tolerance, elicited TI-I205-219 immunoglobin G autoantibodies, and resulted in acute rejection of allogeneic but not syngeneic renal transplants. The graft loss was associated with increased priming of donor-reactive T cells but not with donor-specific alloantibodies elevation. Similarly, passive transfer of anti-TI-I205-219 sera following transplantation increased donor-reactive T cell activation with minimal effects on donor-specific alloantibody levels. The results identify DNA topoisomerase I as a novel self-antigen in transplant settings and demonstrate that autoantibodies enhance activation of donor-reactive T cells following renal transplantation.

Assessment of renal allograft rejection with diffusion tensor imaging.

To investigate the value of DTI in differentiation of renal allograft rejection from well-functioning stable allograft, using fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values. In this prospective study, 22 transplant recipients with well-functioning stable allograft (group A) and 20 patients with renal allograft rejection (group B + C) were recruited over a period of 19 months from January 2018 to July 2019. DTI-MRI was performed in all the patients, and FA and ADC values were measured in cortical and medullary regions of the transplanted kidney. On biopsy, graft rejection was classified as acute (group B) (n = 7) and chronic graft rejection (group C) (n = 13) based on the BANNF scoring system. Statistical analysis was performed using STATA v.14.0. Statistically significant difference between group A and group B + C was noted for cortical (p < 0.001), and medullary (p = 0.003) FA values, and cortical (p = 0.020), and medullary (p = 0.046) ADC values. Cortical(p < 0.001) and Medullary(p = 0.020) FA values showed statistically significant difference between group A and group C, and cortical FA value(p = 0.012) also showed statistically significant difference between group B and group C. AUC (to differentiate between renal allograft rejection and well-functioning stable allograft) for cortical, and medullary FA values and cortical and medullary ADC values were 0.853(p < 0.001), 0.757(p = 0.004), 0.709(p = 0.021) and 0.736(p = 0.009), respectively. DTI is a promising functional MRI technique for the non-invasive assessment of renal allograft function. Diffusion parameters, such as FA and ADC values, can be useful in the differentiation of renal allograft rejection from well-functioning stable allograft.

Donor-Derived Cell-Free DNA and Active Rejection in Renal Allografts.

Renal allograft rejection contributes to significant morbidity and graft loss. In this setting, early detection of rejection is of paramount importance, which currently relies on histopathology. A reliable non-invasive marker to predict rejection would make surveillance and decision-making easier. Donor-derived cell-free DNA (dd-Cf-DNA) has recently been reported as an emerging tool to predict rejection noninvasively. The utility of cell-free DNA in clinical practice has so far not been studied in an Indian setting. As it offers direct clinical application, we have chosen to investigate this biomarker as a tool to predict rejection. A pilot study with convenient sample size was designed, as this is the first of its kind study so far reported from India. Patients being evaluated with a graft biopsy for graft dysfunction were included. Patients with stable graft function, defined as creatinine within 10% of their best creatinine and no proteinuria for the preceding 12 months, were also included. Ten milliliters of whole blood from each of the recipients was collected in DNA isolation tubes. Two milliliters of donor blood was also obtained in ethylenediaminetetraacetic acid (EDTA) tubes. All recipients also provided a buccal swab. Total cell-free DNA was extracted from 2 ml of recipient plasma using circulating DNA isolation kit. Upon identification of the donor-specific DNA marker for each of the patients from the paired donor sample, presence of the cell-free DNA fraction in the recipient's plasma was detected and quantified. Renal biopsy reports and clinical details were also recorded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were analyzed. Receiver operating characteristic (ROC) curve analysis was also performed. A total of 31 patients were recruited. Twenty patients underwent graft biopsies for graft dysfunction, of which 12 patients had features of active rejection and eight had nonrejection causes of graft dysfunction. Eleven patients with stable graft were included in the study. In our study, dd-Cf-DNA performed best in predicting antibody-mediated rejection (ABMR) and higher grades of T-cell-mediated rejection (TCMR) (1B). It did not detect TCMR 1A accurately. It serves as a good marker to rule out rejection. It gave a NPV of 100% for TCMR 1B or ABMR, 100% for ABMR alone, and 81% for any rejection. dd-Cf-DNA percentages outperform absolute concentrations in their discriminatory ability. We have demonstrated the diagnostic accuracy of dd-Cf-DNA in predicting active rejection of the renal allograft. It performs well in ABMR and higher grades of TCMR. This is the first of its kind study reported from India, to the best of our knowledge. This tool serves as a good rule out test for ABMR and higher grades of TCMR. It performs poorly in TCMR 1A.

