Acute Renal Allograft Rejection Research Articles

Impact of CD 28, CD86, CTLA-4 and PD-1 genes polymorphisms on acute renal allograft rejection and graft survival among Egyptian recipients

To study the impact of four gene polymorphisms on acute renal allograft rejection (AR) and graft survival among Egyptian population. These 4 gene polymorphisms include: (1) CD 28 (rs3116496), (2) CD86 (rs1129055), (3) CTLA-4 (rs3087243), (4) PD-1 (rs2227982). This is a non-concurrent cohort study including 50 kidney transplant recipients diagnosed histopathologically as (AR) [study group] and another 50 matched allograft recipients without AR [control group]. Blood samples were taken from both groups and subjected to genotyping for the selected four genetic polymorphisms by TaqMan genotyping assay. The difference in genotypic distribution of CD 28: rs3116496 and CD86: rs1129055 wasn't statistically significant between the study and control groups (P = 0.22 and 0.33 respectively) and also both polymorphisms had no effect on graft survival (P = 0.36 and 0.74 respectively) while the addition of C allele to IVS3 +17T/C polymorphism in CD28 gene showed a protective effect against AR (P = 0.03). CTLA-4: rs3087243 AG genotype showed a protective effect against AR as it was more frequent in no rejection group compared to those with AR (P = 0.001) with a statistically significant impact on graft survival (P < 0.001), while PD-1: rs2227982 AG genotype was equally distributed between both groups (variant of unknown significance). There was no detected association between CD86 polymorphism: rs1129055 and CD 28 polymorphism: rs3116496 with the development of AR. However, C allele of CD 28 IVS3 +17T/C polymorphism and CTLA-4 polymorphism: rs3087243AG genotype both demonstrated a protective effect against AR.

Prediction of acute rejection in renal allografts using shear-wave dispersion slope

Prediction of acute rejection in renal allografts using shear-wave dispersion slope

Gene Expression and Functional Analysis in Patients with Acute and Chronic Renal Allograft Rejection

Kidney transplantation is the therapy of choice for patients with end-stage kidney disease (ESKD). Nevertheless, the main limitation for long-term graft survival is immune-mediated rejection. Some authors have proposed that differences in immune effector mechanisms are influenced by underlying molecular mechanisms; thereby, the identification of differentially expressed genes in acute or chronic rejection in non-invasive samples such as urine may be essential for the identification of potential biomarkers and biological processes associated with allograft outcomes. Our aim was to explore differences in gene expression and functional categories associated with acute and chronic kidney rejection in blood, biopsy, and urine of kidney transplant patients using RNA-Seq. RNA was isolated and sequenced implementing standard protocols. Analyses were addressed to identify differentially expressed genes (DEGs) and Functional Categories of Gene Ontology comparing between samples. Then we focused on immune genes and pathways to identify their association with the allograft. We identified a significant transcriptional similarity between biopsy and urine, in comparison with blood in acute and chronic rejection. Functional analyses suggested an enrichment of immune processes such as antigen processing and presentation, and regulation of B cell receptor signaling pathway in blood of acute and chronic rejection, respectively. Additionally, we observed an increase in expression of chemokines in biopsy and urine of both outcomes along with an increase in chemokine receptors in blood. Our findings suggest that urine is suitable for identifying potential biomarkers and biological processes related to renal allograft rejection, as it shares a significant number of regulated genes with biopsy.

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.

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.

#5189 THE ASSOCIATION BETWEEN CD86 +1057G&amp;gt;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 &amp;gt;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&amp;gt;A polymorphism may provide a nonsignificant protection against acute kidney allograft rejection among Egyptian patients.

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.

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. The cumulative incidence ratio of non-melanoma skin cancer has been estimated to be > 60% compared to the general population. 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. Data regarding the use of cemiplimab in SOTR and particularly in KTR are scarce. 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. Retrospective study of kidney transplant recipients, suffering from advanced cSCC treated with cemiplimab. Sept patients suffering from advanced cSCC, treated with cemiplimab, between 2018 and 2022, in Belgium were identified. 3 patients were on corticosteroid monotherapy, 1 patient on tacrolimus monotherapy and 3 patients were on at least 2 immunosuppressive treatments at start of cemiplimab. The ORR was 42.8%, SD was seen in 14.3% and PD was found in 42.8% of the patients, respectively. Biopsy-proven acute renal allograft rejection was observed in 1 patient, who eventually lost his graft function but showed a complete tumor response to treatment. Low grade skin toxicity was seen in 1 patient of the cohort ( Fig. 1 ). The present case series shows that the use of cemiplimab in KTR with advanced cSCC who failed to respond to conventional treatment is associated with an ORR of 42.8% with minimal risk of graft rejection (14.3%) and good tolerance. Cemiplimab may therefore be a feasible treatment for KTR with advanced cSCC and this treatment should therefore not be withheld in this difficult to treat patient population.

