Browsing by Author "Shaw, Brian I"

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    Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021-09) Xu, He; Lee, Hui-Jie; Schmitz, Robin; Shaw, Brian I; Li, Shu; Kirk, Allan D
    Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naïve T (TNaïve ) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaïve cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+ CD31+ ) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+ CD31+ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57- cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction. Trial Registration: ClinicalTrials.gov - NCT00565773.
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    An age-independent gene signature for monitoring acute rejection in kidney transplantation.
    (Theranostics, 2020-01) Shaw, Brian I; Cheng, Daniel K; Acharya, Chaitanya R; Ettenger, Robert B; Lyerly, Herbert Kim; Cheng, Qing; Kirk, Allan D; Chambers, Eileen T
    Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. Methods: To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. Results: We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. Conclusion: We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.
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    Correlation of pre-operative imaging characteristics with donor outcomes and operative difficulty in laparoscopic donor nephrectomy.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2019-09-25) Schwartz, Fides R; Shaw, Brian I; Lerebours, Reginald; Vernuccio, Federica; Rigiroli, Francesca; Gonzalez, Fernando; Luo, Sheng; Rege, Aparna S; Vikraman, Deepak; Hurwitz-Koweek, Lynne; Marin, Daniele; Ravindra, Kadiyala
    This study aimed to understand the relationship of pre-operative measurements and risk factors on operative time and outcomes of laparoscopic donor nephrectomy. 242 kidney donors between 2010 and 2017 were identified. Patient's demographic, anthropomorphic and operative characteristics were abstracted from the electronic medical record. Glomerular filtration rates (GFR) were documented before surgery, within 24 hours, 6, 12 and 24 months after surgery. Standard radiological measures and kidney volumes, subcutaneous and perinephric fat thicknesses were assessed by three radiologists. Data were analyzed using standard statistical measures. There was significant correlation between cranio-caudal and latero-lateral diameters (p<0.0001) and kidney volume. The left kidney was transplanted in 92.6% of cases and the larger kidney in 69.2%. Kidney choice (smaller vs larger) had no statistically significant impact on the rate of change of donor kidney function over time adjusting for age, sex and race (p=0.61). Perinephric fat thickness (+4.08 min) and surgery after 2011 were significantly correlated with operative time (p≤0.01). In conclusion, cranio-caudal diameters can be used as a surrogate measure for volume in the majority of donors. Size may not be a decisive factor for long-term donor kidney function. Perinephric fat around the donor kidney should be reported to facilitate operative planning.
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    Ensuring equity in psychosocial risk assessment for solid organ transplantation: a review
    (Current Opinion in Organ Transplantation) Obayemi, Joy E; Shaw, Brian I; Greenberg, Goni-Katz; Henson, Jackie; McElroy, Lisa M
    Purpose of review This review summarizes the different instruments for evaluating the psychosocial health of transplant candidates, the evidence demonstrating how these instruments relate to probability of transplant waitlisting and transplant outcomes, and the critical knowledge gaps that exist in the causal pathway between psychosocial health and clinical transplant trajectory. Recent findings The current literature reveals that psychosocial assessments are a common reason for racial and ethnic minorities to be denied access to the transplant list. Given evidence that a lack of clinician consensus exists regarding the definition of, importance of, and reproducibility of psychosocial support evaluations, this facet of the holistic evaluation process may create a unique challenge for already vulnerable patient populations. Though recent evidence shows that psychosocial evaluation scores predict select transplant outcomes, these findings remain inconsistent. Summary Multiple instruments for psychosocial transplant evaluation exist, though the utility of these instruments remains uncertain. As equity becomes an increasingly urgent priority for the transplant system, rigorous interrogation of the causal pathway between psychosocial health and transplant longevity is still needed.
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    HLA Loci and Recurrence of Focal Segmental Glomerulosclerosis in Pediatric Kidney Transplantation.
    (Transplantation direct, 2021-10) Shaw, Brian I; Ochoa, Alejandro; Chan, Cliburn; Nobuhara, Chloe; Gbadegesin, Rasheed; Jackson, Annette M; Chambers, Eileen T
    Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation accounts for the majority of allograft failures in children with primary FSGS. Although current research focuses on FSGS pathophysiology, a common etiology and mechanisms of disease recurrence remain elusive.

    Methods

    We performed a retrospective review of the Scientific Registry of Transplant Recipients to determine the association of specific HLA recurrence of FSGS. Kidney transplants recipients under the age of 19 who were diagnosed with FSGS, who were transplanted after January 1, 2000, and who had complete HLA data were included in the study. We performed simple logistic regression on all HLA A, B, C, DR, and DQ represented in the dataset and FSGS recurrence and then determined those associated with recurrence using the Benjamini-Hochberg method for multiple comparisons. For those HLAs that were associated with recurrence, we further determined the effect of matching recipient and donor HLA with recurrence.

    Results

    HLA DR7, DR53, DQ2, DR52, and DQ7 were associated with increased or decreased risk of recurrent disease after transplantation. We identified a risk haplotype consisting of HLA-DR7, DR53, and DQ2 that was consistently associated with an increased risk of recurrence (odds ratio 1.91; 95% confidence interval, 1.44-2.54, P < 0.001). We also found that donor/recipient concordance for HLA-DQ7 was associated with a decreased risk of recurrence (odds ratio 0.42; 95% confidence interval, 0.37-0.53, P = 0.009).

    Conclusions

    HLA profiles may be used for risk stratification of recurrence of FSGS in pediatric kidney transplant recipients and deserves further study.
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    IFI16-STING-NF-κB signaling controls exogenous mitochondrion-induced endothelial activation.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2022-06) Li, Shu; Xu, He; Song, Mingqing; Shaw, Brian I; Li, Qi-Jing; Kirk, Allan D
    Mitochondria released from injured cells activate endothelial cells (ECs), fostering inflammatory processes, including allograft rejection. The stimulator of interferon genes (STING) senses endogenous mitochondrial DNA, triggering innate immune activation via NF-κB signaling. Here, we show that exogenous mitochondria exposure induces EC STING-NF-κB activation, promoting EC/effector memory T cell adhesion, which is abrogated by NF-κB and STING inhibitors. STING activation in mitochondrion-activated ECs is independent of canonical cGMP-AMP synthetase sensing/signaling, but rather is mediated by interferon gamma-inducible factor 16 (IFI16) and can be inhibited by IFI16 inhibition. Internalized mitochondria undergo mitofusion and STING-dependent mitophagy, leading to selective sequestration of internalized mitochondria. The exposure of donor hearts to exogenous mitochondria activates murine heart ECs in vivo. Collectively, our results suggest that IFI16-STING-NF-κB signaling regulates exogenous mitochondrion-induced EC activation and mitophagy, and exogenous mitochondria foster T cell-mediated CoBRR. These data suggest a novel, donor-directed, therapeutic approach toward mitigating perioperative allograft immunogenicity.
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    Organ donation during the coronavirus pandemic: an evolving saga in uncharted waters.
    (Transplant international : official journal of the European Society for Organ Transplantation, 2020-04-12) Moris, Dimitrios; Shaw, Brian I; Dimitrokallis, Nikolaos; Barbas, Andrew S
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    Very Late Recurrence of Hepatocellular Carcinoma After Orthotopic Liver Transplantation: Presentation and Management.
    (Transplantation direct, 2019-09) Shaw, Brian I; Lucander, Aaron; Ravindra, Kadiyala V