Clinical Outcomes of T-Cell-Mediated Rejection in Renal Allografts

Clinical Outcomes of T-Cell-Mediated Rejection in Renal Allografts

A Machine Learning Analysis of Prognostic Genes Associated With Allograft Tolerance After Renal Transplantation

In this study, we aimed to identify transplantation tolerance (TOL)-related gene signature and use it to predict the different types of renal allograft rejection performances in kidney transplantation. Gene expression data were obtained from the Gene Expression Omnibus (GEO) database, differently expressed genes (DEGs) were performed, and the gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted. The machine learning methods were combined to analyze the feature TOL-related genes and verify their predictive performance. Afterward, the gene expression levels and predictive performances of TOL-related genes were conducted in the context of acute rejection (AR), chronic rejection (CR), and graft loss through heatmap plots and the receiver operating characteristic (ROC) curves, and their respective immune infiltration results were also performed. Furthermore, the TOL-related gene signature for graft survival was conducted to discover gene immune cell enrichment. A total of 25 TOL-related DEGs were founded, and the GO and KEGG results indicated that DEGs mainly enriched in B cell-related functions and pathways. 7 TOL-related gene signature was constructed and performed delightedly in TOL groups and different types of allograft rejection. The immune infiltration analysis suggested that gene signature was correlated with different types of immune cells. The Kaplan–Meier (KM) survival analysis demonstrated that BLNK and MZB1 were the prognostic TOL-related genes. Our study proposed a novel gene signature that may influence TOL in kidney transplantation, providing possible guidance for immunosuppressive therapy in kidney transplant patients.

Integrative metagenomic and metabolomic analyses reveal the role of gut microbiota in antibody-mediated renal allograft rejection

BackgroundAntibody-mediated rejection (AMR) remains one of the major barriers for graft survival after kidney transplantation. Our previous study suggested a gut microbiota dysbiosis in kidney transplantation recipients with AMR. However, alternations in gut microbial function and structure at species level have not been identified. In the present study, we investigated the metagenomic and metabolic patterns of gut microbiota in AMR patients to provide a comprehensive and in-depth understanding of gut microbiota dysbiosis in AMR.MethodsWe enrolled 60 kidney transplantation recipients, 28 showed AMR and 32 were non-AMR controls with stable post-transplant renal functions. Shotgun sequencing and untargeted LC/MS metabolomic profiling of fecal samples were performed in kidney transplantation recipients with AMR and controls.ResultsTotally, we identified 311 down-regulated and 27 up-regulated gut microbial species associated with AMR after kidney transplantation, resulting in the altered expression levels of 437 genes enriched in 22 pathways, of which 13 were related to metabolism. Moreover, 32 differential fecal metabolites were found in recipients with AMR. Among them, alterations in 3b-hydroxy-5-cholenoic acid, l-pipecolic acid, taurocholate, and 6k-PGF1alpha-d4 directly correlated with changes in gut microbial species and functions. Specific differential fecal species and metabolites were strongly associated with clinical indexes (Cr, BUN, etc.), and could distinguish the recipients with AMR from controls as potential biomarkers.ConclusionsAltogether, our findings provided a comprehensive and in-depth understanding of the correlation between AMR and gut microbiota, which is important for the etiological and diagnostic study of AMR after kidney transplantation.

Co-inhibition of immunoproteasome subunits LMP2 and LMP7 enables prevention of transplant arteriosclerosis.