Changes and Significance of IL-17 in Acute Renal Allograft Rejection in Rats

To investigate the changes and significance of interleukin-17 (IL-17) in acute rejection following rat kidney transplantation. Using inbred Sprague Dawley rats as donors and Wistar rats as recipients, an acute rejection model of kidney transplantation was established to evaluate the effects of IL-17. Reverse transcription polymerase chain reaction and immunohistochemistry were used to detect IL-17. Compared with those in the normal control group, the rats in the allogeneic transplantation (ATX) group had different degrees of acute rejection 3, 5, and 7 days after operation, and the expression of IL-17 mRNA in the transplanted kidney was significantly increased (P < .05). In the ATX group, acute rejection was observed 7 days after operation, and the integrated optical density (IOD) value of IL-17 was significantly increased (P < .05). Compared with the normal control group, acute rejection occurred in varying degrees at 3, 5, and 7 days after operation in the ATX group, and the IOD value of IL-17 significantly increased (P < .05). IL-17 expression is increased in acute rejection after renal transplantation in rats. Other surgical factors in addition to acute rejection had no effect on IL-17 expression in rat kidney transplants. The immunosuppressant cyclosporin A was used to prevent the expression of IL-17 in rats with acute rejection.

Through the Looking Glass: Unraveling the Stage-Shift of Acute Rejection in Renal Allografts.

Sub-optimal sensitivity and specificity in current allograft monitoring methodologies underscore the need for more accurate and reflexive immunosurveillance to uncover the flux in alloimmunity between allograft health and the onset and progression of rejection. QSant—a urine based multi-analyte diagnostic test—was developed to profile renal transplant health and prognosticate injury, risk of evolution, and resolution of acute rejection. Q-Score—the composite score, across measurements of DNA, protein and metabolic biomarkers in the QSant assay—enables this risk prognostication. The domain of immune quiescence—below a Q-Score threshold of 32—is well established, based on published AUC of 98% for QSant. However, the trajectory of rejection is variable, given that causality is multi-factorial. Injury and subtypes of rejection are captured by the progression of Q-Score. This publication explores the clinical utility of QSant across the alloimmunity gradient of 32–100 for the early diagnosis of allograft injury and rejection.

A Rat Orthotopic Renal Transplantation Model for Renal Allograft Rejection.

Renal allograft rejection limits the long-term survival of patients after renal transplantation. Rat orthotopic renal transplantation is an essential model to investigate the mechanism of renal allograft rejection in pre-clinical studies and could aid in the development of novel approaches to improve the long-term survival of renal allografts. Donor kidney implantation in rat orthotopic renal transplantation is commonly performed by end-to-side anastomosis to recipients' aorta and inferior vena cava. In this model, the donor's kidney was implanted using end-to-end anastomosis to the recipients' renal artery and renal vein. The donor's ureter was anastomosed to the recipient's bladder in an end-to-side 'tunnel' method. This model contributes to better healing of ureter-bladder anastomosis and increases the recipients' survival by avoiding interference with blood supply and venous reflux of the lower body. This model can be used to investigate the mechanisms of acute and chronic immune and pathologic rejection of renal allografts. Here, the study describes the detailed protocols of this orthotopic renal transplantation between rats.

POS-918 ADVERSE EVENTS OF COVID-19 VACCINES IN RENAL TRANSPLANT RECIPIENTS

Immunocompromised patients are particularly at increased risk of getting severe Covid-19 infection and this includes patients with renal transplant. Thus, it is pivotal for this group of patients to receive Covid-19 vaccination which was shown to reduce morbidity and mortality. However, this cohort of patients may have vaccine hesitancy as these vaccines were not tested among renal transplant recipients in clinical trials. There were also reports of acute renal allograft rejection following Covid-19 vaccination.