The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts. However, the role and mechanisms of selective inhibition of a single immunoproteasome subunit to prevent immune-mediated vascular allograft rejection and TA is not clear. The effect and potential mechanism of combined or individual inhibition of peptidolytically active immunoproteasome LMP7 (β5i) and LMP2 (β1i) subunits on immune rejection-mediated TA was investigated using the epoxyketone inhibitor ONX 0914, and the recently developed LMP7-selective inhibitor KZR-329 and LMP2-selective inhibitor KZR-504 in a rat aorta transplantation model. We find that co-inhibition of LMP7 and LMP2 in allogeneic recipients significantly suppressed T-cell activation and function by expressing inhibitory surface markers and then activating inhibitory signals. Moreover, co-inhibition of LMP7 and LMP2 substantially reduced the number of immunoglobulin G-secreting cells and plasma cells and production of alloantibodies through activating the unfolded protein response and incapacitating the survival niche of plasma cells in the bone marrow. Consequentially, the accumulation of inflammatory cytokines, complement, and antibodies is reduced and the apoptosis of vascular wall cells decreased in aortic allografts via LMP7 and LMP2 co-inhibition with ONX 0914 treatment or combined KZR-329 and KZR-504 treatment. However, neither individual inhibition of LMP7 by KZR-329 nor individual inhibition of LMP2 by KZR-504 showed suppression of immune rejection and TA. We define a critical role of LMP7 and LMP2 in TA and strongly propose co-inhibition of both immunoproteasome subunits as promising therapeutic approach to suppress TA and allograft rejection.

Quantitative ultrasound for non-invasive evaluation of subclinical rejection in renal transplantation.

This study aimed to investigate the predictive efficacy of shear-wave elastography, superb microvascular imaging (SMI), and CEUS for allograft rejection in kidney transplants without graft dysfunction. From January 2021 to November 2021, 72 consecutive patients who underwent both allograft biopsy and ultrasound were evaluated. Blood test results were obtained within a week of the ultrasound examinations, which were performed before the protocol biopsy. Resistive index (RI), tissue viscoelasticity, vascular index, and quantitative CEUS parameters were measured. Patients were divided based on biopsy results into the rejection and non-rejection groups. Among the 72 patients, 21 patients had pathological characteristics of acute rejection. RI of allograft was significantly higher in the rejection group (p = 0.007), compared to the non-rejection group. There were no significant between-group differences in vascular indices of SMI, mean elasticity, and mean viscosity. Meanwhile, among the parameters obtained by the time-intensity curve on CEUS, the cortical and medullary ratios of average contrast signal intensity, peak enhancement, wash-in area AUC, wash-in perfusion index, wash-out AUC, and wash-in and wash-out AUC were significantly different between the two groups (p < 0.05). In the receiver operating characteristic curve analysis for predicting allograft rejection, the AUC was 0.853 for the combination of six CEUS parameters, RI, and blood urea nitrogen. Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for diagnosing subclinical allograft rejection. Furthermore, the combination of CEUS parameters, RI, and blood urea nitrogen may be helpful for the early detection of renal allograft rejection. • Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for the diagnosis of subclinical allograft rejection. • On CEUS, the C/M ratios of MeanLin, PE, WiAUC, WiPI, WoAUC, and WiWoAUC are significantly lower in the rejection group; the combination of these showed reliable predictive performance for rejection. • The combination of CEUS parameters, RI, and BUN has a high predictive capability for subclinical allograft rejection.

Immune checkpoint inhibitors to metastatic melanoma and renal allograft rejection: A case report

A male patient who underwent a pre-emptive renal allograft and, nine years after the transplant, was diagnosed with nodular melanoma

Level-Set-Based Kidney Segmentation from DCE-MRI Using Fuzzy Clustering with Population-Based and Subject-Specific Shape Statistics.

The segmentation of dynamic contrast-enhanced magnetic resonance images (DCE-MRI) of the kidney is a fundamental step in the early and noninvasive detection of acute renal allograft rejection. In this paper, a new and accurate DCE‑MRI kidney segmentation method is proposed. In this method, fuzzy c-means (FCM) clustering is embedded into a level set method, with the fuzzy memberships being iteratively updated during the level set contour evolution. Moreover, population‑based shape (PB-shape) and subject-specific shape (SS-shape) statistics are both exploited. The PB-shape model is trained offline from ground-truth kidney segmentations of various subjects, whereas the SS-shape model is trained on the fly using the segmentation results that are obtained for a specific subject. The proposed method was evaluated on the real medical datasets of 45 subjects and reports a Dice similarity coefficient (DSC) of 0.953 ± 0.018, an intersection-over-union (IoU) of 0.91 ± 0.033, and 1.10 ± 1.4 in the 95-percentile of Hausdorff distance (HD95). Extensive experiments confirm the superiority of the proposed method over several state-of-the-art level set methods, with an average improvement of 0.7 in terms of HD95. It also offers an HD95 improvement of 9.5 and 3.8 over two deep neural networks based on the U-Net architecture. The accuracy improvements have been experimentally found to be more prominent on low-contrast and noisy images.

Cemiplimab for advanced cutaneous squamous cell carcinoma in kidney transplant recipients.

Kidney transplant recipients (KTR) are at increased risk of cancer due to chronic immunosuppression. Non-melanoma skin cancer has an excess risk of approximately 250 times higher than the general population. Moreover, in solid organ transplant recipients (SOTR) these cancers have a more aggressive behavior, with an increased risk of metastasis and death. Cemiplimab, a human monoclonal IgG4 antibody against programmed cell death (PD-1) has shown considerable clinical activity in metastatic and locally advanced cutaneous squamous cell carcinoma (cSCC) in patients for whom no widely accepted standard of care exists. Cemiplimab has therefore been approved since 2018 for the treatment of advanced cSCC. However, data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce and based on published case reports and small case series. In this study, we report on the real-life outcome of cemiplimab use in a Belgian cohort of seven KTR suffering from advanced cSCC. To report on the overall response rate (ORR) and safety of cemiplimab in KTR in Belgium. Seven patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. Three patients were on corticosteroid monotherapy, one patient on tacrolimus monotherapy and three patients were on at least 2 immunosuppressants at start of cemiplimab. The ORR was 42.8%, stable disease was seen in 14.3% and progressive disease was found in 42.8% of the patients, respectively. The median administered number of cycles was 12, interquartile range (IQR) 25-75 [3.5 - 13.5]. All patients were treated with surgery before administration of cemiplimab, 71.4% received additional radiotherapy and only 1 patient was treated with chemotherapy prior to receiving cemiplimab. Biopsy-proven acute renal allograft rejection was observed in one patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in one patient of the cohort. The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to previous surgery, chemo - and/or radiotherapy treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance.

Allograft Rejection in Kidney Transplantation – A Retrospective Study of Impact on Graft and Patient Outcome

Background: Renal allograft rejection is a major cause of graft dysfunction, and it is a predictor of long-term allograft loss. Advances in immunosuppression have decreased the influence of acute rejection on graft survival. In this study, we assessed clinicopathological profile and immediate and long-term treatment outcomes of different types of allograft rejections in our institute. Materials and Methods: We retrospectively analyzed patients who underwent renal transplantation and had biopsy-proven renal allograft rejections from January 2010 to December 2019 in our institute. Recipient–donor characteristics at the time of transplantation and graft function post transplantation were documented. Patients were followed up till graft loss or patient loss or a minimum 12-month period after rejection episode for all survived patients. Results: Allograft rejection occurred in 88/424 (20.75%) renal transplant recipients during the study period. Active antibody-mediated rejection (ABMR) was the most common type of rejection (40.9%) and was common in early posttransplant period also (54.5%). Graft dysfunction was the dominant presentation in all groups except chronic active ABMR, where heavy proteinuria was common. Chronic active ABMR was common (37.5%) in second episode of rejection. Overall graft survival, death-censored graft survival, and patient survival at the end of the study were 52.27%, 82.95%, and 69.3%, respectively. Conclusion: Renal allograft rejection decreases both graft and patient survival. Hence recommend regular surveillance for early detection and treatment.