Pre-transplant Transcriptional Signature in Peripheral Blood Mononuclear Cells of Acute Renal Allograft Rejection.

Acute rejection (AR) is closely associated with renal allograft dysfunction. Here, we utilised RNA sequencing (RNA-Seq) and bioinformatic methods to characterise the peripheral blood mononuclear cells (PBMCs) of patients with acute renal allograft rejection. Pretransplant blood samples were collected from 32 kidney allograft donors and 42 corresponding recipients with biopsies classified as T cell-mediated rejection (TCMR, n = 18), antibody-mediated rejection (ABMR, n = 5), and normal/non-specific changes (non-AR, n = 19). The patients with TCMR and ABMR were assigned to the AR group, and the patients with normal/non-specific changes (n = 19) were assigned to the non-AR group. We analysed RNA-Seq data for identifying differentially expressed genes (DEGs), and then gene ontology (GO) analysis, Reactome, and ingenuity pathway analysis (IPA), protein—protein interaction (PPI) network, and cell-type enrichment analysis were utilised for bioinformatics analysis. We identified DEGs in the PBMCs of the non-AR group when compared with the AR, ABMR, and TCMR groups. Pathway and GO analysis showed significant inflammatory responses, complement activation, interleukin-10 (IL-10) signalling pathways, classical antibody-mediated complement activation pathways, etc., which were significantly enriched in the DEGs. PPI analysis showed that IL-10, VEGFA, CXCL8, MMP9, and several histone-related genes were the hub genes with the highest degree scores. Moreover, IPA analysis showed that several proinflammatory pathways were upregulated, whereas antiinflammatory pathways were downregulated. The combination of NFSF14+TANK+ANKRD 33 B +HSPA1B was able to discriminate between AR and non-AR with an AUC of 92.3% (95% CI 82.8–100). Characterisation of PBMCs by RNA-Seq and bioinformatics analysis demonstrated gene signatures and biological pathways associated with AR. Our study may provide the foundation for the discovery of biomarkers and an in-depth understanding of acute renal allograft rejection.

The Impact of Cardio Renal Syndrome (CRS) in Renal Transplant Recipients: A Systematic Review

Cardiovascular disease is a major cause of morbidity and mortality in patients with CKD. This risk is increased fivefold in renal transplant patients when compared to an age-matched population. This study aims to explore and focus on the risk factors, management, and outcomes of cardiorenal syndrome in renal transplant recipients and to estimate its deleterious effect on the heart and renal allograft, opening the door for future randomized clinical trials to look at the problem in more depth. The current literature has little information and data on the impact of cardiorenal syndrome on the renal allograft and heart regardless of the specific type of cardiorenal syndrome. Renal transplant recipients can develop any one of the five types of the cardiorenal syndrome because of having both conventional and established risk factors for developing CRS. These risk factors particularly the established ones or best described as non-traditional risk factors such as immunosuppressive medications, acute renal allograft rejection, suboptimal renal allograft function, anemia, infections, proteinuria, and hyperparathyroidism are usually neglected after renal transplantation. Although the prevalence of CRS is low among renal transplant recipients, we believe that is due to under diagnosis and lack of clinical trials leading to a knowledge gap in this subject area. Methodology: The present study conducted a systematic literature review and selected four Clinical trials of CRS in renal transplant recipients for datasets analysis to gain more knowledge about the risk factors contributing to CRS in renal transplant recipients and to produce a strategy to prevent CRS and manage such patients better. Results: This systematic review of the current literature revealed that the presence of non-traditional risk factors post-renal transplantation when combined with traditional risk factors can significantly increase the risk of developing CRS where the prognosis is almost always poor in such patients. The study also showed no difference in the preventive measures and management of CRS between renal transplant recipients and non-renal transplant recipients. Conclusion: Renal transplant recipients are at increased risk of developing CRS with poor outcomes compared to non-renal transplant recipients because of the additional non-traditional risk factors post-renal transplantation. However, the preventive measures and management of CRS in renal transplant recipients are similar to those used for the general population but more attention should be paid to the correction of non-traditional risk factors.

550 ARTACUS: An open-label, multicenter, phase 1b/2 study of RP1 in solid organ transplant recipients with advanced cutaneous malignancies

BackgroundSolid organ transplantation (SOT) has emerged as an important lifesaving procedure for patients with a wide range of end-organ diseases characterized by dysfunction or specific organ function failure. SOT rejection is a major complication requiring patients (pts) to undergo lifelong immunosuppression to prevent allograft rejection.1Skin cancers (SCs) including cutaneous squamous cell carcinoma (CSCC) are common post transplant malignancies.2 SC in SOT pts is generally managed with surgical resection, radiation therapy and chemotherapy or targeted therapy. Use of immune checkpoint inhibitors in SOT recipients has improved outcomes but are associated with the high risk of allograft rejection.3–5 Thus, there is a high unmet need for a safe and effective treatment that also protects pts from allograft rejection. RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity6 and clinical data in combination with nivolumab has demonstrated a high rate of deep and durable response in patients with advanced SCs.7 The objective of this study is to assess the safety and efficacy of single agent RP1 in kidney and liver transplant recipients with SCs, with focus on CSCC. After determining the safety and tolerability in the initial cohort with kidney and liver transplants the study may also enroll heart and lung transplant recipients.MethodsThis study will enroll up to 65 evaluable allograft transplantation pts with locally advanced or metastatic SCs. Key inclusion criteria are pts with confirmed recurrent, locally advanced or metastatic CSCC and up to 10 pts with non-CSCC SC, stable allograft function and ECOG performance status of ≤1. Pts with prior systemic anti-cancer treatment are allowed. Key exclusion criteria are prior treatment with an oncolytic therapy, active herpetic infections or prior complications of HSV-1 infection and a history of organ graft rejection within 12 months. Pts will receive an initial dose of 1 x 10^6 plaque-forming units (PFU) of RP1. Two weeks later they will receive 1 x 10^7 PFU of RP1 and continue every two weeks until pre-specified study endpoints are met. RP1 will be administered by intra-tumoral injection including through imaging guidance as clinically appropriate. The primary objective of the trial is to assess efficacy determined by ORR and safety of single agent RP1. Additional secondary endpoints include DOR, CR, DCR, PFS and OS.Trial RegistrationNCT04349436ReferencesFrohn C, Fricke L, Puchta JC, Kirchner H. The effect of HLA-C matching on acute renal transplant rejection. Nephrol Dial Transplant 2001;16(2):355–60.Madeleine MM, Patel NS, Plasmeijer EI, Engels EA, Bouwes Bavinck JN, Toland AE, Green AC; the Keratinocyte Carcinoma Consortium (KeraCon) Immunosuppression Working Group. Epidemiology of keratinocyte carcinomas after organ transplantation. Br J Dermatol 2017;177(5):1208–1216.Spain L, Higgins R, Gopalakrishnan K, Turajlic S, Gore M, Larkin J. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Ann Oncol 2016;27(6):1135–1137.Herz S, Höfer T, Papapanagiotou M, Leyh JC, Meyenburg S, Schadendorf D, Ugurel S, Roesch A, Livingstone E, Schilling B, Franklin C. Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient. Eur J Cancer 2016;67:66-72.Kittai AS, Oldham H, Cetnar J, Taylor M. Immune checkpoint inhibitors in organ transplant ptss. J Immunother 2017;40(7):277–281.Thomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, Smith H, Kaufman HL, Harrington KJ, Coffin RS. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer 2019 10;7(1):214.Middleton M, Aroldi F, Sacco J, Milhem M, Curti B, Vanderwalde A, Baum S, Samson A, Pavlick A, Chesney J, Niu J, Rhodes T, Bowles T, Conry R, Olsson-Brown A, Earl-Laux D, Kaufman H, Bommareddy P, Deterding A, Samakoglu S, Coffin R, Harrington K. 422 An open-label, multicenter, phase 1/2 clinical trial of RP1, an enhanced potency oncolytic HSV, combined with nivolumab: updated results from the skin cancer cohorts. J Immunother Cancer 2020;8(3): doi: 10.1136/jitc-2020-SITC2020.0422Ethics ApprovalThe study was approved by institutional review board or the local ethics committee at each participating site. Informed consent was obtained from patients before participating in the trial.