Frequency of Histological Patterns of Renal Allograft Biopsies– One Year of Renal Allograft Experience

Objective: To ascertain the frequency and spectrum of histopathological findings in renal allograft rejection cases received in one year.&#x0D; Study Design: Cross-sectional study.&#x0D; Place and Duration of Study: Histopathology Department of Armed Forces Institute of Pathology, Rawalpindi Pakistan from Jun 2020 to May 2021.&#x0D; Methodology: Renal allograft rejection biopsy cases of 62 male and female patients between the ages of 15-60 years having undergone renal transplant with prior end-stage renal disease over one year were collected. Frequency and histopathological findings were studied after classifying them according to the Banff Classification.&#x0D; Results: Cellular (T-cell mediated) rejection accounted for more than half of the cases under study, making it the most common cause of transplant rejection in our demographical area. It accounted for 28 (45.2%) slides of all the biopsies studied. Antibody-mediated rejection followed next with 17 (27.4%) slides, with seven slides (11.3%) of the cases borderline for changes accounting for a T-Cell mediated rejection. About 10 (16.2%) were non-specific changes negative for transplant rejection criteria.&#x0D; Conclusion: Our study was instrumental in establishing rejection patterns and major rejection sub-types while classified under the Banff Classification in our demographical area. The cataloguing of the cases and the major underlying cause would help minimize rejection rates resulting in better clinical outcomes and increased patient survival.

P8.031: Outcome of Simultaneous Pancreas Kidney Transplantation A Single Center Experience

Introduction: Simultaneous simultaneous pancreas-kidney (SPK) transplantation is one of the treatment options for type 1 diabetes mellitus (T1DM) patients with chronic kidney disease stage 5. The SPKT outcomes are reported to be excellent with a 5 year patient, kidney and pancreas graft survival of 88%, 77% and 69% respectively. Here, we present data regarding outcome of the SPKT done at our institution. Method: We studied patients who underwent SPKT in our institution. 11 T1DM patients who were CKD-5 underwent SPKT from 2014 to 2022. Their graft function and complications were analysed. Results: A total of 12 patients were studied. 50 % were males and 50% were females. Mean age at diagnosis was 14 ± 4 years. Mean age at transplantation was 32 ± 6 years. Mean hemodialysis (HD) vintage was 22 ± 14 months. Mean age of donor was 31 ± 10 years. Induction was with Basiliximab in 1 patient, Alemtuzumab in 5 patients and ATG in 6 patients. Maintenance immunosuppression was tacrolimus and mycophenolate in 8 patients; and, tacrolimus, mycophenolate and everolimus in 2 patients Mean duration of hospital stay was 30 ± 18 days. Mean graft kidney function at 1 month was 1.38 ± 0.48 mg/dl. Mean graft kidney function at 6 months was 1.30 ± 0.47 mg/dl. At 1 year, one patient had severe renal graft dysfunction requiring HD. Among the other 10 patients who completed one year, mean kidney graft function at 1 year was 1.25 ± 0.23 mg/dl. Three (25%) patients had renal allograft loss with need for initiation of HD after 30, 21 and 6 months. Two patients with renal allograft loss required insulin after 19 and 25 months. Three (25%) patients had delayed graft function. Five (41.7%) patients had renal allograft rejection at 1 month. Among the five, three had another episode of rejection at 17, 11 and 4 months. Three (25%) patients had suspected pancreatic graft rejection at POD 13, 13 and 14, which resolved with intravenous steroids. Eight (66.6%) patients had infections in the first year following transplant which included urosepsis, LRTI, tuberculosis, varicella, CMV, cellulitis, periodontal abscess, dental caries and esophagial candidiasis. Seven (58.3%) had surgical complications including pseudo aneurysm of graft pancreas, urinoma, perinephric hematoma, abdominal bleed and DIC, jejujno-jejunal anastomotic site bleed, kinked renal vein requiring re-exploration, graft pancreas fat necrosis with impending GB rupture and peritonitis, and splenic vein thrombosis requiring re-exploration. Other complications noted were incisional hernia, subacute intestinal obstruction, bilateral femoral head avascular necrosis and acute myeloid leukemia. Conclusion: The graft survival and outcomes in our institution is comparable to that of international standards. Surgical complications were noted to be higher compared to renal transplantation. SPK remains to be treatment of choice in T1DM patients with ESRD.