Relation of Left Ventricular Assist Device Infections With Cardiac Transplant Outcomes

Left ventricular assist device (LVAD)-specific infections (LSIs) are common in patients on LVAD support awaiting heart transplant (HT), yet their impact on post-HT outcomes is not completely understood. We hypothesized that LSIs would result in vasoplegia and negatively affect post-HT 30-day and 1-year outcomes. LSI was defined as driveline, pump, or pocket infection. The short-term outcome was a composite of acute renal failure, allograft rejection, and mortality at 30 days after HT. The long-term outcome was a composite of allograft rejection and death within 1 year after HT. We performed a retrospective analysis of 111 HT recipients bridged with durable LVAD support at our institution from May 2012 to August 2019. Of these, 63 patients had LSIs, with 94% of the infections being driveline infections. Vasoplegia was more prevalent in the LSI group but not significantly (7 vs 2 persons, p=0.3). There was no difference in the composite end point of acute renal failure, rejection, or death at 30 days (30% vs 25%, p=0.55) or 1-year end point of rejection and death (38% vs 40%, p=0.87) in patients with LSI versus those without LSI. In conclusion, LSIs were common in patients on LVAD who underwent HT in our single-center contemporary cohort. However, LSI was not associated with adverse outcomes at 30 days or at 1 year after HT.

Variable selection for longitudinal zero-inflated power series transition model

ABSTRACT In modeling many longitudinal count clinical studies, the excess of zeros is a common problem. To take into account the extra zeros, the zero-inflated power series (ZIPS) models have been applied. These models assume a latent mixture model consisting of a count component and a degenerated zero component that has a unit point mass at zero. Usually, the current response measurement in a longitudinal sequence is a function of previous outcomes. For example, in a study about acute renal allograft rejection, the number of acute rejection episodes for a patient in current time is a function of this outcome at previous follow-up times. In this paper, we consider a transition model for accounting the dependence of current outcome on the previous outcomes in the presence of excess zeros. New variable selection methods for the ZIPS transition model using least absolute shrinkage and selection operator (LASSO), minimax concave penalty (MCP) and smoothly clipped absolute deviation (SCAD) penalties are proposed. An expectation-maximization (EM) algorithm using the penalized likelihood is applied for both parameters estimations and conducting variable selection. Some simulation studies are performed to investigate the performance of the proposed approach and the approach is applied to analyze a real dataset.

18F]FDG PET/CT imaging disproves renal allograft acute rejection in kidney transplant recipients with acute kidney dysfunction: a validation cohort.

[18F]FDG PET/CT may predict the absence of acute allograft rejection (AR) in kidney transplant recipients (KTRs) with acute kidney injury (AKI). Still, the proposed threshold of 1.6 of the mean of mean standardized uptake values (mSUVmean) in the renal parenchyma needs validation. We prospectively performed 86 [18F]FDG PET/CT in 79 adult KTRs who underwent per-cause transplant biopsy for suspected AR. Biopsy-proven polyoma BK nephropathies (n = 7) were excluded. PET/CT was performed 192 ± 18min after administration of 254.4 ± 30.4MBq of [18F]FDG. The SUVmean was measured in both upper and lower poles of the renal allograft. One-way analysis of variance (ANOVA) and Tukey's studentized range test were sequentially performed. The receiver operating characteristic (ROC) curve was drawn to discriminate "AR" from non-pathological ("normal" + "borderline") conditions. The median age of the cohort was 55 [43; 63] years, with M/F gender ratio of 47/39. The mean eGFR was 31.9 ± 14.6ml/min/1.73m2. Biopsies were categorized in 4 groups: "normal" (n = 54), "borderline" (n = 9), "AR" (n = 14), or "others" (n = 2). The median [min; max] mSUVmean reached 1.72 [1.02; 2.07], 1.97 [1.55; 2.11], 2.13 [1.65, 3.12], and 1.84 [1.57; 2.12] in "normal," "borderline," "AR," and "others" groups, respectively. ANOVA demonstrated a significant difference of mSUVmean among groups (F = 13.25, p < 0.0001). The ROC area under the curve was 0.86. Test sensitivity and specificity corresponding to the threshold value of 1.6 were 100% and 30%, respectively. [18F]FDG PET/CT may help noninvasively prevent inessential transplant biopsies in KTR with AKI.

Differentiating Acute Rejection From Preeclampsia After Kidney Transplantation.

To evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses. We conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time. There were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2). In pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients. The Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.